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Sandoval KC, Rychlik J, Choe KY. Calcium Dynamics in Hypothalamic Paraventricular Oxytocin Neurons and Astrocytes Associated with Social and Stress Stimuli. eNeuro 2025; 12:ENEURO.0196-24.2025. [PMID: 40262904 PMCID: PMC12071343 DOI: 10.1523/eneuro.0196-24.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 04/13/2025] [Accepted: 04/17/2025] [Indexed: 04/24/2025] Open
Abstract
Activation of hypothalamic paraventricular oxytocin (OXTPVN) neurons by social or stress stimuli triggers OXT release to promote social investigation and buffer adverse effects of stress, respectively. Astrocytes, a type of glial cells, can bidirectionally interact with hypothalamic neurons to participate in local activity regulation within the paraventricular nucleus (PVN). It remains unknown whether contextual factors related to stimuli, as well as biological factors such as sex, influence OXTPVN neuronal or astrocyte activity and/or their interactions. To address this question, we performed dual-color fiber photometry in freely behaving male and female mice to simultaneously record Ca2+ dynamics in OXTPVN neurons and astrocytes during acute social (i.e., interactions with familiar vs. unfamiliar conspecifics) and stress (i.e., looming shadow) stimuli. During social stimuli, we observed the most pronounced Ca2+ changes in OXTPVN neurons in females, revealing sex and familiarity context specificity. No astrocyte Ca2+ changes were detected in either sex regardless of conspecific familiarity. In contrast, looming shadow stress increased Ca2+ in both OXTPVN neurons and astrocytes in both sexes during an active escape ("run") strategy. Ca2+ level changes in OXTPVN neurons and astrocytes were significantly correlated during social investigations in both sexes regardless of conspecific familiarity. During looming shadow, this functional coupling was only observed in females during active escape. Together, our results suggest that sex, context, and behavioral strategy serve as major factors that shape the activity of OXTPVN neurons and astrocytes, as well as their functional coupling, to potentially aid the adaptive response to social or stress stimuli.
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Affiliation(s)
- Katy Celina Sandoval
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Joshua Rychlik
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Katrina Y Choe
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada
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2
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Rastogi K, Weerts EM, Ellis JD. Oxytocin as a treatment for alcohol use disorder and heavy drinking: A narrative review. Exp Clin Psychopharmacol 2024; 32:625-638. [PMID: 39298263 PMCID: PMC11995404 DOI: 10.1037/pha0000741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Oxytocin is increasingly being studied for treating symptoms of alcohol use disorders and heavy drinking behavior. The neuropeptide oxytocin facilitates social relationships and modulates the body's stress response by strengthening coping mechanisms and reducing anxiety. Relatedly, oxytocin is also thought to play a role in processes associated with craving and withdrawal from alcohol. This review aims to primarily provide an overview of preclinical and clinical literature on the applications of oxytocin in alcohol use, and additionally discuss a framework for types of trials and the variety of parameters that affect different study designs. A review of the existing literature in this area suggests that while low dosages of oxytocin do not affect drinking behavior and tolerance, higher dosages taken prior to alcohol exposure have varying behavioral and physiological results. Depending on quantity and timing, oxytocin treatments resulted in declines in withdrawal symptoms and alcohol self-administration in preclinical studies and may decrease neural cue reactivity and withdrawal symptoms in clinical studies. Current ongoing trials are expanding on this work to thoroughly explore clinical applications of oxytocin. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Affiliation(s)
- Kriti Rastogi
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health
| | - Elise M Weerts
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine
| | - Jennifer D Ellis
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine
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3
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Francesconi W, Olivera-Pasilio V, Berton F, Olson SL, Chudoba R, Monroy LM, Krabichler Q, Grinevich V, Dabrowska J. Like sisters but not twins - vasopressin and oxytocin excite BNST neurons via cell type-specific expression of oxytocin receptor to reduce anxious arousal. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.06.611656. [PMID: 39282380 PMCID: PMC11398521 DOI: 10.1101/2024.09.06.611656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to dorsolateral bed nucleus of stria terminalis (BNSTDL), which expresses oxytocin receptors (OTR) and vasopressin receptors and mediates fear responses. However, understanding the integrated role of neurohypophysial hormones is complicated by the cross-reactivity of AVP and OT and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by input specificity and cell type-specific receptor selectivity. We show that OTR-expressing BNSTDL neurons, excited by hypothalamic OT and AVP inputs via OTR, play a major role in regulating BNSTDL excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNSTDL neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs.
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Affiliation(s)
- Walter Francesconi
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
| | - Valentina Olivera-Pasilio
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
- Center for Psychiatric Neuroscience, Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, 60611, USA
| | - Fulvia Berton
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
| | - Susan L. Olson
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
| | - Rachel Chudoba
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
| | - Lorena M. Monroy
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
- Neuroscience Program, Lake Forest College, Lake Forest, IL, 60045, USA
| | - Quirin Krabichler
- Department of Neuropeptide Research in Psychiatry, German Center for Mental Health (DZPG), Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany
| | - Valery Grinevich
- Department of Neuropeptide Research in Psychiatry, German Center for Mental Health (DZPG), Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany
| | - Joanna Dabrowska
- Center for Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA
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4
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Zhou H, Zhu R, Xia Y, Zhang X, Wang Z, Lorimer GH, Ghiladi RA, Bayram H, Wang J. Neuropeptides affecting social behavior in mammals: Oxytocin. Peptides 2024; 177:171223. [PMID: 38626843 DOI: 10.1016/j.peptides.2024.171223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/24/2024] [Accepted: 04/13/2024] [Indexed: 04/30/2024]
Abstract
Oxytocin (OXT), a neuropeptide consisting of only nine amino acids, is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OXT is best known for its role in lactation and parturition, recent research has shown that it also has a significant impact on social behaviors in mammals. However, a comprehensive review of this topic is still lacking. In this paper, we systematically reviewed the effects of OXT on social behavior in mammals. These effects of OXT from the perspective of five key behavioral dimensions were summarized: parental behavior, anxiety, aggression, attachment, and empathy. To date, researchers have agreed that OXT plays a positive regulatory role in a wide range of social behaviors, but there have been controversially reported results. In this review, we have provided a detailed panorama of the role of OXT in social behavior and, for the first time, delved into the underlying regulatory mechanisms, which may help better understand the multifaceted role of OXT. Levels of OXT in previous human studies were also summarized to provide insights for diagnosis of mental disorders.
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Affiliation(s)
- Hong Zhou
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, Hubei 430068, China; International Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei 430068, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Rui Zhu
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, Hubei 430068, China; International Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei 430068, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Yuqing Xia
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, Hubei 430068, China; International Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei 430068, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Xinming Zhang
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, Hubei 430068, China; International Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei 430068, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Zixu Wang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China
| | | | - Reza A Ghiladi
- Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA
| | - Hasan Bayram
- Department of Pulmonary Medicine, Koç University School of Medicine, Istanbul 34450, Turkey
| | - Jun Wang
- Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, Hubei 430068, China; International Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei 430068, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, Hubei 430068, China.
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5
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Groenink L, Verdouw PM, Zhao Y, Ter Heegde F, Wever KE, Bijlsma EY. Pharmacological modulation of conditioned fear in the fear-potentiated startle test: a systematic review and meta-analysis of animal studies. Psychopharmacology (Berl) 2023; 240:2361-2401. [PMID: 36651922 PMCID: PMC10593622 DOI: 10.1007/s00213-022-06307-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 12/21/2022] [Indexed: 01/19/2023]
Abstract
RATIONALE AND OBJECTIVES Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. METHODS Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. RESULTS Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT1A agonists, 5-HT1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain. CONCLUSIONS The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review.
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Affiliation(s)
- Lucianne Groenink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
| | - P Monika Verdouw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Yulong Zhao
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Freija Ter Heegde
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Kimberley E Wever
- Department of Anaesthesiology, Pain and Palliative Medicine, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands
| | - Elisabeth Y Bijlsma
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
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6
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Olivera-Pasilio V, Dabrowska J. Fear-Conditioning to Unpredictable Threats Reveals Sex and Strain Differences in Rat Fear-Potentiated Startle (FPS). Neuroscience 2023; 530:108-132. [PMID: 37640137 PMCID: PMC10726736 DOI: 10.1016/j.neuroscience.2023.08.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 08/31/2023]
Abstract
Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women.
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Affiliation(s)
- Valentina Olivera-Pasilio
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, USA
| | - Joanna Dabrowska
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, USA.
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7
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Marzoratti A, Liu ME, Krol KM, Sjobeck GR, Lipscomb DJ, Hofkens TL, Boker SM, Pelphrey KA, Connelly JJ, Evans TM. Epigenetic modification of the oxytocin receptor gene is associated with child-parent neural synchrony during competition. Dev Cogn Neurosci 2023; 63:101302. [PMID: 37734257 PMCID: PMC10518595 DOI: 10.1016/j.dcn.2023.101302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/09/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
Interpersonal neural synchrony (INS) occurs when neural electrical activity temporally aligns between individuals during social interactions. It has been used as a metric for interpersonal closeness, often during naturalistic child-parent interactions. This study evaluated whether other biological correlates of social processing predicted the prevalence of INS during child-parent interactions, and whether their observed cooperativity modulated this association. Child-parent dyads (n = 27) performed a visuospatial tower-building task in cooperative and competitive conditions. Neural activity was recorded using mobile electroencephalogram (EEG) headsets, and experimenters coded video-recordings post-hoc for behavioral attunement. DNA methylation of the oxytocin receptor gene (OXTRm) was measured, an epigenetic modification associated with reduced oxytocin activity and socioemotional functioning. Greater INS during competition was associated with lower child OXTRm, while greater behavioral attunement during competition and cooperation was associated with higher parent OXTRm. These differential relationships suggest that interpersonal dynamics as measured by INS may be similarly reflected by other biological markers of social functioning, irrespective of observed behavior. Children's self-perceived communication skill also showed opposite associations with parent and child OXTRm, suggesting complex relationships between children's and their parents' social functioning. Our findings have implications for ongoing developmental research, supporting the utility of biological metrics in characterizing interpersonal relationships.
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Affiliation(s)
- Analia Marzoratti
- School of Education and Human Development, University of Virginia, Charlottesville, VA, USA
| | - Megan E Liu
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Kathleen M Krol
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Gus R Sjobeck
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Daniel J Lipscomb
- School of Education and Human Development, University of Virginia, Charlottesville, VA, USA
| | - Tara L Hofkens
- School of Education and Human Development, University of Virginia, Charlottesville, VA, USA
| | - Steven M Boker
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Kevin A Pelphrey
- School of Education and Human Development, University of Virginia, Charlottesville, VA, USA; Department of Psychology, University of Virginia, Charlottesville, VA, USA; Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - Jessica J Connelly
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Tanya M Evans
- School of Education and Human Development, University of Virginia, Charlottesville, VA, USA; Department of Psychology, University of Virginia, Charlottesville, VA, USA; Department of Neurology, University of Virginia, Charlottesville, VA, USA.
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8
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Wilfur SM, McNeely EC, Lackan AA, Bowers CP, Leong KC. Oxytocin Attenuates Yohimbine-Induced Reinstatement of Alcohol-Seeking in Female Rats via the Central Amygdala. Behav Sci (Basel) 2023; 13:556. [PMID: 37504003 PMCID: PMC10376410 DOI: 10.3390/bs13070556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/20/2023] [Accepted: 07/02/2023] [Indexed: 07/29/2023] Open
Abstract
Alcohol use disorder is a significant public health concern, further exacerbated by an increased risk of relapse due to stress. In addition, factors such as biological sex may contribute to the progression of addiction, as females are especially susceptible to stress-induced relapse. While there have been many studies surrounding potential pharmacological interventions for male stress-induced ethanol reinstatement, research regarding females is scarce. Recently, the neuropeptide oxytocin has gained interest as a possible pharmacological intervention for relapse. The present study examines how oxytocin affects yohimbine-induced reinstatement of ethanol-seeking in female rats using a self-administration paradigm. Adult female rats were trained to press a lever to access ethanol in daily self-administration sessions. Rats then underwent extinction training before a yohimbine-induced reinstatement test. Rats administered with yohimbine demonstrated significantly higher lever response indicating a reinstatement of ethanol-seeking behavior. Oxytocin administration, both systemically and directly into the central amygdala, attenuated the effect of yohimbine-induced reinstatement of ethanol-seeking behavior. The findings from this study establish that oxytocin is effective at attenuating alcohol-relapse behavior mediated by the pharmacological stressor yohimbine and that this effect is modulated by the central amygdala in females. This provides valuable insight regarding oxytocin's potential therapeutic effect in female stress-induced alcohol relapse.
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Affiliation(s)
- Samantha M Wilfur
- Department of Psychology, Trinity University, San Antonio, TX 78212, USA
| | | | - Aliya A Lackan
- Department of Psychology, Trinity University, San Antonio, TX 78212, USA
| | - Cassie P Bowers
- Department of Psychology, Trinity University, San Antonio, TX 78212, USA
| | - Kah-Chung Leong
- Department of Psychology, Trinity University, San Antonio, TX 78212, USA
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9
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Boyle CA, Lei S. Neuromedin B excites central lateral amygdala neurons and reduces cardiovascular output and fear-potentiated startle. J Cell Physiol 2023; 238:1381-1404. [PMID: 37186390 PMCID: PMC10330072 DOI: 10.1002/jcp.31020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023]
Abstract
Neuromedin B (NMB) and gastrin-releasing peptide (GRP) are the two mammalian analogs in the bombesin peptide family that exert a variety of actions including emotional processing, appetitive behaviors, cognition, and tumor growth. The bombesin-like peptides interact with three receptors: the NMB-preferring bombesin 1 (BB1) receptors, the GRP-preferring bombesin 2 (BB2) receptors and the orphan bombesin 3 (BB3) receptors. Whereas, injection of bombesin into the central amygdala reduces satiety and modulates blood pressure, the underlying cellular and molecular mechanisms have not been determined. As administration of bombesin induces the expression of Fos in the lateral nucleus of the central amygdala (CeL) which expresses BB1 receptors, we probed the effects of NMB on CeL neurons using in vitro and in vivo approaches. We showed that activation of the BB1 receptors increased action potential firing frequency recorded from CeL neurons via inhibition of the inwardly rectifying K+ (Kir) channels. Activities of phospholipase Cβ and protein kinase C were required, whereas intracellular Ca2+ release was unnecessary for BB1 receptor-elicited potentiation of neuronal excitability. Application of NMB directly into the CeA reduced blood pressure and heart rate and significantly reduced fear-potentiated startle. We may provide a cellular and molecular mechanism whereby bombesin-like peptides modulate anxiety and fear responses in the amygdala.
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Affiliation(s)
- Cody A. Boyle
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA
| | - Saobo Lei
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA
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10
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Chbeir S, Carrión V. Resilience by design: How nature, nurture, environment, and microbiome mitigate stress and allostatic load. World J Psychiatry 2023; 13:144-159. [PMID: 37303926 PMCID: PMC10251360 DOI: 10.5498/wjp.v13.i5.144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/11/2023] [Accepted: 04/17/2023] [Indexed: 05/19/2023] Open
Abstract
Resilience to psychological stress is defined as adaption to challenging life experiences and not the absence of adverse life events. Determinants of resilience include personality traits, genetic/epigenetic modifications of genes involved in the stress response, cognitive and behavioral flexibility, secure attachment with a caregiver, social and community support systems, nutrition and exercise, and alignment of circadian rhythm to the natural light/dark cycle. Therefore, resilience is a dynamic and flexible process that continually evolves by the intersection of different domains in human’s life; biological, social, and psychological. The objective of this minireview is to summarize the existing knowledge about the multitude factors and molecular alterations that result from resilience to stress response. Given the multiple contributing factors in building resilience, we set out a goal to identify which factors were most supportive of a causal role by the current literature. We focused on resilience-related molecular alterations resulting from mind-body homeostasis in connection with psychosocial and environmental factors. We conclude that there is no one causal factor that differentiates a resilient person from a vulnerable one. Instead, building resilience requires an intricate network of positive experiences and a healthy lifestyle that contribute to a balanced mind-body connection. Therefore, a holistic approach must be adopted in future research on stress response to address the multiple elements that promote resilience and prevent illnesses and psychopathology related to stress allostatic load.
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Affiliation(s)
- Souhad Chbeir
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Victor Carrión
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
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11
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Guoynes CD, Marler CA. Acute intranasal oxytocin dose enhances social preference for parents over peers in male but not female peri-adolescent California mice (Peromyscus californicus). Gen Comp Endocrinol 2023; 335:114230. [PMID: 36781024 DOI: 10.1016/j.ygcen.2023.114230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/10/2022] [Accepted: 02/08/2023] [Indexed: 02/13/2023]
Abstract
Peri-adolescence is a critical developmental stage marked by profound changes in the valence of social interactions with parents and peers. We hypothesized that the oxytocin (OXT) and vasopressin (AVP) systems, known for influencing social behavior, would be involved in the maintenance and breaking of bonding behavior expressed by very early peri-adolescent males and females. In rodents, OXT is associated with mother-pup bonding and may promote social attachment to members of the natal territory. AVP, on the other hand, can act in contrasting ways to OXT and has been associated with aggression and territoriality. Specifically, we predicted that in peri-adolescent male and female juveniles of the biparental and territorial California mouse (Peromyscus californicus), a) OXT would increase the social preferences for the parents over unfamiliar age-matched peers (one male and one female), and b) AVP would break the parent-offspring bond and either increase time in the neutral chamber and/or approach to their unfamiliar and novel peers. We examined anxiety and exploratory behavior using an elevated plus maze and a novel object task as a control. Peri-adolescent mice were administered an acute intranasal (IN) treatment of 0.5 IU/kg IN AVP, 0.5 IU/kg IN OXT, or saline control; five minutes later, the behavioral tests were conducted. As predicted, we found that IN OXT enhanced social preference for parents; however, this was only in male and not female peri-adolescent mice. IN AVP did not influence social preference in either sex. These effects appear specific to social behavior and not anxiety, as neither IN OXT nor AVP influenced behavior during the elevated plus maze or novel object tasks. To our knowledge, this is the first evidence indicating that OXT may play a role in promoting peri-adolescent social preferences for parents and delaying weaning in males.
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Affiliation(s)
- Caleigh D Guoynes
- Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA; Center for Neuroscience Research, Children's National Hospital, Washington, DC, USA.
| | - Catherine A Marler
- Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA.
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12
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Olivera-Pasilio V, Dabrowska J. Fear-conditioning to unpredictable threats reveals sex differences in rat fear-potentiated startle (FPS). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.06.531430. [PMID: 36945466 PMCID: PMC10028867 DOI: 10.1101/2023.03.06.531430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies have shown higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies often use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock unpaired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females demonstrate higher shock reactivity during fear-conditioning. Both sexes demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS but females show reduced fear discrimination vs. males. Fear-conditioning with 70% contingency or backward order (cue co-starts with shock) induces similar levels of cued, non-cued, and contextual fear in both sexes but they differ in contextual fear extinction. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning protocol (cue and shock un-paired), with females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women. Highlights Male and female rats have comparable startle amplitudes when corrected for body weightFemale rats show higher foot-shock reactivity than males during fear-conditioningFemale rats show reduced fear discrimination vs. males in the classic FPSReversed signal-threat order increases contextual fear in both sexesExposure to unpredictable threats increases startle in general and contextual fear only in females.
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Affiliation(s)
- Valentina Olivera-Pasilio
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois, USA
| | - Joanna Dabrowska
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois, USA
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13
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Asker M, Krieger JP, Liles A, Tinsley IC, Borner T, Maric I, Doebley S, Furst CD, Börchers S, Longo F, Bhat YR, De Jonghe BC, Hayes MR, Doyle RP, Skibicka KP. Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects. Diabetes Obes Metab 2023; 25:856-877. [PMID: 36495318 PMCID: PMC9987651 DOI: 10.1111/dom.14937] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/21/2022] [Accepted: 12/02/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Oxytocin (OT) has a well-established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT-R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT-R activation is sufficient to alter energy intake and expenditure. METHODS AND RESULTS We first show that systemic OT potently reduced food intake and food-motivated behaviour for a high-fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood-brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled-OT (fAF546-OT, Roxy), for the presence of IP-injected Roxy in CNS tissue relevant to feeding control and compared such with BBB-impermeable fluorescent OT-B12 (fCy5-OT-B12; BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT-R, we generated a novel BBB-impermeable OT (OT-B12 ), with equipotent binding at OT-R in vitro. In vivo, IP-injected OT and OT-B12 were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT-R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT-B12 did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose-dependent reduction of emesis in male shrews. While both OT and OT-B12 proved to have similar effects on body temperature, only OT resulted in home-cage locomotor depression. CONCLUSIONS Together our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT-R may be a viable strategy to achieve appetite suppression with better patient outcomes.
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Affiliation(s)
- Mohammed Asker
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden
| | - Jean-Philippe Krieger
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Amber Liles
- Department of Chemistry, Syracuse University, Syracuse, New York, USA
| | - Ian C Tinsley
- Department of Chemistry, Syracuse University, Syracuse, New York, USA
| | - Tito Borner
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ivana Maric
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Department of Chemistry, Syracuse University, Syracuse, New York, USA
- Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Sarah Doebley
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA
| | - C Daniel Furst
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA
| | - Stina Börchers
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden
| | - Francesco Longo
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Yashaswini R Bhat
- Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Bart C De Jonghe
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Robert P Doyle
- Department of Chemistry, Syracuse University, Syracuse, New York, USA
- Departments of Medicine and Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, USA
| | - Karolina P Skibicka
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA
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14
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Guo W, Fan S, Xiao D, He C, Guan M, Xiong W. A midbrain-reticulotegmental circuit underlies exaggerated startle under fear emotions. Mol Psychiatry 2022; 27:4881-4892. [PMID: 36117214 DOI: 10.1038/s41380-022-01782-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 01/19/2023]
Abstract
Exaggerated startle has been recognized as a core hyperarousal symptom of multiple fear-related anxiety disorders, such as post-traumatic stress disorder (PTSD) and panic disorder. However, the mechanisms driving this symptom are poorly understood. Here we reveal a neural projection from dorsal raphe nucleus (DRN) to a startle-controlling center reticulotegmental nucleus (RtTg) that mediates enhanced startle response under fear condition. Within RtTg, we identify an inhibitory microcircuit comprising GABAergic neurons in pericentral RtTg (RtTgP) and glutamatergic neurons in central RtTg (RtTgC). Inhibition of this RtTgP-RtTgC microcircuit leads to elevated startle amplitudes. Furthermore, we demonstrate that the conditioned fear-activated DRN 5-HTergic neurons send inhibitory projections to RtTgP GABAergic neurons, which in turn upregulate neuronal activities of RtTgC glutamatergic neurons. Chemogenetic activation of the DRN-RtTgP projections mimics the increased startle response under fear emotions. Moreover, conditional deletion of 5-HT1B receptor from RtTgP GABAergic neurons largely reverses the exaggeration of startle during conditioned fear. Thus, our study establishes the disinhibitory DRN-RtTgP-RtTgC circuit as a critical mechanism underlying exaggerated startle under fear emotions, and provides 5-HT1B receptor as a potential therapeutic target for treating hyperarousal symptom in fear-associated psychiatric disorders.
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Affiliation(s)
- Weiwei Guo
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Sijia Fan
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Dan Xiao
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Chen He
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Mengyuan Guan
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Wei Xiong
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China. .,Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China. .,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
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15
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Kou J, Zhang Y, Zhou F, Gao Z, Yao S, Zhao W, Li H, Lei Y, Gao S, Kendrick KM, Becker B. Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent. PSYCHOTHERAPY AND PSYCHOSOMATICS 2022; 91:253-264. [PMID: 35086102 DOI: 10.1159/000521348] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 11/29/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Anxiety disorders are prevalent mental conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols, previous human studies have exclusively focused on single-dose (acute) intranasal OT effects. OBJECTIVE To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. METHODS In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the acute (single dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity were assessed in n = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). RESULTS OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. CONCLUSIONS The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.
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Affiliation(s)
- Juan Kou
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China.,Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Yingying Zhang
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China.,Department of Molecular Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Feng Zhou
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhao Gao
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Shuxia Yao
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Weihua Zhao
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Li
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Yi Lei
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Shan Gao
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Keith M Kendrick
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Benjamin Becker
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
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16
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Faraji J, Lotfi H, Moharrerie A, Jafari SY, Soltanpour N, Tamannaiee R, Marjani K, Roudaki S, Naseri F, Moeeini R, Metz GAS. Regional Differences in BDNF Expression and Behavior as a Function of Sex and Enrichment Type: Oxytocin Matters. Cereb Cortex 2022; 32:2985-2999. [PMID: 35059698 DOI: 10.1093/cercor/bhab395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 01/03/2025] Open
Abstract
The early environment is critical to brain development, but the relative contribution of physical versus social stimulation is unclear. Here, we investigated in male and female rats the response to early physical and social environmental enrichment in relation to oxytocin (OT) and brain-derived neurotrophic factor (BDNF) expression. The findings show that males and females respond differently to prolonged sensorimotor stimulation from postnatal days 21-110 in terms of functional, structural, and molecular changes in the hippocampus versus medial prefrontal cortex (mPFC). Physical enrichment promoted motor and cognitive functions and hippocampal BDNF mRNA and protein expression in both sexes. Combined physical and social enrichment, however, promoted functional and structural gain in females. These changes were accompanied by elevated plasma oxytocin (OT) levels and BDNF mRNA expression in the mPFC, while the hippocampus was not affected. Administration of an OT antagonist in females blocked the beneficial effects of enrichment and led to reduced cortical BDNF signaling. These findings suggest that an OT-based mechanism selectively stimulates a region-specific BDNF response which is dependent on the type of experience.
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Affiliation(s)
- Jamshid Faraji
- Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge T1K3M4, Canada
- Faculty of Nursing and Midwifery, Golestan University of Medical Sciences, Gorgan 4918936316, Iran
| | - Hamid Lotfi
- Department of Psychology, Islamic Azad University, Tonekabon 4684161167, Iran
| | - Alireza Moharrerie
- Department of Anatomy, Golestan University of Medical Sciences, Gorgan 4918936316, Iran
| | - S Yaghoob Jafari
- Faculty of Nursing and Midwifery, Golestan University of Medical Sciences, Gorgan 4918936316, Iran
| | - Nasrin Soltanpour
- Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge T1K3M4, Canada
| | - Rosa Tamannaiee
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd 4467330219, Iran
| | - Kameran Marjani
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd 4467330219, Iran
| | - Shabnam Roudaki
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd 4467330219, Iran
| | | | - Reza Moeeini
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd 4467330219, Iran
| | - Gerlinde A S Metz
- Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge T1K3M4, Canada
- Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge T1K3M4, Canada
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17
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Stauffer CS, Morrison TE, Meinzer NK, Leung D, Buffington J, Sheh EG, Neylan TC, O’Donovan A, Woolley JD. Effects of oxytocin administration on fear-potentiated acoustic startle in co-occurring PTSD and alcohol use disorder: A randomized clinical trial. Psychiatry Res 2022; 308:114340. [PMID: 34983010 PMCID: PMC9074818 DOI: 10.1016/j.psychres.2021.114340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 02/03/2023]
Abstract
Co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and particularly associated with elevation of hyperarousal compared to PTSD alone. Treatment options are limited. Oxytocin regulates physiological stress response. Intranasal oxytocin administration has demonstrated potential in reducing symptoms of both PTSD and AUD. This study addresses a gap in the literature by investigating effects of intranasal oxytocin on startle reactivity, an important potential marker of both PTSD and AUD symptomatology. This is a randomized, double-blind, placebo-controlled, within- and between-participant, crossover, dose-ranging study examining the effects of a single administration of oxytocin 20 IU versus 40 IU versus placebo on psychophysiological responses to a common laboratory fear-potentiated acoustic startle paradigm in participants with PTSD-AUD (n = 47) and controls (n = 37) under three different levels of threat. Contrary to our hypothesis, for the PTSD-AUD group, oxytocin 20 IU had no effect on startle reactivity, while oxytocin 40 IU increased measures of startle reactivity. Additionally, for PTSD-AUD only, ambiguous versus low threat was associated with an elevated skin conductance response. For controls only, oxytocin 20 IU versus placebo was associated with reduced startle reactivity.
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Affiliation(s)
- Christopher S. Stauffer
- Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA,Portland Veterans Affairs Health Care Center, Portland, OR, USA,Corresponding author. (C.S. Stauffer)
| | - Tyler E. Morrison
- Department of Psychiatry, University of California, San Diego, San Diego, CA, USA
| | | | - David Leung
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | | | - Evan G. Sheh
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Thomas C. Neylan
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA,Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | - Aoife O’Donovan
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA,Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
| | - Joshua D. Woolley
- San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA,Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
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18
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Oxytocin Attenuates the Stress-Induced Reinstatement of Alcohol-Seeking in Male Rats: Role of the Central Amygdala. Biomedicines 2021; 9:biomedicines9121919. [PMID: 34944734 PMCID: PMC8698625 DOI: 10.3390/biomedicines9121919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 12/21/2022] Open
Abstract
Factors such as stress and anxiety often contribute to alcohol-dependent behavior and can trigger a relapse of alcohol addiction and use. Therefore, it is important to investigate potential pharmacological interventions that may alleviate the influence of stress on addiction-related behaviors. Previous studies have demonstrated that the neuropeptide oxytocin has promising anxiolytic potential in mammals and may offer a pharmacological target to diminish the emotional impact on reinstatement of alcohol-seeking. The purpose of the present study was to investigate the effect of oxytocin on stress-induced alcohol relapse and identify a neural structure mediating this effect through the use of an ethanol self-administration and yohimbine-induced reinstatement paradigm. While yohimbine administration resulted in the reinstatement of ethanol-seeking behavior, the concurrent administration of yohimbine and oxytocin attenuated this effect, suggesting that oxytocin may disrupt stress-induced ethanol-seeking behavior. The central amygdala (CeA) is a structure that drives emotional responses and robustly expresses oxytocin receptors. Intra-CeA oxytocin similarly attenuated the yohimbine-induced reinstatement of ethanol-seeking behavior. These results demonstrate that oxytocin has the potential to attenuate stress-induced relapse into ethanol-seeking behavior, and that this mechanism occurs specifically within the central amygdala.
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19
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He FQ, Fan MY, Hui YN, Lai RJ, Chen X, Yang MJ, Cheng XX, Wang ZJ, Yu B, Yan BJ, Tian Z. Effects of treadmill exercise on anxiety-like behavior in association with changes in estrogen receptors ERα, ERβ and oxytocin of C57BL/6J female mice. IBRO Neurosci Rep 2021; 11:164-174. [PMID: 34746914 PMCID: PMC8551837 DOI: 10.1016/j.ibneur.2021.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 10/04/2021] [Indexed: 11/28/2022] Open
Abstract
Exercise can reduce the incidence of stress-related mental diseases, such as depression and anxiety. Control group was neither exposed to CVMS nor TRE (noCVMS/noTRE). Females were tested and levels of serum17-beta-oestradiol (E2), estrogen receptors α immunoreactive neurons (ERα-IRs), estrogen receptors β immunoreactive neurons (ERβ-IRs) and oxytocin immunoreactive neurons (OT-IRs) were measured. The results showed there's increased anxiety-like behaviors for mice from CVMS/noTRE, CVMS/higher speed TRE (CVMS/HTRE) and noCVMS/HTRE groups when they were put in open field and elevated maze tests. They had lower serum E2 levels than mice from CVMS/low-moderate speed TRE (CVMS/LMTRE), noCVMS/LMTRE and noCVMS/noTRE groups. The three groups of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice had more ERα-IRs and less ERβ-IRs in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA), hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The number of OT-IRs in PVN and SON of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice was also lower than that of mice from CVMS/LMTRE, noCVMS/LMTRE and noCVMS/noTRE groups. Interestingly, CVMS/LMTRE and noCVMS/LMTRE mice were similar to noCVMS/noTRE mice in that they did not show anxiety, while CVMS/HTRE and noCVMS/HTRE mice did not, which were similar to the mice in CVMS/noTRE. We propose that LMTRE instead of HTRE changes the serum concentration of E2. ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behavior in female mice exposed to anxiety-inducing stress conditions.
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Key Words
- BNST, bed nucleus of the stria terminalis
- CVMS, chronic variable moderate stress
- Chronic variable moderate stress (CVMS)
- E2, 17-beta-oestradiol
- ELISA, enzyme-linked immunosorbent assay
- EPM, elevated plusmazetest
- ERα-IRs, estrogen receptors αimmunoreactive neurons
- ERβ-IRs, estrogen receptor β immunoreactive neurons
- Estrogen receptor α (ERα)
- Estrogen receptor β (ERβ)
- HPA, hypothalamic–pituitary–adrenal
- HRP, horseradishperoxidase
- HTRE, higher speed TRE
- LMTRE, low-moderate speed TRE
- MeA, medial amygdaloid nucleus
- OF, open field test
- OT-IRs, Oxytocin immunoreactive neurons
- Oxytocin (OT)
- PBS, phosphatebufferedsolution
- PVN, paraventricular nucleus
- SON, supraoptic nucleus
- TRE, treadmill exercise
- Treadmill exercise (TRE)
- mPOA, medial preopticarea
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Affiliation(s)
- Feng-Qin He
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Mei-Yang Fan
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Yu-Nan Hui
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Rui-Juan Lai
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Xin Chen
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Ming-Juan Yang
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Xiao-Xia Cheng
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Zi-Jian Wang
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Bin Yu
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Bing-Jie Yan
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
| | - Zhen Tian
- Key Laboratory of Natural Product Development and Anticancer Innovative Drug Research in Qinling, Xi'an 710065, China.,Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an 710065, China
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20
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Kreutzmann JC, Fendt M. Intranasal oxytocin compensates for estrus cycle-specific reduction of conditioned safety memory in rats: Implications for psychiatric disorders. Neurobiol Stress 2021; 14:100313. [PMID: 33778132 PMCID: PMC7985696 DOI: 10.1016/j.ynstr.2021.100313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/06/2021] [Accepted: 02/25/2021] [Indexed: 01/12/2023] Open
Abstract
Stress and anxiety disorder patients frequently fail to benefit from psychotherapies which often consist of inhibitory fear learning paradigms. One option to improve the therapy outcome is medication-enhanced psychotherapy. Research in humans and laboratory rodents has demonstrated that oxytocin (OT) reduces fear and facilitates fear extinction. However, the role of OT in conditioned safety learning, an understudied but highly suitable type of inhibitory fear learning, remains to be investigated. The present study aimed at investigating the effect of intranasal OT on conditioned safety. To test this, Sprague Dawley rats (♂n = 57; ♀n = 72) were safety conditioned. The effects of pre-training or pre-testing intranasal OT on conditioned safety and contextual fear, both measured by the acoustic startle response, and on corticosterone plasma levels were assessed. Furthermore, the involvement of the estrous cycle was analyzed. The present data show that intranasal OT administration before the acquisition or recall sessions enhanced conditioned safety memory in female rats while OT had no effects in male rats. Further analysis of the estrus cycle revealed that vehicle-treated female rats in the metestrus showed reduced safety memory which was compensated by OT-treatment. Moreover, all vehicle-treated rats, regardless of sex, expressed robust contextual fear following conditioning. Intranasal OT-treated rats showed a decrease in contextual fear, along with reduced plasma corticosterone levels. The present data demonstrate that intranasal OT has the capacity to compensate deficits in safety learning, along with a reduction in contextual fear and corticosterone levels. Therefore, add-on treatment with intranasal OT could optimize the therapy of anxiety disorders.
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Affiliation(s)
- Judith C Kreutzmann
- Institute for Pharmacology & Toxicology, Otto-von-Guericke University Magdeburg, Germany.,Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Markus Fendt
- Institute for Pharmacology & Toxicology, Otto-von-Guericke University Magdeburg, Germany.,Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Germany
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21
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Marvar PJ, Andero R, Hurlemann R, Lago TR, Zelikowsky M, Dabrowska J. Limbic Neuropeptidergic Modulators of Emotion and Their Therapeutic Potential for Anxiety and Post-Traumatic Stress Disorder. J Neurosci 2021; 41:901-910. [PMID: 33472824 PMCID: PMC7880296 DOI: 10.1523/jneurosci.1647-20.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 12/20/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is characterized by hypervigilance, increased reactivity to unpredictable versus predictable threat signals, deficits in fear extinction, and an inability to discriminate between threat and safety. First-line pharmacotherapies for psychiatric disorders have limited therapeutic efficacy in PTSD. However, recent studies have advanced our understanding of the roles of several limbic neuropeptides in the regulation of defensive behaviors and in the neural processes that are disrupted in PTSD. For example, preclinical studies have shown that blockers of tachykinin pathways, such as the Tac2 pathway, attenuate fear memory consolidation in mice and thus might have unique potential as early post-trauma interventions to prevent PTSD development. Targeting this pathway might also be beneficial in regulating other symptoms of PTSD, including trauma-induced aggressive behavior. In addition, preclinical and clinical studies have shown the important role of angiotensin receptors in fear extinction and the promise of using angiotensin II receptor blockade to reduce PTSD symptom severity. Additional preclinical studies have demonstrated that the oxytocin receptors foster accurate fear discrimination by facilitating fear responses to predictable versus unpredictable threats. Complementary human imaging studies demonstrate unique neural targets of intranasal oxytocin and compare its efficacy with well-established anxiolytic treatments. Finally, promising data from human subjects have demonstrated that a selective vasopressin 1A receptor antagonist reduces anxiety induced by unpredictable threats. This review highlights these novel promising targets for the treatment of unique core elements of PTSD pathophysiology.
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Affiliation(s)
- Paul J Marvar
- Department of Pharmacology & Physiology, Department of Psychiatry and Behavioral Sciences, George Washington Institute for Neuroscience, George Washington University, Washington, DC, 20037
| | - Raül Andero
- Departament de Psicobiologia i de Metodologia de les Ciències de la Salut, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain, 08193. Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain, 28029. ICREA, Pg. Lluís Companys 23, Barcelona, Spain, 08010
| | - Rene Hurlemann
- Department of Psychiatry, School of Medicine & Health Sciences, and Research Center Neurosensory Science, University of Oldenburg, Oldenburg, 26129, Germany
| | - Tiffany R Lago
- Department of Psychiatry, Veterans Administration Boston Healthcare System, Boston, Massachusetts, 02130
| | - Moriel Zelikowsky
- Department of Neurobiology and Anatomy, University of Utah, School of Medicine, Salt Lake City, Utah, 84112
| | - Joanna Dabrowska
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, 60064
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22
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Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors. Mol Psychiatry 2021; 26:7270-7279. [PMID: 34489531 PMCID: PMC8873014 DOI: 10.1038/s41380-021-01283-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 08/14/2021] [Accepted: 08/25/2021] [Indexed: 02/08/2023]
Abstract
The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.
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23
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Olivera-Pasilio V, Dabrowska J. Oxytocin Promotes Accurate Fear Discrimination and Adaptive Defensive Behaviors. Front Neurosci 2020; 14:583878. [PMID: 33071751 PMCID: PMC7538630 DOI: 10.3389/fnins.2020.583878] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/24/2020] [Indexed: 12/21/2022] Open
Abstract
The nonapeptide, oxytocin (OT), known for its role in social bonding and attachment formation, has demonstrated anxiolytic properties in animal models and human studies. However, its role in the regulation of fear responses appears more complex, brain site-specific, sex-specific, and dependent on a prior stress history. Studies have shown that OT neurons in the hypothalamus are activated during cued and contextual fear conditioning and during fear recall, highlighting the recruitment of endogenous oxytocin system in fear learning. OT is released into the extended amygdala, which contains the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), both critical for the regulation of fear and anxiety-like behaviors. Behavioral studies report that OT in the CeA reduces contextual fear responses; whereas in the BNST, OT receptor (OTR) neurotransmission facilitates cued fear and reduces fear responses to un-signaled, diffuse threats. These ostensibly contrasting behavioral effects support growing evidence that OT works to promote fear discrimination by reducing contextual fear or fear of diffuse threats, yet strengthening fear responses to imminent and predictable threats. Recent studies from the basolateral nucleus of the amygdala (BLA) support this notion and show that activation of OTR in the BLA facilitates fear discrimination by increasing fear responses to discrete cues. Also, OTR transmission in the CeA has been shown to mediate a switch from passive freezing to active escape behaviors in confrontation with an imminent, yet escapable threat but reduce reactivity to distant threats. Therefore, OT appears to increase the salience of relevant threat-signaling cues yet reduce fear responses to un-signaled, distant, or diffuse threats. Lastly, OTR signaling has been shown to underlie emotional discrimination between conspecifics during time of distress, social transmission of fear, and social buffering of fear. As OT has been shown to enhance salience of both positive and negative social experiences, it can also serve as a warning system against potential threats in social networks. Here, we extend the social salience hypothesis by proposing that OT enhances the salience of relevant environmental cues also in non-social contexts, and as such promotes active defensive behaviors.
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Affiliation(s)
- Valentina Olivera-Pasilio
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,Discipline of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Joanna Dabrowska
- Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,Discipline of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.,School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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24
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Tapp DN, Singstock MD, Gottliebson MS, McMurray MS. Central but not peripheral oxytocin administration reduces risk-based decision-making in male rats. Horm Behav 2020; 125:104840. [PMID: 32795469 DOI: 10.1016/j.yhbeh.2020.104840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022]
Abstract
The hormone oxytocin has long been associated with social behaviors, but recent evidence suggests that it may also affect reward processing in non-social contexts. Decisions are an integral component of many social and reward-based behavioral paradigms. Thus, a broad role for oxytocin in decision-making may explain the wide variety of effects that have been previously observed and resolve controversies in the literature about its role. To determine if oxytocin can selectively modulate decision-making in male rats, we assessed the dose-dependent effects of central (intracerebroventricular) or peripheral (intraperitoneal) administration of oxytocin on probability and delay discounting, two commonly used decision-making tasks that are free of social contexts. Our results showed that central administration of oxytocin dose-dependently reduced preference for risky outcomes in the probability discounting task, but had no impact on delay discounting or reward sensitivity. This effect was blocked by the co-administration of an oxytocin antagonist. Additionally, we found no effect of peripheral oxytocin administration on any task. To identify potential cognitive mechanisms of central oxytocin's effect on decision-making, we determined if central or peripheral oxytocin affects reward sensitivity using an intracranial self-stimulation task, and motivation using a progressive ratio task. These results showed that at the dosage that affects decision-making, central oxytocin had a mild and short-lasting effect on motivation, but no observable effect on reward sensitivity. This pattern of results suggests that oxytocin may selectively reduce risky decisions in male rats, even at dosages that have no major effects on reward processing and motivation. These findings highlight a potentially novel role for oxytocin in non-social cognitive processes and expand our understanding of the mechanism by which oxytocin may regulate social behavior.
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Affiliation(s)
- Danielle N Tapp
- Department of Psychology, Miami University, 90 N. Patterson Ave., Oxford, OH 45056, USA
| | - Mitchell D Singstock
- Department of Psychology, Miami University, 90 N. Patterson Ave., Oxford, OH 45056, USA
| | | | - Matthew S McMurray
- Department of Psychology, Miami University, 90 N. Patterson Ave., Oxford, OH 45056, USA.
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25
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Kozhemyakina RV, Shikhevich SG, Konoshenko MY, Gulevich RG. Adolescent oxytocin treatment affects resident behavior in aggressive but not tame adult rats. Physiol Behav 2020; 224:113046. [PMID: 32619528 DOI: 10.1016/j.physbeh.2020.113046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/28/2020] [Accepted: 06/30/2020] [Indexed: 11/26/2022]
Abstract
There are indications that exposing adolescent rodents to oxytocin (OT) promotes social activity and reduces anxiety in adulthood. Adult male gray rats selected for elimination and enhancement of the aggressive response to humans, when exposed to OT, showed divergent changes in the resident behavior towards the intruder. It could be assumed that adolescent administration of both OT and antagonist of OT receptor (OTR) would also have different long-term effects on resident behavior and startle reflex in adult aggressive and tame rats. The aim of this work is to study the long-term effects of adolescent administration of both OT and antagonist of OT receptor (OTR) on resident behavior and startle reflex in adult tame and aggressive male gray rats. Starting at the age of 28 days, the animals received nasal applications of 5 μL of oxytocin solution (1 μg / μL) or saline for 5 days (daily). At the age of two months, the acoustic startle amplitude was assessed in two series of 5 acoustic stimuli. The resident-intruder test was performed one week later. Antagonist of OT receptor l-368,899 was administered intraperitoneally (i.p.) once at a dose of 5 mg/kg at the age of 30-33 days. Subsequent startle reflex tests were performed 20 days later, at the age of 50-53 days. A week later, the resident-intruder test was performed on the same rats. The startle amplitude in aggressive rats of the control group (in two series of acoustic stimuli) and those having received saline (in the first series) was larger than in the corresponding tame groups. Oxytocin and saline solutions did not significantly affect the startle amplitude compared to control animals. After saline administration, the attack latency in tame rats was longer than in aggressive rats (P <0.05). Oxytocin treatment caused a prolongation of this period in aggressive males compared with control animals receiving saline solution (P <0.01). In addition, oxytocin administration in aggressive males caused an increase in the time of social behavior, which did not include aggressive and same-sex behavior, as compared with the corresponding control animals (P <0.05). Exogenous oxytocin receptor antagonist (l-368,899) did not affect the startle amplitude and behavior in the resident-intruder test in aggressive and tame male rats. Adolescent OT treatment causes a prolongation of both the attack latency and social behavior in the resident-intruder test in adult aggressive male rats, but does not affect these parameters in tame rats.
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Affiliation(s)
- R V Kozhemyakina
- Laboratory of Evolutionary Genetics, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 10 Lavrent'ev Ave, Novosibirsk 630090, Russia.
| | - S G Shikhevich
- Laboratory of Evolutionary Genetics, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 10 Lavrent'ev Ave, Novosibirsk 630090, Russia.
| | - M Yu Konoshenko
- Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russia.
| | - R G Gulevich
- Laboratory of Evolutionary Genetics, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 10 Lavrent'ev Ave, Novosibirsk 630090, Russia.
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26
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Le Dorze C, Borreca A, Pignataro A, Ammassari-Teule M, Gisquet-Verrier P. Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD. Transl Psychiatry 2020; 10:27. [PMID: 32066681 PMCID: PMC7026036 DOI: 10.1038/s41398-020-0714-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 01/21/2023] Open
Abstract
Recent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3-14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep re-processing of traumatic memories and durable attenuation of the PTSD symptomatology.
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Affiliation(s)
- Claire Le Dorze
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91190, Gif-sur-Yvette, France
| | - Antonella Borreca
- Santa Lucia Foundation, via del fosso di fiorano 64, 00143, Rome, Italy
| | - Annabella Pignataro
- Santa Lucia Foundation, via del fosso di fiorano 64, 00143, Rome, Italy
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | | | - Pascale Gisquet-Verrier
- Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, 91190, Gif-sur-Yvette, France.
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27
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Thakur P, Shrivastava R, Shrivastava VK. Effects of exogenous oxytocin and atosiban antagonist on GABA in different region of brain. IBRO Rep 2019; 6:185-189. [PMID: 31211283 PMCID: PMC6562178 DOI: 10.1016/j.ibror.2019.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 04/16/2019] [Indexed: 12/23/2022] Open
Abstract
Gamma amino butyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebral central nervous system. It functions by altering the membrane conductance of Cl- ions, maintaining the membrane potential close to the resting potential. The hormone oxytocin (OT) has a central action where it acts as a neuromodulatory peptide and exerts its action depending upon the distribution of OT receptors (OTR) in the target site. OTRs are G-protein-coupled receptors (GPCRs) comprising different subunits (Gq, Gi, and Gs). The G- protein isoforms have the ability to activate different pathways, but specific agonists and antagonists may show different affinities to OTRs, depending on the specific G-protein isoform to which they are coupled. It is well documented that OTR distribution varies with age and species and in regions of the brain. In this study, we attempted to observe the impact of OT and atosiban (OTA), an OT antagonist, on GABA levels in different regions of the brain. Study animals were exposed intraperitoneally (i.p.) to normal saline (0.89%), OT 0.0116 mg/kg, and OTA 1 mg/kg in different combinations, for 30days. It was observed that OT and OTA administration modulated GABA levels in different regions of brain, while normal saline had no effect. It may be due to OTR receptor expression in different regions of the brain. This is significant because region-specific expression of different receptors could be important in the development of new drugs targeting specific neuropsychiatric disorders.
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Affiliation(s)
- Pratibha Thakur
- Endocrinology Unit, Department of Biosciences, Barkatullah University, Bhopal, Madhya Pradesh 462026, India
| | - Renu Shrivastava
- Sri Satya Sai College for Women BHEL, Bhopal, Madhya Pradesh 462024, India
| | - Vinoy K. Shrivastava
- Endocrinology Unit, Department of Biosciences, Barkatullah University, Bhopal, Madhya Pradesh 462026, India
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28
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Dayi A, Kiray M, Sisman A, Ozbal S, Baykara B, Aksu I, Uysal N. Dose dependent effects of oxytocin on cognitive defects and anxiety disorders in adult rats following acute infantile maternal deprivation stress. Biotech Histochem 2019; 94:469-480. [PMID: 31104534 DOI: 10.1080/10520295.2018.1528384] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Maternal deprivation at an early age is a powerful stressor that causes permanent alterations in cognitive and behavioral functions during the later stages of life. We investigated the effects of oxytocin on cognitive defects and anxiety disorders caused by acute infantile maternal deprivation in adult rats. We used 18-day-old Wistar albino rats of both sexes. The experimental groups included control (C), maternally deprived (MD), maternally deprived and treated with 0.02 μg/kg oxytocin (MD-0.02 µg/kg oxy), maternally deprived and treated with 2 μg/kg oxytocin (MD-2 µg/kg oxy). When the rats were 60 days old, the open field (OF) and elevated plus maze (EPM) behavioral tests, and the Morris water maze (MWM) test for spatial learning and memory were performed. In addition, the number of neurons in the hippocampus, prefrontal cortex (PFC) and amygdala were determined using quantitative histology. We also measured vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in the PFC. In both sexes, the MD group failed the learning test and the MD-2 μg/kg oxy group failed in the memory test. The MD-0.02 μg/kg oxy group spent more time in the open arm of the EPM device and their locomotor activities were greater in the OF test. The VEGF and BDNF levels in the PFC were higher in the MD-0.02 μg/kg oxy groups than the other maternally deprived groups (oxytocin ±). The number of PFC neurons was low in all male maternally deprived (oxytocin ±) groups, while the number of amygdala neurons was low in both female and male maternally deprived (oxytocin ±) groups. Male rats were more affected by maternal deprivation; administration of oxytocin had dose-dependent biphasic effects on learning, memory and anxiety.
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Affiliation(s)
- A Dayi
- Departments of Physiology, Dokuz Eylul University Medical School , Izmir , Turkey
| | - M Kiray
- Departments of Physiology, Dokuz Eylul University Medical School , Izmir , Turkey
| | - Ali Sisman
- Departments of Biochemistry, Dokuz Eylul University Medical School , Balcova , Turkey
| | - S Ozbal
- Departments of Histology and Embryology, Dokuz Eylul University Medical School , Izmir , Turkey
| | - B Baykara
- Departments of Histology and Embryology, Dokuz Eylul University Medical School , Izmir , Turkey
| | - I Aksu
- Departments of Physiology, Dokuz Eylul University Medical School , Izmir , Turkey
| | - N Uysal
- Departments of Physiology, Dokuz Eylul University Medical School , Izmir , Turkey
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29
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Martinon D, Lis P, Roman AN, Tornesi P, Applebey SV, Buechner G, Olivera V, Dabrowska J. Oxytocin receptors in the dorsolateral bed nucleus of the stria terminalis (BNST) bias fear learning toward temporally predictable cued fear. Transl Psychiatry 2019; 9:140. [PMID: 31000694 PMCID: PMC6472379 DOI: 10.1038/s41398-019-0474-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/19/2019] [Accepted: 04/01/2019] [Indexed: 11/18/2022] Open
Abstract
The inability to discriminate between threat and safety is a hallmark of stress-induced psychiatric disorders, including post-traumatic stress disorder. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) is critically involved in the modulation of fear and anxiety, and has been proposed to regulate discrimination between signaled (cued, predictable) and unsignaled (unpredictable) threats. We recently showed that oxytocin receptors (OTRs) in the BNSTdl facilitate acquisition of cued fear measured in a fear-potentiated startle (FPS). In the current study, using in vivo microdialysis in awake male Sprague-Dawley rats, a double immunofluorescence approach with confocal microscopy, as well as retrograde tracing of hypothalamic BNST-projecting OT neurons, we investigated whether fear conditioning activates OT system and modulates OT release. To determine the role of OTR in fear memory formation, we also infused OTR antagonist or OT into the BNSTdl before fear conditioning and measured rats' ability to discriminate between cued (signaled) and non-cued (unsignaled) fear using FPS. In contrast to acute stress (exposure to forced swim stress or foot shocks alone), cued fear conditioning increases OT content in BNSTdl microdialysates. In addition, fear conditioning induces moderate activation of OT neurons in the paraventricular nucleus of the hypothalamus and robust activation in the supraoptic and accessory nuclei of the hypothalamus. Application of OT into the BNSTdl facilitates fear learning toward signaled, predictable threats, whereas blocking OTR attenuates this effect. We conclude that OTR neurotransmission in the BNSTdl plays a pivotal role in strengthening fear learning of temporally predictable, signaled threats.
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Affiliation(s)
- Daisy Martinon
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Paulina Lis
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Alexandra N. Roman
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Patricio Tornesi
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Sarah V. Applebey
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Garrett Buechner
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Valentina Olivera
- 0000 0004 0388 7807grid.262641.5Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA ,0000 0004 0388 7807grid.262641.5Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA ,0000 0004 0388 7807grid.262641.5School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 USA
| | - Joanna Dabrowska
- Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA. .,Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA. .,School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
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Yamagishi A, Okada M, Masuda M, Sato N. Oxytocin administration modulates rats' helping behavior depending on social context. Neurosci Res 2019; 153:56-61. [PMID: 30953682 DOI: 10.1016/j.neures.2019.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/19/2019] [Accepted: 04/02/2019] [Indexed: 02/08/2023]
Abstract
The affiliative effect of oxytocin on behavior toward other individuals can be modulated by positive and negative aspects of those individuals. However, the context-dependent effect of oxytocin on helping behavior is still unclear. In this study, we examined the effect of oxytocin administration on helping behavior in rats. The rats learned to open a door to help a cagemate soaked with water. The rats were divided into Pair and Solo groups. The rats in the Pair group were housed with their cagemates and those in the Solo group were housed individually. The rats in both groups received oxytocin (1.0 mg/kg) or saline injections intraperitoneally for 5 consecutive days before starting the experimental sessions. In the rats injected with oxytocin, the Solo group showed helping behavior faster than those in the Pair group. The results suggest that the effects of oxytocin administration on helping behavior are dependent on the social context.
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Affiliation(s)
- Atsuhito Yamagishi
- Department of Psychological Sciences, Kwansei Gakuin University, 1-1-155, Uegahara, Nishinomiya, Hyogo 662-8501, Japan
| | - Maya Okada
- Department of Psychological Sciences, Kwansei Gakuin University, 1-1-155, Uegahara, Nishinomiya, Hyogo 662-8501, Japan
| | - Masatoshi Masuda
- Department of Psychological Sciences, Kwansei Gakuin University, 1-1-155, Uegahara, Nishinomiya, Hyogo 662-8501, Japan
| | - Nobuya Sato
- Department of Psychological Sciences, Kwansei Gakuin University, 1-1-155, Uegahara, Nishinomiya, Hyogo 662-8501, Japan.
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Onaka T, Takayanagi Y. Role of oxytocin in the control of stress and food intake. J Neuroendocrinol 2019; 31:e12700. [PMID: 30786104 PMCID: PMC7217012 DOI: 10.1111/jne.12700] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/12/2019] [Accepted: 02/15/2019] [Indexed: 12/20/2022]
Abstract
Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information-processing cerebral cortex; the cognitive information-processing prefrontal cortex; reward-related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress-related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis-controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.
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Affiliation(s)
- Tatsushi Onaka
- Division of Brain and NeurophysiologyDepartment of PhysiologyJichi Medical UniversityShimotsuke‐shiJapan
| | - Yuki Takayanagi
- Division of Brain and NeurophysiologyDepartment of PhysiologyJichi Medical UniversityShimotsuke‐shiJapan
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32
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Zhao Y, Bijlsma EY, ter Heegde F, Verdouw MP, Garssen J, Newman-Tancredi A, Groenink L. Activation of somatodendritic 5-HT 1A autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test. Psychopharmacology (Berl) 2019; 236:1171-1185. [PMID: 30539269 PMCID: PMC6591185 DOI: 10.1007/s00213-018-5124-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 11/14/2018] [Indexed: 11/29/2022]
Abstract
RATIONALE Fear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT)1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT1A autoreceptors and post-synaptic 5-HT1A heteroreceptors in fear conditioning is still unclear. OBJECTIVE To determine the role of pre- and post-synaptic 5-HT1A receptors in the acquisition and expression of cued and contextual conditioned fear. METHODS We studied the acute effects of four 5-HT1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT1A receptors biased agonists F13714 (0-0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT1A autoreceptors, or F15599 (0-0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT1A heteroreceptors, with the prototypical 5-HT1A receptor agonist R(+)8-OH-DPAT (0-0.3 mg/kg, SC) or the 5-HT1A receptor antagonist WAY100,635 (0-1.0 mg/kg, SC). RESULTS F13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04-0.16 mg/kg) and R(+)-8-OH-DPAT (0.1-0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03-1.0 mg/kg) reduced the overall startle response. CONCLUSIONS The current findings indicate that activation of somatodendritic 5-HT1A autoreceptors reduces cued fear learning, whereas 5-HT1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT1A heteroreceptors in the expression of conditioned fear.
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Affiliation(s)
- Yulong Zhao
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Elisabeth Y. Bijlsma
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Freija ter Heegde
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Monika P. Verdouw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - J. Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | | | - Lucianne Groenink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands. .,Brain Center Rudolf Magnus (BCRM), UMC Utrecht, Utrecht, The Netherlands.
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Faraji J, Karimi M, Soltanpour N, Moharrerie A, Rouhzadeh Z, Lotfi H, Hosseini SA, Jafari SY, Roudaki S, Moeeini R, Metz GA. Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking. eLife 2018; 7:40262. [PMID: 30422111 PMCID: PMC6277206 DOI: 10.7554/elife.40262] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 11/12/2018] [Indexed: 12/28/2022] Open
Abstract
The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL), and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may, therefore, provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations.
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Affiliation(s)
- Jamshid Faraji
- Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Canada.,Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mitra Karimi
- Inclusive-Integrated Education Program for Children with Special Needs, Exceptional Education Organization, Tehran, Iran
| | - Nabiollah Soltanpour
- Department of Anatomical Sciences, Babol University of Medical Sciences, Babol, Iran
| | - Alireza Moharrerie
- Department of Anatomy, Golestan University of Medical Sciences, Gorgan, Iran
| | - Zahra Rouhzadeh
- Department of Psychology, Islamic Azad University, Sari, Iran
| | - Hamid Lotfi
- Department of Psychology, Islamic Azad University, Tonekabon, Iran
| | - S Abedin Hosseini
- Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran
| | - S Yaghoob Jafari
- Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shabnam Roudaki
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd, Iran
| | - Reza Moeeini
- Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd, Iran
| | - Gerlinde As Metz
- Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Canada
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Wolfe M, Wisniewska H, Tariga H, Ibanez G, Collins JC, Wisniewski K, Qi S, Srinivasan K, Hargrove D, Lindstrom BF. Selective and non-selective OT receptor agonists induce different locomotor behaviors in male rats via central OT receptors and peripheral V1a receptors. Neuropeptides 2018; 70:64-75. [PMID: 29807652 DOI: 10.1016/j.npep.2018.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 05/18/2018] [Accepted: 05/19/2018] [Indexed: 10/16/2022]
Abstract
Oxytocin (OT) continues to inspire much research due to its diverse physiological effects. While the best-understood actions of OT are uterine contraction and milk ejection, OT is also implicated in maternal and bonding behaviors, and potentially in CNS disorders such as autism, schizophrenia, and pain. The dissection of the mechanism of action of OT is complicated by the fact that this peptide activates not only its cognate receptor but also vasopressin type 1a (V1a) receptors. In this study, we evaluated OT and a selective OT receptor (OTR) agonist, FE 204409, in an automated assay that measures rat locomotor activity. The results showed: 1) Subcutaneous (sc) administration of OT decreased locomotor behavior (distance traveled, stereotypy, and rearing). This effect was reversed by a V1a receptor (V1aR) antagonist ([Pmp1,Tyr(ME)2]AVP, sc), suggesting that OT acts through peripheral V1aR to inhibit locomotor activity. 2) A selective OTR agonist (FE 204409, sc) increased stereotypy. This effect was reversed by an OTR antagonist dosed icv, suggesting a central OTR site of action. Our findings identify distinct behavioral effects for OT and the selective agonist FE 204409, adding to the growing body of evidence that the V1aR mediates many effects attributed to OT and that peptides administered systemically at supra-physiological doses may activate receptors in the brain. Our studies further emphasize the importance of utilizing selective agonists and antagonists to assess therapeutic indications.
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Affiliation(s)
- Monica Wolfe
- Ferring Research Institute, Inc, San Diego, CA, United States
| | | | - Hiroe Tariga
- Ferring Research Institute, Inc, San Diego, CA, United States
| | - Gerardo Ibanez
- Ferring Research Institute, Inc, San Diego, CA, United States
| | - James C Collins
- Ferring Research Institute, Inc, San Diego, CA, United States
| | | | - Steve Qi
- Ferring Research Institute, Inc, San Diego, CA, United States
| | | | - Diane Hargrove
- Ferring Research Institute, Inc, San Diego, CA, United States
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Janeček M, Dabrowska J. Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies-potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST). Cell Tissue Res 2018; 375:143-172. [PMID: 30054732 DOI: 10.1007/s00441-018-2889-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/04/2018] [Indexed: 01/28/2023]
Abstract
Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT's role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.
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Affiliation(s)
- Michael Janeček
- Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Joanna Dabrowska
- Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA. .,Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
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36
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Intergenerational Sex-Specific Transmission of Maternal Social Experience. Sci Rep 2018; 8:10529. [PMID: 30002484 PMCID: PMC6043535 DOI: 10.1038/s41598-018-28729-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 06/27/2018] [Indexed: 02/07/2023] Open
Abstract
The social environment is a major determinant of individual stress response and lifetime health. The present study shows that (1) social enrichment has a significant impact on neuroplasticity and behaviour particularly in females; and (2) social enrichment in females can be transmitted to their unexposed female descendants. Two generations (F0 and F1) of male and female rats raised in standard and social housing conditions were examined for neurohormonal and molecular alterations along with changes in four behavioural modalities. In addition to higher cortical neuronal density and cortical thickness, social experience in mothers reduced hypothalamic-pituitary-adrenal (HPA) axis activity in F0 rats and their F1 non-social housing offspring. Only F0 social mothers and their F1 non-social daughters displayed improved novelty-seeking exploratory behaviour and reduced anxiety-related behaviour whereas their motor and cognitive performance remained unchanged. Also, cortical and mRNA measurements in the F1 generation were affected by social experience intergenerationally via the female lineage (mother-to-daughter). These findings indicate that social experience promotes cortical neuroplasticity, neurohormonal and behavioural outcomes, and these changes can be transmitted to the F1 non-social offspring in a sexually dimorphic manner. Thus, a socially stimulating environment may form new biobehavioural phenotypes not only in exposed individuals, but also in their intergenerationally programmed descendants.
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37
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Renicker MD, Cysewski N, Palmer S, Nakonechnyy D, Keef A, Thomas M, Magori K, Daberkow DP. Ameliorating Impact of Prophylactic Intranasal Oxytocin on Signs of Fear in a Rat Model of Traumatic Stress. Front Behav Neurosci 2018; 12:105. [PMID: 29892216 PMCID: PMC5985313 DOI: 10.3389/fnbeh.2018.00105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 05/07/2018] [Indexed: 12/17/2022] Open
Abstract
Oxytocin treatment reduces signs of long-term emotional stress after exposure to trauma; however, little is known about the potential protective effects of oxytocin treatment on behavioral and physiological changes associated with extreme stress exposure. The objective of this study was to investigate oxytocin treatment as a prophylactic measure against rat signs of fear. Two separate experiments were conducted in which the time of intranasal oxytocin administration differed. Intranasal oxytocin (1.0 μg/kg) was administered 5 min after daily exposure to foot shock in Experiment #1 and 1 h before foot shock in Experiment #2. In Experiment #1, possible massage-evoked oxytocin release (5 min after foot shock) was also investigated. In both experiments, a contextual fear conditioning procedure was employed in which stress was induced via inescapable foot shock (3 days, 40 shocks/day, 8 mA/shock) in a fear conditioning chamber. Male Sprague-Dawley rats (n = 24) were divided into four groups (n = 6, per group) for each experiment. Experiment #1 groups: Control Exp#1 (intranasal saline and no foot shock); Stress Exp#1 (intranasal saline 5 min after foot shock); Massage+Stress Exp#1 (massage-like stroking and intranasal saline 5 min after foot shock); Oxytocin+Stress Exp#1 (intranasal oxytocin 5 min after foot shock). Experiment #2 groups: Control Exp#2 (intranasal saline and no foot shock); Stress Exp#2 (intranasal saline 1 h before foot shock); Oxytocin Exp#2 (intranasal oxytocin and no foot shock); Oxytocin+Stress Exp#2 (intranasal oxytocin 1 h before foot shock). One week after fear conditioning (and other treatments), rats were independently evaluated for behavioral signs of fear. Two weeks after conditioning, physiological signs of fear were also assessed (Experiment #1). Relative to controls, rats treated with intranasal oxytocin 5 min after daily foot shock sessions exhibited significantly less immobility upon re-exposure to the shock chamber and attenuated physiological responses related to fear (e.g., elevated heart rate and blood pressure). Furthermore, intranasal oxytocin treatment given 1 h before daily foot shock sessions significantly decreased immobility and defecation upon re-exposure to the shock chamber, relative to controls. The results of this study suggest that prophylactic intranasal oxytocin, administered contemporaneously with aversive stimuli, mitigates behavioral and physiological responses associated with traumatic stress.
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Affiliation(s)
- Micah D Renicker
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Nicholas Cysewski
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Samuel Palmer
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Dmytro Nakonechnyy
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Andrew Keef
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Morgan Thomas
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Krisztian Magori
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - David P Daberkow
- Department of Biology, Eastern Washington University, Cheney, WA, United States
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Pałasz A, Janas-Kozik M, Borrow A, Arias-Carrión O, Worthington JJ. The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa. Neurochem Int 2018; 113:120-136. [DOI: 10.1016/j.neuint.2017.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/13/2017] [Accepted: 12/14/2017] [Indexed: 02/07/2023]
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Schumacher S, Oe M, Wilhelm FH, Rufer M, Heinrichs M, Weidt S, Moergeli H, Martin-Soelch C. Does trait anxiety influence effects of oxytocin on eye-blink startle reactivity? A randomized, double-blind, placebo-controlled crossover study. PLoS One 2018; 13:e0190809. [PMID: 29300752 PMCID: PMC5754118 DOI: 10.1371/journal.pone.0190809] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 12/20/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Previous research has demonstrated that the neuropeptide oxytocin modulates social behaviors and reduces anxiety. However, effects of oxytocin on startle reactivity, a well-validated measure of defense system activation related to fear and anxiety, have been inconsistent. Here we investigated the influence of oxytocin on startle reactivity with particular focus on the role of trait anxiety. METHODS Forty-four healthy male participants attended two experimental sessions. They received intranasal oxytocin (24 IU) in one session and placebo in the other. Startle probes were presented in combination with pictures of social and non-social content. Eye-blink startle magnitude was measured by electromyography over the musculus orbicularis oculi in response to 95 dB noise bursts. Participants were assigned to groups of high vs. low trait anxiety based on their scores on the trait form of the Spielberger State-Trait Anxiety Inventory (STAI). RESULTS A significant interaction effect of oxytocin with STAI confirmed that trait anxiety moderated the effect of oxytocin on startle reactivity. Post-hoc tests indicated that for participants with elevated trait anxiety, oxytocin increased startle magnitude, particularly when watching non-social pictures, while this was not the case for participants with low trait anxiety. CONCLUSION Results indicate that effects of oxytocin on defense system activation depend on individual differences in trait anxiety. Trait anxiety may be an important moderator variable that should be considered in human studies on oxytocin effects.
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Affiliation(s)
- Sonja Schumacher
- Department of Psychiatry and Psychotherapy, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Misari Oe
- Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Japan
| | - Frank H. Wilhelm
- Division of Clinical Psychology, Psychotherapy, and Health Psychology, Department of Psychology, University of Salzburg, Salzburg, Austria
| | - Michael Rufer
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Markus Heinrichs
- Department of Psychology, Laboratory for Biological and Personality Psychology, University of Freiburg, Freiburg, Germany
- Freiburg Brain Imaging Center, University Medical Center, University of Freiburg, Freiburg, Germany
| | - Steffi Weidt
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | - Hanspeter Moergeli
- Department of Psychiatry and Psychotherapy, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Chantal Martin-Soelch
- Division of Clinical and Health Psychology, Department of Psychology, University of Fribourg, Fribourg, Switzerland
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Beneficial effects of chronic oxytocin administration and social co-housing in a rodent model of post-traumatic stress disorder. Behav Pharmacol 2018; 27:704-717. [PMID: 27740964 DOI: 10.1097/fbp.0000000000000270] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Post-traumatic stress disorder (PTSD) is in part due to a deficit in memory consolidation and extinction. Oxytocin (OXT) has anxiolytic effects and promotes prosocial behaviors in both rodents and humans, and evidence suggests that it plays a role in memory consolidation. We studied the effects of administered OXT and social co-housing in a rodent model of PTSD. Acute OXT yielded a short-term increase in the recall of the traumatic memory if administered immediately after trauma. Low doses of OXT delivered chronically had a cumulating anxiolytic effect that became apparent after 4 days and persisted. Repeated injections of OXT after short re-exposures to the trauma apparatus yielded a long-term reduction in anxiety. Co-housing with naive nonshocked animals decreased the memory of the traumatic context compared with single-housed animals. In the long term, these animals showed less thigmotaxis and increased interest in novel objects, and a low OXT plasma level. Co-housed PTSD animals showed an increase in risk-taking behavior. These results suggest beneficial effects of OXT if administered chronically through increases in memory consolidation after re-exposure to a safe trauma context. We also show differences between the benefits of social co-housing with naive rats and co-housing with other shocked animals on trauma-induced long-term anxiety.
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41
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He F, Wang Z, Guo G. Postnatal separation prevents the development of prenatal stress-induced anxiety in association with changes in oestrogen receptor and oxytocin immunoreactivity in female mandarin vole (Microtus mandarinus) offspring. Eur J Neurosci 2017; 47:95-108. [PMID: 29205599 DOI: 10.1111/ejn.13788] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 11/15/2017] [Accepted: 11/23/2017] [Indexed: 11/27/2022]
Abstract
Oestrogen has both anxiogenic and anxiolytic effects because of variation in opposing action on alpha (ERα) and beta (ERβ) estrogen receptors in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA). Oxytocin (OT) reverses some of the anxiogenic effects of oestrogen in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). Because anxiety disorders are twice as common in women as in men, and oestrogen and OT are more important in females, we examined interactions between prenatal restraint stress (GS) and postnatal early short-term maternal separation (MS) and female mandarin vole behaviour, estrogen receptors and OT. The results show that adult female offspring from GS/noMS mothers showed increased anxiety in open-field and elevated plus-maze tests and had lower serum 17-beta-oestradiol (E2 ) levels than female offspring from GS/MS, noGS/MS and noGS/noMS mothers. GS/noMS females had more immunoreactive neurons for ERα in several brain regions and less ERβ- and OT-immunoreactive neurons in brain areas compared to GS/MS, noGS/MS and noGS/noMS offspring. Interestingly, noGS/MS and GS/MS offspring were similar to noGS/noMS offspring in that they did not develop anxiety as adults. We propose that MS alters the serum concentration of E2 and that the ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behaviour in adult female offspring initially exposed to anxiety-inducing conditions via an adverse foetal environment.
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Affiliation(s)
- Fengqin He
- Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an, Shaanxi, 710065, China
| | - Zijian Wang
- Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an, Shaanxi, 710065, China
| | - Guanlin Guo
- Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an, Shaanxi, 710065, China
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Moaddab M, Dabrowska J. Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats. Neuropharmacology 2017; 121:130-139. [PMID: 28456687 PMCID: PMC5553312 DOI: 10.1016/j.neuropharm.2017.04.039] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/04/2017] [Accepted: 04/25/2017] [Indexed: 01/25/2023]
Abstract
Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) plays a critical role in the regulation of fear and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNSTdl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNSTdl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNSTdl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNSTdl administration of specific OTR antagonist (OTA), (d(CH2)51, Tyr(Me)2, Thr4, Orn8, des-Gly-NH29)-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNSTdl in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNSTdl in learning to discriminate between threatening and safe stimuli.
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Affiliation(s)
- Mahsa Moaddab
- Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | - Joanna Dabrowska
- Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA; Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
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Sabihi S, Dong SM, Maurer SD, Post C, Leuner B. Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action. Neuropharmacology 2017; 125:1-12. [PMID: 28655609 DOI: 10.1016/j.neuropharm.2017.06.024] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 01/12/2023]
Abstract
Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.
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Affiliation(s)
- Sara Sabihi
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Shirley M Dong
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Skyler D Maurer
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Caitlin Post
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Benedetta Leuner
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States; The Ohio State University, Department of Neuroscience, Columbus, OH 43210, United States; The Ohio State University, Behavioral Neuroendocrinology Group, Columbus, OH 43210, United States.
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Abstract
Objective Patient-physician interaction is continually examined in an era prioritizing patient-centered approaches, yet elaboration beyond aspects of communication and empathy is lacking. Major chronic conditions would benefit tremendously from understanding interpersonal aspects of patient-physician encounters. This review intends to provide a concise introduction to the interpersonal model of attachment theory and how it informs both the patient-physician interaction and medical outcomes in chronic care. Methods A narrative review of the theoretical, neurobiological, epidemiological, investigational, and clinical literature on attachment theory and its impact on medical outcomes was conducted, utilizing a variety of key words as searched on PubMed database. Studies and reviews included were of a variety of sources, including textbooks and peer-reviewed journals. Reports in languages other than English were excluded. Results Measurable, discrete attachment styles and behavioral patterns correlate with poor medical outcomes, including nonadherence in insecure dismissing attachment and care overutilization in insecure preoccupied attachment. Furthermore, insecure dismissing attachment is associated with significant mortality. These variables can be easily assessed, and their effects are reversible, as evidenced by collaborative care outcome data. Discussion Attachment theory is useful a model with application in clinical and investigational aspects of chronic illness care. Implications and guidelines are explored.
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Affiliation(s)
- Xavier F Jimenez
- Department of Psychiatry and Psychology, Cleveland Clinic Foundation, USA
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Modi ME, Majchrzak MJ, Fonseca KR, Doran A, Osgood S, Vanase-Frawley M, Feyfant E, McInnes H, Darvari R, Buhl DL, Kablaoui NM. Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing. J Pharmacol Exp Ther 2016; 358:164-72. [PMID: 27217590 PMCID: PMC4959095 DOI: 10.1124/jpet.116.232702] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 05/11/2016] [Indexed: 01/05/2023] Open
Abstract
Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response.
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Affiliation(s)
- Meera E Modi
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Mark J Majchrzak
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Kari R Fonseca
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Angela Doran
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Sarah Osgood
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Michelle Vanase-Frawley
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Eric Feyfant
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Heather McInnes
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Ramin Darvari
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Derek L Buhl
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
| | - Natasha M Kablaoui
- Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)
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Proctor D, Calcutt SE, Burke K, de Waal FBM. Intranasal Oxytocin Failed to Affect Chimpanzee ( Pan troglodytes) Social Behavior. ANIMAL BEHAVIOR AND COGNITION 2016; 3:150-158. [PMID: 28845444 PMCID: PMC5571871 DOI: 10.12966/abc.04.08.2016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Oxytocin has been suggested as a treatment to promote positive social interactions in people with Autism Spectrum Disorders (ASD). However, it is difficult to test this effect outside of the laboratory in realistic social situations. One way to resolve this issue is to study behavioral changes in closely related species with complex social relationships, such as chimpanzees. Here, we use captive, socially housed chimpanzees to evaluate the effects of oxytocin in a socially complex environment. After administering intranasal oxytocin or a placebo to an individual chimpanzee (total n = 8), she was returned to her social group. An experimenter blind to the condition measured the subject's social behavior. We failed to find a behavioral difference between conditions. As one of the goals for oxytocin administration as a treatment for ASD is increasing prosocial behaviors during 'real world' encounters, it is problematic that we failed to detect behavioral changes in our closest living relatives. However, our null findings may be related to methodological challenges such as determining an effective dose of oxytocin for chimpanzees and how long oxytocin takes to cross the blood-brain barrier. Thus, more research on intranasal oxytocin dosing and uptake are needed to continue exploring whether oxytocin changes social behavior in naturalistic settings and as a treatment for ASD.
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Affiliation(s)
- Darby Proctor
- Living Links, Yerkes National Primate Research Center, Lawrenceville, GA, USA
- Department of Psychology, Florida Institute of Technology, Melbourne, FL, USA
| | - Sarah E Calcutt
- Living Links, Yerkes National Primate Research Center, Lawrenceville, GA, USA
| | - Kimberly Burke
- Living Links, Yerkes National Primate Research Center, Lawrenceville, GA, USA
| | - Frans B M de Waal
- Living Links, Yerkes National Primate Research Center, Lawrenceville, GA, USA
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Ayers L, Agostini A, Schulkin J, Rosen JB. Effects of oxytocin on background anxiety in rats with high or low baseline startle. Psychopharmacology (Berl) 2016; 233:2165-2172. [PMID: 27004789 PMCID: PMC4864502 DOI: 10.1007/s00213-016-4267-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 02/29/2016] [Indexed: 01/17/2023]
Abstract
RATIONALE Oxytocin has antianxiety properties in humans and rodents. However, the antianxiety effects have been variable. OBJECTIVES To reduce variability and to strengthen the antianxiety effect of oxytocin in fear-potentiated startle, two experiments were performed. First, different amounts of light-shock pairings were given to determine the optimal levels of cue-specific fear conditioning and non-predictable startle (background anxiety). Second, the antianxiety effects of oxytocin were examined in rats with high and low pre-fear conditioning baseline startle to determine if oxytocin differentially affects high and low trait anxiety rats. METHODS Baseline pre-fear conditioning startle responses were first measured. Rats then received 1, 5, or 10 light-shock pairings. Fear-potentiated startle was then tested with two trial types: light-cued startle and non-cued startle trials. In the second experiment, rats fear conditioned with 10 light-shock pairings were administered either saline or oxytocin before a fear-potentiated startle test. Rats were categorized as low or high startlers by their pre-fear conditioning startle amplitude. RESULTS Ten shock pairings produced the largest non-cued startle responses (background anxiety), without increasing cue-specific fear-potentiated startle compared to one and five light-shock pairings. Cue-specific fear-potentiated startle was unaffected by oxytocin. Oxytocin reduced background anxiety only in rats with low pre-fear startle responses. CONCLUSIONS Oxytocin has population selective antianxiety effects on non-cued unpredictable threat, but only in rats with low pre-fear baseline startle responses. The low startle responses are reminiscent of humans with low startle responses and high trait anxiety.
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Affiliation(s)
- Luke Ayers
- Department of Psychology, Widener University, Chester, PA
| | - Andrew Agostini
- Department of Psychological and Brain Sciences, University of
Delaware, Newark, DE
| | - Jay Schulkin
- Department of Neuroscience, Georgetown University, Washington,
DC
| | - Jeffrey B. Rosen
- Department of Psychological and Brain Sciences, University of
Delaware, Newark, DE
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Finkenwirth C, Martins E, Deschner T, Burkart JM. Oxytocin is associated with infant-care behavior and motivation in cooperatively breeding marmoset monkeys. Horm Behav 2016; 80:10-18. [PMID: 26836769 DOI: 10.1016/j.yhbeh.2016.01.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 12/22/2015] [Accepted: 01/29/2016] [Indexed: 01/26/2023]
Abstract
The neurohormone oxytocin (OT) is positively involved in the regulation of parenting and social bonding in mammals, and may thus also be important for the mediation of alloparental care. In cooperatively breeding marmosets, infants are raised in teamwork by parents and adult and sub-adult non-reproductive helpers (usually older siblings). Despite high intrinsic motivation, which may be mediated by hormonal priming, not all individuals are always equally able to contribute to infant-care due to competition among care-takers. Among the various care-taking behaviors, proactive food sharing may reflect motivational levels best, since it can be performed ad libitum by several individuals even if competition among surplus care-takers constrains access to infants. Our aim was to study the link between urinary OT levels and care-taking behaviors in group-living marmosets, while taking affiliation with other adults and infant age into account. Over eight reproductive cycles, 26 individuals were monitored for urinary baseline OT, care-taking behaviors (baby-licking, -grooming, -carrying, and proactive food sharing), and adult-directed affiliation. Mean OT levels were generally highest in female breeders and OT increased significantly in all individuals after birth. During early infancy, high urinary OT levels were associated with increased infant-licking but low levels of adult-affiliation, and during late infancy, with increased proactive food sharing. Our results show that, in marmoset parents and alloparents, OT is positively involved in the regulation of care-taking, thereby reflecting the changing needs during infant development. This particularly included behaviors that are more likely to reflect intrinsic care motivation, suggesting a positive link between OT and motivational regulation of infant-care.
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Affiliation(s)
- Christa Finkenwirth
- Anthropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
| | - Eloisa Martins
- Anthropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Tobias Deschner
- Max-Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103 Leipzig, Germany
| | - Judith M Burkart
- Anthropological Institute and Museum, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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49
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Hoffman KL. New dimensions in the use of rodent behavioral tests for novel drug discovery and development. Expert Opin Drug Discov 2016; 11:343-53. [DOI: 10.1517/17460441.2016.1153624] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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50
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Waller C, Wittfoth M, Fritzsche K, Timm L, Wittfoth-Schardt D, Rottler E, Heinrichs M, Buchheim A, Kiefer M, Gündel H. Attachment representation modulates oxytocin effects on the processing of own-child faces in fathers. Psychoneuroendocrinology 2015. [PMID: 26221767 DOI: 10.1016/j.psyneuen.2015.07.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Oxytocin (OT) plays a crucial role in parental-infant bonding and attachment. Recent functional imaging studies reveal specific attachment and reward related brain regions in individuals or within the parent-child dyad. However, the time course and functional stage of modulatory effects of OT on attachment-related processing, especially in fathers, are poorly understood. To elucidate the functional and neural mechanisms underlying the role of OT in paternal-child attachment, we performed an event-related potential study in 24 healthy fathers who received intranasal OT in a double-blind, placebo-controlled, within-subject experimental design. Participants passively viewed pictures of their own child (oC), a familiar (fC) and an unfamiliar child (ufC) while event-related potentials were recorded. Familiarity of the child's face modulated a broad negativity at occipital and temporo-parietal electrodes within a time window of 300-400ms, presumably reflecting a modulation of the N250 and N300 ERP components. The oC condition elicited a more negative potential compared to the other familiarity conditions suggesting different activation of perceptual memory representations and assignment of emotional valence. Most importantly, this familiarity effect was only observed under placebo (PL) and was abolished under OT, in particular at left temporo-parietal electrodes. This OT induced attenuation of ERP responses was related to habitual attachment representations in fathers. In summary, our results demonstrate an OT-specific effect at later stages of attachment-related face processing presumably reflecting both activation of perceptual memory representations and assignment of emotional value.
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Affiliation(s)
- Christiane Waller
- University of Ulm, Department of Psychosomatic Medicine, Ulm, Germany.
| | - Matthias Wittfoth
- Department of Clinical Psychology and Sexual Medicine, Hannover Medical School, Hannover, Germany
| | | | - Lydia Timm
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Dina Wittfoth-Schardt
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Edit Rottler
- University of Ulm, Department of Psychosomatic Medicine, Ulm, Germany
| | - Markus Heinrichs
- University of Freiburg, Department of Psychology, Freiburg i.Br., Germany
| | - Anna Buchheim
- University of Innsbruck, Department of Psychology, Innsbruck, Austria
| | - Markus Kiefer
- University of Ulm, Department of Psychiatry, Ulm, Germany
| | - Harald Gündel
- University of Ulm, Department of Psychosomatic Medicine, Ulm, Germany
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