|
1
|
Chowdhury A, Rao BSS, Laxmi TR. Saturated and poly-unsaturated fat-rich dietary supplements during adolescence restore risky decision-making behaviour in rats pre-exposed to early-life stress. Physiol Behav 2025; 292:114821. [PMID: 39862942 DOI: 10.1016/j.physbeh.2025.114821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Previous studies suggest that early-life stress (ELS) induced by early maternal separation and isolation (MS) stress during the stress hyporesponsive period (SHRP) leads to increased curiosity-like and increased risky decision-making behaviour in adolescence. Evidence suggests that dietary interventions early in adolescence could play an important role in mitigating the detrimental effects of MS stress on risky decision-making behaviour. Hence, the present study hypothesized that nutritional supplements such as saturated fat (SFA) and/or polyunsaturated fat (PUFA) would be beneficial in ameliorating the impact of MS stress on risky decision-making behaviour when incorporated into the diet during early adolescence. NC and MS rats were subjected to the Risky Decision-Taking Task (RDTT) to assess the rats' ability to make decisions under risky conditions. The results showed that MS rats took less time to cross the risky zone to collect a large reward. However, when an SFA-rich and PUFA-rich diet was provided, the latency of the MS rats increased. Similarly, MS stress-induced reduction in risk assessment was restored to normal with the SFA and PUFA-rich diet. Risk-index (RI) values also showed a similar trend with reduced RI values in MS, but nutritional supplementation increased the RI values making it comparable to that NC. Correlation analysis has further revealed a direct correlation between the anxiety-like behaviour and the risk-taking tendency in MS rats and not in the NC group. SFA-rich diet led to a positive correlation between anxiety-like and risk-taking behaviour. These findings thus support the hypothesis that PUFA- and SFA-rich diet may be introduced at adolescence to mitigate MS-stress induced increased risky decision-making behaviour due to a deficit in risk assessment.
Collapse
Affiliation(s)
- Abanti Chowdhury
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - B S Shankaranarayana Rao
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
| | - T R Laxmi
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India.
| |
Collapse
|
|
2
|
Kirsch D, Nemeroff CM, Lippard ETC. Early Life Stress and Substance Use Disorders: Underlying Neurobiology and Pathways to Adverse Outcomes. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2025; 23:221-238. [PMID: 40235604 PMCID: PMC11995910 DOI: 10.1176/appi.focus.25023013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Early life stress (ELS) has been established as a major risk factor for a multitude of psychiatric and medical disorders. ELS is highly prevalent in the general population and constitutes a major public health concern. The current review will focus on the clinical literature that suggests a link between adverse early life experiences and vulnerability for adolescent and adult substance use disorders. It will investigate the characteristics of ELS that appear to increase risk for disorder onset and a more severe disease course, characterized by earlier onset, greater risk of relapse, and treatment resistance. The authors explore how ELS may increase risk for adverse substance use outcomes through long-lasting changes in the HPA axis and development of stress, reward, and executive control brain systems. The review will also discuss potential pathways to substance use disorder following ELS, with a focus on the role of comorbid mood and anxiety disorders and other modifiable traits. Finally, the authors will discuss how the current body of work presents the potential for prevention and intervention strategies to reduce the psychosocial consequences following early life stress and minimize adverse substance use outcomes. Reprinted from Advers Resil Sci 2020; 1:29-47, with permission from Springer. Copyright © 2020.
Collapse
Affiliation(s)
- Dylan Kirsch
- Department of Psychiatry, Dell Medical School, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Institute for Neuroscience, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Department of Psychology, University of Texas, Austin, TX, USA (Lippard); Institute of Early Life Adversity Research, University of Texas, Austin, TX, USA (Nemeroff, Lippard); Mulva Clinic for Neuroscience, Dell Medical School, University of Texas, Austin, TX, USA (Nemeroff, Lippard)
| | - Charles M Nemeroff
- Department of Psychiatry, Dell Medical School, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Institute for Neuroscience, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Department of Psychology, University of Texas, Austin, TX, USA (Lippard); Institute of Early Life Adversity Research, University of Texas, Austin, TX, USA (Nemeroff, Lippard); Mulva Clinic for Neuroscience, Dell Medical School, University of Texas, Austin, TX, USA (Nemeroff, Lippard)
| | - Elizabeth T C Lippard
- Department of Psychiatry, Dell Medical School, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Institute for Neuroscience, University of Texas, Austin, TX, USA (Kirsch, Nemeroff, Lippard); Department of Psychology, University of Texas, Austin, TX, USA (Lippard); Institute of Early Life Adversity Research, University of Texas, Austin, TX, USA (Nemeroff, Lippard); Mulva Clinic for Neuroscience, Dell Medical School, University of Texas, Austin, TX, USA (Nemeroff, Lippard)
| |
Collapse
|
|
3
|
Favoretto CA, Bertagna NB, Anjos-Santos A, Loss CM, Rodolpho BT, Righi T, Bezerra FR, Bianchi PC, Cruz FC. Impacts of maternal separation stress on ethanol intake and endocannabinoid system in adolescent mice. Neuroscience 2025; 565:124-137. [PMID: 39579855 DOI: 10.1016/j.neuroscience.2024.11.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 10/24/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024]
Abstract
Clinical and preclinical studies suggest that early life stress can increase the risk of developing ethanol use disorder later in life. Although the endocannabinoid (eCB) system plays a role in stress-related behaviors and ethanol consumption, it remains unclear whether the eCB system is affected in response to a combination of both factors. By using male and female adolescent C57BL/6J mice subjected to a maternal separation (MS) stress paradigm from postnatal day (PND) 1 to 14, we explored (1) the consequences of early life stress experiences on ethanol consumption in adolescent mice and (2) how these events affect the eCB system and neuronal activation in brain regions associated with the reward system. In Experiment 1, we found that MS increased involuntary ethanol consumption specifically during the first exposure to the drug (during a 24 h-long trial on PND 28) and decreased the active/inactive nose poke ratio (discrimination index) specifically when mice were subjected to 1 h-sessions (PND 82-86) in an operant ethanol self-administration paradigm. In Experiment 2, during a two-bottle free choice paradigm, we found that MS increased mice preference for high ethanol concentrations (15 % and 20 %) but not lower ethanol concentrations (5 % and 10 %). Except for Mgll gene expression in the dorsal striatum (DS) in Experiment 2, no statistically significant effects of MS were observed regarding neuronal activation on the prefrontal cortex, DS, globus pallidus, and substantia nigra following a binge operant ethanol self-administration session (Experiment 1) or the eCB system molecules (Cnr1 and Faah gene expression) in the DS (Experiment 2).
Collapse
Affiliation(s)
- C A Favoretto
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
| | - N B Bertagna
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A Anjos-Santos
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - C M Loss
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil; Stiles-Nicholson Brain Institute, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA; National Institute for Translational Medicine (INCT-TM), National Council for Scientific and Technological Development (CNPq/CAPES/FAPESP), Ribeirão Preto, Brazil.
| | - B T Rodolpho
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - T Righi
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - F R Bezerra
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil; Laboratory of Experimental and Clinical Neuroscience, INSERM, U1084 Université de Poitiers, France
| | - P C Bianchi
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - F C Cruz
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil.
| |
Collapse
|
|
4
|
Choe JY, Jones HP. Methods for Modeling Early Life Stress in Rodents. Methods Mol Biol 2025; 2868:205-219. [PMID: 39546232 DOI: 10.1007/978-1-0716-4200-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Animal models of early life stress/adversity (ELS) have provided a foundation from which our understanding of the psychoneuroimmunology of childhood trauma has expanded over recent decades. Rodent models are a cornerstone of the ELS literature with many studies utilizing paradigms based on early life separation/deprivation protocols and manipulating the cage environment. However, no animal model is perfect. In particular, the lack of standardization across ELS models has led to inconsistent results and raised questions regarding the translational value of common preclinical models. In this chapter, we present an overview of the history of ELS rodent models and discuss considerations relevant to the ongoing efforts to both improve existing models and generate novel paradigms to meet the evolving needs of molecular- and mechanism-based ELS research.
Collapse
Affiliation(s)
- Jamie Y Choe
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Harlan P Jones
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA.
- Institute for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, USA.
| |
Collapse
|
|
5
|
Talani G, Biggio F, Mostallino MC, Batzu E, Biggio G, Sanna E. Sex-specific changes in voluntary alcohol consumption and nucleus accumbens synaptic plasticity in C57BL/6J mice exposed to neonatal maternal separation. Neuropharmacology 2025; 262:110212. [PMID: 39521040 DOI: 10.1016/j.neuropharm.2024.110212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/31/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
The long-term influence of early-life stress on brain neurophysiology has been extensively investigated using different animal models. Among these, repeated maternal separation (RMS) in rodents is one of the most commonly adopted. In this study, we elucidated the long-lasting effects of exposure to postnatal RMS in C57BL/6J adult mice on voluntary alcohol consumption and nucleus accumbens (NAc) neurophysiology. Mice were separated from their dam for 360 min daily from postnatal day 2 (PND2) to PND17, and experiments were then performed in adult (PND60) animals. In addition, as recent evidence showed that circulating estrogens may play a protective role against stress effects on brain function, including the organization and activation of neuronal structures, we also evaluated the effect of a single injection of β-estradiol 3-benzoate (EB) at PND2, which is known to disrupt male sex differentiation, in male RMS mice. The RMS exposure was associated with an increased voluntary alcohol consumption and preference in male mice, but not in female mice or male mice treated with a single injection of EB. Patch clamp experiments conducted in NAc medium spiny neurons (MSNs) revealed that excitatory but not inhibitory synaptic transmission and long-term plasticity of glutamatergic synapses were significantly impaired in male but not in female mice exposed to the RMS protocol. This effect was again prevented in RMS male mice treated with EB. Our findings strengthen the idea of a sex-dependent influence of early-life stress on long-lasting modifications in synaptic transmission and plasticity in brain areas involved in goal-directed behavior and alcohol intake.
Collapse
Affiliation(s)
- Giuseppe Talani
- CNR Institute of Neuroscience, National Research Council, 09042, Monserrato, CA, Italy.
| | - Francesca Biggio
- Department of Life and Environmental Sciences, Section of Neuroscience and Anthropology, University of Cagliari, 09042, Monserrato, CA, Italy
| | | | - Elisabetta Batzu
- CNR Institute of Neuroscience, National Research Council, 09042, Monserrato, CA, Italy
| | - Giovanni Biggio
- CNR Institute of Neuroscience, National Research Council, 09042, Monserrato, CA, Italy; Department of Life and Environmental Sciences, Section of Neuroscience and Anthropology, University of Cagliari, 09042, Monserrato, CA, Italy
| | - Enrico Sanna
- CNR Institute of Neuroscience, National Research Council, 09042, Monserrato, CA, Italy; Department of Life and Environmental Sciences, Section of Neuroscience and Anthropology, University of Cagliari, 09042, Monserrato, CA, Italy
| |
Collapse
|
|
6
|
Speranza L, Filiz KD, Lippiello P, Ferraro MG, Pascarella S, Miniaci MC, Volpicelli F. Enduring Neurobiological Consequences of Early-Life Stress: Insights from Rodent Behavioral Paradigms. Biomedicines 2024; 12:1978. [PMID: 39335492 PMCID: PMC11429222 DOI: 10.3390/biomedicines12091978] [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: 06/17/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Stress profoundly affects physical and mental health, particularly when experienced early in life. Early-life stress (ELS) encompasses adverse childhood experiences such as abuse, neglect, violence, or chronic poverty. These stressors can induce long-lasting changes in brain structure and function, impacting areas involved in emotion regulation, cognition, and stress response. Consequently, individuals exposed to high levels of ELS are at an increased risk for mental health disorders like depression, anxiety, and post-traumatic stress disorders, as well as physical health issues, including metabolic disorders, cardiovascular disease, and cancer. This review explores the biological and psychological consequences of early-life adversity paradigms in rodents, such as maternal separation or deprivation and limited bedding or nesting. The study of these experimental models have revealed that the organism's response to ELS is complex, involving genetic and epigenetic mechanisms, and is associated with the dysregulation of physiological systems like the nervous, neuroendocrine, and immune systems, in a sex-dependent fashion. Understanding the impact of ELS is crucial for developing effective interventions and preventive strategies in humans exposed to stressful or traumatic experiences in childhood.
Collapse
Affiliation(s)
- Luisa Speranza
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| | - Kardelen Dalim Filiz
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| | - Pellegrino Lippiello
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| | - Maria Grazia Ferraro
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy;
| | - Silvia Pascarella
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| | - Maria Concetta Miniaci
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| | - Floriana Volpicelli
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (L.S.); (K.D.F.); (P.L.); (S.P.)
| |
Collapse
|
|
7
|
Heesbeen EJ, van Kampen T, Verdouw PM, van Lissa C, Bijlsma EY, Groenink L. The effect of SSRIs on unconditioned anxiety: a systematic review and meta-analysis of animal studies. Psychopharmacology (Berl) 2024; 241:1731-1755. [PMID: 38980348 PMCID: PMC11339141 DOI: 10.1007/s00213-024-06645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024]
Abstract
RATIONALE Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders. However, which aspects of anxiety are affected by SSRIs is not yet fully understood. OBJECTIVE We aimed to systematically review the effect of six clinically effective SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour (elevated plus maze), repetitive behaviour (marble burying), distress behaviour (ultrasonic vocalization), and activation of the autonomous nervous system (stress-induced hyperthermia). METHODS We identified publications by searching Medline and Embase databases and assessed the risk of bias. A random effects meta-analysis was performed and moderator effects were analysed with Bayesian penalized meta-regression. RESULTS Our search yielded 105 elevated plus maze, 63 marble burying, 11 ultrasonic vocalization, and 7 stress-induced hyperthermia articles. Meta-analysis suggested that SSRIs reduce anxiety-like behaviour in the elevated plus maze, marble burying and ultrasonic vocalization test and that effects are moderated by pre-existing stress conditions (elevated plus maze) and dose dependency (marble burying) but not by duration of treatment or type of SSRI. The reporting quality was low, publication bias was likely, and heterogeneity was high. CONCLUSION SSRIs seem to reduce a broad range of unconditioned anxiety-associated behaviours. These results should be interpreted with caution due to a high risk of bias, likely occurrence of publication bias, substantial heterogeneity and limited moderator data availability. Our review demonstrates the importance of including bias assessments when interpreting meta-analysis results. We further recommend improving the reporting quality, the conduct of animal research, and the publication of all results regardless of significance.
Collapse
Affiliation(s)
- Elise J Heesbeen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Tatum van Kampen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - P Monika Verdouw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Caspar van Lissa
- Department of Methodology, Tilburg University, Tilburg, The Netherlands
| | - Elisabeth Y Bijlsma
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Lucianne Groenink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
| |
Collapse
|
|
8
|
Burenkova OV, Grigorenko EL. The role of epigenetic mechanisms in the long-term effects of early-life adversity and mother-infant relationship on physiology and behavior of offspring in laboratory rats and mice. Dev Psychobiol 2024; 66:e22479. [PMID: 38470450 PMCID: PMC10959231 DOI: 10.1002/dev.22479] [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: 09/15/2023] [Revised: 01/23/2024] [Accepted: 02/16/2024] [Indexed: 03/13/2024]
Abstract
Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.
Collapse
Affiliation(s)
- Olga V. Burenkova
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada
| | - Elena L. Grigorenko
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Center for Cognitive Sciences, Sirius University of Science and Technology, Sochi, Russia
- Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Child Study Center, Yale University, New Haven, Connecticut, USA
- Research Administration, Moscow State University for Psychology and Education, Moscow, Russia
| |
Collapse
|
|
9
|
Chou S, Wu R, Li M. Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders. Behav Brain Res 2024; 461:114831. [PMID: 38142861 PMCID: PMC10872411 DOI: 10.1016/j.bbr.2023.114831] [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: 11/12/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0-6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.
Collapse
Affiliation(s)
- Shinnyi Chou
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ruiyong Wu
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
| | - Ming Li
- Department of Psychology, Nanjing University, Nanjing, China.
| |
Collapse
|
|
10
|
Biswas B, Eapen V, Morris MJ, Jones NM. Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring. Biomolecules 2024; 14:197. [PMID: 38397434 PMCID: PMC10886936 DOI: 10.3390/biom14020197] [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: 11/17/2023] [Revised: 01/14/2024] [Accepted: 01/22/2024] [Indexed: 02/25/2024] Open
Abstract
Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.
Collapse
Affiliation(s)
- Bharti Biswas
- School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia; (B.B.); (V.E.)
- School of Biomedical Sciences, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia
| | - Valsamma Eapen
- School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia; (B.B.); (V.E.)
| | - Margaret J. Morris
- School of Biomedical Sciences, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia
| | - Nicole M. Jones
- School of Biomedical Sciences, Faculty of Medicine & Health, UNSW Sydney, Kensington, NSW 2052, Australia
| |
Collapse
|
|
11
|
Gildawie KR, Wang K, Budge KE, Byrnes EM. Effects of Maternal Separation on Effort-based Responding for Sucrose Are Associated with c-Fos Expression in the Nucleus Accumbens Core. Neuroscience 2024; 537:174-188. [PMID: 38036058 PMCID: PMC10872495 DOI: 10.1016/j.neuroscience.2023.11.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/06/2023] [Accepted: 11/26/2023] [Indexed: 12/02/2023]
Abstract
In both people and animals, exposure to adverse experiences early in life can alter neurodevelopment and lead to long-term behavioral effects, including effects on reward processing. In the current study, we use a well-validated rodent model of maternal neglect, maternal separation (MS), to investigate the impact of early life adversity on reward learning and motivation and identify associated modifications in cellular activation in reward-relevant areas. Litters of Long-Evans rats were separated from the dam for either 15 min (brief) or 180 min (prolonged)/day from postnatal day (PND)2 to PND14. As adults, offspring were trained to lever press for a sucrose pellet using fixed ratio (FR) schedules and motivation was tested using a progressive ratio (PR) schedule over 10 daily sessions to assess sustained effects on effort-based responding. Immunohistochemical staining for c-Fos was conducted in a subset of animals that underwent an additional PR session. While there were no effects on reward learning, both MS180 males and females demonstrated increased effort-based responding on the first day of PR testing, while only MS180 males demonstrated a sustained increase in effort across all 10 days. MS180-induced changes in c-Fos expression in the dorsal and ventral striatum were observed, with subregion-specific effects along the rostrocaudal axis. Moreover, regression analyses suggest that motivated responding for a sucrose food reward in MS180-exposed, but not MS15-exposed animals, was associated with increased c-Fos expression in the rostral nucleus accumbens core. These findings implicate specific striatal regions in sex-specific modulation of sustained effort-based reward behavior following early life adversity.
Collapse
Affiliation(s)
- Kelsea R Gildawie
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Katherine Wang
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Kerri E Budge
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Elizabeth M Byrnes
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA.
| |
Collapse
|
|
12
|
Abraham M, Schmerder K, Hedtstück M, Bösing K, Mundorf A, Freund N. Maternal separation and its developmental consequences on anxiety and parvalbumin interneurons in the amygdala. J Neural Transm (Vienna) 2023; 130:1167-1175. [PMID: 37294327 PMCID: PMC10460741 DOI: 10.1007/s00702-023-02657-y] [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: 12/28/2022] [Accepted: 05/22/2023] [Indexed: 06/10/2023]
Abstract
The early postnatal period represents an exceptionally vulnerable phase for the development of neurobiological alterations, aberrant behavior, and psychiatric disorders. Altered GABAergic activity in the hippocampus and the amygdala have been identified in humans diagnosed with depression or anxiety disorders, as well as in respective animal models. Changes in GABAergic activity can be visualized by immunohistochemical staining of parvalbumin (PV) protein. Therewith, alterations in PV intensity as well as in the integrity of the perineural net surrounding PV positive (PV+) interneurons have been reported as consequences of early stress. In the current study, maternal separation (MS) was used to induce early life stress. Female and male Sprague-Dawley rats were subjected to MS over 4 h from postnatal days 2-20. Then, anxiety behavior and PV+ interneurons in the amygdala were analyzed using immunohistochemistry in adolescence or adulthood. MS induced increased anxiety behavior in the marble-burying test in adolescence as well as in the elevated plus maze in adulthood. No effect of sex was found. Concerning alterations of parvalbumin expression in the amygdala, a trend towards a lower number of parvalbumin-positive inhibitory interneurons was shown in the amygdala after MS in adolescence, with no differences in the total number of cells. The current study offers a developmental perspective, suggesting that the kind of anxiety behavior expressed by rats following MS changes over time from active to passive avoidance, indicating that effects of MS are highly dependent on developmental state. Moreover, a cell-type-specific effect of MS on the cellular composition of the amygdala is discussed. The presented study demonstrates the long-lasting consequences of early stress on behavior, offers a possible neurobiological correlate, and discusses possible mediators in the development of these alterations.
Collapse
Affiliation(s)
- Mate Abraham
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany
| | - Kirsten Schmerder
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany
| | - Malin Hedtstück
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany
| | - Kimberly Bösing
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany
| | - Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Universitätsstraße 150, 44780, Bochum, Germany.
| |
Collapse
|
|
13
|
Favoretto CA, Bertagna NB, Righi T, Rodolpho BT, Anjos-Santos A, Silva FBR, Bianchi PC, Cruz FC. Impacts of maternal separation stress on ethanol-related responses, anxiety- and depressive-like behaviors in adolescent mice. Neurosci Lett 2023; 809:137295. [PMID: 37182574 DOI: 10.1016/j.neulet.2023.137295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/18/2023] [Accepted: 05/08/2023] [Indexed: 05/16/2023]
Abstract
The present work evaluated the consequences of chronic maternal separation (MS), an animal model of early-life stress, on ethanol intake and striatal Fos expression induced by ethanol consumption. Furthermore, we analyzed MS impacts on anxiety- and depressive-like behaviors and on locomotor and plasma corticosterone responses to intraperitoneal treatment with ethanol in adolescent mice. For that, male and female C57BL/6J mice were exposed or not to MS stress, for 3 h per day, from postnatal day (PND) 1 to 14, and submitted to behavioral tests from PND 28. In Experiment 1, MS and control groups of mice were submitted to an involuntary ethanol intake protocol, and striatal Fos expression following ethanol exposure was analyzed. In Experiment 2, mice behavior was assessed in elevated plus-maze, sucrose splash, saccharin preference, and open field tests. Locomotor and plasma corticosterone responses induced by a systemic dose of ethanol (1.75 g/kg) were also evaluated. Our results demonstrated that MS increased ethanol intake only in an acute manner and did not impact ethanol-induced Fos expression in the dorsal striatum and nucleus accumbens (NAc) core and shell subregions. MS did not change the parameters analyzed during elevated plus-maze, sucrose splash, preference for saccharin, and open field tests. MS did not affect locomotor activity following ethanol injection nor plasma corticosterone response to the drug. Thus, our data showed that MS transiently increased ethanol intake. However, early-life stress did not impact Fos, locomotor, or plasma corticosterone responses to the drug. In addition, MS did not affect anxiety- and depressive-like behaviors in adolescent mice.
Collapse
Affiliation(s)
- C A Favoretto
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - N B Bertagna
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - T Righi
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - B T Rodolpho
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - A Anjos-Santos
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - F B R Silva
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - P C Bianchi
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil
| | - F C Cruz
- Molecular and Behavioral Neuroscience Laboratory, Pharmacology Department, Universidade Federal de São Paulo, São Paulo, Brazil.
| |
Collapse
|
|
14
|
Chowdhury A, Rao BSS, Laxmi TR. Risky Decision-taking Task: a novel paradigm to assess the risk-taking behaviour in rats predisposed to early-life stress. J Neurosci Methods 2023; 392:109864. [PMID: 37080434 DOI: 10.1016/j.jneumeth.2023.109864] [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: 12/26/2022] [Revised: 03/31/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
One of the characteristic features of adolescence is risk-taking behavioural traits. Uncontrolled risk-taking without proper assessment may have harmful impact on mental health later in life. Therefore, it is essential to identify it early for the preventable health problems. In the present study, we have designed a novel paradigm, viz. Risky Decision-taking Task (RDTT), to evaluate the spontaneous risk-taking behavioural repertoire in adolescent rodents. The task was designed based on both risk and cognitive factors. To validate and compare the risk-taking tendency, we have used early maternal separation and isolation (MS) stress model, as it is known to increase anxiety and curiosity-like behaviour at adolescence. We have used Sprague-Dawley rats of both sexes. Rats were exposed to MS stress for 10 days daily for six hours during stress hyporesponsive period (SHRP) from postnatal day 4 to 13. These rats were subjected to RDTT during adolescence. This task is a reward-based task where the latency to collect reward in the presence or absence of a risk factor is assessed. It consists of habituation, training to find the location of small and large rewards, reward preference for small and large reward and testing period under risky situation. Rats were trained individually to retrieve the valuation-based rewards under the risky, but innate aversive environments. The results from RDTT showed that as compared to controls, MS rats from both sexes showed reduced latency to collect large reward in the presence of a risk element and a reduced risk-index which is indicative of a higher risk-taking tendency in these rats. In addition, MS rats showed a trend towards anxiety-like behaviour as compared to controls in the Light-Dark Test. These results together show decreased risk latency for the large reward and reduced risk assessment in MS rats which is suggestive of more risk-taking tendency in these rats. Thus, we propose that RDTT paradigm can be used to evaluate the spontaneous risk-taking behavioural repertoire based on innate, spontaneous aversion and cognitive factors in rats.
Collapse
Affiliation(s)
- Abanti Chowdhury
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029
| | - B S Shankaranarayana Rao
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029
| | - T R Laxmi
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029.
| |
Collapse
|
|
15
|
Scopano MR, Jones HE, Stea SG, Freeman MZ, Grisel JE. Age, β-endorphin, and sex dependent effects of maternal separation on locomotor activity, anxiety-like behavior, and alcohol reward. Front Behav Neurosci 2023; 17:1155647. [PMID: 37091593 PMCID: PMC10113444 DOI: 10.3389/fnbeh.2023.1155647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/07/2023] [Indexed: 04/09/2023] Open
Abstract
IntroductionChildhood adversity is pervasive and linked to numerous disadvantages in adulthood, including physical health problems, mental illness, and substance use disorders. Initial sensitivity to the rewarding effects of alcohol predicts the risk of developing an alcohol use disorder, and may be linked to developmental stress. The opioid peptide β-endorphin (β-E) regulates the stress response and is also implicated in the risk for excessive alcohol consumption.MethodsWe explored the influence of β-E in an animal model of early life adversity using controlled maternal separation by evaluating changes in locomotor activity, anxiety-like behavior, and the initial rewarding effects of alcohol in a single exposure conditioned place preference paradigm in control C57BL/6J and β-E deficient β-E +/+ 0.129S2-Pomc tm1Low/J; β-E −/− mice. Maternal separation (MS) occurred for 3 h each day from post-natal days (PND) 5–18 in approximately half the subjects.ResultsMaternal interactions increased following the separation protocol equally in both genotypes. MS and control subjects were tested as adolescents (PND 26–32) or adults (PND 58–72); the effects of MS were generally more pronounced in older subjects. Adults were more active than adolescents in the open field, and MS decreased activity in adolescent mice but increased it in adults. The increase in adult activity as a result of early life stress depended on both β-E and sex. β-E also influenced the effect of maternal separation on anxiety-like behavior in the Elevated Plus Maze. MS promoted rewarding effects of alcohol in male β-E deficient mice of either age, but had no effect in other groups.DiscussionTaken together, these results suggest that the effects of MS develop over time and are β-E and sex dependent and may aid understanding of how individual differences influence the impact of adverse childhood experiences.
Collapse
|
|
16
|
Fang H, Li J, Lu L, Yang J, Feng H, Yin X, Wang S, He X, Song L, Shi Y, Gao Y, Shi H, Yin X. Long-lasting and sex-dependent effects of late lactational maternal deprivation on socioemotional behaviors in adult mice. Neurosci Lett 2023; 799:137096. [PMID: 36738955 DOI: 10.1016/j.neulet.2023.137096] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 12/30/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023]
Abstract
The lactation period is an important period for individual development and a sensitive period for the behavioral phenotypes and plasticity of individual offspring. Early life experiences (e.g., maternal deprivation (MD) and neglect) have significant long-lasting and dual effects on individual stress reactivities during adulthood. Theoretically, stress inoculation can improve the adaptive capacity of the body, but overstress can lead to dysfunction when adaptive mechanisms fail.To date, the potential effects of late lactational MD on the socioemotional behaviors of mouse offspring during adulthood are still not fully understood. In the present study, mice were subjected to early deprivation by individually separating pups from their dam for 0 min, 15 min, and 3 h per day from PND 13-25. The social dominance test (SDT), social interaction test (SI), open field test (OFT), and forced swim test (FST) were carried out during adulthood. The results showed that the social dominance of male mice in the 15 min/d MD group significantly increased, especially in low-rank mice. In the 3 h/d MD group, the social dominance of female mice was decreased, especially in the lower-rank mice. The anxiolytic and antidepressant-like effects of the 15 min/d MD group were significantly increased in male mice. Our study provides direct evidence that MD during late lactation period results in long-lasting effects on social dominance as well as on anxiety and depression phenotypes in a sex-dependent manner.
Collapse
Affiliation(s)
- Hanlu Fang
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Jiabo Li
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Liuhua Lu
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Jingyu Yang
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Hao Feng
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Xueyong Yin
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Shuang Wang
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Xinyue He
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China
| | - Li Song
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medical University, 050017, China
| | - Yun Shi
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medical University, 050017, China
| | - Yuan Gao
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medical University, 050017, China
| | - Haishui Shi
- Neuroscience Research Center, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medical University, 050017, China.
| | - Xi Yin
- Department of Functional Region of Diagnosis, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
| |
Collapse
|
|
17
|
Yurtdas C, Zortul H, Yilmaz B, Aricioglu F. Microglial Activation Mediates Maternal Separation-Induced Depressive-Like Behavior in Rats: A Neurodevelopmental Depression Model. JOURNAL OF AFFECTIVE DISORDERS REPORTS 2023. [DOI: 10.1016/j.jadr.2023.100462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|
|
18
|
Pardo GVE, Alfaro Saca EE, Becerra Flores CT, Delgado Casós WF, Pacheco-Otalora LF. Limited bedding nesting paradigm alters maternal behavior and pup's early developmental milestones but did not induce anxiety- or depressive-like behavior in two different inbred mice. Dev Psychobiol 2023; 65:e22357. [PMID: 36567650 DOI: 10.1002/dev.22357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 12/24/2022]
Abstract
Animal models are crucial to understanding the mechanisms underlying the deleterious consequences of early-life stress. Here, we aimed to examine the effect of the limited bedding nesting (LBN) paradigm on early life development milestones and anxiety- and/or depression-like behavior in adolescent and adult mice from two inbred mice of both sexes. C57BL/6NCrl and BALB/c litters were exposed to the LBN paradigm postnatal day (PND) 2-9. Maternal behavior recording occurred on PND 3-9, and pups were weighed daily and examined to verify the eye-opening on PND 10-22. The male and female offspring underwent evaluation in the open field test, elevated plus-maze, and the forced swimming test during adolescence (PND 45-49) and adulthood (PND 75-79). We found that LBN impaired the maternal behavior patterns of both strain dams, mainly on C57BL/6NCrl strain. Also, LBN delayed the pup's eye-opening time and reduced body weight gain, impacting C57BL/6NCrl pups more. We also found that LBN decreased anxiety-related indices in adolescent and adult male but not female mice of both strains. Furthermore, LBN decreased depression-related indices only adolescent female and male BALB/c and female but not male C57BL/6NCrl mice. These findings reinforce the evidence that the LBN paradigm impairs the maternal behavior pattern and pup's early developmental milestones but does not induce anxiety- or depressive-like behavior outcomes during later life.
Collapse
Affiliation(s)
- Grace V E Pardo
- Laboratorio de Investigación en Neurociencia, Instituto Científico de Investigación, Universidad Andina del Cusco, Cuzco, Peru
| | - Eros Emanuel Alfaro Saca
- Laboratorio de Investigación en Neurociencia, Instituto Científico de Investigación, Universidad Andina del Cusco, Cuzco, Peru
| | | | - Walter Fares Delgado Casós
- Laboratorio de Investigación en Neurociencia, Instituto Científico de Investigación, Universidad Andina del Cusco, Cuzco, Peru
| | - Luis F Pacheco-Otalora
- Laboratorio de Investigación en Neurociencia, Instituto Científico de Investigación, Universidad Andina del Cusco, Cuzco, Peru
| |
Collapse
|
|
19
|
Sex differences in addiction-relevant behavioral outcomes in rodents following early life stress. ADDICTION NEUROSCIENCE 2023; 6. [PMID: 37101684 PMCID: PMC10124992 DOI: 10.1016/j.addicn.2023.100067] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In humans, exposure to early life stress (ELS) is an established risk factor for the development of substance use disorders (SUDs) during later life. Similarly, rodents exposed to ELS involving disrupted mother-infant interactions, such as maternal separation (MS) or adverse caregiving due to scarcity-adversity induced by limited bedding and nesting (LBN) conditions, also exhibit long-term alterations in alcohol and drug consumption. In both humans and rodents, there is a range of addiction-related behaviors that are associated with drug use and even predictive of subsequent SUDs. In rodents, these include increased anxiety-like behavior, impulsivity, and novelty-seeking, altered alcohol and drug intake patterns, as well as disrupted reward-related processes involving consummatory and social behaviors. Importantly, the expression of these behaviors often varies throughout the lifespan. Moreover, preclinical studies suggest that sex differences play a role in how exposure to ELS impacts reward and addiction-related phenotypes as well as underlying brain reward circuitry. Here, addiction-relevant behavioral outcomes and mesolimbic dopamine (DA) dysfunction resulting from ELS in the form of MS and LBN are discussed with a focus on age- and sex-dependent effects. Overall, these findings suggest that ELS may increase susceptibility for later life drug use and SUDs by interfering with the normal maturation of reward-related brain and behavioral function.
Collapse
|
|
20
|
Smiley CE, Wood SK. Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders. Pharmacol Ther 2022; 239:108212. [PMID: 35580690 DOI: 10.1016/j.pharmthera.2022.108212] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 10/18/2022]
Abstract
Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the "dual-hit" hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.
Collapse
Affiliation(s)
- Cora E Smiley
- Department of Pharmacology, Physiology, and Neuroscience; University of South Carolina School of Medicine, Columbia, SC 29209, United States of America; WJB Dorn Veterans Administration Medical Center, Columbia, SC 29209, United States of America.
| | - Susan K Wood
- Department of Pharmacology, Physiology, and Neuroscience; University of South Carolina School of Medicine, Columbia, SC 29209, United States of America; WJB Dorn Veterans Administration Medical Center, Columbia, SC 29209, United States of America.
| |
Collapse
|
|
21
|
Sinani A, Vassi A, Tsotsokou G, Nikolakopoulou M, Kouvelas ED, Mitsacos A. Early life stress influences basal ganglia dopamine receptors and novel object recognition of adolescent and adult rats. IBRO Neurosci Rep 2022; 12:342-354. [PMID: 35572456 PMCID: PMC9092503 DOI: 10.1016/j.ibneur.2022.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022] Open
Abstract
Environmental stimuli in early life are recognized to affect brain development and behavior. Mother-pup interaction constitutes a determinant stimulus during this critical period. It is known that the dopaminergic system undergoes significant reorganization during adolescence and that dopamine receptors are involved in recognition memory. Based on the above, we examined the effects of brief and prolonged maternal separation during the neonatal period (15 or 180 min daily) on basal ganglia dopamine receptors and on the behavior in the novel object recognition task of adolescent and adult male rats. Using the NOR task, we observed that the discrimination index (DI) was decreased in rats with brief maternal separations independent of age. Using receptor autoradiography, we observed that brief maternal separation induced decreases in D1, D2 and D4 receptor binding levels in adult basal ganglia nuclei, while prolonged maternal separation induced increases in D1 receptor binding levels in caudate - putamen (CPu) of adolescent rats. With immunoblotting experiments, we found decreases in D1 and increases in D2 total protein levels in CPu of adult rats with prolonged maternal separations. Α positive correlation was observed between DI and D1 binding levels in CPu, internal globus pallidus and substantia nigra, and D2 binding levels in nucleus accumbens core in adult rats, using the Pearson correlation coefficient. Our results indicate that the long-lasting effects of neonatal mother-offspring separation on dopamine receptors depend on the duration of maternal separation and age and that this early life experience impairs recognition memory in adolescent and adult rats. Furthermore, the present results suggest that modulation of striatal dopamine receptors might underlie the reduced recognition memory of adult rats with brief neonatal maternal separations.
Collapse
Affiliation(s)
- Ada Sinani
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Andriana Vassi
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Giota Tsotsokou
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Maria Nikolakopoulou
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Elias D Kouvelas
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Ada Mitsacos
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| |
Collapse
|
|
22
|
Carvalho M, Morais-Silva G, Caixeta GAB, Marin MT, Amaral VCS. Alcohol Deprivation Differentially Changes Alcohol Intake in Female and Male Rats Depending on Early-Life Stressful Experience. NEUROSCI 2022; 3:214-225. [PMID: 39483372 PMCID: PMC11523756 DOI: 10.3390/neurosci3020016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/07/2022] [Indexed: 11/03/2024] Open
Abstract
Experiencing early-life adverse events has enduring effects on individual vulnerability to alcohol abuse and the development of addiction-related behaviors. In rodents, it can be studied using maternal separation (MS) stress. Studies have shown that, depending on the protocol used, MS can affect the mother and pups' behavior and are associated with behavioral alterations later in adulthood, associated with both positive or negative outcomes. However, it is not fully elucidated how MS affects relapse-like behaviors when experienced by female or male individuals. Therefore, the aim of our study was to evaluate the effects of brief and prolonged MS on the alcohol deprivation effect (ADE) in female and male rats. Female and male Wistar rats were exposed to brief (15 min/day) or prolonged (180 min/day) MS from postnatal day (PND) 2 to 10. Later, during adulthood (PND 70), animals were submitted to an ADE protocol. Brief MS exposure prevented the ADE in both females and males, while prolonged MS exposure also prevented the ADE in female rats. Moreover, the ADE was more robust in females when compared to males. In conclusion, we showed that male and female rats are differentially affected by alcohol deprivation periods depending on their early-life experiences.
Collapse
Affiliation(s)
- Marielly Carvalho
- Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products, State University of Goias, Exact and Technological Sciences Campus, Anapolis 75132-903, CO, Brazil; (M.C.); (G.A.B.C.)
- Graduate Program in Sciences Applied to Health Products (PPGCAPS) UEG, Anápolis 75132-903, GO, Brazil
| | - Gessynger Morais-Silva
- Laboratory of Pharmacology, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil; (G.M.-S.); (M.T.M.)
- Joint Graduate Program in Physiological Sciences (PIPGCF) UFSCar/UNESP, São Carlos, Araraquara 14801-903, SP, Brazil
| | - Graziele Alícia Batista Caixeta
- Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products, State University of Goias, Exact and Technological Sciences Campus, Anapolis 75132-903, CO, Brazil; (M.C.); (G.A.B.C.)
- Graduate Program in Sciences Applied to Health Products (PPGCAPS) UEG, Anápolis 75132-903, GO, Brazil
| | - Marcelo T Marin
- Laboratory of Pharmacology, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil; (G.M.-S.); (M.T.M.)
- Joint Graduate Program in Physiological Sciences (PIPGCF) UFSCar/UNESP, São Carlos, Araraquara 14801-903, SP, Brazil
| | - Vanessa C S Amaral
- Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products, State University of Goias, Exact and Technological Sciences Campus, Anapolis 75132-903, CO, Brazil; (M.C.); (G.A.B.C.)
- Graduate Program in Sciences Applied to Health Products (PPGCAPS) UEG, Anápolis 75132-903, GO, Brazil
| |
Collapse
|
|
23
|
Filarowska-Jurko J, Komsta L, Smaga I, Surowka P, Marszalek-Grabska M, Grochecki P, Nizio D, Filip M, Kotlinska JH. Maternal Separation Alters Ethanol Drinking and Reversal Learning Processes in Adolescent Rats: The Impact of Sex and Glycine Transporter Type 1 (GlyT1) Inhibitor. Int J Mol Sci 2022; 23:5350. [PMID: 35628160 PMCID: PMC9141364 DOI: 10.3390/ijms23105350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 11/16/2022] Open
Abstract
Adverse early life experiences are associated with an enhanced risk for mental and physical health problems, including substance abuse. Despite clinical evidence, the mechanisms underlying these relationships are not fully understood. Maternal separation (MS) is a commonly used animal model of early neglect. The aim of the current study is to determine whether the N-methyl-D-aspartate receptor (NMDAR)/glycine sites are involved in vulnerability to alcohol consumption (two-bottle choice paradigm) and reversal learning deficits (Barnes maze task) in adolescent rats subjected to the MS procedure and whether these effects are sex dependent. By using ELISA, we evaluated MS-induced changes in the NMDAR subunits (GluN1, GluN2A, GluN2B) expression, especially in the glycine-binding subunit, GluN1, in the prefrontal cortex (PFC) and ventral striatum (vSTR) of male/female rats. Next, we investigated whether Org 24598, a glycine transporter 1 (GlyT1) inhibitor, was able to modify ethanol drinking in adolescent and adult male/female rats with prior MS experience and reversal learning in the Barnes maze task. Our findings revealed that adolescent MS female rats consumed more alcohol which may be associated with a substantial increase in GluN1 subunit of NMDAR in the PFC and vSTR. Org 24598 decreased ethanol intake in both sexes with a more pronounced decrease in ethanol consumption in adolescent female rats. Furthermore, MS showed deficits in reversal learning in both sexes. Org 24598 ameliorated reversal learning deficits, and this effect was reversed by the NMDAR/glycine site inhibitor, L-701,324. Collectively, our results suggest that NMDAR/glycine sites might be targeted in the treatment of alcohol abuse in adolescents with early MS, especially females.
Collapse
Affiliation(s)
- Joanna Filarowska-Jurko
- Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland; (J.F.-J.); (P.G.)
| | - Lukasz Komsta
- Department of Medicinal Chemistry, Medical University, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Irena Smaga
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-324 Krakow, Poland; (I.S.); (P.S.); (M.F.)
| | - Paulina Surowka
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-324 Krakow, Poland; (I.S.); (P.S.); (M.F.)
| | - Marta Marszalek-Grabska
- Department of Experimental and Clinical Pharmacology, Medical University, Jaczewskiego 8b, 20-090 Lublin, Poland;
| | - Pawel Grochecki
- Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland; (J.F.-J.); (P.G.)
| | - Dorota Nizio
- Experimental Medicine Center, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Malgorzata Filip
- Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-324 Krakow, Poland; (I.S.); (P.S.); (M.F.)
| | - Jolanta H. Kotlinska
- Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland; (J.F.-J.); (P.G.)
| |
Collapse
|
|
24
|
Levis SC, Baram TZ, Mahler SV. Neurodevelopmental origins of substance use disorders: Evidence from animal models of early-life adversity and addiction. Eur J Neurosci 2022; 55:2170-2195. [PMID: 33825217 PMCID: PMC8494863 DOI: 10.1111/ejn.15223] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 03/18/2021] [Accepted: 04/01/2021] [Indexed: 01/06/2023]
Abstract
Addiction is a chronic relapsing disorder with devastating personal, societal, and economic consequences. In humans, early-life adversity (ELA) such as trauma, neglect, and resource scarcity are linked with increased risk of later-life addiction, but the brain mechanisms underlying this link are still poorly understood. Here, we focus on data from rodent models of ELA and addiction, in which causal effects of ELA on later-life responses to drugs and the neurodevelopmental mechanisms by which ELA increases vulnerability to addiction can be determined. We first summarize evidence for a link between ELA and addiction in humans, then describe how ELA is commonly modeled in rodents. Since addiction is a heterogeneous disease with many individually varying behavioral aspects that may be impacted by ELA, we next discuss common rodent assays of addiction-like behaviors. We then summarize the specific addiction-relevant behavioral phenotypes caused by ELA in male and female rodents and discuss some of the underlying changes in brain reward and stress circuits that are likely responsible. By better understanding the behavioral and neural mechanisms by which ELA promotes addiction vulnerability, we hope to facilitate development of new approaches for preventing or treating addiction in those with a history of ELA.
Collapse
Affiliation(s)
- Sophia C. Levis
- Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA
| | - Tallie Z. Baram
- Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA
- Department of Pediatrics, University of California Irvine, Irvine, CA
| | - Stephen V. Mahler
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA
| |
Collapse
|
|
25
|
Lippard ETC, Nemeroff CB. Going beyond risk factor: Childhood maltreatment and associated modifiable targets to improve life-long outcomes in mood disorders. Pharmacol Biochem Behav 2022; 215:173361. [PMID: 35219755 DOI: 10.1016/j.pbb.2022.173361] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/17/2022] [Accepted: 02/20/2022] [Indexed: 01/26/2023]
Abstract
Childhood maltreatment increases risk for mood disorders and is associated with earlier onset-and more pernicious disease course following onset-of mood disorders. While the majority of studies to date have been cross-sectional, longitudinal studies are emerging and support the devastating role(s) childhood maltreatment has on development of, and illness course in, mood disorders. This manuscript extends prior reviews to emphasize more recent work, highlighting longitudinal data, and discusses treatment studies that provide clues to mechanisms that mediate disease risk, course, relapse, and treatment response. Evidence suggesting systemic inflammation, alterations in hypothalamic-pituitary-adrenal (HPA) axis function and corticotropin-releasing factor (CRF) neural systems, genetic and other familial factors as mechanisms that mediate risk and onset of, and illness course in, mood disorders following childhood maltreatment is discussed. Risky behaviors following maltreatment, e.g., substance use and unhealthy lifestyles, may further exacerbate alterations in the HPA axis, CRF neural systems, and systematic inflammation to contribute to a more pernicious disease course. More research on sex differences and the impact of maltreatment in vulnerable populations is needed. Future research needs to be aimed at leveraging knowledge on modifiable targets, going beyond childhood maltreatment as a risk factor, to inform prevention and treatment strategies and foster trauma-informed care.
Collapse
Affiliation(s)
- Elizabeth T C Lippard
- Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas, Austin, TX, USA; Institute of Early Life Adversity Research, Dell Medical School, University of Texas, Austin, TX, USA; Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX, USA; Department of Psychology, University of Texas, Austin, TX, USA; Mulva Clinic for Neuroscience, Dell Medical School, University of Texas, Austin, TX, USA.
| | - Charles B Nemeroff
- Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas, Austin, TX, USA; Institute of Early Life Adversity Research, Dell Medical School, University of Texas, Austin, TX, USA; Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX, USA; Mulva Clinic for Neuroscience, Dell Medical School, University of Texas, Austin, TX, USA
| |
Collapse
|
|
26
|
Kirsch DE, Lippard ET. Early life stress and substance use disorders: The critical role of adolescent substance use. Pharmacol Biochem Behav 2022; 215:173360. [PMID: 35219756 PMCID: PMC8983562 DOI: 10.1016/j.pbb.2022.173360] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 12/06/2021] [Accepted: 02/20/2022] [Indexed: 12/12/2022]
Abstract
Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain-particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control-in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS.
Collapse
|
|
27
|
Abstract
The overarching objective is to review how early exposure to adversity interacts with inflammation to alter brain maturation. Both adversity and inflammation are significant risk factors for psychopathology. Literature relevant to the effects of adversity in children and adolescents on brain development is reviewed. These studies are supported by research in animals exposed to species-relevant stressors during development. While it is known that exposure to adversity at any age increases inflammation, the effects of inflammation are exacerbated at developmental stages when the immature brain is uniquely sensitive to experiences. Microglia play a vital role in this process, as they scavenge cellular debris and prune synapses to optimize performance. In essence, microglia modify the synapse to match environmental demands, which is necessary for someone with a history of adversity. Overall, by piecing together clinical and preclinical research areas, what emerges is a picture of how adversity uniquely sculpts the brain. Microglia interactions with the inhibitory neurotransmitter GABA (specifically, the subtype expressing parvalbumin) are discussed within contexts of development and adversity. A review of inflammation markers in individuals with a history of abuse is combined with preclinical studies to describe their effects on maturation. Inconsistencies within the literature are discussed, with a call for standardizing methodologies relating to the age of assessing adversity effects, measures to quantify stress and inflammation, and more brain-based measures of biochemistry. Preclinical studies pave the way for interventions using anti-inflammation-based agents (COX-2 inhibitors, CB2 agonists, meditation/yoga) by identifying where, when, and how the developmental trajectory goes awry.
Collapse
|
|
28
|
Miczek KA, DiLeo A, Newman EL, Akdilek N, Covington HE. Neurobiological Bases of Alcohol Consumption After Social Stress. Curr Top Behav Neurosci 2022; 54:245-281. [PMID: 34964935 PMCID: PMC9698769 DOI: 10.1007/7854_2021_273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption. Increasingly discrete regions and connections within the prefrontal cortex, the ventral and dorsal striatum, thalamic and hypothalamic nuclei, tegmental areas as well as brain stem structures begin to be identified as critical for reacting to and coping with social stress while seeking and consuming alcohol. Several candidate molecules that modulate signals within these neural connections have been targeted in order to reduce excessive drinking and relapse. In spite of some early clinical failures, neuropeptides such as CRF, opioids, or oxytocin continue to be examined for their role in attenuating stress-escalated drinking. Recent work has focused on neural sites of action for peptides and steroids, most likely in neuroinflammatory processes as a result of interactive effects of episodic social stress and excessive alcohol seeking and drinking.
Collapse
Affiliation(s)
- Klaus A. Miczek
- Department of Psychology, Tufts University, Medford, MA, USA,Department of Neuroscience, Tufts University, Boston, MA, USA
| | - Alyssa DiLeo
- Department of Neuroscience, Tufts University, Boston, MA, USA
| | - Emily L. Newman
- Department of Psychiatry, Harvard Medical School, Belmont, MA, USA
| | - Naz Akdilek
- Department of Psychology, Tufts University, Medford, MA, USA
| | | |
Collapse
|
|
29
|
Knox D, Stout-Oswald SA, Tan M, George SA, Liberzon I. Maternal Separation Induces Sex-Specific Differences in Sensitivity to Traumatic Stress. Front Behav Neurosci 2021; 15:766505. [PMID: 34955778 PMCID: PMC8708561 DOI: 10.3389/fnbeh.2021.766505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a high economic burden. Two risk factors for increasing the chances of developing PTSD are sex (being female) and early life stress. These risk factors suggest that early life stress-induced changes and sex differences in emotional circuits and neuroendocrinological systems lead to susceptibility to traumatic stress. Exploring mechanisms via which stress leads to specific effects can be accomplished in animal models, but reliable animal models that allow for an examination of how early life stress interacts with sex to increase susceptibility to traumatic stress is lacking. To address this, we examined the effects of early life stress [using the maternal separation (MS) model] and late adolescence/early adult traumatic stress [using the single prolonged stress (SPS) model] on startle reactivity, anxiety-like behavior in the open field (OF), and basal corticosterone levels in male and female rats. Female rats exposed to MS and SPS (MS/SPS) showed enhanced startle reactivity relative to MS/control female rats. Enhanced startle reactivity was not observed in MS/SPS male rats. Instead, non-maternally separated male rats that were exposed to SPS showed enhanced startle reactivity relative to controls. Female rats had enhanced locomotor activity in the OF and higher basal corticosterone levels in comparison to males, but measures in the OF and basal corticosterone were not affected by MS or SPS. Overall the results suggest that the combined MS and SPS models can be used to explore how changes in maternal care during infancy lead to sex differences in sensitivity to the effects of traumatic stress as adolescents and adults.
Collapse
Affiliation(s)
- Dayan Knox
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States
| | - Stephanie A Stout-Oswald
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.,Veterans Affairs Hospital, Ann Arbor, MI, United States
| | - Melissa Tan
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.,Veterans Affairs Hospital, Ann Arbor, MI, United States
| | - Sophie A George
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
| | - Israel Liberzon
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryant, TX, United States
| |
Collapse
|
|
30
|
Bertagna NB, Favoretto CA, Rodolpho BT, Palombo P, Yokoyama TS, Righi T, Loss CM, Leão RM, Miguel TT, Cruz FC. Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner. Front Physiol 2021; 12:775404. [PMID: 34950053 PMCID: PMC8691459 DOI: 10.3389/fphys.2021.775404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/26/2021] [Indexed: 01/20/2023] Open
Abstract
Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.
Collapse
Affiliation(s)
- Natalia Bonetti Bertagna
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Cristiane Aparecida Favoretto
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Ben Tagami Rodolpho
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Paola Palombo
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Thais Suemi Yokoyama
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Thamires Righi
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| | - Cássio Morais Loss
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,National Institute for Translational Medicine (INCT-TM), National Council for Scientific and Technological Development (CNPq/CAPES/FAPESP), Ribeirão Preto, Brazil
| | - Rodrigo Molini Leão
- Pharmacology Laboratory, Department of Pharmacology, Biomedical Sciences Institute, Federal University of Uberlândia, Uberlândia, Brazil
| | - Tarciso Tadeu Miguel
- Pharmacology Laboratory, Department of Pharmacology, Biomedical Sciences Institute, Federal University of Uberlândia, Uberlândia, Brazil
| | - Fábio Cardoso Cruz
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
31
|
Carloni E, Ramos A, Hayes LN. Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk. Int J Mol Sci 2021; 22:13035. [PMID: 34884841 PMCID: PMC8657756 DOI: 10.3390/ijms222313035] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/26/2022] Open
Abstract
Many types of stressors have an impact on brain development, function, and disease susceptibility including immune stressors, psychosocial stressors, and exposure to drugs of abuse. We propose that these diverse developmental stressors may utilize a common mechanism that underlies impaired cognitive function and neurodevelopmental disorders such as schizophrenia, autism, and mood disorders that can develop in later life as a result of developmental stressors. While these stressors are directed at critical developmental windows, their impacts are long-lasting. Immune activation is a shared pathophysiology across several different developmental stressors and may thus be a targetable treatment to mitigate the later behavioral deficits. In this review, we explore different types of prenatal and perinatal stressors and their contribution to disease risk and underlying molecular mechanisms. We highlight the impact of developmental stressors on microglia biology because of their early infiltration into the brain, their critical role in brain development and function, and their long-lived status in the brain throughout life. Furthermore, we introduce innate immune memory as a potential underlying mechanism for developmental stressors' impact on disease. Finally, we highlight the molecular and epigenetic reprogramming that is known to underlie innate immune memory and explain how similar molecular mechanisms may be at work for cells to retain a long-term perturbation after exposure to developmental stressors.
Collapse
Affiliation(s)
- Elisa Carloni
- Department of Molecular and Cellular Biology, Dartmouth College, Hanover, NH 03755, USA;
| | - Adriana Ramos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Lindsay N. Hayes
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| |
Collapse
|
|
32
|
Mejía-Chávez S, Venebra-Muñoz A, García-García F, Corona-Morales AA, Orozco-Vargas AE. Maternal Separation Modifies the Activity of Social Processing Brain Nuclei Upon Social Novelty Exposure. Front Behav Neurosci 2021; 15:651263. [PMID: 34803620 PMCID: PMC8599987 DOI: 10.3389/fnbeh.2021.651263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022] Open
Abstract
Maternal separation has been shown to disrupt proper brain development and maturation, having profound consequences on the neuroendocrine systems in charge of the stress response, and has been shown to induce behavioral and cognitive abnormalities. At the behavioral level, maternal separation has been shown to increase offensive play-fighting in juvenile individuals and reduce social interest in adulthood. Since most of the studies that have evaluated the consequences of maternal separation on social behavior have focused on behavioral analysis, there is a need for a further understanding of the neuronal mechanisms underlying the changes in social behavior induced by maternal separation. Therefore, the aim of the present research was to assess the long-term effects of maternal separation on social interaction behavior and to assess the activity of several brain regions involved in the processing of social cues and reward upon social novelty exposure, using c-Fos immunohistochemistry as a marker of neuronal activity. Male Wistar rats were subjected to 4 h maternal separation during the neonatal period, 9:00 h-13:00 h from postnatal day 1 to 21, and exposed to social novelty during adulthood. After social novelty exposure, brains were fixed and coronal sections of the medial amygdala, lateral septum (LS), paraventricular nucleus of the hypothalamus, nucleus accumbens, and medial prefrontal cortex were obtained for c-Fos immunohistochemistry. Maternally separated rats spent less time investigating the novel peer, suggesting that maternal separation reduces social approach motivation. Furthermore, maternal separation reduced the number of c-Fos positive cells of the medial amygdala, paraventricular nucleus of the hypothalamus, LS, nucleus accumbens, and medial prefrontal cortex upon social novelty exposure. These findings suggest that maternal separation can reduce the plastic capacity of several brain nuclei, which constitute a physiological basis for the emergence of behavioral disorders presented later in life reported to be linked to early life adversity.
Collapse
Affiliation(s)
- Sara Mejía-Chávez
- Laboratorio de Neurobiología de la Adicción y Plasticidad Cerebral, Facultad de Ciencias, Universidad Autónoma del Estado de Mexico, Toluca, Mexico
| | - Arturo Venebra-Muñoz
- Laboratorio de Neurobiología de la Adicción y Plasticidad Cerebral, Facultad de Ciencias, Universidad Autónoma del Estado de Mexico, Toluca, Mexico
| | - Fabio García-García
- Laboratorio de Biología de Sueño, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | | | | |
Collapse
|
|
33
|
Shahraki S, Esmaeilpour K, Shabani M, Sepehri G, Rajizadeh MA, Maneshian M, Joushi S, Sheibani V. Choline chloride modulates learning, memory, and synaptic plasticity impairments in maternally separated adolescent male rats. Int J Dev Neurosci 2021; 82:19-38. [PMID: 34727391 DOI: 10.1002/jdn.10155] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 11/06/2022] Open
Abstract
Maternal separation (MS) is a model to induce permanent alternations in the central nervous system (CNS) and is associated with increased levels of anxiety and cognitive deficiencies. Since Methyl donor choline (Ch) has been shown to play a significant role in learning and memory and enhances synaptic plasticity, the authors hypothesized that Ch may attenuate MS-induced impairments in synaptic plasticity and cognitive performance. Rat pups underwent a MS protocol for 180 min/day from postnatal day (PND) 1 to 21. Ch was administered subcutaneously (100 mg/kg, 21 days) to the Choline chloride and MS + Choline chloride groups from PND 29 to 49. Anxiety-like behavior, recognition memory, spatial and passive avoidance learning and memory were measured in the adolescent rats. In addition, evoked field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 region of the hippocampus. MS induced higher anxiety-like behavior in the animals. It also impaired learning and memory. However, MS had no effect on locomotor activity. Subcutaneous administration of Ch attenuated MS-induced cognitive deficits and enhanced the learning and memory of MS rats. Ch also decreased anxiety-like behavior in the open field test. The present results showed that long-term potentiation (LTP) was induced in all groups except MS and MS + saline animals. However, Ch injection induced LTP and had maintenance in MS + choline chloride, but it was not statistically significant compared with the MS group. In summary, the present findings indicate that MS can interfere with normal animal's cognition and subcutaneous of Ch may be considered an appropriate therapeutic strategy for promoting cognitive dysfunctions in MS animals.
Collapse
Affiliation(s)
- Sarieh Shahraki
- Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.,Department of Physiology & pharmacology, school of medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Khadijeh Esmaeilpour
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.,Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada
| | - Mohammad Shabani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Sepehri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Amin Rajizadeh
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Marzieh Maneshian
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Joushi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.,Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| |
Collapse
|
|
34
|
Hien DA, López-Castro T, Fitzpatrick S, Ruglass LM, Fertuck EA, Melara R. A unifying translational framework to advance treatment research for comorbid PTSD and substance use disorders. Neurosci Biobehav Rev 2021; 127:779-794. [PMID: 34062208 DOI: 10.1016/j.neubiorev.2021.05.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 05/13/2021] [Accepted: 05/20/2021] [Indexed: 11/20/2022]
Abstract
We provide a unifying translational framework that can be used to synthesize extant lines of human laboratory research in four neurofunctional domains that underlie the co-occurrence of posttraumatic stress and substance use disorders (PTSD+SUD). We draw upon the Alcohol and Addiction Research Domain Criteria (AARDOC) to include executive functioning, negative emotionality, reward, and added social cognition from the National Institute of Mental Health (NIMH) Research Domain Criteria into our framework. We review research findings across each of the four domains, emphasizing human experimental studies in PTSD, SUD, and PTSD+SUD for each domain. We also discuss the implications of research findings for treatment development by considering new ways of conceptualizing risk factors and outcomes at the level of the individual patient, which will enhance treatment matching and advance innovations in intervention.
Collapse
Affiliation(s)
- Denise A Hien
- Center of Alcohol & Substance Use Studies, Graduate School of Applied and Professional Psychology, Rutgers University-New Brunswick, Piscataway, New Jersey, United States.
| | - Teresa López-Castro
- Psychology Department, The City College of New York, New York, NY, United States
| | | | - Lesia M Ruglass
- Center of Alcohol & Substance Use Studies, Graduate School of Applied and Professional Psychology, Rutgers University-New Brunswick, Piscataway, New Jersey, United States; Psychology Department, The City College of New York, New York, NY, United States
| | - Eric A Fertuck
- Psychology Department, The City College of New York, New York, NY, United States
| | - Robert Melara
- Psychology Department, The City College of New York, New York, NY, United States
| |
Collapse
|
|
35
|
Čater M, Majdič G. How early maternal deprivation changes the brain and behavior? Eur J Neurosci 2021; 55:2058-2075. [PMID: 33870558 DOI: 10.1111/ejn.15238] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 01/30/2023]
Abstract
Early life stress can adversely influence brain development and reprogram brain function and consequently behavior in adult life. Adequate maternal care in early childhood is therefore particularly important for the normal brain development, and adverse early life experiences can lead to altered emotional, behavioral, and neuroendocrine stress responses in the adulthood. As a form of neonatal stress, maternal deprivation/separation is often used in behavioral studies to examine the effects of early life stress and for modeling the development of certain psychiatric disorders and brain pathologies in animal models. The temporary loss of maternal care during the critical postpartum periods remodels the offspring's brain and provokes long-term effects on learning and cognition, the development of mental disorders, aggression, and an increased tendency for the drug abuse. Early life stress through maternal deprivation affects neuroendocrine responses to stress in adolescence and adulthood by dysregulating the hypothalamic-pituitary-adrenal axis and permanently disrupts stress resilience. In this review, we focused on how improper maternal care during early postnatal life affects brain development resulting in modified behavior later in life.
Collapse
Affiliation(s)
- Maša Čater
- Veterinary Faculty, Laboratory for Animal Genomics, Institute for Preclinical Studies, University of Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, Institute of Physiology, University of Maribor, Maribor, Slovenia
| | - Gregor Majdič
- Veterinary Faculty, Laboratory for Animal Genomics, Institute for Preclinical Studies, University of Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, Institute of Physiology, University of Maribor, Maribor, Slovenia
| |
Collapse
|
|
36
|
Bardo MT, Hammerslag LR, Malone SG. Effect of early life social adversity on drug abuse vulnerability: Focus on corticotropin-releasing factor and oxytocin. Neuropharmacology 2021; 191:108567. [PMID: 33862030 DOI: 10.1016/j.neuropharm.2021.108567] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 02/16/2021] [Accepted: 04/09/2021] [Indexed: 12/20/2022]
Abstract
Early life adversity can set the trajectory for later psychiatric disorders, including substance use disorders. There are a host of neurobiological factors that may play a role in the negative trajectory. The current review examines preclinical evidence suggesting that early life adversity specifically involving social factors (maternal separation, adolescent social isolation and adolescent social defeat) may influence drug abuse vulnerability by strengthening corticotropin-releasing factor (CRF) systems and weakening oxytocin (OT) systems. In adulthood, pharmacological and genetic evidence indicates that both CRF and OT systems are directly involved in drug reward processes. With early life adversity, numerous studies show an increase in drug abuse vulnerability measured in adulthood, along a concomitant strengthening of CRF systems and a weakening of OT systems. Mechanistic studies, while relatively few in number, are generally consistent with the theme that strengthened CRF systems and weakened OT systems mediate, at least in part, the link between early life adversity and drug abuse vulnerability. Establishing a direct role of CRF and OT in mediating the relation between early life social stressors and drug abuse vulnerability will inform clinical researchers and practitioners toward the development of intervention strategies to reduce risk among those suffering from early life adversities. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.
Collapse
Affiliation(s)
- Michael T Bardo
- Department of Psychology, University of Kentucky, Lexington, KY, 40536-0509, USA.
| | - Lindsey R Hammerslag
- Department of Psychology, University of Kentucky, Lexington, KY, 40536-0509, USA
| | - Samantha G Malone
- Department of Psychology, University of Kentucky, Lexington, KY, 40536-0509, USA
| |
Collapse
|
|
37
|
Quigley JA, Logsdon MK, Turner CA, Gonzalez IL, Leonardo NB, Becker JB. Sex differences in vulnerability to addiction. Neuropharmacology 2021; 187:108491. [PMID: 33567305 PMCID: PMC7979496 DOI: 10.1016/j.neuropharm.2021.108491] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/27/2021] [Accepted: 02/04/2021] [Indexed: 02/07/2023]
Abstract
This article reviews evidence for sex differences in vulnerability to addiction with an emphasis on the neural mechanisms underlying these differences. Sex differences in the way that the gonadal hormone, estradiol, interacts with the ascending telencephalic dopamine system results in sex differences in motivated behaviors, including drug-seeking. In rodents, repeated psychostimulant exposure enhances incentive sensitization to a greater extent in females than males. Estradiol increases females' motivation to attain psychostimulants and enhances the value of drug related cues, which ultimately increases their susceptibility towards spontaneous relapse. This, along with females' dampened ability to alter decisions regarding risky behaviors, enhances their vulnerability for escalation of drug use. In males, recent evidence suggests that estradiol may be protective against susceptibility towards drug-preference. Sex differences in the actions of estradiol are reviewed to provide a foundation for understanding how future research might enhance understanding of the mechanisms of sex differences in addiction-related behaviors, which are dependent on estradiol receptor (ER) subtype and the region of the brain they are acting in. A comprehensive review of the distribution of ERα, ERβ, and GPER1 throughout the rodent brain are provided along with a discussion of the possible ways in which these patterns differentially regulate drug-taking between the sexes. The article concludes with a brief discussion of the actions of gonadal hormones on the circuitry of the stress system, including the hypothalamic pituitary adrenal axis and regulation of corticotropin-releasing factor. Sex differences in the stress system can also contribute to females' enhanced vulnerability towards addiction.
Collapse
Affiliation(s)
- Jacqueline A Quigley
- Psychology Department, Ann Arbor MI, 48109 USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA
| | - Molly K Logsdon
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA
| | - Christopher A Turner
- Psychology Department, Ann Arbor MI, 48109 USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA
| | - Ivette L Gonzalez
- Psychology Department, Ann Arbor MI, 48109 USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA
| | - N B Leonardo
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA
| | - Jill B Becker
- Psychology Department, Ann Arbor MI, 48109 USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA.
| |
Collapse
|
|
38
|
Lundgaard Donovan L, Henningsen K, Flou Kristensen A, Wiborg O, Nieland JD, Lichota J. Maternal Separation Followed by Chronic Mild Stress in Adulthood Is Associated with Concerted Epigenetic Regulation of AP-1 Complex Genes. J Pers Med 2021; 11:jpm11030209. [PMID: 33809485 PMCID: PMC8002051 DOI: 10.3390/jpm11030209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 01/03/2023] Open
Abstract
Depression is one of the most prevalent mental diseases worldwide. Patients with psychiatric diseases often have a history of childhood neglect, indicating that early-life experiences predispose to psychiatric diseases in adulthood. Two strong models were used in the present study: the maternal separation/early deprivation model (MS) and the chronic mild stress model (CMS). In both models, we found changes in the expression of a number of genes such as Creb and Npy. Strikingly, there was a clear regulation of expression of four genes involved in the AP-1 complex: c-Fos, c-Jun, FosB, and Jun-B. Interestingly, different expression levels were observed depending on the model, whereas the combination of the models resulted in a normal level of gene expression. The effects of MS and CMS on gene expression were associated with distinct histone methylation/acetylation patterns of all four genes. The epigenetic changes, like gene expression, were also dependent on the specific stressor or their combination. The obtained results suggest that single life events leave a mark on gene expression and the epigenetic signature of gene promoters, but a combination of different stressors at different life stages can further change gene expression through epigenetic factors, possibly causing the long-lasting adverse effects of stress.
Collapse
Affiliation(s)
- Lene Lundgaard Donovan
- Neurobiology Research and Drug Delivery Group, Department of Health Science and Technology, Aalborg University, 9220 Aalborg Øst, Denmark; (L.L.D.); (A.F.K.); (O.W.)
| | - Kim Henningsen
- Department of Biomedicine-Dandrite, Takeuchi Team, Aarhus University, 8000 Aarhus C, Denmark;
| | - Anne Flou Kristensen
- Neurobiology Research and Drug Delivery Group, Department of Health Science and Technology, Aalborg University, 9220 Aalborg Øst, Denmark; (L.L.D.); (A.F.K.); (O.W.)
| | - Ove Wiborg
- Neurobiology Research and Drug Delivery Group, Department of Health Science and Technology, Aalborg University, 9220 Aalborg Øst, Denmark; (L.L.D.); (A.F.K.); (O.W.)
| | - John Dirk Nieland
- Molecular Pharmacology Group, Department of Health Science and Technology, Aalborg University, 9220 Aalborg Øst, Denmark;
| | - Jacek Lichota
- Molecular Pharmacology Group, Department of Health Science and Technology, Aalborg University, 9220 Aalborg Øst, Denmark;
- Correspondence:
| |
Collapse
|
|
39
|
Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging. Int J Mol Sci 2021; 22:ijms22052522. [PMID: 33802338 PMCID: PMC7959121 DOI: 10.3390/ijms22052522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 11/22/2022] Open
Abstract
Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.
Collapse
|
|
40
|
Sanchez CM, Titus DJ, Wilson NM, Freund JE, Atkins CM. Early Life Stress Exacerbates Outcome after Traumatic Brain Injury. J Neurotrauma 2021; 38:555-565. [PMID: 32862765 PMCID: PMC8020564 DOI: 10.1089/neu.2020.7267] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The neurocognitive impairments associated with mild traumatic brain injury (TBI) often resolve within 1-2 weeks; however, a subset of people exhibit persistent cognitive dysfunction for weeks to months after injury. The factors that contribute to these persistent deficits are unknown. One potential risk factor for worsened outcome after TBI is a history of stress experienced by a person early in life. Early life stress (ELS) includes maltreatment such as neglect, and interferes with the normal construction of cortical and hippocampal circuits. We hypothesized that a history of ELS contributes to persistent learning and memory dysfunction following a TBI. To explore this interaction, we modeled ELS by separating Sprague Dawley pups from their nursing mothers from post-natal days 2-14 for 3 h daily. At 2 months of age, male rats received sham surgery or mild to moderate parasagittal fluid-percussion brain injury. We found that the combination of ELS with TBI in adulthood impaired hippocampal-dependent learning, as assessed with contextual fear conditioning, the water maze task, and spatial working memory. Cortical atrophy was significantly exacerbated in TBI animals exposed to ELS compared with normal-reared TBI animals. Changes in corticosterone in response to restraint stress were prolonged in TBI animals that received ELS compared with TBI animals that were normally reared or sham animals that received ELS. Our findings indicate that ELS is a risk factor for worsened outcome after TBI, and results in persistent learning and memory deficits, worsened cortical pathology, and an exacerbation of the hormonal stress response.
Collapse
Affiliation(s)
- Chantal M. Sanchez
- The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - David J. Titus
- The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nicole M. Wilson
- The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Julie E. Freund
- The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Coleen M. Atkins
- The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| |
Collapse
|
|
41
|
Wilmes L, Collins JM, O'Riordan KJ, O'Mahony SM, Cryan JF, Clarke G. Of bowels, brain and behavior: A role for the gut microbiota in psychiatric comorbidities in irritable bowel syndrome. Neurogastroenterol Motil 2021; 33:e14095. [PMID: 33580895 DOI: 10.1111/nmo.14095] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The gastrointestinal microbiota has emerged as a key regulator of gut-brain axis signalling with important implications for neurogastroenterology. There is continuous bidirectional communication between the gut and the brain facilitated by neuronal, endocrine, metabolic, and immune pathways. The microbiota influences these signalling pathways via several mechanisms. Studies have shown compositional and functional alterations in the gut microbiota in stress-related psychiatric disorders. Gut microbiota reconfigurations are also a feature of irritable bowel syndrome (IBS), a gut-brain axis disorder sharing high levels of psychiatric comorbidity including both anxiety and depression. It remains unclear how the gut microbiota alterations in IBS align with both core symptoms and these psychiatric comorbidities. METHODS In this review, we highlight common and disparate features of these microbial signatures as well as the associated gut-brain axis signalling pathways. Studies suggest that patients with either IBS, depression or anxiety, alone or comorbid, present with alterations in gut microbiota composition and harbor immune, endocrine, and serotonergic system alterations relevant to the common pathophysiology of these comorbid conditions. KEY RESULTS Research has illustrated the utility of fecal microbiota transplantation in animal models, expanding the evidence base for a potential causal role of disorder-specific gut microbiota compositions in symptom set expression. Moreover, an exciting study by Constante and colleagues in this issue highlights the possibility of counteracting this microbiota-associated aberrant behavioral phenotype with a probiotic yeast, Saccharomyces boulardii CNCM I-745. CONCLUSIONS AND INFERENCES Such data highlights the potential for therapeutic targeting of the gut microbiota as a valuable strategy for the management of comorbid psychiatric symptoms in IBS.
Collapse
Affiliation(s)
- Lars Wilmes
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
| | - James M Collins
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Siobhain M O'Mahony
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Behavioural Science, University College Cork, Cork, Ireland
| |
Collapse
|
|
42
|
Babicola L, Ventura R, D'Addario SL, Ielpo D, Andolina D, Di Segni M. Long term effects of early life stress on HPA circuit in rodent models. Mol Cell Endocrinol 2021; 521:111125. [PMID: 33333214 DOI: 10.1016/j.mce.2020.111125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/23/2020] [Accepted: 12/10/2020] [Indexed: 01/06/2023]
Abstract
Adaptation to environmental challenges represents a critical process for survival, requiring the complex integration of information derived from both external cues and internal signals regarding current conditions and previous experiences. The Hypothalamic-pituitary-adrenal axis plays a central role in this process inducing the activation of a neuroendocrine signaling cascade that affects the delicate balance of activity and cross-talk between areas that are involved in sensorial, emotional, and cognitive processing such as the hippocampus, amygdala, Prefrontal Cortex, Ventral Tegmental Area, and dorsal raphe. Early life stress, especially early critical experiences with caregivers, influences the functional and structural organization of these areas, affects these processes in a long-lasting manner and may result in long-term maladaptive and psychopathological outcomes, depending on the complex interaction between genetic and environmental factors. This review summarizes the results of studies that have modeled this early postnatal stress in rodents during the first 2 postnatal weeks, focusing on the long-term effects on molecular and structural alteration in brain areas involved in Hypothalamic-pituitary-adrenal axis function. Moreover, a brief investigation of epigenetic mechanisms and specific genetic targets mediating the long-term effects of these early environmental manipulations and at the basis of differential neurobiological and behavioral effects during adulthood is provided.
Collapse
Affiliation(s)
- Lucy Babicola
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy
| | - Rossella Ventura
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy.
| | - Sebastian Luca D'Addario
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy; Behavioral Neuroscience PhD Programme, Sapienza University, Piazzale Aldo Moro 5, 00184, Rome, Italy
| | - Donald Ielpo
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy; Behavioral Neuroscience PhD Programme, Sapienza University, Piazzale Aldo Moro 5, 00184, Rome, Italy
| | - Diego Andolina
- Dept. of Psychology and Center "Daniel Bovet", Sapienza University, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy
| | - Matteo Di Segni
- IRCCS Fondazione Santa Lucia, Via Del Fosso di Fiorano, 64, 00143, Rome, Italy.
| |
Collapse
|
|
43
|
Sprowles JLN, Vorhees CV, Williams MT. Impact of preweaning stress on long-term neurobehavioral outcomes in Sprague-Dawley rats: Differential effects of barren cage rearing, pup isolation, and the combination. Neurotoxicol Teratol 2021; 84:106956. [PMID: 33524508 DOI: 10.1016/j.ntt.2021.106956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 01/06/2021] [Accepted: 01/17/2021] [Indexed: 12/23/2022]
Abstract
Two developmental stressors were compared in preweaning rats exposed to either one stressor or both. Stressors were barren cage rearing or maternal separation (pup isolation). 40 gravid Sprague-Dawley CD/IGS rats were randomly assigned to two cage conditions: standard (Std) cage or barren cage (Bar), 20 litters/condition throughout gestation and lactation. After delivery, litters were randomly culled to 4 males and 4 females. The second stressor was maternal separation: Two male/female pairs per litter were isolated from their dam 4 h/day (Iso) and two pairs were not (Norm). Hence, there were 4 conditions: Std-Norm, Std-Iso, Bar-Norm, and Bar-Iso. One pair/litter/stress condition received the following: elevated zero-maze (EZM), open-field, swim channel, Cincinnati water maze, conditioned fear, and open-field with methamphetamine challenge. The second pair/litter/condition received the light-dark test, swim channel, Morris water maze, forced swim, and EZM with diazepam challenge. Barren rearing reduced EZM time-in-open, whereas isolation rearing reduced open-field activity in males and increased it in females. Effects on straight channel swimming were minor. In the Cincinnati water maze test of egocentric learning, isolation rearing increased errors whereas barren cage housing reduced errors in combination with normal rearing. Barren cage with maternal separation (pup isolation) increased Cincinnati water maze escape latency but not errors. Barren cage housing reduced hyperactivity in response to methamphetamine. Isolation rearing increased time in open in the EZM after diazepam challenge. Trends were seen in the Morris water maze. These suggested that barren cage and isolation rearing in combination reduced latency on acquisition on days 1 and 2 in males, whereas females had increased latency on days 2 and 3. Combined exposure to two developmental stressors did not induce additive or synergistic effects, however the data show that these stressors had long-term effects with some evidence that the combination of both caused effects when either stressor alone did not, but synergism was not observed.
Collapse
Affiliation(s)
- Jenna L N Sprowles
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Charles V Vorhees
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Neurology, Cincinnati Children's Research Foundation, Cincinnati, OH, USA.
| | - Michael T Williams
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Neurology, Cincinnati Children's Research Foundation, Cincinnati, OH, USA.
| |
Collapse
|
|
44
|
Masrouri H, Azadi M, Semnanian S, Azizi H. Early life maternal deprivation attenuates morphine induced inhibition in lateral paragigantocellularis neurons in adult rats. Brain Res Bull 2021; 169:128-135. [PMID: 33482287 DOI: 10.1016/j.brainresbull.2021.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/29/2020] [Accepted: 01/15/2021] [Indexed: 02/04/2023]
Abstract
Early life stress can serve as one of the principle sources leading to individual differences in confronting challenges throughout the lifetime. Maternal deprivation (MD), a model of early life stress, can cause persistent alterations in brain function, and it may constitute a risk factor for later incidence of drug addiction. It is becoming more apparent that early life MD predisposes opiate abuse in adulthood. Although several behavioral and molecular studies have addressed this issue, changes in electrophysiological features of the neurons are yet to be understood. The lateral paragigantocellularis (LPGi) nucleus, which participates in the mediation of opiate dependence and withdrawal, may be susceptible to modifications following MD. This study sought to find whether early life MD can alter the discharge activity of LPGi neurons and their response to acute morphine administration in adult rats. Male Wistar rats experienced MD on postnatal days (PNDs) 1-14 for three h per day. Afterward, they were left undisturbed until PND 70, during which the extracellular activities of LPGi neurons were recorded in anesthetized animals at baseline and in response to acute morphine. In both MD and control groups, acute morphine administration induced heterogeneous (excitatory, inhibitory, and no effect) responses in LPGi neurons. At baseline recording, the interspike interval variability of the LPGi neurons was attenuated in both inhibitory and excitatory responses in animals with the history of MD. The extent of morphine-induced discharge inhibition was also lower in deprived animals compared to the control group. These findings suggest that early life MD induces long-term alterations in LPGi neuronal activity in response to acute administration of morphine. Therefore, the MD may alter the vulnerability to develop opiate abuse in adulthood.
Collapse
Affiliation(s)
- Hossein Masrouri
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Azadi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Azizi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
|
45
|
Dudek KA, Dion‐Albert L, Kaufmann FN, Tuck E, Lebel M, Menard C. Neurobiology of resilience in depression: immune and vascular insights from human and animal studies. Eur J Neurosci 2021; 53:183-221. [PMID: 31421056 PMCID: PMC7891571 DOI: 10.1111/ejn.14547] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 07/22/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022]
Abstract
Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.
Collapse
Affiliation(s)
- Katarzyna A. Dudek
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQuebec CityQCCanada
| | - Laurence Dion‐Albert
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQuebec CityQCCanada
| | - Fernanda Neutzling Kaufmann
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQuebec CityQCCanada
| | - Ellen Tuck
- Smurfit Institute of GeneticsTrinity CollegeDublinIreland
| | - Manon Lebel
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQuebec CityQCCanada
| | - Caroline Menard
- Department of Psychiatry and NeuroscienceFaculty of Medicine and CERVO Brain Research CenterUniversité LavalQuebec CityQCCanada
| |
Collapse
|
|
46
|
Kestering-Ferreira E, Tractenberg SG, Lumertz FS, Orso R, Creutzberg KC, Wearick-Silva LE, Viola TW, Grassi-Oliveira R. Long-term Effects of Maternal Separation on Anxiety-Like Behavior and Neuroendocrine Parameters in Adult Balb/c Mice. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2021; 5:24705470211067181. [PMID: 34993376 PMCID: PMC8725222 DOI: 10.1177/24705470211067181] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/30/2021] [Indexed: 11/17/2022]
Abstract
Introduction: Disruption of maternal care using maternal separation (MS) models has provided significant evidence of the deleterious long-term effects of early life stress. Several preclinical studies investigating MS showed multiple behavioral and biomolecular alterations. However, there is still conflicting results from MS studies, which represents a challenge for reliability and replicability of those findings. Objective: To address that, this study was conducted to investigate whether MS would affect anxiety-like behaviors using a battery of classical tasks, as well as central and peripheral stress-related biomarkers. Methods: Male Balb/c mice were exposed to MS from postnatal day (PND) 2 to 14 for 180-min per day. Two independent cohorts were performed to evaluate both baseline and anxiety-like behavior responses to MS at PND60. We performed composite scores to evaluate MS effects on anxiety and risk assessment phenotypes. Also, we assessed mRNA gene expression in the medial pre-frontal cortex (mPFC) of glucocorticoid and mineralocorticoid receptors (GR and MR) using real-time PCR and peripheral corticosterone levels (CORT) to investigate possible neurobiological correlates to anxiety behaviors. Results: We found increased anxiety-like behavior and decreased risk assessment and exploratory behaviors in MS mice. The animals exposed to MS also presented a decrease in MR mRNA expression and higher levels of CORT compared to controls. Conclusions: Our findings reinforce the body of evidence suggesting that long-term MS induces effects on anxiety and risk assessment phenotypes following the exposure to a standardized MS protocol. Moreover, MS affected the expression of MR mRNA and induced significant changes on CORT response. This data highlights that the reprograming MS effects on HPA axis could be mediate by MR gene expression in mPFC and chronic overactivity of peripheral CORT levels.
Collapse
Affiliation(s)
- Erika Kestering-Ferreira
- Developmental Cognitive Neuroscience Lab
(DCNL), Pontifical University Catholic of Rio Grande do Sul
| | - Saulo Gantes Tractenberg
- Developmental Cognitive Neuroscience Lab
(DCNL), Pontifical University Catholic of Rio Grande do Sul
| | | | - Rodrigo Orso
- Developmental Cognitive Neuroscience Lab
(DCNL), Pontifical University Catholic of Rio Grande do Sul
| | | | | | - Thiago Wendt Viola
- Developmental Cognitive Neuroscience Lab
(DCNL), Pontifical University Catholic of Rio Grande do Sul
| | - Rodrigo Grassi-Oliveira
- Developmental Cognitive Neuroscience Lab
(DCNL), Pontifical University Catholic of Rio Grande do Sul
- Aarhus University, Denmark
| |
Collapse
|
|
47
|
Menezes FP, Padilha de Sousa I, Luchiari AC. Early Mistreatment Contributes to Social Behavior Disorders in Zebrafish. Front Behav Neurosci 2020; 14:578242. [PMID: 33177998 PMCID: PMC7596165 DOI: 10.3389/fnbeh.2020.578242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Adverse experiences during childhood have been the focus of a series of studies due to the psychological damage observed in individuals who suffered abuse during their youth. Studies with model animals that can mimic these observations can significantly contribute to understanding the mechanisms behind this phenomenon. In our experiments, young zebrafish (20 dpf) were exposed to aggressive alcoholized male adults for 30 min for 10 days. At 30 dpf, the animals were tested for shoal formation, and at 60 dpf, locomotion and aggression were evaluated. Animals that suffered oppression from adults showed greater group cohesion and lower attack emission and higher distance from the image in the mirror test. Locomotor parameters were not changed. These results show that the stress caused by aggression exposure in the juvenile phase led to increased fear and avoidance behavior later in life. Moreover, we confirm the importance of the zebrafish as a sensitive tool for studies on the effects of early mistreatment and its consequences to adult behavior.
Collapse
Affiliation(s)
- Fabiano Peres Menezes
- Departamento de Fisiologia e Comportamento, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | - Igo Padilha de Sousa
- Departamento de Fisiologia e Comportamento, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | - Ana Carolina Luchiari
- Departamento de Fisiologia e Comportamento, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| |
Collapse
|
|
48
|
Popa N, Boyer F, Jaouen F, Belzeaux R, Gascon E. Social Isolation and Enrichment Induce Unique miRNA Signatures in the Prefrontal Cortex and Behavioral Changes in Mice. iScience 2020; 23:101790. [PMID: 33294798 PMCID: PMC7701176 DOI: 10.1016/j.isci.2020.101790] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 09/14/2020] [Accepted: 11/06/2020] [Indexed: 01/19/2023] Open
Abstract
An extensive body of evidence supports the notion that exposure to an enriched/impoverished environment alters brain functions via epigenetic changes. However, how specific modifications of social environment modulate brain functions remains poorly understood. To address this issue, we investigate the molecular and behavioral consequences of briefly manipulating social settings in young and middle-aged wild-type mice. We observe that, modifications of the social context, only affect the performance in socially related tasks. Social enrichment increases sociability whereas isolation leads to the opposite effect. Our work also pointed out specific miRNA signatures associated to each social environment. These miRNA alterations are reversible and found selectively in the medial prefrontal cortex. Finally, we show that miRNA modifications linked to social enrichment or isolation might target rather different intracellular pathways. Together, these observations suggest that the prefrontal cortex may be a key brain area integrating social information via the modification of precise miRNA networks.
Collapse
Affiliation(s)
- Natalia Popa
- Aix-Marseille Université, CNRS, INT, Inst Neurosci Timone, UMR7289, 27, Boulevard Jean Moulin, 13005 Marseille, France
| | - Flora Boyer
- Aix-Marseille Université, CNRS, INT, Inst Neurosci Timone, UMR7289, 27, Boulevard Jean Moulin, 13005 Marseille, France
| | - Florence Jaouen
- Aix-Marseille Université, CNRS, INT, Inst Neurosci Timone, UMR7289, 27, Boulevard Jean Moulin, 13005 Marseille, France
- NeuroBioTools Facility (NeuroVir), Aix Marseille Université, CNRS, INT, Inst Neurosci Timone, Marseille, France
| | - Raoul Belzeaux
- Aix-Marseille Université, CNRS, INT, Inst Neurosci Timone, UMR7289, 27, Boulevard Jean Moulin, 13005 Marseille, France
- Assistance Publique Hôpitaux de Marseille, Sainte Marguerite Hospital, Pôle de Psychiatrie Universitaire Solaris, Marseille, France
| | - Eduardo Gascon
- Aix-Marseille Université, CNRS, INT, Inst Neurosci Timone, UMR7289, 27, Boulevard Jean Moulin, 13005 Marseille, France
- Corresponding author
| |
Collapse
|
|
49
|
Masrouri H, Azadi M, Semnanian S, Azizi H. Maternal deprivation induces persistent adaptations in putative dopamine neurons in rat ventral tegmental area: in vivo electrophysiological study. Exp Brain Res 2020; 238:2221-2228. [PMID: 32705295 DOI: 10.1007/s00221-020-05884-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022]
Abstract
Early life aversive experiences can trigger persistent deficits in neuronal signaling within the mesolimbic pathway, most notably in the dopamine (DA) neurons of the ventral tegmental area (VTA). The identity of such cellular mechanisms currently appears as an important issue. To address this concern, we investigated whether early life maternal deprivation (MD) would affect the electrical activity of VTA DA neurons, via in vivo extracellular single-unit recording. Male Wistar rats were deprived of their dams for 3 h per day from postnatal days (PND) 1-14. Thereafter, the adult animals (PND 70-80) were tested for the discharge activity of putative VTA DA neurons. The VTA DA neurons displayed a decrease in firing rate and an increase in the variability of baseline discharge activity in deprived animals. MD also caused a decrease in burst firing of VTA DA neurons compared to control subjects. In summary, early life MD induces a hypoactive VTA DA system, which may contribute to lifespan psychopathologies.
Collapse
Affiliation(s)
- Hossein Masrouri
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Azadi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Azizi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
|
50
|
Nishi M. Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents. Int J Mol Sci 2020; 21:E7212. [PMID: 33003605 PMCID: PMC7584021 DOI: 10.3390/ijms21197212] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/18/2020] [Accepted: 09/25/2020] [Indexed: 01/06/2023] Open
Abstract
Early-life stress during the prenatal and postnatal periods affects the formation of neural networks that influence brain function throughout life. Previous studies have indicated that maternal separation (MS), a typical rodent model equivalent to early-life stress and, more specifically, to child abuse and/or neglect in humans, can modulate the hypothalamic-pituitary-adrenal (HPA) axis, affecting subsequent neuronal function and emotional behavior. However, the neural basis of the long-lasting effects of early-life stress on brain function has not been clarified. In the present review, we describe the alterations in the HPA-axis activity-focusing on serum corticosterone (CORT)-and in the end products of the HPA axis as well as on the CORT receptor in rodents. We then introduce the brain regions activated during various patterns of MS, including repeated MS and single exposure to MS at various stages before weaning, via an investigation of c-Fos expression, which is a biological marker of neuronal activity. Furthermore, we discuss the alterations in behavior and gene expression in the brains of adult mice exposed to MS. Finally, we ask whether MS repeats itself and whether intergenerational transmission of child abuse and neglect is possible.
Collapse
Affiliation(s)
- Mayumi Nishi
- Department of Anatomy and Cell Biology, Nara Medical University, Kashihara 634-8521, Japan
| |
Collapse
|