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Ubri CE, Farrugia AM, Cohen AS. Mild Traumatic Brain Injury Impairs Fear Extinction and Network Excitability in the Infralimbic Cortex. J Neurotrauma 2025. [PMID: 40401451 DOI: 10.1089/neu.2025.0046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with mild TBI (concussions) representing over 80% of cases. Although often considered benign, mild TBI is associated with persistent neuropsychiatric conditions, including post-traumatic stress disorder, anxiety, and depression. A hallmark of these conditions is impaired fear extinction (FE), the process by which learned fear responses are inhibited in safe contexts. This dysfunction contributes to maladaptive fear expression and is linked to altered neurocircuitry, particularly in the infralimbic cortex (IL), a key region in FE. Despite extensive evidence of impaired FE in patients with mild TBI and animal models, the specific mechanisms underlying this deficit remain poorly understood. This study aimed to address this gap by combining cued-FE behavior, local field potential recordings, and whole-cell patch-clamp techniques to investigate how mild TBI affects IL network activity and excitability in a mouse model of TBI. Our results demonstrate that mild lateral fluid percussion injury significantly impairs FE memory, as evidenced by an elevated cued-fear response during extinction testing 10 days post-injury. Field potential recordings revealed decreased activation of the IL network in both layers II/III and V, which was consistent with the observed behavioral deficits. Further analysis of synaptic physiology revealed an imbalance in excitatory and inhibitory neurotransmission (E/I imbalance) in the IL, characterized by reduced excitatory input and enhanced inhibitory input to neurons in both layers. Moreover, intrinsic excitability was altered in IL neurons after mild TBI. This study provides novel insights into how mild TBI disrupts the neurocircuitry underlying FE, specifically by suppressing IL excitability. These results highlight the importance of understanding the mechanistic disruptions in IL activity for developing therapeutic strategies to address fear-based disorders in patients with mild TBI.
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Affiliation(s)
- Catherine E Ubri
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Anthony M Farrugia
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Akiva S Cohen
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Raskin M, Keller NE, Agee LA, Malone CA, Quevedo S, Hilz EN, Roquet RF, Shumake J, Smits JAJ, Telch MJ, Otto MW, Lee HJ, Monfils MH. Associations of CO 2 reactivity and orexin activity with extinction memory to fear and reward cues: results from a large sample of male rats across multiple studies. Physiol Behav 2025; 298:114949. [PMID: 40350068 DOI: 10.1016/j.physbeh.2025.114949] [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: 03/11/2025] [Revised: 04/27/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
Pavlovian conditioning can be used to model maladaptive associations seen in anxiety/trauma and substance use disorders. One approach to attenuate conditioned responses is extinction learning (which underlies exposure therapy), wherein cues are repeatedly presented without the expected fearful or rewarding outcome. Extinction is not effective for all; therefore, identifying biomarkers that can phenotype non-responders is necessary to optimize treatment. The orexin system is involved in fear and reward extinction and responses to CO2 exposure. We previously found that CO2 reactivity predicts fear extinction memory and CO2-induced orexin activity, and orexin activity is associated with extinction memory. In a separate study, we replicated the finding that CO2 reactivity predicts fear extinction memory and extended this finding to appetitive extinction memory. Here, we combined behavioral and orexin activity data from these three studies in male rats to examine whether we might identify new or common associations of fear and reward extinction with CO2 reactivity and orexin in a larger combined sample. We found that neither CO2 reactivity nor CO2-induced orexin activity associate with extinction memory in the combined fear and appetitive sample. We found common CO2 reactivity predictors in the combined fear sample, including a new predictor associated with orexin activity. In an expanded analysis, we found that prior CO2 exposure may affect subsequent CO2 reactivity and decrease orexin activity. Our findings support the potential of CO2 reactivity to serve as a screening tool for identifying likely responders to exposure-based therapy, though specific predictors may differ by reinforcer valence.
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Affiliation(s)
- Marissa Raskin
- Interdisciplinary Neuroscience Program, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712
| | - Nicole E Keller
- Interdisciplinary Neuroscience Program, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712
| | - Laura A Agee
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Cassidy A Malone
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Silvia Quevedo
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Emily N Hilz
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Rheall F Roquet
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Jason Shumake
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Jasper A J Smits
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Michael J Telch
- Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - Michael W Otto
- Department of Psychological & Brain Sciences, Boston University, 64 Cummington Mall, Room 149, Boston, MA 02215
| | - Hongjoo J Lee
- Interdisciplinary Neuroscience Program, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712; Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712
| | - M H Monfils
- Interdisciplinary Neuroscience Program, The University of Texas at Austin, 1 University Station, Stop C7000, Austin, TX 78712; Department of Psychology, University of Texas at Austin, 108 E. Dean Keeton Street, Stop A8000, Austin, TX 78712.
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Trent S, Abdullah MH, Parwana K, Valdivieso MA, Hassan Z, Müller CP. Fear conditioning: Insights into learning, memory and extinction and its relevance to clinical disorders. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111310. [PMID: 40056965 DOI: 10.1016/j.pnpbp.2025.111310] [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: 12/10/2024] [Revised: 02/26/2025] [Accepted: 03/02/2025] [Indexed: 03/15/2025]
Abstract
Fear, whether innate or learned, is an essential emotion required for survival. The learning, and subsequent memory, of fearful events enhances our ability to recognise and respond to threats, aiding adaptation to new, ever-changing environments. Considerable research has leveraged associative learning protocols such as contextual or auditory forms of fear conditioning in rodents, to understand fear learning, memory consolidation and extinction phases of memory. Such assays have led to detailed characterisation of the underlying neurocircuitry and neurobiology supporting fear learning processes. Given fear processing is conserved across rodents and humans, fear conditioning experiments provide translational insights into fundamental memory processes and fear-related pathologies. This review examines associative learning protocols used to measure fear learning, memory and extinction, before providing an overview on the underlying complex neurocircuitry including the amygdala, hippocampus and medial prefrontal cortex. This is followed by an in-depth commentary on the neurobiology, particularly synaptic plasticity mechanisms, which regulate fear learning, memory and extinction. Next, we consider how fear conditioning assays in rodents can inform our understanding of disrupted fear memory in human disorders such as post-traumatic stress disorder (PTSD), anxiety and psychiatric disorders including schizophrenia. Lastly, we critically evaluate fear conditioning protocols, highlighting some of the experimental and theoretical limitations and the considerations required when conducting such assays, alongside recent methodological advancements in the field. Overall, rodent-based fear conditioning assays remain central to making progress in uncovering fundamental memory phenomena and understanding the aetiological mechanisms that underpin fear associated disorders, alongside the development of effective therapeutic strategies.
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Affiliation(s)
- Simon Trent
- School of Life Sciences, Faculty of Natural Sciences, Huxley Building, Keele University, Keele ST5 5BG, UK.
| | | | - Krishma Parwana
- School of Life Sciences, Faculty of Natural Sciences, Huxley Building, Keele University, Keele ST5 5BG, UK
| | - Maria Alcocer Valdivieso
- School of Life Sciences, Faculty of Natural Sciences, Huxley Building, Keele University, Keele ST5 5BG, UK
| | - Zurina Hassan
- Centre for Drug Research, Universiti Malaysia (USM), 11800 Penang, Malaysia
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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Wu L, Geng S, Zhou Y, Jiao R, Ouyang H, Cheng S, Shang Z, Yan W, Wang J, Jia Y, Li X, Liu W. Direct and Indirect Effects of Risk Perception and Risk Information on PTSD in Frontline Healthcare Workers. Neuropsychiatr Dis Treat 2025; 21:663-676. [PMID: 40134761 PMCID: PMC11934884 DOI: 10.2147/ndt.s491046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/24/2025] [Indexed: 03/27/2025] Open
Abstract
Background The COVID-19 Delta variant caused an outbreak in Guangdong in mid-May 2021. The risk information and risk perception of COVID-19 have been considered factors associated with mental health statuses, especially posttraumatic stress disorder (PTSD), in frontline healthcare workers. Objective The aim of this study is to investigate the interactive relationship in risk information and risk perception of COVID-19 and PTSD in healthcare personnel from the emergency department. Design We conducted a survey one month after the outbreak. A cross-sectional survey design is adopted, and 3078 participants are enrolled. The PTSD checklist for DSM-5 (PCL-5), risk information questionnaire, and risk perception questionnaire are utilized to collect data. Methods Bivariate correlation analysis and structural equation modelling are performed to analyze the mediating role of risk perception in the relationship between risk information and PTSD. Results The estimated prevalence of PTSD among frontline healthcare workers is 28.2%. The risk information for COVID-19, risk perception, and PTSD symptoms are mutually correlated. The specific paths from risk perception to PTSD show significant effects, in which two had negative effects and one had a positive effect. The risk perception feature in 2020 differed from that in 2019, which is largely due to the risk perception of the virus. Conclusion The estimated prevalence of PTSD among frontline healthcare workers remains high. Risk information for COVID-19 has dual effects on PTSD through the mediation of risk perceptions. Unfamiliarity with the SAR-COVID-2 Delta variant increased the risk perception of COVID-19. Effective risk communication regarding COVID-19 can have a positive effect on the mental health of frontline healthcare workers.
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Affiliation(s)
- Lili Wu
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Shiyu Geng
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
| | - Yaoguang Zhou
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Runda Jiao
- Graduate School, PLA General Hospital, Beijing, 100853, People’s Republic of China
| | - Hui Ouyang
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Suhui Cheng
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Zhilei Shang
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Wenjie Yan
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Jing Wang
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Yanpu Jia
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
| | - Xu Li
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
| | - Weizhi Liu
- Lab for Post-Traumatic Stress Disorder, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Navy Medical University, Shanghai, 200433, People’s Republic of China
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Blasi E, Di Cesare B, Pisaneschi A, Campolongo P, Morena M. Social buffering during fear extinction rescues long-term trauma-induced memory and emotional behavioral alterations in rats. Transl Psychiatry 2025; 15:64. [PMID: 39984453 PMCID: PMC11845759 DOI: 10.1038/s41398-025-03285-8] [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] [Received: 02/15/2024] [Revised: 01/14/2025] [Accepted: 02/12/2025] [Indexed: 02/23/2025] Open
Abstract
Post-Traumatic Stress Disorder (PTSD) is a psychiatric disease that may develop after experiencing a traumatic event and it is characterized by resistance to extinction of the traumatic memory. Psychotherapy, which mainly focuses on favoring fear memory extinction, represents the first-line treatment for PTSD. However, this approach is not always successful. Emerging evidence suggests the importance of a social support in alleviating PTSD symptomatology; however, the efficacy of group therapy for PTSD remains controversial. Here, we evaluated the impact of social support on the efficacy of fear extinction sessions in a chronic PTSD-like rat model. We tested the hypothesis that the presence of a social partner during temporally spaced extinction sessions (to mimic the presence of a social support during therapy) or after the extinction sessions in a neutral environment (to mimic the presence of a social support outside of the therapy setting) would ameliorate long-term PTSD-like symptomatology. Extinction sessions were carried out under different conditions: (i) alone; (ii) with a social partner never exposed to the trauma; (iii) with a trauma-exposed partner. In a separate set of experiments, rats were exposed to the extinction sessions alone and, immediately thereafter, paired with a social partner, as indicated above, in a different context. Extinction sessions carried out in the presence of a social partner never exposed to the traumatic experience rescued long-term trauma-induced PTSD-like symptomatology. We provide evidence of beneficial effects of a "healthy" social support during extinction sessions in ameliorating both immediate and persistent over time cognitive and emotional PTSD-like symptoms.
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Affiliation(s)
- Eleonora Blasi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Neuropharmacology Unit, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, Rome, Italy
| | - Benedetta Di Cesare
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Neuropharmacology Unit, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, Rome, Italy
| | - Arianna Pisaneschi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Neuropharmacology Unit, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, Rome, Italy
| | - Patrizia Campolongo
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Neuropharmacology Unit, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, Rome, Italy
| | - Maria Morena
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
- Neuropharmacology Unit, European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, Rome, Italy.
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6
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Gielow MR, Headley DB, Herzallah MM, Paré D. Common Neocortical and Hippocampal Correlates of Performance Errors in a Timing Task. J Neurosci 2025; 45:e2003232024. [PMID: 39794130 PMCID: PMC11823390 DOI: 10.1523/jneurosci.2003-23.2024] [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: 10/24/2023] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
We aimed to identify the neuronal correlates of performance errors in a difficult timing task. Male rats were trained to seek rewards and avoid shocks depending on the position of photic conditioned stimuli (CS-R and CS-S, respectively). Then, they were exposed to conflict trials where they had to time the interval between the CS-R and CS-S to obtain rewards while avoiding footshocks. There were pronounced individual differences in behavioral strategies on conflict trials. When presented with a CS-S, some rats quickly left the shock sector, forsaking the option of earning a reward, and rarely got shocked. Others earned rewards by delaying avoidance based on the interval between the CS-R and CS-S but were shocked more often. The probability rats would fail a given trial was not stable across trials as rats engaged in incorrect trial runs that were longer than expected by chance. Since this finding suggested that rats shift between two quasi-stable processing modes, we next examined the neuronal correlates of errors. Incorrect trials coincided with reduced firing rates in CA1 and sensory cortical neurons. Moreover, trial-to-trial variations in the firing rates of simultaneously recorded neurons were more strongly correlated on error than correct trials. Last, the power of low-frequency local field potential oscillations was higher during incorrect trials. The finding that the neuronal correlates of correct and error trials are similar in the hippocampus and neocortex lead us to hypothesize that they depend on changes in the activity of common afferents, such as neuromodulatory inputs.
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Affiliation(s)
- Matthew R Gielow
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
| | - Drew B Headley
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
| | - Mohammad M Herzallah
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
- Palestinian Neuroscience Initiative, Al-Quds University, Jerusalem, Palestine
| | - Denis Paré
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
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Sachdeva J, Shukla R. Exploring the Mediating Influence of Psychological Flexibility and Self-Compassion on the Relationship Between Adverse Childhood Experiences and Post-Traumatic Growth among Young Adults in India. Psychol Rep 2024:332941241302318. [PMID: 39606864 DOI: 10.1177/00332941241302318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Through the course of the last few decades researchers have observed that Adverse Childhood Experiences (ACE) can act as a breeding ground for transformative positive changes to develop in the face of adversity. This process of enhanced growth is systematically studied as 'Post Traumatic Growth' (PTG). Though there is an existing association between ACE and PTG, yet there is a paucity of studies that explores the mediating variables in this relationship. The current study aims to explore the role of self-compassion (SC) and psychological flexibility (PF) between ACE and PTG among Indian young adults. The study was conducted on 298 Indian participants who were in the age bracket of 18-25 years. The study variables were assessed using self-administered rating scales. Participants were screened for ACE using Adverse Childhood Experiences (ACEs) Questionnaire. Additionally, Self-Compassion Scale (SCS-SF), Acceptance and Action Questionnaire-II (AAQ-II), Posttraumatic Growth Inventory- Short Form were other tools used. The results have indicated that both Psychological Flexibility and Self-Compassion mediate the relationship of ACE with PTG. The current findings have emphasized on the role of Psychological Flexibility and Self-Compassion in moving towards Post Traumatic Growth. These findings reassert that Psychological Flexibility and Self-Compassion are foundational to Acceptance Commitment Therapy and highly useful especially while working with trauma affected populations.
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Affiliation(s)
- Jasmine Sachdeva
- Clinical Psychology, CHRIST (Deemed to be University), Ghaziabad, India
| | - Ridhima Shukla
- Department of Psychology, CHRIST (Deemed to be University), Ghaziabad, India
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8
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Raskin M, Keller NE, Agee LA, Shumake J, Smits JA, Telch MJ, Otto MW, Lee HJ, Monfils MH. Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100310. [PMID: 38680941 PMCID: PMC11047292 DOI: 10.1016/j.bpsgos.2024.100310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 02/11/2024] [Accepted: 03/11/2024] [Indexed: 05/01/2024] Open
Abstract
Background Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction. Methods Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test. Results We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree. Conclusions CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.
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Affiliation(s)
- Marissa Raskin
- Institute for Neuroscience, University of Texas at Austin, Austin, Texas
| | - Nicole E. Keller
- Institute for Neuroscience, University of Texas at Austin, Austin, Texas
| | - Laura A. Agee
- Department of Neuroscience, University of Texas at Austin, Austin, Texas
| | - Jason Shumake
- Department of Psychology, University of Texas at Austin, Austin, Texas
| | - Jasper A.J. Smits
- Department of Psychology, University of Texas at Austin, Austin, Texas
| | - Michael J. Telch
- Department of Psychology, University of Texas at Austin, Austin, Texas
| | - Michael W. Otto
- Department of Psychological & Brain Sciences, Boston University, Boston, Massachusetts
| | - Hongjoo J. Lee
- Institute for Neuroscience, University of Texas at Austin, Austin, Texas
- Department of Psychology, University of Texas at Austin, Austin, Texas
| | - Marie-H. Monfils
- Institute for Neuroscience, University of Texas at Austin, Austin, Texas
- Department of Psychology, University of Texas at Austin, Austin, Texas
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9
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Sep MSC, Sarabdjitsingh RA, Geuze E, Joels M. Pre-trauma memory contextualization as predictor for PTSD-like behavior in male rats. J Psychiatr Res 2024; 171:84-94. [PMID: 38262164 DOI: 10.1016/j.jpsychires.2024.01.029] [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: 11/09/2023] [Accepted: 01/15/2024] [Indexed: 01/25/2024]
Abstract
While many people experience potentially threatening events during their life, only a minority develops posttraumatic stress disorder (PTSD). The identification of individuals at risk among those exposed to trauma is crucial for PTSD prevention in the future. Since re-experiencing trauma elements outside of the original trauma-context is a core feature of PTSD, we investigate if the ability to bind memories to their original encoding context (i.e. memory contextualization) predicts PTSD vulnerability. We hypothesize that pre-trauma neutral memory contextualization (under stress) negatively relates to PTSD-like behavior, in a prospective design using the cut-off behavioral criteria rat model for PTSD. 72 male Sprague Dawley rats were divided in two experimental groups to assess the predictive value of 1) memory contextualization without acute stress (NS-group) and 2) memory contextualization during the recovery phase of the acute stress-response (S-group) for susceptibility to PTSD-like behavior. A powerful extension to regression analysis -path analysis-was used to test this specific hypothesis, together with secondary research questions. Following traumatic predator scent stress, 19.4% of the rats displayed PTSD-like behavior. Results showed a negative relation between pre-trauma memory contextualization and PTSD-like behavior, but only in the NS-group. Pre-trauma memory contextualization was positively related to fear association in the trauma environment, again only in the NS group. If the predictive value of pre-trauma contextualization of neutral information under non-stressful conditions for PTSD susceptibility is replicated in prospective studies in humans, this factor would supplement already known vulnerability factors for PTSD and improve the identification of individuals at risk among the trauma exposed, especially those at high trauma risk such as soldiers deployed on a mission.
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Affiliation(s)
- Milou S C Sep
- Brain Research and Innovation Centre, Ministry of Defence, Utrecht, the Netherlands; Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, the Netherlands; Department of Psychiatry, Amsterdam University Medical Center location Vrije Universiteit, Amsterdam, the Netherlands; GGZ inGeest Mental Health Care, Amsterdam, the Netherlands; Amsterdam Neuroscience, Mood Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands; Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands.
| | - R Angela Sarabdjitsingh
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, the Netherlands
| | - Elbert Geuze
- Brain Research and Innovation Centre, Ministry of Defence, Utrecht, the Netherlands; Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands
| | - Marian Joels
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, the Netherlands; University of Groningen, University Medical Center Groningen, the Netherlands
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Sep MSC, Geuze E, Joëls M. Impaired learning, memory, and extinction in posttraumatic stress disorder: translational meta-analysis of clinical and preclinical studies. Transl Psychiatry 2023; 13:376. [PMID: 38062029 PMCID: PMC10703817 DOI: 10.1038/s41398-023-02660-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 10/28/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023] Open
Abstract
Current evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically informed approaches are urgently needed. Clinical and translational neuroscience point to altered learning and memory processes as key in (models of) PTSD psychopathology. We extended this notion by clarifying at a meta-level (i) the role of information valence, i.e. neutral versus emotional/fearful, and (ii) comparability, as far as applicable, between clinical and preclinical phenotypes. We hypothesized that cross-species, neutral versus emotional/fearful information processing is, respectively, impaired and enhanced in PTSD. This preregistered meta-analysis involved a literature search on PTSD+Learning/Memory+Behavior, performed in PubMed. First, the effect of information valence was estimated with a random-effects meta-regression. The sources of variation were explored with a random forest-based analysis. The analyses included 92 clinical (N = 6732 humans) and 182 preclinical (N = 6834 animals) studies. A general impairment of learning, memory and extinction processes was observed in PTSD patients, regardless of information valence. Impaired neutral learning/memory and fear extinction were also present in animal models of PTSD. Yet, PTSD models enhanced fear/trauma memory in preclinical studies and PTSD impaired emotional memory in patients. Clinical data on fear/trauma memory was limited. Mnemonic phase and valence explained most variation in rodents but not humans. Impaired neutral learning/memory and fear extinction show stable cross-species PTSD phenotypes. These could be targeted for novel PTSD treatments, using information gained from neurobiological animal studies. We argue that apparent cross-species discrepancies in emotional/fearful memory deserve further in-depth study; until then, animal models targeting this phenotype should be applied with utmost care.
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Affiliation(s)
- Milou S C Sep
- Brain Research and Innovation Centre, Ministry of Defence, Utrecht, the Netherlands.
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
- GGZ inGeest Mental Health Care, Amsterdam, The Netherlands.
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, The Netherlands.
- Amsterdam Public Health, Mental Health Program, Amsterdam, The Netherlands.
- Department of Psychiatry, Amsterdam University Medical Center location Vrije Universiteit, Amsterdam, The Netherlands.
| | - Elbert Geuze
- Brain Research and Innovation Centre, Ministry of Defence, Utrecht, the Netherlands
- Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Marian Joëls
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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11
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Heesbeen EJ, Bijlsma EY, Verdouw PM, van Lissa C, Hooijmans C, Groenink L. The effect of SSRIs on fear learning: a systematic review and meta-analysis. Psychopharmacology (Berl) 2023; 240:2335-2359. [PMID: 36847831 PMCID: PMC10593621 DOI: 10.1007/s00213-023-06333-7] [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] [Received: 07/04/2022] [Accepted: 01/31/2023] [Indexed: 03/01/2023]
Abstract
RATIONALE Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. OBJECTIVE We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. METHODS We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. RESULTS Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. CONCLUSIONS This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.
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Affiliation(s)
- Elise J Heesbeen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Elisabeth Y Bijlsma
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - P Monika Verdouw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Caspar van Lissa
- Department of Methodology, Tilburg University, Tilburg, Netherlands
| | - Carlijn Hooijmans
- Department of Anaesthesiology, Pain and Palliative Care, Radboud University Medical Center, Nijmegen, Netherlands
| | - Lucianne Groenink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
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12
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Zhao Y, Shao H, Wang H, Li H, Xue Q. Age-related impairment in fear memory extinction is restored by ketamine in middle-aged mice. COGNITIVE, AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2023; 23:1374-1383. [PMID: 37420092 DOI: 10.3758/s13415-023-01118-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/12/2023] [Indexed: 07/09/2023]
Abstract
Posttraumatic stress disorder (PTSD), a disabling and chronic condition after exposure to an extreme traumatic event, affects approximately 8% of the population worldwide. However, the underlying mechanisms of PTSD are not clear. The ability to manage fear memories is critical for PTSD. Differences in stress responsiveness and coping strategies by age represent an important starting point for the understanding and prevention of PTSD. However, we do not know whether the ability to cope with fear memories is decreased in middle-aged mice. To investigate this, we compared fear memory extinction among different age groups of mice. We found that middle-aged mice exhibited impaired fear memory extinction, which was accompanied by sustained enhanced long-term potentiation (LTP) induction in the extinction process. Most interestingly, ketamine treatment restored the impaired fear memory extinction in middle-aged mice. Moreover, ketamine could ameliorate the increased LTP during the extinction process through a presynaptic mechanism. Altogether, our results indicated that middle-aged mice were unable to extinguish fear memories, which could be treated with ketamine via presynaptic-mediated synaptic plasticity in middle-aged mice, suggesting that ketamine administration may be a new strategy for the treatment of PTSD.
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Affiliation(s)
- Yingying Zhao
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Hua Shao
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Haitao Wang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Huijuan Li
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qiong Xue
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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13
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Laricchiuta D, Gimenez J, Sciamanna G, Termine A, Fabrizio C, Della Valle F, Caioli S, Saba L, De Bardi M, Balsamo F, Panuccio A, Passarello N, Mattioni A, Bisicchia E, Zona C, Orlando V, Petrosini L. Synaptic and transcriptomic features of cortical and amygdala pyramidal neurons predict inefficient fear extinction. Cell Rep 2023; 42:113066. [PMID: 37656620 DOI: 10.1016/j.celrep.2023.113066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 04/08/2023] [Accepted: 08/17/2023] [Indexed: 09/03/2023] Open
Abstract
Fear-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterize mouse phenotypes that spontaneously show fear-independent behavioral traits predicting adaptive or maladaptive fear extinction. We find that, already before fear conditioning, specific morphological, electrophysiological, and transcriptomic patterns of cortical and amygdala pyramidal neurons predispose to fear-related disorders. Finally, by using an optogenetic approach, we show the possibility to rescue inefficient fear extinction by activating infralimbic pyramidal neurons and to impair fear extinction by activating prelimbic pyramidal neurons.
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Affiliation(s)
| | | | - Giuseppe Sciamanna
- IRCCS Santa Lucia Foundation, 00143 Rome, Italy; Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy
| | | | | | - Francesco Della Valle
- King Abdullah University of Science and Technology (KAUST), Biological Environmental Science and Engineering Division, KAUST Environmental Epigenetics Program, Thuwal 23955-6900, Saudi Arabia
| | - Silvia Caioli
- Unit of Neurology, IRCCS Neuromed, 86077 Pozzilli, Isernia, Italy
| | - Luana Saba
- University of Campus Biomedico, 00128 Rome, Italy
| | | | - Francesca Balsamo
- IRCCS Santa Lucia Foundation, 00143 Rome, Italy; Department of Human Sciences, Guglielmo Marconi University, 00166 Rome, Italy
| | - Anna Panuccio
- IRCCS Santa Lucia Foundation, 00143 Rome, Italy; Department of Psychology, University Sapienza of Rome, 00185 Rome, Italy
| | - Noemi Passarello
- IRCCS Santa Lucia Foundation, 00143 Rome, Italy; Department of Humanities, Federico II University of Naples, 80138 Naples, Italy
| | | | | | - Cristina Zona
- Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Valerio Orlando
- King Abdullah University of Science and Technology (KAUST), Biological Environmental Science and Engineering Division, KAUST Environmental Epigenetics Program, Thuwal 23955-6900, Saudi Arabia.
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14
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Raskin M, Malone C, Hilz EN, Smits JAJ, Telch MJ, Otto MW, Shumake J, Lee HJ, Monfils MH. CO 2 reactivity is associated with individual differences in appetitive extinction memory. Physiol Behav 2023; 266:114183. [PMID: 37031791 PMCID: PMC10840099 DOI: 10.1016/j.physbeh.2023.114183] [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: 12/21/2022] [Revised: 03/17/2023] [Accepted: 04/04/2023] [Indexed: 04/11/2023]
Abstract
Pavlovian conditioning can underly the maladaptive behaviors seen in psychiatric disorders such as anxiety and addiction. In both the lab and the clinic, these responses can be attenuated through extinction learning, but often return with the passage of time, stress, or a change in context. Extinction to fear and reward cues are both subject to these return of behavior phenomena and have overlap in neurocircuitry, yet it is unknown whether they share any common predictors. The orexin system has been implicated in both fear and appetitive extinction and can be activated through a CO2 challenge. We previously found that behavioral CO2 reactivity predicts fear extinction and orexin activation. Here, we sought to extend our previous findings to determine whether CO2 reactivity might also predict extinction memory for appetitive light-food conditioning. We find that the same subcomponent of behavioral CO2 reactivity that predicted fear extinction also predicts appetitive extinction, but in the opposite direction. We show evidence that this subcomponent remains stable across two CO2 challenges, suggesting it may be a stable trait of both behavioral CO2 reactivity and appetitive extinction phenotype. Our findings further the possibility for CO2 reactivity to be used as a transdiagnostic screening tool to determine whether an individual would be a good candidate for exposure therapy.
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Affiliation(s)
- Marissa Raskin
- The University of Texas at Austin, Institute for Neuroscience, United States
| | - Cassidy Malone
- The University of Texas at Austin, Department of Psychology, United States
| | - Emily N Hilz
- The University of Texas at Austin, Department of Psychology, United States
| | - Jasper A J Smits
- The University of Texas at Austin, Department of Psychology, United States; The University of Texas at Austin, Institute for Mental Health Research, United States
| | - Michael J Telch
- The University of Texas at Austin, Department of Psychology, United States; The University of Texas at Austin, Institute for Mental Health Research, United States
| | | | - Jason Shumake
- The University of Texas at Austin, Department of Psychology, United States; The University of Texas at Austin, Institute for Mental Health Research, United States
| | - Hongjoo J Lee
- The University of Texas at Austin, Institute for Neuroscience, United States; The University of Texas at Austin, Department of Psychology, United States
| | - Marie-H Monfils
- The University of Texas at Austin, Institute for Neuroscience, United States; The University of Texas at Austin, Department of Psychology, United States; The University of Texas at Austin, Institute for Mental Health Research, United States.
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15
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Fritz EM, Pierre A, De Bundel D, Singewald N. Ghrelin receptor agonist MK0677 and overnight fasting do not rescue deficient fear extinction in 129S1/SvImJ mice. Front Psychiatry 2023; 14:1094948. [PMID: 36846243 PMCID: PMC9947350 DOI: 10.3389/fpsyt.2023.1094948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/03/2023] [Indexed: 02/11/2023] Open
Abstract
The hunger hormone ghrelin has been implicated in the modulation of anxiety- and fear-related behaviors in rodents and humans, while its dysregulation may be associated with psychiatric illness. Along these lines, the ghrelin system has been suggested as a potential target to facilitate fear extinction, which is the main mechanism underlying cognitive behavioral therapy. So far, this hypothesis has not been tested in individuals that have difficulties to extinguish fear. Thus, we investigated pharmacological (ghrelin receptor agonist MK0677) and non-pharmacological (overnight fasting) strategies to target the ghrelin system in the 129S1/SvImJ (S1) mouse strain, which models the endophenotype of impaired fear extinction that has been associated with treatment resistance in anxiety and PTSD patients. MK0677 induced food intake and overnight fasting increased plasma ghrelin levels in S1 mice, suggesting that the ghrelin system is responsive in the S1 strain. However, neither systemic administration of MK0677 nor overnight fasting had an effect on fear extinction in S1 mice. Similarly, our groups previously reported that both interventions did not attenuate fear in extinction-competent C57BL/6J mice. In summary, our findings are in contrast to several studies reporting beneficial effects of GHSR agonism and overnight fasting on fear- and anxiety-related behaviors in rodents. Rather, our data agree with accumulating evidence of divergent behavioral effects of ghrelin system activation and underscore the hypothesis that potential benefits of targeting the ghrelin system in fear extinction may be dependent on factors (e.g., previous stress exposure) that are not yet fully understood.
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Affiliation(s)
- Eva Maria Fritz
- Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria
| | - Anouk Pierre
- Department of Pharmaceutical Sciences, Research Group Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
| | - Dimitri De Bundel
- Department of Pharmaceutical Sciences, Research Group Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
| | - Nicolas Singewald
- Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria
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16
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Espinosa L, Bonsall MB, Becker N, Holmes EA, Olsson A. Pavlovian threat conditioning can generate intrusive memories that persist over time. Behav Res Ther 2022; 157:104161. [DOI: 10.1016/j.brat.2022.104161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 06/27/2022] [Accepted: 07/08/2022] [Indexed: 11/02/2022]
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17
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Guedes VA, Lai C, Devoto C, Edwards KA, Mithani S, Sass D, Vorn R, Qu BX, Rusch HL, Martin CA, Walker WC, Wilde EA, Diaz-Arrastia R, Gill JM, Kenney K. Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury. Front Pharmacol 2021; 12:745348. [PMID: 34690777 PMCID: PMC8526745 DOI: 10.3389/fphar.2021.745348] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/06/2021] [Indexed: 01/20/2023] Open
Abstract
Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139–5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.
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Affiliation(s)
- Vivian A Guedes
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Chen Lai
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Christina Devoto
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States.,Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, United States
| | - Katie A Edwards
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Sara Mithani
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Dilorom Sass
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Rany Vorn
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - Bao-Xi Qu
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States.,Center for Neuroscience and Rehabilitation Medicine, Uniformed Services University of the Health Sciences and National Institutes of Health, Bethesda, MD, United States
| | - Heather L Rusch
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States.,Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
| | - Carina A Martin
- Tissue Injury Branch, National Institutes of Nursing Research, National Institutes of Health, Bethesda, MD, United States
| | - William C Walker
- Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University, Richmond, VA, United States
| | - Elisabeth A Wilde
- CENC Neuroimaging Core, George E. Wahlen VA Salt Lake City Healthcare System and Traumatic Brain Injury and Concussion Center, Department of Neurology, University of Utah, Salt Lake City, UT, United States
| | - Ramon Diaz-Arrastia
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Jessica M Gill
- CENC Biorepository, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.,Johns Hopkins University School of Nursing and Medicine, Baltimore, MD, United States
| | - Kimbra Kenney
- CENC Biorepository, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.,Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
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18
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Tryon SC, Sakamoto IM, Kellis DM, Kaigler KF, Wilson MA. Individual Differences in Conditioned Fear and Extinction in Female Rats. Front Behav Neurosci 2021; 15:740313. [PMID: 34489657 PMCID: PMC8418198 DOI: 10.3389/fnbeh.2021.740313] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 07/29/2021] [Indexed: 11/13/2022] Open
Abstract
The inability to extinguish a traumatic memory is a key aspect of post-traumatic stress disorder (PTSD). While PTSD affects 10–20% of individuals who experience a trauma, women are particularly susceptible to developing the disorder. Despite this notable female vulnerability, few studies have investigated this particular resistance to fear extinction observed in females. Similar to humans, rodent models of Pavlovian fear learning and extinction show a wide range of individual differences in fear learning and extinction, although female rodents are considerably understudied. Therefore, the present study examined individual differences in fear responses, including freezing behavior and ultrasonic vocalizations (USVs), of female Long–Evans rats during acquisition of fear conditioning and cued fear extinction. Similar to prior studies in males, female rats displayed individual variation in freezing during cued fear extinction and were divided into extinction competent (EC) and extinction resistant (ER) phenotypes. Differences in freezing between ER and EC females were accompanied by shifts in rearing during extinction, but no darting was seen in any trial. Freezing behavior during fear learning did not differ between the EC and ER females. Vocalizations emitted in the 22 and 50 kHz ranges during fear learning and extinction were also examined. Unlike vocalizations seen in previous studies in males, very few 22 kHz distress vocalizations were emitted by female rats during fear acquisition and extinction, with no difference between ER and EC groups. Interestingly, all female rats produced significant levels of 50 kHz USVs, and EC females emitted significantly more 50 kHz USVs than ER rats. This difference in 50 kHz USVs was most apparent during initial exposure to the testing environment. These results suggest that like males, female rodents show individual differences in both freezing and USVs during fear extinction, although females appear to vocalize more in the 50 kHz range, especially during initial periods of exposure to the testing environment, and emit very few of the 22 kHz distress calls that are typically observed in males during fear learning or extinction paradigms. Overall, these findings show that female rodents display fear behavior repertoires divergent from males.
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Affiliation(s)
- Sarah C Tryon
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Iris M Sakamoto
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Devin M Kellis
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Kris F Kaigler
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Marlene A Wilson
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States.,Columbia VA Health Care System, Columbia, SC, United States
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19
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Zhou YG, Shang ZL, Zhang F, Wu LL, Sun LN, Jia YP, Yu HB, Liu WZ. PTSD: Past, present and future implications for China. Chin J Traumatol 2021; 24:187-208. [PMID: 33994278 PMCID: PMC8343811 DOI: 10.1016/j.cjtee.2021.04.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/30/2021] [Accepted: 04/18/2021] [Indexed: 02/04/2023] Open
Abstract
There has been a long history since human beings began to realize the existence of post-traumatic symptoms. Posttraumatic stress disorder (PTSD), a diagnostic category adopted in 1980 in the Diagnostic and Statistical Manual of Mental Disorders-Ⅲ, described typical clusters of psychiatric symptoms occurring after traumatic events. Abundant researches have helped deepen the understanding of PTSD in terms of epidemiological features, biological mechanisms, and treatment options. The prevalence of PTSD in general population ranged from 6.4% to 7.8% and was significantly higher among groups who underwent major public traumatic events. There has been a long way in the studies of animal models and genetic characteristics of PTSD. However, the high comorbidity with other stress-related psychiatric disorders and complexity in the pathogenesis of PTSD hindered the effort to find specific biological targets for PTSD. Neuroimage was widely used to elucidate the underlying neurophysiological mechanisms of PTSD. Functional MRI studies have showed that PTSD was linked to medial prefrontal cortex, anterior cingulate cortex and sub-cortical structures like amygdala and hippocampus, and to explore the functional connectivity among these brain areas which might reveal the possible neurobiological mechanism related to PTSD symptoms. For now, cognitive behavior therapy-based psychotherapy, including combination with adjunctive medication, showed evident treatment effects on PTSD. The emergence of more effective PTSD pharmacotherapies awaits novel biomarkers from further fundamental research. Several natural disasters and emergencies have inevitably increased the possibility of suffering from PTSD in the last two decades, making it critical to strengthen PTSD research in China. To boost PTSD study in China, the following suggestions might be helpful: (1) establishing a national psychological trauma recover project, and (2) exploring the mechanisms of PTSD with joint effort and strengthening the indigenized treatment of PTSD.
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Affiliation(s)
- Yao-Guang Zhou
- Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Zhi-Lei Shang
- The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Fan Zhang
- Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Li-Li Wu
- Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Lu-Na Sun
- Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Yan-Pu Jia
- Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China
| | - Hai-Bo Yu
- Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,Corresponding author.
| | - Wei-Zhi Liu
- Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,The Emotion & Cognition Lab, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China,Corresponding author. Lab for Post-traumatic Stress Disorder, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai, 200433, China.
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Willadsen M, Uengoer M, Sługocka A, Schwarting RK, Homberg JR, Wöhr M. Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter. Int J Mol Sci 2021; 22:ijms22137088. [PMID: 34209318 PMCID: PMC8268876 DOI: 10.3390/ijms22137088] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 11/28/2022] Open
Abstract
Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Fear-related behavior displayed during acquisition, extinction, and recovery, was measured through quantification of immobility and alarm 22-kHz ultrasonic vocalizations (USV). Trait-like inter-individual differences in novelty-seeking, anxiety-related behavior, habituation learning, cognitive performance, and pain sensitivity were examined for their predictive value in forecasting fear extinction. Our results show that SERT deficiency strongly affected the emission of 22-kHz USV during differential fear conditioning. During acquisition, extinction, and recovery, SERT deficiency consistently led to a reduction in 22-kHz USV emission. While SERT deficiency did not affect immobility during acquisition, genotype differences started to emerge during extinction, and during recovery rats lacking SERT showed higher levels of immobility than wildtype littermate controls. Recovery was reflected in increased levels of immobility but not 22-kHz USV emission. Prominent sex differences were evident. Among several measures for trait-like inter-individual differences, anxiety-related behavior had the best predictive quality.
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Affiliation(s)
- Maria Willadsen
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany; (M.W.); (R.K.W.S.)
| | - Metin Uengoer
- Associative Learning, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany;
| | - Anna Sługocka
- Department for Experimental Medicine, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 4, 40-752 Katowice, Poland;
- Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
| | - Rainer K.W. Schwarting
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany; (M.W.); (R.K.W.S.)
- Center for Mind, Brain and Behavior, Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
| | - Judith R. Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands;
| | - Markus Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany; (M.W.); (R.K.W.S.)
- Center for Mind, Brain and Behavior, Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
- KU Leuven, Faculty of Psychology and Educational Sciences, Research Unit Brain and Cognition, Laboratory of Biological Psychology, Social and Affective Neuroscience Research Group, B-3000 Leuven, Belgium
- KU Leuven, Leuven Brain Institute, B-3000 Leuven, Belgium
- Correspondence: ; Tel.: +32–16–19–45–57
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Fritz EM, Kreuzer M, Altunkaya A, Singewald N, Fenzl T. Altered sleep behavior in a genetic mouse model of impaired fear extinction. Sci Rep 2021; 11:8978. [PMID: 33903668 PMCID: PMC8076259 DOI: 10.1038/s41598-021-88475-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/13/2021] [Indexed: 02/03/2023] Open
Abstract
Sleep disturbances are a common complaint of anxiety patients and constitute a hallmark feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that poor sleep is not only a secondary symptom of anxiety- and trauma-related disorders but represents a risk factor in their development, for example by interfering with emotional memory processing. Fear extinction is a critical mechanism for the attenuation of fearful and traumatic memories and multiple studies suggest that healthy sleep is crucial for the formation of extinction memories. However, fear extinction is often impaired in anxiety- and trauma-related disorders-an endophenotype that is perfectly modelled in the 129S1/SvImJ inbred mouse strain. To investigate whether these mice exhibit altered sleep at baseline that could predispose them towards maladaptive fear processing, we compared their circadian sleep/wake patterns to those of typically extinction-competent C57BL/6 mice. We found significant differences regarding diurnal distribution of sleep and wakefulness, but also sleep architecture, spectral features and sleep spindle events. With regard to sleep disturbances reported by anxiety- and PTSD patients, our findings strengthen the 129S1/SvImJ mouse models' face validity and highlight it as a platform to investigate novel, sleep-focused diagnostic and therapeutic strategies. Whether the identified alterations causally contribute to its pathological anxiety/PTSD-like phenotype will, however, have to be addressed in future studies.
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Affiliation(s)
- Eva Maria Fritz
- Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria
| | - Matthias Kreuzer
- Department of Anesthesiology and Intensive Care, School of Medicine, Klinikum Rechts Der Isar, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany
| | - Alp Altunkaya
- Department of Anesthesiology and Intensive Care, School of Medicine, Klinikum Rechts Der Isar, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany
| | - Nicolas Singewald
- Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria
| | - Thomas Fenzl
- Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, University of Innsbruck, Innsbruck, Austria.
- Department of Anesthesiology and Intensive Care, School of Medicine, Klinikum Rechts Der Isar, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany.
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Bouton ME, Maren S, McNally GP. BEHAVIORAL AND NEUROBIOLOGICAL MECHANISMS OF PAVLOVIAN AND INSTRUMENTAL EXTINCTION LEARNING. Physiol Rev 2021; 101:611-681. [PMID: 32970967 PMCID: PMC8428921 DOI: 10.1152/physrev.00016.2020] [Citation(s) in RCA: 202] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on erasure of the original learning but instead depends on new inhibitory learning that is primarily expressed in the context in which it is learned, as exemplified by the renewal effect. Although the nature of the inhibition may differ in Pavlovian and operant extinction, in either case the decline in responding may depend on both generalization decrement and the correction of prediction error. At the neural level, Pavlovian extinction requires a tripartite neural circuit involving the amygdala, prefrontal cortex, and hippocampus. Synaptic plasticity in the amygdala is essential for extinction learning, and prefrontal cortical inhibition of amygdala neurons encoding fear memories is involved in extinction retrieval. Hippocampal-prefrontal circuits mediate fear relapse phenomena, including renewal. Instrumental extinction involves distinct ensembles in corticostriatal, striatopallidal, and striatohypothalamic circuits as well as their thalamic returns for inhibitory (extinction) and excitatory (renewal and other relapse phenomena) control over operant responding. The field has made significant progress in recent decades, although a fully integrated biobehavioral understanding still awaits.
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Affiliation(s)
- Mark E Bouton
- Department of Psychological Science, University of Vermont, Burlington, Vermont
| | - Stephen Maren
- Department of Psychological and Brain Sciences and Institute for Neuroscience, Texas A&M University, College Station, Texas
| | - Gavan P McNally
- School of Psychology, University of New South Wales, Sydney, Australia
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23
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Taylor WW, Imhoff BR, Sathi ZS, Liu WY, Garza KM, Dias BG. Contributions of glucocorticoid receptors in cortical astrocytes to memory recall. Learn Mem 2021; 28:126-133. [PMID: 33723032 PMCID: PMC7970741 DOI: 10.1101/lm.053041.120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/14/2021] [Indexed: 01/15/2023]
Abstract
Dysfunctions in memory recall lead to pathological fear; a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). Both, heightened recall of an association between a cue and trauma, as well as impoverished recall that a previously trauma-related cue is no longer a threat, result in a debilitating fear toward the cue. Glucocorticoid-mediated action via the glucocorticoid receptor (GR) influences memory recall. This literature has primarily focused on GRs expressed in neurons or ignored cell-type specific contributions. To ask how GR action in nonneuronal cells influences memory recall, we combined auditory fear conditioning in mice and the knockout of GRs in astrocytes in the prefrontal cortex (PFC), a brain region implicated in memory recall. We found that knocking out GRs in astrocytes of the PFC disrupted memory recall. Specifically, we found that knocking out GRs in astrocytes in the PFC (AstroGRKO) after fear conditioning resulted in higher levels of freezing to the CS+ tone when compared with controls (AstroGRintact). While we did not find any differences in extinction of fear toward the CS+ between these groups, AstroGRKO female but not male mice showed impaired recall of extinction training. These results suggest that GRs in cortical astrocytes contribute to memory recall. These data demonstrate the need to examine GR action in cortical astrocytes to elucidate the basic neurobiology underlying memory recall and potential mechanisms that underlie female-specific biases in the incidence of PTSD.
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Affiliation(s)
- William W Taylor
- Neuroscience Graduate Program, Emory University, Atlanta, Georgia 30322, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90007, USA
- Developmental Neuroscience and Neurogenetics Program, Division of Research on Children, Youth, and Families, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA
| | - Barry R Imhoff
- Division of Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA
| | - Zakia Sultana Sathi
- Division of Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA
| | - Wei Y Liu
- Developmental Neuroscience and Neurogenetics Program, Division of Research on Children, Youth, and Families, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA
| | - Kristie M Garza
- Neuroscience Graduate Program, Emory University, Atlanta, Georgia 30322, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA
| | - Brian G Dias
- Neuroscience Graduate Program, Emory University, Atlanta, Georgia 30322, USA
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90007, USA
- Developmental Neuroscience and Neurogenetics Program, Division of Research on Children, Youth, and Families, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA
- Division of Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA
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Bonn-Miller MO, Sisley S, Riggs P, Yazar-Klosinski B, Wang JB, Loflin MJE, Shechet B, Hennigan C, Matthews R, Emerson A, Doblin R. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial. PLoS One 2021; 16:e0246990. [PMID: 33730032 PMCID: PMC7968689 DOI: 10.1371/journal.pone.0246990] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 01/26/2021] [Indexed: 12/01/2022] Open
Abstract
IMPORTANCE There is a pressing need for development of novel pharmacology for the treatment of Posttraumatic Stress Disorder (PTSD). Given increasing use of medical cannabis among US military veterans to self-treat PTSD, there is strong public interest in whether cannabis may be a safe and effective treatment for PTSD. OBJECTIVE The aim of the present study was to collect preliminary data on the safety and potential efficacy of three active concentrations of smoked cannabis (i.e., High THC = approximately 12% THC and < 0.05% CBD; High CBD = 11% CBD and 0.50% THC; THC+CBD = approximately 7.9% THC and 8.1% CBD, and placebo = < 0.03% THC and < 0.01% CBD) compared to placebo in the treatment of PTSD among military veterans. METHODS The study used a double-blind, cross-over design, where participants were randomly assigned to receive three weeks of either active treatment or placebo in Stage 1 (N = 80), and then were re-randomized after a 2-week washout period to receive one of the other three active treatments in Stage 2 (N = 74). The primary outcome measure was change in PTSD symptom severity from baseline to end of treatment in Stage 1. RESULTS The study did not find a significant difference in change in PTSD symptom severity between the active cannabis concentrations and placebo by the end of Stage 1. All three active concentrations of smoked cannabis were generally well tolerated. CONCLUSIONS AND RELEVANCE The present study is the first randomized placebo-controlled trial of smoked cannabis for PTSD. All treatment groups, including placebo, showed good tolerability and significant improvements in PTSD symptoms during three weeks of treatment, but no active treatment statistically outperformed placebo in this brief, preliminary trial. Additional well-controlled and adequately powered studies with cannabis suitable for FDA drug development are needed to determine whether smoked cannabis improves symptoms of PTSD. TRIAL REGISTRATION Identifier: NCT02759185; ClinicalTrials.gov.
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Affiliation(s)
- Marcel O. Bonn-Miller
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Sue Sisley
- Scottsdale Research Institute, Scottsdale, Arizona, United States of America
| | - Paula Riggs
- School of Medicine, University of Colorado, Aurora, Colorado, United States of America
| | - Berra Yazar-Klosinski
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Julie B. Wang
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Mallory J. E. Loflin
- Center of Excellence for Stress and Mental Health & National Center for PTSD, VA San Diego Healthcare System, San Diego, California, United States of America
- San Diego School of Medicine, Department of Psychiatry, University of California, San Diego, California, United States of America
| | - Benjamin Shechet
- Scottsdale Research Institute, Scottsdale, Arizona, United States of America
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Colin Hennigan
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Rebecca Matthews
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Amy Emerson
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
| | - Rick Doblin
- Multidisciplinary Association for Psychedelic Studies, Santa Cruz, California, United States of America
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25
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Intra-prefrontal cyclosporine potentiates ketamine-induced fear extinction in rats. Exp Brain Res 2021; 239:1401-1415. [PMID: 33666692 DOI: 10.1007/s00221-021-06050-7] [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: 11/14/2020] [Accepted: 01/25/2021] [Indexed: 10/22/2022]
Abstract
Several brain regions, including the medial prefrontal cortex (mPFC), are important in the process of fear extinction learning. Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, which is shown to play a role in extinction modulation. Ketamine and calcineurin (CN), an intracellular protein phosphatase, have several common targets in the cells. Therefore, in the present study, our aim is to investigate the possible role of calcineurin in the mPFC on the enhancing effects of ketamine in fear extinction. First, different doses of a CN inhibitor, cyclosporine-A (CsA), were micro-injected into the infralimbic (IL) region of the mPFC prior to extinction training in a classical conditioning model in rats. Next, sub-effective doses of CsA (Intra-mPFC) and ketamine (i.p.) were co-administered in another cohort of rats to find their possible interactions. Enzymatic activity of calcineurin was measured in the IL-mPFC following drug administration. We used the elevated plus-maze (EPM) and open field (OF) test for further behavioral assessments. The results showed that CsA can enhance the extinction of conditioned fear and inhibit the enzyme CN at a dose of 20 nM. The combination of sub-effective doses of CsA (5 nM) and ketamine (10 mg/kg) could again enhance the extinction of fear and reduce CN activity in the region. Our results propose that inhibition of CN in the IL-mPFC is involved in the extinction of fear and ketamine enhancement of extinction is probably mediated by reducing CN activity in this part of the brain.
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Laricchiuta D, Sciamanna G, Gimenez J, Termine A, Fabrizio C, Caioli S, Balsamo F, Panuccio A, De Bardi M, Saba L, Passarello N, Cutuli D, Mattioni A, Zona C, Orlando V, Petrosini L. Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome. Int J Mol Sci 2021; 22:ijms22020810. [PMID: 33467450 PMCID: PMC7830910 DOI: 10.3390/ijms22020810] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/12/2021] [Accepted: 01/12/2021] [Indexed: 12/26/2022] Open
Abstract
Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
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Affiliation(s)
- Daniela Laricchiuta
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Correspondence:
| | - Giuseppe Sciamanna
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Juliette Gimenez
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Andrea Termine
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy;
| | - Carlo Fabrizio
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy;
| | - Silvia Caioli
- Unit of Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy;
| | - Francesca Balsamo
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Anna Panuccio
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Department of Psychology, University “Sapienza” of Rome, 00185 Rome, Italy
| | - Marco De Bardi
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Luana Saba
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Noemi Passarello
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Debora Cutuli
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Department of Psychology, University “Sapienza” of Rome, 00185 Rome, Italy
| | - Anna Mattioni
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
| | - Cristina Zona
- Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy;
| | - Valerio Orlando
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
- Biological Environmental Science and Engineering Division, KAUST Environmental Epigenetics Program, Thuwal 23955-6900, Saudi Arabia
| | - Laura Petrosini
- Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; (G.S.); (J.G.); (A.T.); (C.F.); (F.B.); (A.P.); (M.D.B.); (L.S.); (N.P.); (D.C.); (A.M.); (V.O.); (L.P.)
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Harmon-Jones SK, Cowan CS, Shnier N, Richardson R. Is good memory always a good thing? An early offset of infantile amnesia predicts anxiety-like behavior throughout development in rats. Behav Res Ther 2020; 135:103763. [DOI: 10.1016/j.brat.2020.103763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/06/2020] [Accepted: 10/28/2020] [Indexed: 01/01/2023]
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Prajapati SK, Krishnamurthy S. Non-selective orexin-receptor antagonist attenuates stress-re-stress-induced core PTSD-like symptoms in rats: Behavioural and neurochemical analyses. Behav Brain Res 2020; 399:113015. [PMID: 33212086 DOI: 10.1016/j.bbr.2020.113015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/02/2020] [Accepted: 11/09/2020] [Indexed: 01/21/2023]
Abstract
Post-traumatic stress disorder (PTSD) is a psychological disorder affecting many around the world. Growing evidence suggests that orexin-A is involved in the pathophysiology of depression and panic anxiety disorder. However, the role of orexin-A in PTSD remains unclear. Therefore, pharmacological manipulation of orexin-A can be a potential approach for the treatment of PTSD. Male Wistar rats were subjected to stress re-stress (SRS) by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day-2 (D-2). Then the rats were weekly exposed to FS as re-stress cue . Suvorexant, an orexin antagonist (10, 20 and 30 mg/kg p.o.) and paroxetine (10 mg/kg p.o.) were administered from D-8 to D-32. Plasma and cerebrospinal fluid (CSF) were collected for corticosterone and orexin-A measurement. The analysis of serotonin and corticotropin-releasing factor receptor-1 (CRF-R1) were performed in the amygdalar tissue. SRS-induced PTSD-like symptoms like fear response, anxiety-like behaviour and hypocorticosteronism were attenuated by suvorexant and paroxetine. Interestingly, SRS exposed rats showed activation of orexin-A and serotonergic systems, which were also attenuated by suvorexant. Additionally, suvorexant ameliorated the extrahypothalamic induced upregulation of CRH-R1 in SRS-exposed rats. Therefore, orexin-A may be considered as a neurochemical-marker for PTSD and suvorexant alleviated PTSD-like symptoms through modulating orexinergic, serotonergic and neuroendocrine systems.
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Affiliation(s)
- Santosh Kumar Prajapati
- Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi- 221 005, U.P., India
| | - Sairam Krishnamurthy
- Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi- 221 005, U.P., India.
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Kellis DM, Kaigler KF, Witherspoon E, Fadel JR, Wilson MA. Cholinergic neurotransmission in the basolateral amygdala during cued fear extinction. Neurobiol Stress 2020; 13:100279. [PMID: 33344731 PMCID: PMC7739185 DOI: 10.1016/j.ynstr.2020.100279] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/20/2020] [Accepted: 11/20/2020] [Indexed: 01/06/2023] Open
Abstract
Cholinergic neuromodulation plays an important role in numerous cognitive functions including regulating arousal and attention, as well as associative learning and extinction processes. Further, studies demonstrate that cholinergic inputs from the basal forebrain cholinergic system influence physiological responses in the basolateral amygdala (BLA) as well as fear extinction processes. Since rodent models display individual differences in conditioned fear and extinction responses, this study investigated if cholinergic transmission in the BLA during fear extinction could contribute to differences between extinction resistant and extinction competent phenotypes in outbred Long-Evans male rats. Experiment 1 used in vivo microdialysis to test the hypothesis that acetylcholine (ACH) efflux in the BLA would increase with presentation of an auditory conditioned stimulus (CS+) during extinction learning. Acetylcholine efflux was compared in rats exposed to the CS+, a CS- (the tone never paired with a footshock), or to a context shift alone (without CS+ tone presentation). Consistent with acetylcholine's role in attention and arousal, ACH efflux in the BLA was increased in all three groups (CS+, CS-, Shift Alone) by the initial context shift into the extinction learning chamber, but returned more rapidly to baseline levels in the Shift Alone group (no CS+). In contrast, in the group exposed to the CS+, ACH efflux in the BLA remained elevated during continued presentation of conditioned cues and returned to baseline more slowly, leading to an overall increase in ACH efflux compared with the Shift Alone group. Based on the very dense staining in the BLA for acetylcholinesterase (ACHE), Experiment 2 examined if individual differences in fear extinction were associated with differences in cholinesterase enzyme activity (CHE) in the BLA and/or plasma with a separate cohort of animals. Cholinesterase activity (post-testing) in both the BLA and plasma was higher in extinction competent rats versus rats resistant to extinction learning. There was also a significant negative correlation between BLA CHE activity and freezing during extinction learning. Taken together, our results support a role for ACH efflux in the BLA during cued fear extinction that may be modulated by individual differences in ACHE activity, and are associated with behavioral responses during fear extinction. These findings implicate individual differences in cholinergic regulation in the susceptibility to disorders with dysregulation of extinction learning, such post-traumatic stress disorder (PTSD) in humans.
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Affiliation(s)
- Devin M. Kellis
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States
| | - Kris Ford Kaigler
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States
| | - Eric Witherspoon
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States
| | - Jim R. Fadel
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States
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30
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Rodriguez G, Moore SJ, Neff RC, Glass ED, Stevenson TK, Stinnett GS, Seasholtz AF, Murphy GG, Cazares VA. Deficits across multiple behavioral domains align with susceptibility to stress in 129S1/SvImJ mice. Neurobiol Stress 2020; 13:100262. [PMID: 33344715 PMCID: PMC7739066 DOI: 10.1016/j.ynstr.2020.100262] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/07/2020] [Accepted: 10/16/2020] [Indexed: 01/08/2023] Open
Abstract
Acute physical or psychological stress can elicit adaptive behaviors that allow an organism maintain homeostasis. However, intense and/or prolonged stressors often have the opposite effect, resulting in maladaptive behaviors and curbing goal-directed action; in the extreme, this may contribute to the development of psychiatric conditions like generalized anxiety disorder, major depressive disorder, or post-traumatic stress disorder. While treatment of these disorders generally focuses on reducing reactivity to potentially threatening stimuli, there are in fact impairments across multiple domains including valence, arousal, and cognition. Here, we use the genetically stress-susceptible 129S1 mouse strain to explore the effects of stress across multiple domains. We find that 129S1 mice exhibit a potentiated neuroendocrine response across many environments and paradigms, and that this is associated with reduced exploration, neophobia, decreased novelty- and reward-seeking, and spatial learning and memory impairments. Taken together, our results suggest that the 129S1 strain may provide a useful model for elucidating mechanisms underlying myriad aspects of stress-linked psychiatric disorders as well as potential treatments that may ameliorate symptoms.
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Affiliation(s)
- G Rodriguez
- Michigan Neuroscience Institute, USA.,Neuroscience Graduate Program, USA
| | - S J Moore
- Department of Molecular and Integrative Physiology, USA.,Michigan Neuroscience Institute, USA
| | - R C Neff
- Department of Molecular and Integrative Physiology, USA
| | - E D Glass
- Department of Molecular and Integrative Physiology, USA.,Michigan Neuroscience Institute, USA
| | | | | | - A F Seasholtz
- Michigan Neuroscience Institute, USA.,Neuroscience Graduate Program, USA.,Department of Biological Chemistry University of Michigan, Ann Arbor, MI, USA
| | - G G Murphy
- Department of Molecular and Integrative Physiology, USA.,Michigan Neuroscience Institute, USA.,Neuroscience Graduate Program, USA
| | - V A Cazares
- Department of Molecular and Integrative Physiology, USA.,Michigan Neuroscience Institute, USA.,Department of Psychology, Williams College, MA, USA
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31
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Ross JA, Van Bockstaele EJ. The role of catecholamines in modulating responses to stress: Sex-specific patterns, implications, and therapeutic potential for post-traumatic stress disorder and opiate withdrawal. Eur J Neurosci 2020; 52:2429-2465. [PMID: 32125035 DOI: 10.1111/ejn.14714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 01/15/2020] [Accepted: 02/20/2020] [Indexed: 12/22/2022]
Abstract
Emotional arousal is one of several factors that determine the strength of a memory and how efficiently it may be retrieved. The systems at play are multifaceted; on one hand, the dopaminergic mesocorticolimbic system evaluates the rewarding or reinforcing potential of a stimulus, while on the other, the noradrenergic stress response system evaluates the risk of threat, commanding attention, and engaging emotional and physical behavioral responses. Sex-specific patterns in the anatomy and function of the arousal system suggest that sexually divergent therapeutic approaches may be advantageous for neurological disorders involving arousal, learning, and memory. From the lens of the triple network model of psychopathology, we argue that post-traumatic stress disorder and opiate substance use disorder arise from maladaptive learning responses that are perpetuated by hyperarousal of the salience network. We present evidence that catecholamine-modulated learning and stress-responsive circuitry exerts substantial influence over the salience network and its dysfunction in stress-related psychiatric disorders, and between the sexes. We discuss the therapeutic potential of targeting the endogenous cannabinoid system; a ubiquitous neuromodulator that influences learning, memory, and responsivity to stress by influencing catecholamine, excitatory, and inhibitory synaptic transmission. Relevant preclinical data in male and female rodents are integrated with clinical data in men and women in an effort to understand how ideal treatment modalities between the sexes may be different.
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Affiliation(s)
- Jennifer A Ross
- Department of Pharmacology and Physiology, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Elisabeth J Van Bockstaele
- Department of Pharmacology and Physiology, College of Medicine, Drexel University, Philadelphia, PA, USA
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32
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Salehabadi S, Abrari K, Elahdadi Salmani M, Nasiri M, Lashkarbolouki T. Investigating the role of the amygdala orexin receptor 1 in memory acquisition and extinction in a rat model of PTSD. Behav Brain Res 2020; 384:112455. [DOI: 10.1016/j.bbr.2019.112455] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/17/2019] [Accepted: 12/26/2019] [Indexed: 11/15/2022]
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33
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Wei MD, Wang YH, Lu K, Lv BJ, Wang Y, Chen WY. Ketamine reverses the impaired fear memory extinction and accompanied depressive-like behaviors in adolescent mice. Behav Brain Res 2020; 379:112342. [DOI: 10.1016/j.bbr.2019.112342] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 10/25/2022]
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Abstract
MicroRNAs as critical regulators of gene expression important for functions including neuronal development, synapse formation, and synaptic plasticity have been linked with the regulation of neurobiological systems that underlie anxiety processing in the brain. In this chapter, we give an update on associative evidence linking regulation of microRNAs with anxiety- and trauma-related disorders. Moving beyond correlative research, functional studies have emerged recently that explore causal relationships between microRNA expression and anxiety-like behavior. It has been demonstrated that experimental up- or downregulation of the candidate microRNAs in important nodes of the anxiety neurocircuitry can indeed modulate anxiety-related behavior in animal models. Improved methodologies for assessing microRNA-mediated modulation have aided such functional studies, revealing a number of anxiety-regulating microRNAs including miR-15a, miR-17-92, miR-34, miR-101, miR-124, miR-135, and miR-155. Important functional target genes of these identified microRNAs are associated with specific neurotransmitter/neuromodulator signaling, neurotrophin (e.g., BDNF) expression and other aspects of synaptic plasticity, as well as with stress-regulatory/hypothalamic-pituitary-axis function. Furthermore, microRNAs have been revealed that are regulated in distinct brain regions following various anxiety-attenuating strategies. These include pharmacological treatments such as antidepressants and other drugs, as well as non-pharmacological interventions such as fear extinction/exposure therapy or positive stimuli such as exposure to environmental enrichment. These are first indications for a role for microRNAs in the mechanism of action of anxiolytic treatments. As research continues, there is much hope that a deeper understanding of the microRNA-mediated mechanisms underlying anxiety-related disorders could open up possibilities for future novel biomarker and treatment strategies.
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35
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Haaker J, Maren S, Andreatta M, Merz CJ, Richter J, Richter SH, Meir Drexler S, Lange MD, Jüngling K, Nees F, Seidenbecher T, Fullana MA, Wotjak CT, Lonsdorf TB. Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning. Neurosci Biobehav Rev 2019; 107:329-345. [PMID: 31521698 PMCID: PMC7822629 DOI: 10.1016/j.neubiorev.2019.09.020] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 07/08/2019] [Accepted: 09/11/2019] [Indexed: 12/22/2022]
Abstract
Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.
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Affiliation(s)
- Jan Haaker
- Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Stephen Maren
- Department of Psychological and Brain Sciences and Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Marta Andreatta
- Department of Psychology, University of Würzburg, Würzburg, Germany; Department of Psychology, Education & Child Studies, Erasmus University Rotterdam, Netherlands
| | - Christian J Merz
- Ruhr University Bochum, Faculty of Psychology, Institute of Cognitive Neuroscience, Department of Cognitive Psychology, Germany
| | - Jan Richter
- Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany
| | - S Helene Richter
- Department of Behavioural Biology, University of Münster, Münster, Germany
| | - Shira Meir Drexler
- Ruhr University Bochum, Faculty of Psychology, Institute of Cognitive Neuroscience, Department of Cognitive Psychology, Germany
| | - Maren D Lange
- Institute of Physiology I, University of Münster, Münster, Germany
| | - Kay Jüngling
- Institute of Physiology I, University of Münster, Münster, Germany
| | - Frauke Nees
- Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Miquel A Fullana
- Institute of Neurosciences, Hospital Clinic, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| | - Carsten T Wotjak
- Neuronal Plasticity Research Group, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804, Munich, Germany
| | - Tina B Lonsdorf
- Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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36
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Mennesson M, Rydgren E, Lipina T, Sokolowska E, Kulesskaya N, Morello F, Ivakine E, Voikar V, Risbrough V, Partanen J, Hovatta I. Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction. Neuropsychopharmacology 2019; 44:1855-1866. [PMID: 30770891 PMCID: PMC6784901 DOI: 10.1038/s41386-019-0344-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/23/2019] [Accepted: 02/12/2019] [Indexed: 11/09/2022]
Abstract
NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They interact with native KAR subunits to modulate multiple aspects of receptor function. Variation in KAR genes has been associated with psychiatric disorders in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2 and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the NETO proteins regulate anxiety and fear through modulation of KARs, we undertook a comprehensive behavioral analysis of adult Neto1-/- and Neto2-/- mice. We observed no differences in anxiety-like behavior. However, in cued fear conditioning, Neto2-/-, but not Neto1-/- mice, showed higher fear expression and delayed extinction compared to wild type mice. We established, by in situ hybridization, that Neto2 was expressed in both excitatory and inhibitory neurons throughout the fear circuit including the medial prefrontal cortex, amygdala, and hippocampus. Finally, we demonstrated that the relative amount of synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and 36.5% lower in the medial prefrontal cortex in Neto2-/- compared to the Neto2+/+ mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and extinction in mice, and that its absence increases conditionability, a phenotype related to post-traumatic stress disorder and propose that this phenotype is mediated by reduced KAR subunit abundance at synapses of fear-associated brain regions.
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Affiliation(s)
- Marie Mennesson
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland ,0000 0004 0410 2071grid.7737.4Department of Psychology and Logopedics, Medicum, University of Helsinki, Helsinki, Finland
| | - Emilie Rydgren
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Tatiana Lipina
- 0000 0004 0626 6184grid.250674.2Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON Canada ,grid.473784.bFederal State Budgetary Scientific Institution, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia ,0000000121896553grid.4605.7Novosibirsk State University, Novosibirsk, Russia ,0000 0001 2157 2938grid.17063.33Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Ewa Sokolowska
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Natalia Kulesskaya
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Francesca Morello
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Evgueni Ivakine
- 0000 0004 0473 9646grid.42327.30Program of Genetics and Genome biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Vootele Voikar
- 0000 0004 0410 2071grid.7737.4Neuroscience Center, University of Helsinki, Helsinki, Finland
| | - Victoria Risbrough
- Veterans Affairs, La Jolla, CA USA ,0000 0001 2107 4242grid.266100.3Department of Psychiatry, University of California, San Diego, CA USA
| | - Juha Partanen
- 0000 0004 0410 2071grid.7737.4Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
| | - Iiris Hovatta
- Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland. .,Department of Psychology and Logopedics, Medicum, University of Helsinki, Helsinki, Finland.
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37
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Bakker GM. A new conception and subsequent taxonomy of clinical psychological problems. BMC Psychol 2019; 7:46. [PMID: 31291999 PMCID: PMC6617608 DOI: 10.1186/s40359-019-0318-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/12/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND A taxonomy of the objects of study, theory, assessment, and intervention is critical to the development of all clinical sciences. Clinical psychology has been conceptually and administratively dominated by the taxonomy of an adjacent discipline - psychiatry's Diagnostic and statistical manual of mental disorders (DSM). Many have called for a 'paradigm shift' away from a medical nosology of diseases toward clinical psychology's own taxonomy of clinical psychological problems (CPPs), without being able to specify what is to be listed and classified. MAIN TEXT An examination of DSM's problems for clinical psychology, especially its lack of clinical utility, and a search for the essence of CPPs in what clinical psychologists actually do, leads to the proposal that: The critical psychological-level phenomenon underlying CPPs is the occurrence of 'problem-maintaining circles' (PMCs) of causally related cognitions, emotions, behaviours, and/or stimuli. This concept provides an empirically-derived, theory-based, treatment-relevant, categorical, essentialist, parsimonious, and nonstigmatizing definition of CPPs. It distinguishes psychological problems in which PMCs have not (yet?) formed, and which may respond to 'counseling', clinical psychological problems in which active PMCs require clinical intervention, and psychopathological problems which are unlikely to be 'cured' by PMC-breaking alone. CONCLUSION A subsequent classification and coding system of PMCs is proposed, and expected benefits to research, communication, and the quality of case formulation in clinical psychology are described, reliant upon a development effort of some meaningful fraction of that which has been devoted to the DSM.
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Affiliation(s)
- Gary M Bakker
- School of Medicine, University of Tasmania, Locked Bag 1377, Launceston, Tasmania, 7250, Australia.
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38
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Russo AS, Lee J, Parsons RG. Individual variability in the recall of fear extinction is associated with phosphorylation of mitogen-activated protein kinase in the infralimbic cortex. Psychopharmacology (Berl) 2019; 236:2039-2048. [PMID: 30798403 DOI: 10.1007/s00213-019-05195-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 02/07/2019] [Indexed: 01/31/2023]
Abstract
RATIONALE Although most individuals will be exposed to trauma at some point, only a small portion of individuals develops posttraumatic stress disorder (PTSD), suggesting there are factors which render some individuals particularly susceptible to the development of this disorder. One cardinal feature of PTSD is the failure to extinguish fear responses to cues that once signaled danger. Rodent studies of fear learning and extinction have provided insight into the neural mechanisms underlying extinction; however, most of these studies have focused on mechanisms involved in typical responses and fewer have identified mechanisms that distinguish animals that extinguish well versus those that do not extinguish their fear responses. Investigation of individual differences in fear extinction might help us better understand the susceptibility to and development of PTSD. OBJECTIVES In order to understand the neural mechanisms underlying such variation, we assessed phosphorylated mitogen-activated protein kinase (P-MAPK) levels in infralimbic cortex (IL), basolateral amygdala (BLA), and dorsal hippocampus in subsets of rats which exhibited good or poor recall of extinction. RESULTS We found a relationship between extinction recall and P-MAPK in the IL such that rats which had good extinction recall had higher levels of P-MAPK than those which had poor extinction recall. We also found that rats which had good extinction recall had higher levels of P-MAPK in the dorsal hippocampus than control rats. CONCLUSIONS Our findings suggest that individual differences in the recall of extinction learning can be explained by altered cell signaling in the IL.
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Affiliation(s)
- Amanda S Russo
- Department of Psychology, Stony Brook University, 100 Nicolls Rd., Stony Brook, NY, 11794, USA
| | - Jessica Lee
- Department of Psychology, Stony Brook University, 100 Nicolls Rd., Stony Brook, NY, 11794, USA
| | - Ryan G Parsons
- Department of Psychology, Stony Brook University, 100 Nicolls Rd., Stony Brook, NY, 11794, USA.
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39
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Cazares VA, Rodriguez G, Parent R, Ouillette L, Glanowska KM, Moore SJ, Murphy GG. Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain. GENES BRAIN AND BEHAVIOR 2019; 18:e12575. [PMID: 30973205 DOI: 10.1111/gbb.12575] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 03/28/2019] [Accepted: 04/09/2019] [Indexed: 10/27/2022]
Abstract
Fear conditioning is an associative learning process by which organisms learn to avoid environmental stimuli that are predictive of aversive outcomes. Fear extinction learning is a process by which avoidance of fear-conditioned stimuli is attenuated when the environmental stimuli is no longer predictive of the aversive outcome. Aberrant fear conditioning and extinction learning are key elements in the development of several anxiety disorders. The 129S1 inbred strain of mice is used as an animal model for maladaptive fear learning because this strain has been shown to generalize fear to other nonaversive stimuli and is less capable of extinguishing fear responses relative to other mouse strains, such as the C57BL/6. Here we report new environmental manipulations that enhance fear and extinction learning, including the ability to discriminate between an aversively paired tone and a neutral tone, in both the 129S1 and C57BL/6 strains of mice. Specifically, we show that discontinuous ("pipped") tone stimuli significantly enhance within-session extinction learning and the discrimination between neutral and aversively paired stimuli in both strains. Furthermore, we find that extinction training in novel contexts significantly enhances the consolidation and recall of extinction learning for both strains. Cumulatively, these results underscore how environmental changes can be leveraged to ameliorate maladaptive learning in animal models and may advance cognitive and behavioral therapeutic strategies.
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Affiliation(s)
- Victor A Cazares
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
| | - Genesis Rodriguez
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
| | - Rachel Parent
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
| | - Lara Ouillette
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
| | | | - Shannon J Moore
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
| | - Geoffrey G Murphy
- Department of Molecular and Integrative Physiology and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan
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40
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Chen X, van Gerven J, Cohen A, Jacobs G. Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety. Acta Pharmacol Sin 2019; 40:571-582. [PMID: 30518829 DOI: 10.1038/s41401-018-0185-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 10/10/2018] [Indexed: 12/11/2022]
Abstract
Anxiety disorders arise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behavioral responses observed in anxiety disorders. There is considerable preclinical evidence that the GABAergic system, in general, and its α2- and/or α5-subunit-containing GABA(A) receptor subtypes, in particular, are involved in the pathophysiology of anxiety disorders. However, the clinical efficacy of GABA-A α2-selective agonists for the treatment of anxiety disorders has not been unequivocally demonstrated. In this review, we present several human pharmacological studies that have been performed with the aim of identifying the pharmacologically active doses/exposure levels of several GABA-A subtype-selective novel compounds with potential anxiolytic effects. The pharmacological selectivity of novel α2-subtype-selective GABA(A) receptor partial agonists has been demonstrated by their distinct effect profiles on the neurophysiological and neuropsychological measurements that reflect the functions of multiple CNS domains compared with those of benzodiazepines, which are nonselective, full GABA(A) agonists. Normalizing the undesired pharmacodynamic side effects against the desired on-target effects on the saccadic peak velocity is a useful approach for presenting the pharmacological features of GABA(A)-ergic modulators. Moreover, combining the anxiogenic symptom provocation paradigm with validated neurophysiological and neuropsychological biomarkers may provide further construct validity for the clinical effects of novel anxiolytic agents. In addition, the observed drug effects on serum prolactin levels support the use of serum prolactin levels as a complementary neuroendocrine biomarker to further validate the pharmacodynamic measurements used during the clinical pharmacological study of novel anxiolytic agents.
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41
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Scarlata MJ, Lee SH, Lee D, Kandigian SE, Hiller AJ, Dishart JG, Mintz GE, Wang Z, Coste GI, Mousley AL, Soler I, Lawson K, Ng AJ, Bezek JL, Bergstrom HC. Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization. Sci Rep 2019; 9:6730. [PMID: 31040357 PMCID: PMC6491487 DOI: 10.1038/s41598-019-43159-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/16/2019] [Indexed: 01/28/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.
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Affiliation(s)
- M J Scarlata
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - S H Lee
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - D Lee
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - S E Kandigian
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A J Hiller
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - J G Dishart
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - G E Mintz
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - Z Wang
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - G I Coste
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A L Mousley
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - I Soler
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - K Lawson
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A J Ng
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - J L Bezek
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - H C Bergstrom
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA.
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Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels. Transl Psychiatry 2019; 9:33. [PMID: 30670681 PMCID: PMC6343029 DOI: 10.1038/s41398-019-0368-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 08/15/2018] [Accepted: 10/05/2018] [Indexed: 01/11/2023] Open
Abstract
Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT-/-) have increased baseline anxiety behaviors, SERT+/- rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/- model. Here we sought to determine if SERT+/- or SERT-/-, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT-/- rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/- (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/- rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT-/- and SERT+/- rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.
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Lisboa SF, Vila-Verde C, Rosa J, Uliana DL, Stern CAJ, Bertoglio LJ, Resstel LB, Guimaraes FS. Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies. Psychopharmacology (Berl) 2019; 236:201-226. [PMID: 30604182 DOI: 10.1007/s00213-018-5127-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 11/14/2018] [Indexed: 01/08/2023]
Abstract
RATIONALE Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory. OBJECTIVE AND METHODS The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated. RESULTS Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen's d ≥ 1.0). The brain areas responsible for the abovementioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation. CONCLUSION Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.
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Affiliation(s)
- Sabrina F Lisboa
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil. .,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
| | - C Vila-Verde
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil.,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - J Rosa
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil.,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - D L Uliana
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil.,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - C A J Stern
- Department of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil
| | - L J Bertoglio
- Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil
| | - L B Resstel
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil.,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - F S Guimaraes
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Av Bandeirantes 3900, Monte Alegre, 14049900, Ribeirão Preto, São Paulo, Brazil.,Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
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Prefrontal cortex rTMS reverses behavioral impairments and differentially activates c-Fos in a mouse model of post-traumatic stress disorder. Brain Stimul 2019; 12:87-95. [DOI: 10.1016/j.brs.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 08/28/2018] [Accepted: 09/06/2018] [Indexed: 12/31/2022] Open
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O’Connor RM, McCafferty CP, Bravo JA, Singewald N, Holmes A, Cryan JF. Increased amygdalar metabotropic glutamate receptor 7 mRNA in a genetic mouse model of impaired fear extinction. Psychopharmacology (Berl) 2019; 236:265-272. [PMID: 30215216 PMCID: PMC6739849 DOI: 10.1007/s00213-018-5031-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/05/2018] [Indexed: 12/18/2022]
Abstract
RATIONALE Post-traumatic stress disorder (PTSD) is a devastating anxiety-related disorder which develops subsequent to a severe psychologically traumatic event. Only ~ 9% of people who experience such a trauma develop PTSD. It is clear that a number of factors, including genetics, influence whether an individual will develop PTSD subsequent to a trauma. The 129S1/SvImJ (S1) inbred mouse strain displays poor fear extinction and may be useful to model this specific aspect of PTSD. The metabotropic glutamate receptor 7 (mGlu7 receptor) has previously been shown to be involved in cognitive processes and anxiety-like behaviour placing it in a key position to regulate fear extinction processes. We sought to compare mGlu7 receptor mRNA levels in the S1 strain with those in the robustly extinguishing C57BL/6J (B6) inbred strain using in situ hybridisation (ISH) in three brain regions associated with fear extinction: the amygdala, hippocampus and prefrontal cortex (PFC). RESULTS Compared to the B6 strain, S1 mice had increased mGlu7 receptor mRNA levels in the lateral amygdala (LA) and basolateral amygdala (BLA) subdivisions. An increase was also seen in the hippocampal CA1 and CA3 subregions of S1 mice. No difference in mGlu7 receptor levels were seen in the central nucleus (CeA) of the amygdala, dentate gyrus (DG) of the hippocampus or prefrontal cortex. CONCLUSIONS These data show altered mGlu7 receptor expression in key brain regions associated with fear extinction in two different inbred mouse strains which differ markedly in their fear extinction behaviour. Altered mGlu7 receptor levels may contribute to the deficit fear extinction processes seen in fear extinction in the S1 strain.
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Affiliation(s)
- Richard M. O’Connor
- Department of Anatomy and Neuroscience and APC Microbiome Institute, University College Cork, Cork, Ireland,Department of Neuroscience, Icahn School of Medicine at Mount Sinai, S10-20 Hess CSM, 1470 Madison Avenue, New York, NY 10029, USA,Present address: Department of Neuroscience, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA
| | - Cian P. McCafferty
- Department of Anatomy and Neuroscience and APC Microbiome Institute, University College Cork, Cork, Ireland,Present address: Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
| | - Javier A. Bravo
- Grupo de NeuroGastroBioquímica, Laboratorio e Química Biológica & Bioquímica de Sistemas, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Nicolas Singewald
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - Andrew Holmes
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
| | - John F. Cryan
- Department of Anatomy and Neuroscience and APC Microbiome Institute, University College Cork, Cork, Ireland
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46
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Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood. Neuropharmacology 2019; 144:345-357. [DOI: 10.1016/j.neuropharm.2018.11.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 10/17/2018] [Accepted: 11/10/2018] [Indexed: 01/21/2023]
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47
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Wellman CL, Moench KM. Preclinical studies of stress, extinction, and prefrontal cortex: intriguing leads and pressing questions. Psychopharmacology (Berl) 2019; 236:59-72. [PMID: 30225660 PMCID: PMC6374178 DOI: 10.1007/s00213-018-5023-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/03/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Stress is associated with cognitive and emotional dysfunction, and increases risk for a variety of psychological disorders, including depression and posttraumatic stress disorder. Prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Extinction of conditioned fear provides an excellent model system for examining how stress-induced changes in corticolimbic structure and function are related to stress-induced changes in neural function and behavior, as the neural circuitry underlying this behavior is well characterized. OBJECTIVES This review examines how acute and chronic stress influences extinction and describes how stress alters the structure and function of the medial prefrontal cortex, a potential neural substrate for these effects. In addition, we identify important unanswered questions about how stress-induced change in prefrontal cortex may mediate extinction deficits and avenues for future research. KEY FINDINGS A substantial body of work demonstrates deficits in extinction after either acute or chronic stress. A separate and substantial literature demonstrates stress-induced neuronal remodeling in medial prefrontal cortex, along with several key neurohormonal contributors to this remodeling, and there is substantial overlap in prefrontal mechanisms underlying extinction and the mechanisms implicated in stress-induced dysfunction of-and neuronal remodeling in-medial prefrontal cortex. However, data directly examining the contribution of changes in prefrontal structure and function to stress-induced extinction deficits is currently lacking. CONCLUSIONS Understanding how stress influences extinction and its neural substrates as well as individual differences in this effect will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in extinction.
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Affiliation(s)
- Cara L. Wellman
- Department of Psychological & Brain Sciences, Indiana University,Department of Psychological, Center for the Integrative Study of Animal Behavior, Indiana University,Department of Psychological, Program in Neuroscience, Indiana University
| | - Kelly M. Moench
- Department of Psychological & Brain Sciences, Indiana University,Department of Psychological, Center for the Integrative Study of Animal Behavior, Indiana University,Department of Psychological, Program in Neuroscience, Indiana University
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Abstract
The measurement of Pavlovian forms of fear extinction offers a relatively simple behavioral preparation that is nonetheless tractable, from a translational perspective, as an approach to study mechanisms of exposure therapy and biological underpinnings of anxiety and trauma-related disorders such as post-traumatic stress disorder (PTSD). Deficient fear extinction is considered a robust clinical endophenotype for these disorders and, as such, has particular significance in the current "age of RDoC (research domain criteria)." Various rodent models of impaired extinction have thus been generated with the objective of approximating this clinical, relapse prone aberrant extinction learning. These models have helped to reveal neurobiological correlates of extinction circuitry failure, gene variants, and other mechanisms underlying deficient fear extinction. In addition, they are increasingly serving as tools to investigate ways to therapeutically overcome poor extinction to support long-term retention of extinction memory and thus protection against various forms of fear relapse; modeled in the laboratory by measuring spontaneous recovery, reinstatement and renewal of fear. In the current article, we review models of impaired extinction built around (1) experimentally induced brain region and neural circuit disruptions (2) spontaneously-arising and laboratory-induced genetic modifications, or (3) exposure to environmental insults, including stress, drugs of abuse, and unhealthy diet. Collectively, these models have been instrumental in advancing in our understanding of extinction failure and underlying susceptibilities at the neural, genetic, molecular, and neurochemical levels; generating renewed interest in developing novel, targeted and effective therapeutic treatments for anxiety and trauma-related disorders.
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Affiliation(s)
- Nicolas Singewald
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
| | - Andrew Holmes
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
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49
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Gunduz-Cinar O, Brockway E, Lederle L, Wilcox T, Halladay LR, Ding Y, Oh H, Busch EF, Kaugars K, Flynn S, Limoges A, Bukalo O, MacPherson KP, Masneuf S, Pinard C, Sibille E, Chesler EJ, Holmes A. Identification of a novel gene regulating amygdala-mediated fear extinction. Mol Psychiatry 2019; 24:601-612. [PMID: 29311651 PMCID: PMC6035889 DOI: 10.1038/s41380-017-0003-3] [Citation(s) in RCA: 27] [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: 09/03/2016] [Revised: 10/08/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022]
Abstract
Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders.
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Affiliation(s)
- Ozge Gunduz-Cinar
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
| | - Emma Brockway
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Lauren Lederle
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Troy Wilcox
- 0000 0004 0374 0039grid.249880.fThe Jackson Laboratory, Bar Harbor, ME USA
| | - Lindsay R. Halladay
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Ying Ding
- Joint Carnegie Mellon University–University of Pittsburgh Ph.D. Program in Computational Biology, Pittsburgh, PA USA
| | - Hyunjung Oh
- 0000 0004 1936 9000grid.21925.3dDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA ,0000 0001 2157 2938grid.17063.33Departments of Psychiatry and Pharmacology & Toxicology, Campbell Family Mental Health Research Institute of CAMH, University of Toronto, Toronto, Canada
| | - Erica F. Busch
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Katie Kaugars
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Shaun Flynn
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Aaron Limoges
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Olena Bukalo
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Kathryn P. MacPherson
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Sophie Masneuf
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Courtney Pinard
- 0000 0004 0481 4802grid.420085.bLaboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD USA
| | - Etienne Sibille
- 0000 0004 1936 9000grid.21925.3dDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA ,0000 0001 2157 2938grid.17063.33Departments of Psychiatry and Pharmacology & Toxicology, Campbell Family Mental Health Research Institute of CAMH, University of Toronto, Toronto, Canada
| | - Elissa J. Chesler
- 0000 0004 0374 0039grid.249880.fThe Jackson Laboratory, Bar Harbor, ME USA
| | - Andrew Holmes
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
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50
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Dustrude ET, Caliman IF, Bernabe CS, Fitz SD, Grafe LA, Bhatnagar S, Bonaventure P, Johnson PL, Molosh AI, Shekhar A. Orexin Depolarizes Central Amygdala Neurons via Orexin Receptor 1, Phospholipase C and Sodium-Calcium Exchanger and Modulates Conditioned Fear. Front Neurosci 2018; 12:934. [PMID: 30618563 PMCID: PMC6305451 DOI: 10.3389/fnins.2018.00934] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 11/27/2018] [Indexed: 01/09/2023] Open
Abstract
Orexins (OX), also known as hypocretins, are excitatory neuropeptides with well-described roles in regulation of wakefulness, arousal, energy homeostasis, and anxiety. An additional and recently recognized role of OX is modulation of fear responses. We studied the OX neurons of the perifornical hypothalamus (PeF) which send projections to the amygdala, a region critical in fear learning and fear expression. Within the amygdala, the highest density of OX-positive fibers was detected in the central nucleus (CeA). The specific mechanisms underlying OX neurotransmission within the CeA were explored utilizing rat brain slice electrophysiology, pharmacology, and chemogenetic stimulation. We show that OX induces postsynaptic depolarization of medial CeA neurons that is mediated by OX receptor 1 (OXR1) but not OX receptor 2 (OXR2). We further characterized the mechanism of CeA depolarization by OX as phospholipase C (PLC)- and sodium-calcium exchanger (NCX)- dependent. Selective chemogenetic stimulation of OX PeF fibers recapitulated OXR1 dependent depolarization of CeA neurons. We also observed that OXR1 activity modified presynaptic release of glutamate within the CeA. Finally, either systemic or intra-CeA perfusion of OXR1 antagonist reduced the expression of conditioned fear. Together, these data suggest the PeF-CeA orexinergic pathway can modulate conditioned fear through a signal transduction mechanism involving PLC and NCX activity and that selective OXR1 antagonism may be a putative treatment for fear-related disorders.
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Affiliation(s)
- Erik T Dustrude
- Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Izabela F Caliman
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Cristian S Bernabe
- Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.,Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Stephanie D Fitz
- Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Laura A Grafe
- Department Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Seema Bhatnagar
- Department Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | | | - Philip L Johnson
- Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Andrei I Molosh
- Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Anantha Shekhar
- Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, IN, United States
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