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1
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Wu L, Sun W, Huang L, Sun L, Dou J, Lu G. Calcium Imaging in Vivo: How to Correctly Select and Apply Fiber Optic Photometric Indicators. Organogenesis 2025; 21:2489667. [PMID: 40186873 PMCID: PMC11980459 DOI: 10.1080/15476278.2025.2489667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/11/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025] Open
Abstract
Fiber-photometric is a novel optogenetic method for recording neural activity in vivo, which allows the use of calcium indicators to observe and study the relationship between neural activity and behavior in free-ranging animals. Calcium indicators also convert changes in calcium concentration in cells or tissues into recordable fluorescent signals, which can then be observed using the system of fiber-photometric. To date, there is a paucity of relevant literature on the proper selection and application of fiber-photometric indicators. Therefore, this paper will detail how to correctly select and apply fiber-photometer indicators in four sections: the basic principle of optical fiber photometry, the selection of calcium fluorescent probes and viral vector systems, and the measurement of specific expression of fluorescent proteins in specific tissues. Therefore, the correct use of suitable fiber optic recording indicators will greatly assist researchers in exploring the link between neuronal activity and neuropsychiatric disorders.
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Affiliation(s)
- Lanxia Wu
- School of Psychology, Shandong Second Medical University, Weifang, Shandong, China
| | - Wenxuan Sun
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
| | - Linjie Huang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
| | - Lin Sun
- School of Psychology, Shandong Second Medical University, Weifang, Shandong, China
| | - Jinhua Dou
- Mental Health Education Center, Shandong Second Medical University, Weifang, Shandong, China
| | - Guohua Lu
- School of Psychology, Shandong Second Medical University, Weifang, Shandong, China
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2
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Peters KZ, Pedan Z, Agbude R, Woods EC, Steele OG, Suto N, Kinghorn SB, Tsaponina O, Koya E. Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking. Neuropsychopharmacology 2025:10.1038/s41386-025-02142-y. [PMID: 40473977 DOI: 10.1038/s41386-025-02142-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 05/09/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025]
Abstract
Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or 'neuronal ensembles' in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify 'anti-craving' relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of 'originally', or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or 'excitatory overdrive'. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting 'inhibitory underdrive'. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory 'overdrive' and inhibitory 'underdrive' likely underlies EE's anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.
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Affiliation(s)
- Kate Z Peters
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Zuzana Pedan
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Romarua Agbude
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Emily C Woods
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Oliver G Steele
- Brighton and Sussex Medical School, University of Sussex, Falmer, UK
| | - Nobuyoshi Suto
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Scott B Kinghorn
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Olga Tsaponina
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK
| | - Eisuke Koya
- Sussex Neuroscience, School of Psychology, University of Sussex, Falmer, UK.
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3
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Parekh PK. Illuminating the impact of stress: In vivo approaches to track stress-related neural adaptations. Neurobiol Stress 2025; 35:100712. [PMID: 40191171 PMCID: PMC11970376 DOI: 10.1016/j.ynstr.2025.100712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/16/2024] [Accepted: 02/06/2025] [Indexed: 04/09/2025] Open
Abstract
Stressful experiences can affect both daily life and long-term health outcomes in a variety of ways. Acute challenges may be adaptive, promoting arousal and enhancing memory and cognitive function. Importantly, however, chronic stress dysregulates the body's physiological regulatory mechanisms consisting of complex hormone interactions throughout the peripheral and central nervous systems. This disrupted signaling consequently alters the balance of synapse formation, maturation and pruning, processes which regulate neural communication, plasticity, learning, cognitive flexibility and adaptive behaviors - hallmarks of a healthy, functional brain. The chronically stressed brain state, therefore, is one which may be uniquely vulnerable. To understand the development of this state, how it is sustained and how behavior and neural function are transiently or indelibly impacted by it, we can turn to a number of advanced approaches in animal models which offer unprecedented insights. This has been the aim of my recent work within the field and the goal of my new independent research program. To achieve this, I have employed methods to uncover how key brain circuits integrate information to support motivated behaviors, how stress impacts their ability to perform this process and how best to operationalize behavioral readouts. Here I present an overview of research contributions that I find most meaningful for advancing our understanding of the impact of stress and propose new avenues which will guide my own framework to address the salient outstanding questions within the field.
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Affiliation(s)
- Puja K. Parekh
- Department of Neuroscience, The University of Texas at Dallas, 860 N. Loop Rd, Richardson, TX, 75080, USA
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4
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Nishitani N, Sasaki Y, Kaneda K. Effects of 3,4-methylenedioxymethamphetamine on neural activity in the nucleus accumbens of male mice engaged in social behavior. Neuropsychopharmacol Rep 2025; 45:e12510. [PMID: 39628031 DOI: 10.1002/npr2.12510] [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: 09/21/2024] [Revised: 10/24/2024] [Accepted: 11/24/2024] [Indexed: 12/25/2024] Open
Abstract
3,4-methylenedioxymethamphetamine (MDMA), a commonly abused recreational drug, induces prosocial effects such as increased sociability and empathy. The nucleus accumbens (NAc) has been suggested to play a crucial role in these MDMA-mediated prosocial effects. However, the relationship between social behavior and NAc neural activity, and the effects of MDMA on this relationship, remain unknown. In this study, we measured NAc neural activity using fiber photometry and classified the behaviors of mice at times of transient increases in NAc neural activity during the social approach test (SAT). We found that NAc neural activity transiently increased at the onset of turning toward and sniffing novel mice during the SAT, although the frequency of turning was relatively low. We then examined the effects of MDMA on behavior and NAc neural activity and found that MDMA decreased the duration of sniffing per bout but did not alter NAc neural activity at the onset of turning toward or sniffing novel mice. These results suggest that MDMA does not affect the transient increase in NAc neural activity at the onset of social behaviors.
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Affiliation(s)
- Naoya Nishitani
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Yuki Sasaki
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
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Luo PX, Trainor BC. Hypocretin modulation of behavioral coping strategies for social stress. Neuroscience 2025; 564:126-134. [PMID: 39547335 DOI: 10.1016/j.neuroscience.2024.11.031] [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: 08/21/2024] [Revised: 10/30/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024]
Abstract
Best known for promoting wakefulness and arousal, the neuropeptide hypocretin (Hcrt) also plays an important role in mediating stress responses, including social stress. However, central and systemic manipulation of the Hcrt system has produced diverse behavioral outcomes in animal models. In this review, we first focus on studies where similar manipulations of the Hcrt system led to divergent coping behaviors. We hypothesize that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and on different cell types. We then focus on region and cell type-specific effects of Hcrt in the ventral pallidum, lateral habenula, ventral tegmental area, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis. Overall, the evidence suggests that rather than enhancing or inhibiting behavioral responses to social stress, Hcrt may signal the heightened arousal associated with stressful contexts. The resulting behavioral effects depend on which circuits Hcrt release occurs in and which receptor types are activated. Further study is needed to determine how and why circuit specific activation of Hcrt neurons occurs.
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Affiliation(s)
- Pei X Luo
- Department of Psychology, University of California - Davis, Davis, CA 95616, USA
| | - Brian C Trainor
- Department of Psychology, University of California - Davis, Davis, CA 95616, USA.
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6
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Silva SADCE, McDonald NJ, Chamaria A, Stujenske JM. Population imaging of internal state circuits relevant to psychiatric disease: a review. NEUROPHOTONICS 2025; 12:S14607. [PMID: 39872404 PMCID: PMC11772092 DOI: 10.1117/1.nph.12.s1.s14607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 12/18/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025]
Abstract
Internal states involve brain-wide changes that subserve coordinated behavioral and physiological responses for adaptation to changing environments and body states. Investigations of single neurons or small populations have yielded exciting discoveries for the field of neuroscience, but it has been increasingly clear that the encoding of internal states involves the simultaneous representation of multiple different variables in distributed neural ensembles. Thus, an understanding of the representation and regulation of internal states requires capturing large population activity and benefits from approaches that allow for parsing intermingled, genetically defined cell populations. We will explain imaging technologies that permit recording from large populations of single neurons in rodents and the unique capabilities of these technologies in comparison to electrophysiological methods. We will focus on findings for appetitive and aversive states given their high relevance to a wide range of psychiatric disorders and briefly explain how these approaches have been applied to models of psychiatric disease in rodents. We discuss challenges for studying internal states which must be addressed with future studies as well as the therapeutic implications of findings from rodents for improving treatments for psychiatric diseases.
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Affiliation(s)
- Sophia Arruda Da Costa E. Silva
- University of Pittsburgh, Department of Psychiatry, Translational Neuroscience Program, Pittsburgh, Pennsylvania, United States
| | - Nicholas J. McDonald
- University of Pittsburgh, Department of Psychiatry, Translational Neuroscience Program, Pittsburgh, Pennsylvania, United States
| | - Arushi Chamaria
- University of Pittsburgh, Kenneth P. Dietrich School of Arts and Sciences, Pittsburgh, Pennsylvania, United States
| | - Joseph M. Stujenske
- University of Pittsburgh, Department of Psychiatry, Translational Neuroscience Program, Pittsburgh, Pennsylvania, United States
- University of Pittsburgh, Center for Neuroscience, Pittsburgh, Pennsylvania, United States
- University of Pittsburgh, Department of Bioengineering, Pittsburgh, Pennsylvania, United States
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7
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Schuler H, Eid RS, Wu S, Tse YC, Cvetkovska V, Lopez J, Quinn R, Zhou D, Meccia J, Dion-Albert L, Bennett SN, Newman EL, Trainor BC, Peña CJ, Menard C, Bagot RC. Data-Driven Analysis Identifies Novel Modulation of Social Behavior in Female Mice Witnessing Chronic Social Defeat Stress. Biol Psychiatry 2024:S0006-3223(24)01786-4. [PMID: 39638223 DOI: 10.1016/j.biopsych.2024.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 11/04/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Chronic social defeat stress is a widely used depression model in male mice. Several proposed adaptations extend this model to females with variable, often marginal effects. We examined if the widely used male-defined metrics of stress are suboptimal in females witnessing defeat. METHODS Using a data-driven method, we comprehensively classified social interaction behavior in 761 male and female mice after chronic social witness/defeat stress, examining social modulation of behavior and associations with conventional metrics (i.e., social interaction ratio). RESULTS Social stress induced distinct behavioral adaptation patterns in defeated males and witness females. Social interaction ratio led to underpowered analyses in witness females with limited utility to differentiate susceptibility/resilience. Data-driven analyses revealed changes in social adaptation in witness females that were captured in attenuated velocity change from no target to target trials. We explored the utility of this metric in 4 female social stress models and in male witnesses. Combining social interaction ratio and velocity change optimally differentiated susceptibility/resilience in witness females and revealed resilient-specific adaptation in a resilience-associated neural circuit in female mice. CONCLUSIONS Chronic witness stress induced behavioral changes in females that were qualitatively distinct from those observed in defeated males and not adequately sampled by standard male-defined metrics. Modulation of locomotion is a robust and easily implementable metric for rigorous research in witness female mice. Overall, our findings highlight the need to critically evaluate sex differences in behavior and implement sex-based considerations in preclinical model design.
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Affiliation(s)
- Heike Schuler
- Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada
| | - Rand S Eid
- Department of Psychology, McGill University, Montréal, Québec, Canada
| | - Serena Wu
- Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada
| | - Yiu-Chung Tse
- Department of Psychology, McGill University, Montréal, Québec, Canada
| | | | - Joëlle Lopez
- Department of Psychology, McGill University, Montréal, Québec, Canada
| | - Rosalie Quinn
- Department of Psychology, McGill University, Montréal, Québec, Canada
| | - Delong Zhou
- Department of Psychology, McGill University, Montréal, Québec, Canada
| | - Juliet Meccia
- Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada
| | - Laurence Dion-Albert
- Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Centre, Québec City, Québec, Canada
| | - Shannon N Bennett
- Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey
| | - Emily L Newman
- Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Depression and Anxiety Disorders, Neurobiology of Fear Laboratory, McLean Hospital, Belmont, Massachusetts
| | - Brian C Trainor
- Department of Psychology, University of California, Davis, Davis, California
| | - Catherine J Peña
- Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey
| | - Caroline Menard
- Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Centre, Québec City, Québec, Canada
| | - Rosemary C Bagot
- Department of Psychology, McGill University, Montréal, Québec, Canada; Ludmer Centre for Neuroinformatics and Mental Health, Montréal, Québec, Canada.
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8
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Gergues MM, Lalani LK, Kheirbek MA. Identifying dysfunctional cell types and circuits in animal models for psychiatric disorders with calcium imaging. Neuropsychopharmacology 2024; 50:274-284. [PMID: 39122815 PMCID: PMC11525937 DOI: 10.1038/s41386-024-01942-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/30/2024] [Accepted: 07/09/2024] [Indexed: 08/12/2024]
Abstract
A central goal of neuroscience is to understand how the brain transforms external stimuli and internal bodily signals into patterns of activity that underlie cognition, emotional states, and behavior. Understanding how these patterns of activity may be disrupted in mental illness is crucial for developing novel therapeutics. It is well appreciated that psychiatric disorders are complex, circuit-based disorders that arise from dysfunctional activity patterns generated in discrete cell types and their connections. Recent advances in large-scale, cell-type specific calcium imaging approaches have shed new light on the cellular, circuit, and network-level dysfunction in animal models for psychiatric disorders. Here, we highlight a series of recent findings over the last ~10 years from in vivo calcium imaging studies that show how aberrant patterns of activity in discrete cell types and circuits may underlie behavioral deficits in animal models for several psychiatric disorders, including depression, anxiety, autism spectrum disorders, and schizophrenia. These advances in calcium imaging in pre-clinical models demonstrate the power of cell-type-specific imaging tools in understanding the underlying dysfunction in cell types, activity patterns, and neural circuits that may contribute to disease and provide new blueprints for developing more targeted therapeutics and treatment strategies.
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Affiliation(s)
- Mark M Gergues
- Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Lahin K Lalani
- Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA, USA
- Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Mazen A Kheirbek
- Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA, USA.
- Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA.
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
- Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA.
- Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA, USA.
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Muir J, Iyer ES, Tse YC, Sorensen J, Wu S, Eid RS, Cvetkovska V, Wassef K, Gostlin S, Vitaro P, Spencer NJ, Bagot RC. Sex-biased neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior. Nat Neurosci 2024; 27:1966-1976. [PMID: 39237654 DOI: 10.1038/s41593-024-01748-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 08/02/2024] [Indexed: 09/07/2024]
Abstract
Learning to predict threat is essential, but equally important-yet often overlooked-is learning about the absence of threat. Here, by recording neural activity in two nucleus accumbens (NAc) glutamatergic afferents during aversive and neutral cues, we reveal sex-biased encoding of threat cue discrimination. In male mice, NAc afferents from the ventral hippocampus are preferentially activated by threat cues. In female mice, these ventral hippocampus-NAc projections are activated by both threat and nonthreat cues, whereas NAc afferents from medial prefrontal cortex are more strongly recruited by footshock and reliably discriminate threat from nonthreat. Chemogenetic pathway-specific inhibition identifies a double dissociation between ventral hippocampus-NAc and medial prefrontal cortex-NAc projections in cue-mediated suppression of reward-motivated behavior in male and female mice, despite similar synaptic connectivity. We suggest that these sex biases may reflect sex differences in behavioral strategies that may have relevance for understanding sex differences in risk of psychiatric disorders.
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Affiliation(s)
- Jessie Muir
- Integrated Program in Neuroscience, McGill University, Montréal, Quebec, Canada
| | - Eshaan S Iyer
- Integrated Program in Neuroscience, McGill University, Montréal, Quebec, Canada
| | - Yiu-Chung Tse
- Department of Psychology, McGill University, Montréal, Quebec, Canada
| | - Julian Sorensen
- College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia
| | - Serena Wu
- Integrated Program in Neuroscience, McGill University, Montréal, Quebec, Canada
| | - Rand S Eid
- Department of Psychology, McGill University, Montréal, Quebec, Canada
| | | | - Karen Wassef
- Department of Psychology, McGill University, Montréal, Quebec, Canada
| | - Sarah Gostlin
- Department of Psychology, McGill University, Montréal, Quebec, Canada
| | - Peter Vitaro
- Department of Psychology, McGill University, Montréal, Quebec, Canada
| | - Nick J Spencer
- College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia
| | - Rosemary C Bagot
- Department of Psychology, McGill University, Montréal, Quebec, Canada.
- Ludmer Centre for Neuroinformatics and Mental Health, Montréal, Quebec, Canada.
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10
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Kim HD, Wei J, Call T, Ma X, Quintus NT, Summers AJ, Carotenuto S, Johnson R, Nguyen A, Cui Y, Park JG, Qiu S, Ferguson D. SIRT1 Coordinates Transcriptional Regulation of Neural Activity and Modulates Depression-Like Behaviors in the Nucleus Accumbens. Biol Psychiatry 2024; 96:495-505. [PMID: 38575105 PMCID: PMC11338727 DOI: 10.1016/j.biopsych.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/16/2024] [Accepted: 03/25/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Major depression and anxiety disorders are significant causes of disability and socioeconomic burden. Despite the prevalence and considerable impact of these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for these conditions. We evaluated the role of SIRT1 in regulating dysfunctional processes of reward by using chronic social defeat stress to induce depression- and anxiety-like behaviors. Chronic social defeat stress induces physiological and behavioral changes that recapitulate depression-like symptomatology and alters gene expression programs in the nucleus accumbens, but cell type-specific changes in this critical structure remain largely unknown. METHODS We examined transcriptional profiles of D1-expressing medium spiny neurons (MSNs) lacking deacetylase activity of SIRT1 by RNA sequencing in a cell type-specific manner using the RiboTag line of mice. We analyzed differentially expressed genes using gene ontology tools including SynGO and EnrichR and further demonstrated functional changes in D1-MSN-specific SIRT1 knockout (KO) mice using electrophysiological and behavioral measurements. RESULTS RNA sequencing revealed altered transcriptional profiles of D1-MSNs lacking functional SIRT1 and showed specific changes in synaptic genes including glutamatergic and GABAergic (gamma-aminobutyric acidergic) receptors in D1-MSNs. These molecular changes may be associated with decreased excitatory and increased inhibitory neural activity in Sirt1 KO D1-MSNs, accompanied by morphological changes. Moreover, the D1-MSN-specific Sirt1 KO mice exhibited proresilient changes in anxiety- and depression-like behaviors. CONCLUSIONS SIRT1 coordinates excitatory and inhibitory synaptic genes to regulate the GABAergic output tone of D1-MSNs. These findings reveal a novel signaling pathway that has potential for the development of innovative treatments for affective disorders.
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Affiliation(s)
- Hee-Dae Kim
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Jing Wei
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Tanessa Call
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Xiaokuang Ma
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Nicole Teru Quintus
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Alexander J Summers
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Samantha Carotenuto
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Ross Johnson
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Angel Nguyen
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Yuehua Cui
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Jin G Park
- Virginia G. Piper Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Shenfeng Qiu
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona
| | - Deveroux Ferguson
- Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona.
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11
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Xu Y, Lin Y, Yu M, Zhou K. The nucleus accumbens in reward and aversion processing: insights and implications. Front Behav Neurosci 2024; 18:1420028. [PMID: 39184934 PMCID: PMC11341389 DOI: 10.3389/fnbeh.2024.1420028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
The nucleus accumbens (NAc), a central component of the brain's reward circuitry, has been implicated in a wide range of behaviors and emotional states. Emerging evidence, primarily drawing from recent rodent studies, suggests that the function of the NAc in reward and aversion processing is multifaceted. Prolonged stress or drug use induces maladaptive neuronal function in the NAc circuitry, which results in pathological conditions. This review aims to provide comprehensive and up-to-date insights on the role of the NAc in motivated behavior regulation and highlights areas that demand further in-depth analysis. It synthesizes the latest findings on how distinct NAc neuronal populations and pathways contribute to the processing of opposite valences. The review examines how a range of neuromodulators, especially monoamines, influence the NAc's control over various motivational states. Furthermore, it delves into the complex underlying mechanisms of psychiatric disorders such as addiction and depression and evaluates prospective interventions to restore NAc functionality.
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Affiliation(s)
| | | | | | - Kuikui Zhou
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China
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12
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Nestler EJ, Russo SJ. Neurobiological basis of stress resilience. Neuron 2024; 112:1911-1929. [PMID: 38795707 PMCID: PMC11189737 DOI: 10.1016/j.neuron.2024.05.001] [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: 01/02/2024] [Revised: 03/21/2024] [Accepted: 05/01/2024] [Indexed: 05/28/2024]
Abstract
A majority of humans faced with severe stress maintain normal physiological and behavioral function, a process referred to as resilience. Such stress resilience has been modeled in laboratory animals and, over the past 15 years, has transformed our understanding of stress responses and how to approach the treatment of human stress disorders such as depression, post-traumatic stress disorder (PTSD), and anxiety disorders. Work in rodents has demonstrated that resilience to chronic stress is an active process that involves much more than simply avoiding the deleterious effects of the stress. Rather, resilience is mediated largely by the induction of adaptations that are associated uniquely with resilience. Such mechanisms of natural resilience in rodents are being characterized at the molecular, cellular, and circuit levels, with an increasing number being validated in human investigations. Such discoveries raise the novel possibility that treatments for human stress disorders, in addition to being geared toward reversing the damaging effects of stress, can also be based on inducing mechanisms of natural resilience in individuals who are inherently more susceptible. This review provides a progress report on this evolving field.
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Affiliation(s)
- Eric J Nestler
- Nash Family Department of Neuroscience and Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Scott J Russo
- Nash Family Department of Neuroscience and Department of Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Montgomery SE, Li L, Russo SJ, Calipari ES, Nestler EJ, Morel C, Han MH. Mesolimbic Neural Response Dynamics Predict Future Individual Alcohol Drinking in Mice. Biol Psychiatry 2024; 95:951-962. [PMID: 38061466 DOI: 10.1016/j.biopsych.2023.11.019] [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: 03/22/2023] [Revised: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 01/27/2024]
Abstract
BACKGROUND Individual variability in response to rewarding stimuli is a striking but understudied phenomenon. The mesolimbic dopamine system is critical in encoding the reinforcing properties of both natural reward and alcohol; however, how innate or baseline differences in the response dynamics of this circuit define individual behavior and shape future vulnerability to alcohol remain unknown. METHODS Using naturalistic behavioral assays, a voluntary alcohol drinking paradigm, in vivo fiber photometry, in vivo electrophysiology, and chemogenetics, we investigated how differences in mesolimbic neural circuit activity contribute to the individual variability seen in reward processing and, by proxy, alcohol drinking. RESULTS We first characterized heterogeneous behavioral and neural responses to natural reward and defined how these baseline responses predicted future individual alcohol-drinking phenotypes in male mice. We then determined spontaneous ventral tegmental area dopamine neuron firing profiles associated with responses to natural reward that predicted alcohol drinking. Using a dual chemogenetic approach, we mimicked specific mesolimbic dopamine neuron firing activity before or during voluntary alcohol drinking to link unique neurophysiological profiles to individual phenotype. We show that hyperdopaminergic individuals exhibit a lower neuronal response to both natural reward and alcohol that predicts lower levels of alcohol consumption in the future. CONCLUSIONS These findings reveal unique, circuit-specific neural signatures that predict future individual vulnerability or resistance to alcohol and expand the current knowledge base on how some individuals are able to titrate their alcohol consumption whereas others go on to engage in unhealthy alcohol-drinking behaviors.
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Affiliation(s)
- Sarah E Montgomery
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Long Li
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott J Russo
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Erin S Calipari
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Departments of Pharmacology, Molecular Physiology and Biophysics, and Psychiatry and Behavioral Sciences, Vanderbilt Center for Addiction Research, Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee
| | - Eric J Nestler
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Carole Morel
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Ming-Hu Han
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute and the Center for Affective Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
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Zhang N, Zhao S, Ma Y, Xiao Z, Xue B, Dong Y, Wang Q, Xu H, Zhang X, Wang Y. Hyperexcitation of ovBNST CRF neurons during stress contributes to female-biased expression of anxiety-like avoidance behaviors. SCIENCE ADVANCES 2024; 10:eadk7636. [PMID: 38728397 PMCID: PMC11086623 DOI: 10.1126/sciadv.adk7636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 04/09/2024] [Indexed: 05/12/2024]
Abstract
Corticotropin releasing factor (CRF) network in the oval nucleus of bed nuclei of the stria terminalis (ovBNST) is generally indicated in stress, but its role in female-biased susceptibility to anxiety is unknown. Here, we established a female-biased stress paradigm. We found that the CRF release in ovBNST during stress showed female-biased pattern, and ovBNST CRF neurons were more prone to be hyperexcited in female mice during stress in both in vitro and in vivo studies. Moreover, optogenetic modulation to exchange the activation pattern of ovBNST CRF neurons during stress between female and male mice could reverse their susceptibility to anxiety. Last, CRF receptor type 1 (CRFR1) mediated the CRF-induced excitation of ovBNST CRF neurons and showed female-biased expression. Specific knockdown of the CRFR1 level in ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. Therefore, we identify that CRFR1-mediated hyperexcitation of ovBNST CRF neurons in female mice encode the female-biased susceptibility to anxiety.
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Affiliation(s)
- Na Zhang
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao 266000, China
| | - Sha Zhao
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Yanqiao Ma
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Zhixin Xiao
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Bao Xue
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Yuan Dong
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Qingyu Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Huamin Xu
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Xia Zhang
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
| | - Ying Wang
- Institute of Neuropsychiatric Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
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Zhao Z, Covelo A, Couderc Y, Mitra A, Varilh M, Wu Y, Jacky D, Fayad R, Cannich A, Bellocchio L, Marsicano G, Beyeler A. Cannabinoids regulate an insula circuit controlling water intake. Curr Biol 2024; 34:1918-1929.e5. [PMID: 38636514 DOI: 10.1016/j.cub.2024.03.053] [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: 03/11/2022] [Revised: 02/29/2024] [Accepted: 03/25/2024] [Indexed: 04/20/2024]
Abstract
The insular cortex, or insula, is a large brain region involved in the detection of thirst and the regulation of water intake. However, our understanding of the topographical, circuit, and molecular mechanisms for controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid (CB1) receptors in the insular cortex cells participate in the regulation of water intake and deconstructed the circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both the anterior insula (aIC) and posterior insula (pIC) increases in response to water intake, yet only the specific removal of CB1 receptors in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we recorded the neurons of the aIC or pIC targeting the BLA (aIC-BLA and pIC-BLA) and found that they decreased their activity upon water drinking. Additionally, chemogenetic activation of pIC-BLA projection neurons decreased water intake. Finally, we uncovered CB1-dependent short-term synaptic plasticity (depolarization-induced suppression of excitation [DSE]) selectively in pIC-BLA, compared with aIC-BLA synapses. Altogether, our results support a model where CB1 receptor signaling promotes water intake by inhibiting the pIC-BLA pathway, thereby contributing to the fine top-down control of thirst responses.
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Affiliation(s)
- Zhe Zhao
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France; Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA
| | - Ana Covelo
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Yoni Couderc
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Arojit Mitra
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Marjorie Varilh
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Yifan Wu
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Débora Jacky
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Rim Fayad
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Astrid Cannich
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Luigi Bellocchio
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France
| | - Giovanni Marsicano
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France.
| | - Anna Beyeler
- INSERM 1215, Neurocentre Magendie, University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France.
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Nghiem TAE, Lee B, Chao THH, Branigan NK, Mistry PK, Shih YYI, Menon V. Space wandering in the rodent default mode network. Proc Natl Acad Sci U S A 2024; 121:e2315167121. [PMID: 38557177 PMCID: PMC11009630 DOI: 10.1073/pnas.2315167121] [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: 09/02/2023] [Accepted: 01/17/2024] [Indexed: 04/04/2024] Open
Abstract
The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here, we use multisite GCaMP (a genetically encoded calcium indicator) fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes-the retrosplenial cortex, cingulate cortex, and prelimbic cortex-as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and found that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.
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Affiliation(s)
| | - Byeongwook Lee
- Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA94304
| | - Tzu-Hao Harry Chao
- Center for Animal MRI, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
- Biomedical Research Imaging Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
| | - Nicholas K. Branigan
- Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA94304
| | - Percy K. Mistry
- Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA94304
| | - Yen-Yu Ian Shih
- Center for Animal MRI, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
- Biomedical Research Imaging Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
- Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC27514
| | - Vinod Menon
- Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA94304
- Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA94304
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA94305
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17
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Leithead AB, Godino A, Barbier M, Harony-Nicolas H. Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus. Biol Psychiatry 2024; 95:112-122. [PMID: 37245781 PMCID: PMC10676449 DOI: 10.1016/j.biopsych.2023.05.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND The posterior intralaminar complex of the thalamus (PIL) is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed. METHODS We used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real time during social and nonsocial interactions. Finally, we used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation. RESULTS We observed significantly more c-fos-positive cells in the PIL of mice exposed to a social stimulus versus an object stimulus or no stimulus. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity was positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time that it took for female mice to form social habituation. CONCLUSIONS Together, these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.
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Affiliation(s)
- Amanda Beth Leithead
- Department of Psychiatry, the Icahn School of Medicine, Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Arthur Godino
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marie Barbier
- Department of Psychiatry, the Icahn School of Medicine, Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hala Harony-Nicolas
- Department of Psychiatry, the Icahn School of Medicine, Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, The Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York.
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18
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Qin C, Yuan Q, Liu M, Zhuang L, Xu L, Wang P. Biohybrid tongue based on hypothalamic neuronal network-on-a-chip for real-time blood glucose sensing and assessment. Biosens Bioelectron 2024; 244:115784. [PMID: 37939416 DOI: 10.1016/j.bios.2023.115784] [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: 08/15/2023] [Revised: 10/14/2023] [Accepted: 10/22/2023] [Indexed: 11/10/2023]
Abstract
The expression of sweet receptors in the hypothalamus has been implicated in energy homeostasis control and the pathogenesis of obesity and diabetes. However, the exact mechanism by which hypothalamic glucose-sensing neurons function remains unclear. Conventional detection methods, such as fiber photometry, optogenetics, brain-machine interfaces, patch clamp and calcium imaging, pose limitations for real-time glucose perception due to their complexity, cytotoxicity and so on. Therefore, this study proposes a biohybrid tongue based on hypothalamic neuronal network (HNN)-on-a-chip coupling with microelectrode array (MEA) for real-time glucose perception. Hypothalamic neuronal cultures were cultivated on a two-dimensional "brain-on-chip" device, enabling the formation of neuronal networks and electrophysiological signal detection. Additionally, we investigated the endogenous expression of sweet taste receptors (T1R2/T1R3) in hypothalamic neuronal cells, providing the basis for the biohybrid tongue based on HNN-on-a-chip's sweetness detection capabilities. The spike signal response to sucrose and glucose stimulation was detected, and concentration-dependent responses were explored with glucose concentrations ranging from 0.01 mM to 8 mM. MEAs allow for real-time recordings, enabling the observation of dynamic changes in neuronal responses to glucose fluctuations over time. The biohybrid tongue based on HNN-on-a-chip can measure various parameters, including spike frequency and amplitude, providing insights into neuronal firing patterns and excitability. Moreover, hypothalamic glucoregulatory neurons that sense and respond to changes in blood glucose was identified, including glucose-excited neurons (GE-Neurons) and glucose-inhibited neurons (GI-Neurons). The detection range for GE-Neurons spans from 0.4 to 6 mM, while GI-Neurons demonstrate sensitivity within the range of 1-8 mM. And the glucose detection limit was firmly established at 0.01 mM. Through non-linear regression analysis, the IC50 for GI-Neurons' spike firing was determined to be 4.18 mM. In conclusion, the biohybrid tongue based on HNN-on-a-chip offers a valuable in vitro tool for studying hypothalamic neurons, elucidating glucose sensing mechanisms, and understanding hypothalamic neuronal function.
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Affiliation(s)
- Chunlian Qin
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China
| | - Qunchen Yuan
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou, 310027, China; Innovation Center for Smart Medical Technologies & Devices, Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, 310053, China
| | - Mengxue Liu
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Liujing Zhuang
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Lizhou Xu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China.
| | - Ping Wang
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou, 310027, China; Innovation Center for Smart Medical Technologies & Devices, Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, 310053, China.
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Le Merrer J, Detraux B, Gandía J, De Groote A, Fonteneau M, de Kerchove d'Exaerde A, Becker JAJ. Balance Between Projecting Neuronal Populations of the Nucleus Accumbens Controls Social Behavior in Mice. Biol Psychiatry 2024; 95:123-135. [PMID: 37207936 DOI: 10.1016/j.biopsych.2023.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/06/2023] [Accepted: 05/02/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Deficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies. In the present study, we further explored the role of the balance of activity between D1 and D2 receptor-expressing striatal projection neurons (D1R- and D2R-SPNs) in the control of social behavior, challenging the hypothesis that excessive D2R-SPN activity, rather than deficient D1R-SPN activity, compromises social behavior. METHODS We selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function, and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the nucleus accumbens (NAc) and pharmacological compounds repressing D2R-SPN. RESULTS Targeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated motor skill learning, and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum. Ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior but impaired motor skill learning and decreased anxiety levels. Deletion of D2R-SPNs in the NAc produced motor stereotypies but facilitated social behavior and impaired motor skill learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and observed a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. CONCLUSIONS Repressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficits in neuropsychiatric disorders.
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Affiliation(s)
- Julie Le Merrer
- Physiologie de la Reproduction et des Comportements, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7247, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 0085, Institut National de la Santé et de la Recherche Médicale, Université de Tours, Nouzilly, France; iBrain, Unité Mixte de Recherche 1253 Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Faculté des Sciences et Techniques, Université de Tours, Tours, France.
| | - Bérangère Detraux
- Neurophy Lab, ULB Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Jorge Gandía
- Physiologie de la Reproduction et des Comportements, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7247, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 0085, Institut National de la Santé et de la Recherche Médicale, Université de Tours, Nouzilly, France
| | - Aurélie De Groote
- Neurophy Lab, ULB Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Mathieu Fonteneau
- iBrain, Unité Mixte de Recherche 1253 Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Faculté des Sciences et Techniques, Université de Tours, Tours, France
| | - Alban de Kerchove d'Exaerde
- Neurophy Lab, ULB Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium; WELBIO, Wavre, Belgium.
| | - Jérôme A J Becker
- Physiologie de la Reproduction et des Comportements, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7247, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 0085, Institut National de la Santé et de la Recherche Médicale, Université de Tours, Nouzilly, France; iBrain, Unité Mixte de Recherche 1253 Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Faculté des Sciences et Techniques, Université de Tours, Tours, France
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Conlisk D, Ceau M, Fiancette JF, Winke N, Darmagnac E, Herry C, Deroche-Gamonet V. Integrating operant behavior and fiber photometry with the open-source python library Pyfiber. Sci Rep 2023; 13:16562. [PMID: 37783729 PMCID: PMC10545777 DOI: 10.1038/s41598-023-43565-1] [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: 04/05/2023] [Accepted: 09/26/2023] [Indexed: 10/04/2023] Open
Abstract
Despite the popularity of fiber photometry (FP), its integration with operant behavior paradigms is progressing slowly. This can be attributed to the complex protocols in operant behavior - resulting in a combination of diverse non-predictable behavioral responses and scheduled events, thereby complicating data analysis. To overcome this, we developed Pyfiber, an open-source python library which facilitates the merge of FP with operant behavior by relating changes in fluorescent signals within a neuronal population to behavioral responses and events. Pyfiber helps to 1. Extract events and responses that occur in operant behavior, 2. Extract and process the FP signals, 3. Select events of interest and align them to the corresponding FP signals, 4. Apply appropriate signal normalization and analysis according to the type of events, 5. Run analysis on multiple individuals and sessions, 6. Collect results in an easily readable format. Pyfiber is suitable for use with many different fluorescent sensors and operant behavior protocols. It was developed using Doric lenses FP systems and Imetronic behavioral systems, but it possesses the capability to process data from alternative systems. This work sets a solid foundation for analyzing the relationship between different dimensions of complex behavioral paradigms with fluorescent signals from brain regions of interest.
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Affiliation(s)
- Dana Conlisk
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Matias Ceau
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | | | - Nanci Winke
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
- UCL, Sainsbury Wellcome Centre, London, UK
| | - Elise Darmagnac
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
| | - Cyril Herry
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000, Bordeaux, France
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Fitzgerald E, Arcego DM, Shen MJ, O'Toole N, Wen X, Nagy C, Mostafavi S, Craig K, Silveira PP, Rayan NA, Diorio J, Meaney MJ, Zhang TY. Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing. EBioMedicine 2023; 95:104749. [PMID: 37549631 PMCID: PMC10432187 DOI: 10.1016/j.ebiom.2023.104749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 06/28/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established. METHODS In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region). FINDINGS We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS). INTERPRETATION Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS. FUNDING This work was supported by funding from the Hope for Depression Research Foundation (MJM).
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Affiliation(s)
- Eamon Fitzgerald
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
| | - Danusa Mar Arcego
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
| | - Mo Jun Shen
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicholas O'Toole
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
| | - Xianglan Wen
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada
| | - Corina Nagy
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
| | - Sara Mostafavi
- Paul G. Allen School of Computer Science and Engineering, University of Washington, 185 E Stevens Way NE, Seattle, WA 9819, USA
| | - Kelly Craig
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
| | - Patricia Pelufo Silveira
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nirmala Arul Rayan
- Translational Neuroscience Program, Singapore Institute for Clinical Sciences and Brain - Body Initiative, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Josie Diorio
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada
| | - Michael J Meaney
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada; Translational Neuroscience Program, Singapore Institute for Clinical Sciences and Brain - Body Initiative, Agency for Science, Technology and Research (A∗STAR), Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Tie-Yuan Zhang
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, H4H 1R3, Canada.
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22
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Hing B, Mitchell SB, Eberle M, Filali Y, Hultman I, Matkovich M, Kasturirangan M, Wyche W, Jimenez A, Velamuri R, Johnson M, Srivastava S, Hultman R. Single Cell Transcriptome of Stress Vulnerability Network in mouse Prefrontal Cortex. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.14.540705. [PMID: 37662266 PMCID: PMC10473598 DOI: 10.1101/2023.05.14.540705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Increased vulnerability to stress is a major risk factor for the manifestation of several mood disorders, including major depressive disorder (MDD). Despite the status of MDD as a significant donor to global disability, the complex integration of genetic and environmental factors that contribute to the behavioral display of such disorders has made a thorough understanding of related etiology elusive. Recent developments suggest that a brain-wide network approach is needed, taking into account the complex interplay of cell types spanning multiple brain regions. Single cell RNA-sequencing technologies can provide transcriptomic profiling at the single-cell level across heterogenous samples. Furthermore, we have previously used local field potential oscillations and machine learning to identify an electrical brain network that is indicative of a predisposed vulnerability state. Thus, this study combined single cell RNA-sequencing (scRNA-Seq) with electrical brain network measures of the stress-vulnerable state, providing a unique opportunity to access the relationship between stress network activity and transcriptomic changes within individual cell types. We found especially high numbers of differentially expressed genes between animals with high and low stress vulnerability brain network activity in astrocytes and glutamatergic neurons but we estimated that vulnerability network activity depends most on GABAergic neurons. High vulnerability network activity included upregulation of microglia and mitochondrial and metabolic pathways, while lower vulnerability involved synaptic regulation. Genes that were differentially regulated with vulnerability network activity significantly overlapped with genes identified as having significant SNPs by human GWAS for depression. Taken together, these data provide the gene expression architecture of a previously uncharacterized stress vulnerability brain state, enabling new understanding and intervention of predisposition to stress susceptibility.
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23
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Nicolas C, Ju A, Wu Y, Eldirdiri H, Delcasso S, Couderc Y, Fornari C, Mitra A, Supiot L, Vérité A, Masson M, Rodriguez-Rozada S, Jacky D, Wiegert JS, Beyeler A. Linking emotional valence and anxiety in a mouse insula-amygdala circuit. Nat Commun 2023; 14:5073. [PMID: 37604802 PMCID: PMC10442438 DOI: 10.1038/s41467-023-40517-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/01/2023] [Indexed: 08/23/2023] Open
Abstract
Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.
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Affiliation(s)
- C Nicolas
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - A Ju
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - Y Wu
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - H Eldirdiri
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - S Delcasso
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - Y Couderc
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - C Fornari
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - A Mitra
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - L Supiot
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - A Vérité
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - M Masson
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - S Rodriguez-Rozada
- Research Group Synaptic Wiring and Information Processing, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - D Jacky
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France
| | - J S Wiegert
- Research Group Synaptic Wiring and Information Processing, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - A Beyeler
- Neurocentre Magendie, INSERM 1215, Université de Bordeaux, Bordeaux, France.
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24
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Sato M, Nakai N, Fujima S, Choe KY, Takumi T. Social circuits and their dysfunction in autism spectrum disorder. Mol Psychiatry 2023; 28:3194-3206. [PMID: 37612363 PMCID: PMC10618103 DOI: 10.1038/s41380-023-02201-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 08/25/2023]
Abstract
Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, and serotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.
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Affiliation(s)
- Masaaki Sato
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Kita, Sapporo, 060-8638, Japan
| | - Nobuhiro Nakai
- Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan
| | - Shuhei Fujima
- Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan
| | - Katrina Y Choe
- Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada
| | - Toru Takumi
- Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, 650-0017, Japan.
- RIKEN Center for Biosystems Dynamics Research, Chuo, Kobe, 650-0047, Japan.
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25
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Ghosal S, Gebara E, Ramos-Fernández E, Chioino A, Grosse J, Guillot de Suduiraut I, Zanoletti O, Schneider B, Zorzano A, Astori S, Sandi C. Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function. Cell Rep 2023; 42:112776. [PMID: 37440411 DOI: 10.1016/j.celrep.2023.112776] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 05/14/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc links anxiety with social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons regulates anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show decreased accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by decreased accumbal mitochondrial functions and decreased excitability in D2-MSNs. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently and likely because of an increase in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.
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Affiliation(s)
- Sriparna Ghosal
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Elias Gebara
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Eva Ramos-Fernández
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Alessandro Chioino
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Jocelyn Grosse
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Isabelle Guillot de Suduiraut
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Olivia Zanoletti
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Bernard Schneider
- Bertarelli Platform for Gene Therapy, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1202 Geneva, Switzerland
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Simone Astori
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
| | - Carmen Sandi
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
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26
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Favoretto CA, Pagliusi M, Morais-Silva G. Involvement of brain cell phenotypes in stress-vulnerability and resilience. Front Neurosci 2023; 17:1175514. [PMID: 37476833 PMCID: PMC10354562 DOI: 10.3389/fnins.2023.1175514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Stress-related disorders' prevalence is epidemically increasing in modern society, leading to a severe impact on individuals' well-being and a great economic burden on public resources. Based on this, it is critical to understand the mechanisms by which stress induces these disorders. The study of stress made great progress in the past decades, from deeper into the hypothalamic-pituitary-adrenal axis to the understanding of the involvement of a single cell subtype on stress outcomes. In fact, many studies have used state-of-the-art tools such as chemogenetic, optogenetic, genetic manipulation, electrophysiology, pharmacology, and immunohistochemistry to investigate the role of specific cell subtypes in the stress response. In this review, we aim to gather studies addressing the involvement of specific brain cell subtypes in stress-related responses, exploring possible mechanisms associated with stress vulnerability versus resilience in preclinical models. We particularly focus on the involvement of the astrocytes, microglia, medium spiny neurons, parvalbumin neurons, pyramidal neurons, serotonergic neurons, and interneurons of different brain areas in stress-induced outcomes, resilience, and vulnerability to stress. We believe that this review can shed light on how diverse molecular mechanisms, involving specific receptors, neurotrophic factors, epigenetic enzymes, and miRNAs, among others, within these brain cell subtypes, are associated with the expression of a stress-susceptible or resilient phenotype, advancing the understanding/knowledge on the specific machinery implicate in those events.
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Affiliation(s)
- Cristiane Aparecida Favoretto
- Molecular and Behavioral Neuroscience Laboratory, Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
| | - Marco Pagliusi
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Gessynger Morais-Silva
- Laboratory of Pharmacology, Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil
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27
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Wallace T, Myers B. Prefrontal representation of affective stimuli: importance of stress, sex, and context. Cereb Cortex 2023; 33:8232-8246. [PMID: 37032618 PMCID: PMC10321111 DOI: 10.1093/cercor/bhad110] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 04/11/2023] Open
Abstract
Stress-related disorders such as depression and anxiety exhibit sex differences in prevalence and negatively impact both mental and physical health. Affective illness is also frequently accompanied by changes in ventromedial prefrontal cortical (vmPFC) function. However, the neurobiology that underlies sex-specific cortical processing of affective stimuli is poorly understood. Although rodent studies have investigated the prefrontal impact of chronic stress, postmortem studies have focused largely on males and yielded mixed results. Therefore, genetically defined population recordings in behaving animals of both sexes were used to test the hypothesis that chronic variable stress (CVS) impairs the neural processing of affective stimuli in the rodent infralimbic region. Here, we targeted expression of a calcium indicator, GCaMP6s, to infralimbic pyramidal cells. In males, CVS reduced infralimbic responses to social interaction and restraint stress but increased responses to novel objects and food reward. In contrast, females did not have CVS-induced changes in infralimbic activity, which was partially dependent on the ovarian status. These results indicate that both male and female vmPFC cells encode social, stress, and reward stimuli. However, chronic stress effects are sex-dependent and behavior-specific. Ultimately, these findings extend the understanding of chronic stress-induced prefrontal dysfunction and indicate that sex is a critical factor for cortical processing of affective stimuli.
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Affiliation(s)
- Tyler Wallace
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Brent Myers
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
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28
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Fetcho RN, Hall BS, Estrin DJ, Walsh AP, Schuette PJ, Kaminsky J, Singh A, Roshgodal J, Bavley CC, Nadkarni V, Antigua S, Huynh TN, Grosenick L, Carthy C, Komer L, Adhikari A, Lee FS, Rajadhyaksha AM, Liston C. Regulation of social interaction in mice by a frontostriatal circuit modulated by established hierarchical relationships. Nat Commun 2023; 14:2487. [PMID: 37120443 PMCID: PMC10148889 DOI: 10.1038/s41467-023-37460-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 03/17/2023] [Indexed: 05/01/2023] Open
Abstract
Social hierarchies exert a powerful influence on behavior, but the neurobiological mechanisms that detect and regulate hierarchical interactions are not well understood, especially at the level of neural circuits. Here, we use fiber photometry and chemogenetic tools to record and manipulate the activity of nucleus accumbens-projecting cells in the ventromedial prefrontal cortex (vmPFC-NAcSh) during tube test social competitions. We show that vmPFC-NAcSh projections signal learned hierarchical relationships, and are selectively recruited by subordinate mice when they initiate effortful social dominance behavior during encounters with a dominant competitor from an established hierarchy. After repeated bouts of social defeat stress, this circuit is preferentially activated during social interactions initiated by stress resilient individuals, and plays a necessary role in supporting social approach behavior in subordinated mice. These results define a necessary role for vmPFC-NAcSh cells in the adaptive regulation of social interaction behavior based on prior hierarchical interactions.
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Affiliation(s)
- Robert N Fetcho
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
| | - Baila S Hall
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - David J Estrin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Alexander P Walsh
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Peter J Schuette
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jesse Kaminsky
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Ashna Singh
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Jacob Roshgodal
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Charlotte C Bavley
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Viraj Nadkarni
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Susan Antigua
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Thu N Huynh
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Logan Grosenick
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Camille Carthy
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Lauren Komer
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Avishek Adhikari
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Francis S Lee
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Anjali M Rajadhyaksha
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
- Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY, USA.
- Weill Cornell Autism Research Program, New York, NY, USA.
| | - Conor Liston
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
- Weill Cornell Autism Research Program, New York, NY, USA.
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A B L, A G, M B, H HN. Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.24.538114. [PMID: 37163009 PMCID: PMC10168253 DOI: 10.1101/2023.04.24.538114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Background The posterior intralaminar (PIL) complex of the thalamus is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed. Methods We used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real-time during social and non-social interactions. Finally, we used inhibitory DREADDs in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation. Results We observed significantly more c-fos -positive cells in the PIL of mice exposed to social versus object or no stimuli. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time it took female mice to form social habituation. Conclusions Together these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.
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Zheng D, Pisano F, Collard L, Balena A, Pisanello M, Spagnolo B, Mach-Batlle R, Tantussi F, Carbone L, De Angelis F, Valiente M, de la Prida LM, Ciracì C, De Vittorio M, Pisanello F. Toward Plasmonic Neural Probes: SERS Detection of Neurotransmitters through Gold-Nanoislands-Decorated Tapered Optical Fibers with Sub-10 nm Gaps. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2200902. [PMID: 36479741 DOI: 10.1002/adma.202200902] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 10/21/2022] [Indexed: 06/17/2023]
Abstract
Integration of plasmonic nanostructures with fiber-optics-based neural probes enables label-free detection of molecular fingerprints via surface-enhanced Raman spectroscopy (SERS), and it represents a fascinating technological horizon to investigate brain function. However, developing neuroplasmonic probes that can interface with deep brain regions with minimal invasiveness while providing the sensitivity to detect biomolecular signatures in a physiological environment is challenging, in particular because the same waveguide must be employed for both delivering excitation light and collecting the resulting scattered photons. Here, a SERS-active neural probe based on a tapered optical fiber (TF) decorated with gold nanoislands (NIs) that can detect neurotransmitters down to the micromolar range is presented. To do this, a novel, nonplanar repeated dewetting technique to fabricate gold NIs with sub-10 nm gaps, uniformly distributed on the wide (square millimeter scale in surface area), highly curved surface of TF is developed. It is experimentally and numerically shown that the amplified broadband near-field enhancement of the high-density NIs layer allows for achieving a limit of detection in aqueous solution of 10-7 m for rhodamine 6G and 10-5 m for serotonin and dopamine through SERS at near-infrared wavelengths. The NIs-TF technology is envisioned as a first step toward the unexplored frontier of in vivo label-free plasmonic neural interfaces.
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Affiliation(s)
- Di Zheng
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Filippo Pisano
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Liam Collard
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Antonio Balena
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Marco Pisanello
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Barbara Spagnolo
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Rosa Mach-Batlle
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Francesco Tantussi
- Istituto Italiano di Tecnologia, Center for Convergent Technologies, Genova, 16163, Italy
| | - Luigi Carbone
- CNR NANOTEC - Institute of Nanotechnology, University of Salento, Lecce, 73100, Italy
| | - Francesco De Angelis
- Istituto Italiano di Tecnologia, Center for Convergent Technologies, Genova, 16163, Italy
| | - Manuel Valiente
- Brain Metastasis Group, Spanish National Cancer Research Center (CNIO), Madrid, 28029, Spain
| | | | - Cristian Ciracì
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
| | - Massimo De Vittorio
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
- Dipartimento di Ingegneria Dell'Innovazione, Università del Salento, Lecce, 73100, Italy
| | - Ferruccio Pisanello
- Istituto Italiano di Tecnologia, Center for Biomolecular Nanotechnologies, Arnesano, LE, 73010, Italy
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31
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Nahvi RJ, Tanelian A, Nwokafor C, Godino A, Parise E, Estill M, Shen L, Nestler EJ, Sabban EL. Transcriptome profiles associated with resilience and susceptibility to single prolonged stress in the locus coeruleus and nucleus accumbens in male sprague-dawley rats. Behav Brain Res 2023; 439:114162. [PMID: 36257560 PMCID: PMC9812303 DOI: 10.1016/j.bbr.2022.114162] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/12/2022] [Accepted: 10/12/2022] [Indexed: 01/07/2023]
Abstract
Although most people are subjected to traumatic stress at least once in their lifetime, only a subset develop long-lasting, stress-triggered neuropsychiatric disorders, such as PTSD. Here we examined different transcriptome profiles within the locus coeruleus (LC) and nucleus accumbens (NAc) that may contribute to stress susceptibility. Sprague Dawley male rats were exposed to the single prolonged stress (SPS) model for PTSD. Two weeks later they were tested for their anxiety/avoidance behavior on the Elevated Plus Maze (EPM) and were divided into high and low anxiety-like subgroups. RNA (n = 5 per group) was subsequently isolated from LC and NAc and subjected to RNAseq. Transcriptome analysis was used to identify differentially-expressed genes (DEGs) which differed by at least 50 % with significance of 0.01. The LC had more than six times the number of DEGs than the NAc. Only one DEG was regulated similarly in both locations. Many of the DEGs in the LC were associated with morphological changes, including regulation of actin cytoskeleton, growth factor activity, regulation of cell size, brain development and memory, with KEGG pathway of regulation of actin cytoskeleton. The DEGs in the NAc were primarily related to DNA repair and synthesis, and differential regulation of cytokine production. The analysis identified MTPN (myotrophin) and NR3C1 (glucocorticoid receptor) as important upstream regulators of stress susceptibility in the LC. Overall the study provides new insight into molecular pathways in the LC and NAc that are associated with anxiety-like behavior triggered by stress susceptibility or resilience.
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Affiliation(s)
- Roxanna J Nahvi
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, United States
| | - Arax Tanelian
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, United States
| | - Chiso Nwokafor
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, United States
| | - Arthur Godino
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Eric Parise
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Molly Estill
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Li Shen
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Eric J Nestler
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Esther L Sabban
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, United States.
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32
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Willmore L, Cameron C, Yang J, Witten IB, Falkner AL. Behavioural and dopaminergic signatures of resilience. Nature 2022; 611:124-132. [PMID: 36261520 PMCID: PMC10026178 DOI: 10.1038/s41586-022-05328-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/07/2022] [Indexed: 12/14/2022]
Abstract
Chronic stress can have lasting adverse consequences in some individuals, yet others are resilient to the same stressor1,2. Susceptible and resilient individuals exhibit differences in the intrinsic properties of mesolimbic dopamine (DA) neurons after the stressful experience is over3-8. However, the causal links between DA, behaviour during stress and individual differences in resilience are unknown. Here we recorded behaviour in mice simultaneously with DA neuron activity in projections to the nucleus accumbens (NAc) (which signals reward9-12) and the tail striatum (TS) (which signals threat13-16) during social defeat. Supervised and unsupervised behavioural quantification revealed that during stress, resilient and susceptible mice use different behavioural strategies and have distinct activity patterns in DA terminals in the NAc (but not the TS). Neurally, resilient mice have greater activity near the aggressor, including at the onset of fighting back. Conversely, susceptible mice have greater activity at the offset of attacks and onset of fleeing. We also performed optogenetic stimulation of NAc-projecting DA neurons in open loop (randomly timed) during defeat or timed to specific behaviours using real-time behavioural classification. Both open-loop and fighting-back-timed activation promoted resilience and reorganized behaviour during defeat towards resilience-associated patterns. Together, these data provide a link between DA neural activity, resilience and resilience-associated behaviour during the experience of stress.
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Affiliation(s)
- Lindsay Willmore
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Courtney Cameron
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - John Yang
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Ilana B Witten
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
- Department of Psychology, Princeton University, Princeton, NJ, USA.
| | - Annegret L Falkner
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
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33
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Dong C, Zheng Y, Long-Iyer K, Wright EC, Li Y, Tian L. Fluorescence Imaging of Neural Activity, Neurochemical Dynamics, and Drug-Specific Receptor Conformation with Genetically Encoded Sensors. Annu Rev Neurosci 2022; 45:273-294. [PMID: 35316611 PMCID: PMC9940643 DOI: 10.1146/annurev-neuro-110520-031137] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent advances in fluorescence imaging permit large-scale recording of neural activity and dynamics of neurochemical release with unprecedented resolution in behaving animals. Calcium imaging with highly optimized genetically encoded indicators provides a mesoscopic view of neural activity from genetically defined populations at cellular and subcellular resolutions. Rigorously improved voltage sensors and microscopy allow for robust spike imaging of populational neurons in various brain regions. In addition, recent protein engineering efforts in the past few years have led to the development of sensors for neurotransmitters and neuromodulators. Here, we discuss the development and applications of these genetically encoded fluorescent indicators in reporting neural activity in response to various behaviors in different biological systems as well as in drug discovery. We also report a simple model to guide sensor selection and optimization.
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Affiliation(s)
- Chunyang Dong
- Graduate Program in Biochemistry, Molecular, Cellular, and Developmental Biology, University of California, Davis, California, USA
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA;
| | - Yu Zheng
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences; PKU-IDG/McGovern Institute for Brain Research; and Peking-Tsinghua Center for Life Sciences, Beijing, China;
| | - Kiran Long-Iyer
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA;
- Neuroscience Graduate Program, University of California, Davis, California, USA
| | - Emily C Wright
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA;
| | - Yulong Li
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences; PKU-IDG/McGovern Institute for Brain Research; and Peking-Tsinghua Center for Life Sciences, Beijing, China;
| | - Lin Tian
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA;
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34
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Seiler JL, Cosme CV, Sherathiya VN, Schaid MD, Bianco JM, Bridgemohan AS, Lerner TN. Dopamine signaling in the dorsomedial striatum promotes compulsive behavior. Curr Biol 2022; 32:1175-1188.e5. [PMID: 35134327 PMCID: PMC8930615 DOI: 10.1016/j.cub.2022.01.055] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/02/2021] [Accepted: 01/20/2022] [Indexed: 12/26/2022]
Abstract
Compulsive behavior is a defining feature of disorders such as substance use disorders. Current evidence suggests that corticostriatal circuits control the expression of established compulsions, but little is known about the mechanisms regulating the development of compulsions. We hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the development of compulsions (defined here as continued reward seeking in the face of punishment). We used dual-site fiber photometry to measure dopamine axon activity in the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) as compulsions emerged. Individual variability in the speed with which compulsions emerged was predicted by DMS dopamine axon activity. Amplifying this dopamine signal accelerated animals' transitions to compulsion, whereas inhibition delayed it. In contrast, amplifying DLS dopamine signaling had no effect on the emergence of compulsions. These results establish DMS dopamine signaling as a key controller of the development of compulsive reward seeking.
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Affiliation(s)
- Jillian L Seiler
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Psychology, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Caitlin V Cosme
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Venus N Sherathiya
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Michael D Schaid
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Joseph M Bianco
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Abigael S Bridgemohan
- Department of Biology, Northwestern University Weinberg College of Arts & Sciences, Evanston, IL 60208, USA
| | - Talia N Lerner
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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35
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Sui K, Meneghetti M, Kaur J, Sørensen JF, Berg RW, Markos C. Adaptive polymer fiber neural device for drug delivery and enlarged illumination angle for neuromodulation. J Neural Eng 2022; 19. [PMID: 35130533 DOI: 10.1088/1741-2552/ac5267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 02/07/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Optical fiber devices constitute significant tools for the modulation and interrogation of neuronal circuitry in the mid and deep brain regions. The illuminated brain area during neuromodulation has a direct impact on the spatio-temporal properties of the brain activity and depends solely on the material and geometrical characteristics of the optical fibers. In the present work, we developed two different flexible polymer optical fibers (POFs) with integrated microfluidic channels (MFCs) and an ultra-high numerical aperture (UHNA) for enlarging the illumination angle to achieve efficient neuromodulation. APPROACH Three distinct thermoplastic polymers: polysulfone (PSU), polycarbonate (PC), and fluorinated ethylene propylene (FEP) were used to fabricate two step-index UHNA POF neural devices using a scalable thermal drawing process. The POFs were characterized in terms of their illumination map as well as their fluid delivery capability in phantom and adult rat brain slices. MAIN RESULTS A 100-fold reduced bending stiffness of the proposed fiber devices compared to their commercially available counterparts has been found. The integrated MFCs can controllably deliver dye (trypan blue) on-demand over a wide range of injection rates spanning from 10 nL/min to 1000 nL/min. Compared with commercial silica fibers, the proposed UHNA POFs exhibited an increased illumination area by 17% and 21% under 470 and 650 nm wavelength, respectively. In addition, a fluorescent light recording experiment has been conducted to demonstrate the ability of our UHNA POFs to be used as optical waveguides in fiber photometry. SIGNIFICANCE Our results overcome the current technological limitations of fiber implants that have limited illumination area and we suggest that soft neural fiber devices can be developed using different custom designs for illumination, collection, and photometry applications. We anticipate our work to pave the way towards the development of next-generation functional optical fibers for neuroscience.
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Affiliation(s)
- Kunyang Sui
- DTU Fotonik, DTU - Lyngby Campus, Ørsteds Plads, 343, Lyngby, 2800, DENMARK
| | - Marcello Meneghetti
- DTU Fotonik, DTU - Lyngby Campus, Ørsteds Plads, 343,, Lyngby, 2800, DENMARK
| | - Jaspreet Kaur
- Department of Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Building: 62, Copenhagen, 2200, DENMARK
| | - Jakob Fleng Sørensen
- Department of Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Building: 62, Copenhagen, 2200, DENMARK
| | - Rune W Berg
- Department of Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Building: 62, Copenhagen, 2200, DENMARK
| | - Christos Markos
- DTU Fotonik, Technical University of Denmark, DTU Fotonik, Ørsteds Plads Building 343, room 022, Kgs.Lyngby, Lyngby, 2800, DENMARK
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36
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Murra D, Hilde KL, Fitzpatrick A, Maras PM, Watson SJ, Akil H. Characterizing the behavioral and neuroendocrine features of susceptibility and resilience to social stress. Neurobiol Stress 2022; 17:100437. [PMID: 35242893 PMCID: PMC8857076 DOI: 10.1016/j.ynstr.2022.100437] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/31/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023] Open
Abstract
Evaluating and coping with stressful social events as they unfold is a critical strategy in overcoming them without long-lasting detrimental effects. Individuals display a wide range of responses to stress, which can manifest in a variety of outcomes for the brain as well as subsequent behavior. Chronic Social Defeat Stress (CSDS) in mice has been widely used to model individual variation following a social stressor. Following a course of repeated intermittent psychological and physical stress, mice diverge into separate populations of social reactivity: resilient (socially interactive) and susceptible (socially avoidant) animals. A rich body of work reveals distinct neurobiological and behavioral consequences of this experience that map onto the resilient and susceptible groups. However, the range of factors that emerge over the course of defeat have not been fully described. Therefore, in the current study, we focused on characterizing behavioral, physiological, and neuroendocrine profiles of mice in three separate phases: before, during, and following CSDS. We found that following CSDS, traditional read-outs of anxiety-like and depression-like behaviors do not map on to the resilient and susceptible groups. By contrast, behavioral coping strategies used during the initial social stress encounter better predict which mice will eventually become resilient or susceptible. In particular, mice that will emerge as susceptible display greater escape behavior on Day 1 of social defeat than those that will emerge as resilient, indicating early differences in coping mechanisms used between the two groups. We further show that the social avoidance phenotype in susceptible mice is specific to the aggressor strain and does not generalize to conspecifics or other strains, indicating that there may be features of threat discrimination that are specific to the susceptible mice. Our findings suggest that there are costs and benefits to both the resilient and susceptible outcomes, reflected in their ability to cope and adapt to the social stressor.
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37
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Millard SJ, Bearden CE, Karlsgodt KH, Sharpe MJ. The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity. Neuropsychopharmacology 2022; 47:628-640. [PMID: 34588607 PMCID: PMC8782867 DOI: 10.1038/s41386-021-01188-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/23/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023]
Abstract
Schizophrenia is a severe psychiatric disorder affecting 21 million people worldwide. People with schizophrenia suffer from symptoms including psychosis and delusions, apathy, anhedonia, and cognitive deficits. Strikingly, schizophrenia is characterised by a learning paradox involving difficulties learning from rewarding events, whilst simultaneously 'overlearning' about irrelevant or neutral information. While dysfunction in dopaminergic signalling has long been linked to the pathophysiology of schizophrenia, a cohesive framework that accounts for this learning paradox remains elusive. Recently, there has been an explosion of new research investigating how dopamine contributes to reinforcement learning, which illustrates that midbrain dopamine contributes in complex ways to reinforcement learning, not previously envisioned. This new data brings new possibilities for how dopamine signalling contributes to the symptomatology of schizophrenia. Building on recent work, we present a new neural framework for how we might envision specific dopamine circuits contributing to this learning paradox in schizophrenia in the context of models of reinforcement learning. Further, we discuss avenues of preclinical research with the use of cutting-edge neuroscience techniques where aspects of this model may be tested. Ultimately, it is hoped that this review will spur to action more research utilising specific reinforcement learning paradigms in preclinical models of schizophrenia, to reconcile seemingly disparate symptomatology and develop more efficient therapeutics.
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Affiliation(s)
- Samuel J Millard
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA.
| | - Carrie E Bearden
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, 90095, USA
| | - Katherine H Karlsgodt
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, 90095, USA
| | - Melissa J Sharpe
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA.
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38
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Shan Q, Hu Y, Chen S, Tian Y. Nucleus accumbens dichotomically controls social dominance in male mice. Neuropsychopharmacology 2022; 47:776-787. [PMID: 34750567 PMCID: PMC8783020 DOI: 10.1038/s41386-021-01220-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 02/05/2023]
Abstract
Social dominance versus social submissiveness is a basic behavioral trait of social animals such as human beings and laboratory mice. The brain regions associated with this behavior have been intensely investigated, and early neuroimaging research on human subjects implies that the nucleus accumbens (NAc) might be involved in encoding social dominance. However, the underlying circuitry and synaptic mechanism are largely unknown. In this study, by introducing lesions to both NAc subregions, the shell and core, a causal relationship is established between social dominance and both NAc subregions. A further electrophysiology investigation on the circuitry of these two subregions revealed that the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D1 dopamine receptors in the shell is negatively correlated, and the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D2 dopamine receptors in the core is positively correlated, with social dominance. Correspondingly, a DREADD investigation revealed that the activities of these respective medium spiny neurons suppress and promote social dominance. These findings identify a neural substrate for social dominance, implying the potential for a therapeutic strategy for treating related psychiatric disorders.
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Affiliation(s)
- Qiang Shan
- Laboratory for Synaptic Plasticity, Shantou University Medical College, Shantou, 515041, Guangdong, China.
| | - You Hu
- Laboratory for Synaptic Plasticity, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Shijie Chen
- Laboratory for Synaptic Plasticity, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Yao Tian
- Chern Institute of Mathematics, Nankai University, 300071, Tianjin, China
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39
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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40
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GuPPy, a Python toolbox for the analysis of fiber photometry data. Sci Rep 2021; 11:24212. [PMID: 34930955 PMCID: PMC8688475 DOI: 10.1038/s41598-021-03626-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/07/2021] [Indexed: 11/18/2022] Open
Abstract
Fiber photometry (FP) is an adaptable method for recording in vivo neural activity in freely behaving animals. It has become a popular tool in neuroscience due to its ease of use, low cost, the ability to combine FP with freely moving behavior, among other advantages. However, analysis of FP data can be challenging for new users, especially those with a limited programming background. Here, we present Guided Photometry Analysis in Python (GuPPy), a free and open-source FP analysis tool. GuPPy is designed to operate across computing platforms and can accept data from a variety of FP data acquisition systems. The program presents users with a set of graphic user interfaces (GUIs) to load data and provide input parameters. Graphs are produced that can be easily exported for integration into scientific figures. As an open-source tool, GuPPy can be modified by users with knowledge of Python to fit their specific needs.
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41
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Cai H, Zhang P, Qi G, Zhang L, Li T, Li M, Lv X, Lei J, Ming J, Tian B. Systematic Input-Output Mapping Reveals Structural Plasticity of VTA Dopamine Neurons-Zona Incerta Loop Underlying the Social Buffering Effects in Learned Helplessness. Mol Neurobiol 2021; 59:856-871. [PMID: 34796463 DOI: 10.1007/s12035-021-02614-4] [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: 08/10/2021] [Accepted: 10/19/2021] [Indexed: 11/28/2022]
Abstract
A common phenomenon called social buffering (SB), communication within conspecific animals is a benefit for a stressed individual to better recover from aversive events, is crucial to all mammals. Although the dopamine reward system has been implicated in SB, it is not clear which neuronal populations are relevant and how they contribute. Here, we adopted a learned helplessness (LH) animal model of depression and found that LH subjects housed with a conspecific partner show better performance in the shuttle box test, showing that SB improves the stress-coping abilities to deal with stress. Bidirectional manipulation of ventral tegmental area (VTA) dopamine neurons by chemogenetic tools can mimic or block the SB effect in LH mice. To screen for SB-induced structure plasticity of VTA dopamine neurons, we employed viral genetic tools for mapping input and output architecture and found LH- and SB-triggered circuit-level changes in neuronal ensembles. Zona incerta (ZI), an overlapping brain region, was significantly changed in both anterograde and retrograde tracing during LH and SB. These results reveal a neural loop with structural plasticity between VTA dopamine neurons and ZI underlies the SB effects in LH and lays a foundation for studying how VTA dopamine neurons regulate SB-related neural circuits.
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Affiliation(s)
- Hongwei Cai
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Pei Zhang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
- Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
- Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Guangjian Qi
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
- Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
- Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Lijun Zhang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Tongxia Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Ming Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Xinyuan Lv
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Jie Lei
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China
| | - Jie Ming
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430022, People's Republic of China.
| | - Bo Tian
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China.
- Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People's Republic of China.
- Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, Hubei Province, 430030, People's Republic of China.
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42
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Chakraborty P, Chattarji S, Jeanneteau F. A salience hypothesis of stress in PTSD. Eur J Neurosci 2021; 54:8029-8051. [PMID: 34766390 DOI: 10.1111/ejn.15526] [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: 07/10/2021] [Revised: 09/13/2021] [Accepted: 10/30/2021] [Indexed: 11/30/2022]
Abstract
Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from post-traumatic stress disorder (PTSD). Interestingly, similar observations have been robustly replicated across many animal models of stress as well. By using evidence from such rodent stress paradigms, in the present review, we explore PTSD through the lens of salience processing. In this context, we propose that interaction between the neurotrophin brain-derived neurotrophic factor (BDNF) and glucocorticoids determines the long lasting cellular and behavioural consequences of stress salience. We also describe the dual effect of glucocorticoid therapy in the amelioration of PTSD symptoms. Finally, by integrating in vivo observations at multiple scales of plasticity, we propose a unifying hypothesis that pivots on a crucial role of glucocorticoid signalling in dynamically orchestrating stress salience.
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Affiliation(s)
- Prabahan Chakraborty
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France.,Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India
| | - Sumantra Chattarji
- Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bellary Road, Bangalore, 560065, India.,Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.,Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Freddy Jeanneteau
- Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France
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43
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Radwan B, Jansen G, Chaudhury D. Sleep-wake dynamics pre- and post-exposure to chronic social stress. iScience 2021; 24:103204. [PMID: 34703999 PMCID: PMC8524188 DOI: 10.1016/j.isci.2021.103204] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/16/2021] [Accepted: 09/28/2021] [Indexed: 10/28/2022] Open
Abstract
An analytical approach combining the statistical distributions of the sleep-wake bouts and the Markov transition matrix is used to explain the under-examined association between the microarchitecture of the sleep-wake cycle and susceptibility to chronic social stress in C57BL/6J mice. We separated the sleep-wake transitions into distinct sleep-wake sequences, NREM↔Wake and NREM→REM→Wake, which are controlled by independent neural circuits. Our findings imply greater pull toward the wake leading to early termination and fragmentation of the sleep bouts in the light in both sleep-wake sequences pre- and post-stress. Moreover, the stability of NREM in the NREM↔Wake transition was lower, and the probability of transitioning to wake was higher in susceptible relative to resilient or stress-naïve mice pre- and post-stress. Our findings help elucidate the mechanistic interplay between sleep and mood by suggesting the potential neural underpinnings of sleep disturbances responsible the aberrant transitions of sleep-wake bouts exhibited by the stress-susceptible phenotype.
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Affiliation(s)
- Basma Radwan
- Department of Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Gloria Jansen
- Wellcome Trust Developmental Mechanisms, Cambridge University, Cambridge, UK
| | - Dipesh Chaudhury
- Department of Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
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44
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Pascual Cuadrado D, Todorov H, Lerner R, Islami L, Bindila L, Gerber S, Lutz B. Long-term molecular differences between resilient and susceptible mice after a single traumatic exposure. Br J Pharmacol 2021; 179:4161-4180. [PMID: 34599847 DOI: 10.1111/bph.15697] [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: 03/16/2021] [Revised: 07/14/2021] [Accepted: 08/25/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE PTSD is a heterogeneous disorder induced by trauma, resulting in severe long-term impairments of an individual's mental health. Interestingly, PTSD does not develop in every individual; thus, some individuals are more resilient than others. However, the underlying molecular mechanisms are poorly understood. Here, we aimed at shedding light on these processes. EXPERIMENTAL APPROACH We used a single-trauma PTSD model in mice to induce long-term maladaptive behaviours and profiled the mice four weeks post-trauma into resilient or susceptible individuals. The phenotype's classification was based on their individual responses in different behavioural experiments. We analysed microbiome, circulating endocannabinoids, and long-term changes in brain phospholipid and transcript levels. KEY RESULTS We found a plethora of molecular differences between resilient and susceptible individuals across multiple molecular domains, including lipidome, transcriptome, and gut microbiome. Some of these differences were stable even several weeks after the trauma, indicating the long-term impact of traumatic stimuli on the organism's physiology. Furthermore, the integration of these multi-layered molecular data revealed that resilient and susceptible individuals have very distinct molecular signatures across various physiological systems. CONCLUSIONS AND IMPLICATIONS We showed that trauma induces individual-specific behavioural responses that, in combination with a longitudinal characterization of mice, can be used to identify distinct sub-phenotypes within the trauma-exposed group. These groups differ significantly not only in their behaviour but also in specific molecular aspects across a variety of tissues and brain regions. This approach may reveal new targets and predictive biomarkers for the pharmacological treatment and prognosis of stress-related disorders.
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Affiliation(s)
- Diego Pascual Cuadrado
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Hristo Todorov
- Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Raissa Lerner
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | | | - Laura Bindila
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Susanne Gerber
- Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.,Leibniz Institute for Resilience Research; Mainz, Germany
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45
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Bravo-Tobar ID, Fernández P, Sáez JC, Dagnino-Subiabre A. Long-term effects of stress resilience: Hippocampal neuroinflammation and behavioral approach in male rats. J Neurosci Res 2021; 99:2493-2510. [PMID: 34184764 DOI: 10.1002/jnr.24902] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/07/2021] [Accepted: 05/26/2021] [Indexed: 01/28/2023]
Abstract
Resilience to stress is the ability to quickly adapt to adversity. There is evidence that exposure to prolonged stress triggers neuroinflammation what produces individual differences in stress vulnerability. However, the relationship between stress resilience, neuroinflammation, and depressive-like behaviors remains unknown. The aim of this study was to analyze the long-term effects of social defeat stress (SDS) on neuroinflammation in the hippocampus and depressive-like behaviors. Male rats were subjected to the SDS paradigm. Social interaction was analyzed 1 and 2 weeks after ending the SDS to determine which animals were susceptible or resilient to stress. Neuroinflammation markers glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and elevated membrane permeability in astrocytes and microglia, as well as depressive-like behaviors in the sucrose preference test and forced swim test were evaluated in all rats. One week after SDS, resilient rats increased their sucrose preference, and time spent in the floating behavior decreased in the forced swim test compared to susceptible rats. Surprisingly, resilient rats became susceptible to stress, and presented neuroinflammation 2 weeks after SDS. These findings suggest that SDS-induced hippocampal neuroinflammation persists in post-stress stages, regardless of whether rats were initially resilient or not. Our study opens a new approach to understanding the neurobiology of stress resilience.
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Affiliation(s)
- Iván D Bravo-Tobar
- Instituto de Neurociencia, Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Paola Fernández
- Instituto de Neurociencia, Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Juan C Sáez
- Instituto de Neurociencia, Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Alexies Dagnino-Subiabre
- Laboratory of Stress Neurobiology, Centre for Integrative Neurobiology and Pathophysiology, Institute of Physiology, Faculty of Sciences, Universidad de Valparaíso, Valparaíso, Chile
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46
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Holly EN, Davatolhagh MF, España RA, Fuccillo MV. Striatal low-threshold spiking interneurons locally gate dopamine. Curr Biol 2021; 31:4139-4147.e6. [PMID: 34302742 DOI: 10.1016/j.cub.2021.06.081] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 05/02/2021] [Accepted: 06/25/2021] [Indexed: 11/27/2022]
Abstract
The dorsomedial striatum (DMS) is a central hub supporting goal-directed learning and motor performance. Recent evidence has revealed unexpected roles for local inhibitory GABAergic networks in modulating striatal output and behavior.1 The sparse low-threshold spiking interneuron subtype (LTSI), which exhibits robust reward-circumscribed population activity, is a bidirectional regulator of initial goal-directed learning.2 Striatal dopamine signaling is a central reward-related neuromodulatory system mediating goal-directed action and performance, serving as a teaching signal,3 facilitating synaptic plasticity,4 and invigorating motor behaviors.5 Given the dynamic modulation of LTSIs during goal-directed behavior, we hypothesized that they could provide a novel GABAergic mechanism of local striatal dopaminergic regulation to shape early learning. We provide anatomical evidence for close proximation of LTSI terminals and dopaminergic processes in striatum, suggesting that LTSIs directly control dopaminergic axon activity. Using in vitro fast scan cyclic voltammetry, we demonstrate that LTSIs directly attenuate optogenetically evoked dopamine via GABAB receptor signaling. In vivo, GRABDA dopamine sensor imaging shows that LTSIs strongly modulate striatal dopamine dynamics during operant learning, while pharmacological stabilization of dopamine via intra-striatal aripiprazole microinjection suppresses the effects of LTSI inhibition on learning. Together, these results uncover an unexpected function for LTSIs in gating striatal dopamine to facilitate goal-directed learning.
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Affiliation(s)
- Elizabeth N Holly
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - M Felicia Davatolhagh
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rodrigo A España
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Marc V Fuccillo
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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47
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Thornton JL, Everett NA, Webb P, Turner AJ, Cornish JL, Baracz SJ. Adolescent oxytocin administration reduces depression-like behaviour induced by early life stress in adult male and female rats. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110279. [PMID: 33567331 DOI: 10.1016/j.pnpbp.2021.110279] [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: 11/30/2020] [Revised: 01/29/2021] [Accepted: 02/05/2021] [Indexed: 01/06/2023]
Abstract
Early life stress (ELS) exposure alters brain development, increasing vulnerability for mental illness in adulthood, including depression. Despite this association, there are no approved pharmacotherapies to protect against the emergence of mental illness resulting from ELS. Recent preclinical work showed that oxytocin (OT) administration in adulthood reduced depressive-like behaviour in male rats with a history of ELS. However, the ability of an OT treatment regime in adolescence, a critical developmental window for the OT system, to prevent the expression of depressive-like behaviours following ELS has not been investigated. Therefore, the present study aimed to determine whether chronic OT administration can ameliorate the enduring effects of ELS on depressive-like behaviours in both male and female rats. Following birth, Long Evans rat pups (N = 107) underwent maternal separation (MS) for either 15 min (MS15) or 6 h (MS360) on postnatal days (PND) 1-21. During adolescence (PND 28-42), rats received a daily injection of either OT (1 mg/kg) or saline. During adulthood (PND 57 onwards), effort-related motivation was measured using a model of effortful choice (EC), while behavioural despair was measured using the forced swim test (FST). Lastly, body and organ weights were measured to examine the physiological impacts of ELS and chronic OT administration. Overall, in both sexes, MS360 increased behavioural despair yet had no impact on effort-related motivation. Importantly, adolescent OT administration prevented the MS360-induced increase in behavioural despair in both males and females. Additionally, MS360 resulted in persistent reductions in body weight in both sexes post-weaning and increased spleen weight in males and adrenal weight in females. OT treatment had no impact on body weight in either sex, but prevented the MS-induced increase in adrenal gland weight in females. Overall, these findings have important implications for using oxytocin as a preventative pharmacotherapy after ELS.
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Affiliation(s)
- Jade L Thornton
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Nicholas A Everett
- School of Psychology, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Paige Webb
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Anita J Turner
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Jennifer L Cornish
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia; Centre for Emotional Health, Macquarie University, North Ryde, NSW 2109, Australia
| | - Sarah J Baracz
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia; Centre for Emotional Health, Macquarie University, North Ryde, NSW 2109, Australia; School of Psychology, University of New South Wales, Randwick, NSW, 2052, Australia.
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48
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Ben-Ami Bartal I, Breton JM, Sheng H, Long KL, Chen S, Halliday A, Kenney JW, Wheeler AL, Frankland P, Shilyansky C, Deisseroth K, Keltner D, Kaufer D. Neural correlates of ingroup bias for prosociality in rats. eLife 2021; 10:65582. [PMID: 34253289 PMCID: PMC8277352 DOI: 10.7554/elife.65582] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 06/16/2021] [Indexed: 01/25/2023] Open
Abstract
Prosocial behavior, in particular helping others in need, occurs preferentially in response to distress of one’s own group members. In order to explore the neural mechanisms promoting mammalian helping behavior, a discovery-based approach was used here to identify brain-wide activity correlated with helping behavior in rats. Demonstrating social selectivity, rats helped others of their strain (‘ingroup’), but not rats of an unfamiliar strain (‘outgroup’), by releasing them from a restrainer. Analysis of brain-wide neural activity via quantification of the early-immediate gene c-Fos identified a shared network, including frontal and insular cortices, that was active in the helping test irrespective of group membership. In contrast, the striatum was selectively active for ingroup members, and activity in the nucleus accumbens, a central network hub, correlated with helping. In vivo calcium imaging showed accumbens activity when rats approached a trapped ingroup member, and retrograde tracing identified a subpopulation of accumbens-projecting cells that was correlated with helping. These findings demonstrate that motivation and reward networks are associated with helping an ingroup member and provide the first description of neural correlates of ingroup bias in rodents.
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Affiliation(s)
- Inbal Ben-Ami Bartal
- Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel.,School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel.,Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
| | - Jocelyn M Breton
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
| | - Huanjie Sheng
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States
| | - Kimberly Lp Long
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
| | - Stella Chen
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
| | - Aline Halliday
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States
| | - Justin W Kenney
- The Hospital for Sick Children, Toronto, Neuroscience and Mental Health Program, Toronto, Canada
| | - Anne L Wheeler
- The Hospital for Sick Children, Toronto, Neuroscience and Mental Health Program, Toronto, Canada.,Physiology Department, University of Toronto, Toronto, Canada
| | - Paul Frankland
- The Hospital for Sick Children, Toronto, Neuroscience and Mental Health Program, Toronto, Canada.,Physiology Department, University of Toronto, Toronto, Canada.,Canadian Institute for Advanced Research, Toronto, Canada
| | - Carrie Shilyansky
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, United States
| | - Karl Deisseroth
- Department of Bioengineering, Stanford University, Stanford, United States.,Department of Psychiatry, Stanford University, Stanford, United States.,Howard Hughes Medical Institute, Stanford University, Stanford, United States
| | - Dacher Keltner
- Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States.,Department of Psychology, University of California, Berkeley, Berkeley, United States
| | - Daniela Kaufer
- Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States.,Canadian Institute for Advanced Research, Toronto, Canada
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49
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Post MR, Sulzer D. The chemical tools for imaging dopamine release. Cell Chem Biol 2021; 28:748-764. [PMID: 33894160 PMCID: PMC8532025 DOI: 10.1016/j.chembiol.2021.04.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/23/2021] [Accepted: 04/06/2021] [Indexed: 02/07/2023]
Abstract
Dopamine is a modulatory neurotransmitter involved in learning, motor functions, and reward. Many neuropsychiatric disorders, including Parkinson's disease, autism, and schizophrenia, are associated with imbalances or dysfunction in the dopaminergic system. Yet, our understanding of these pervasive public health issues is limited by our ability to effectively image dopamine in humans, which has long been a goal for chemists and neuroscientists. The last two decades have witnessed the development of many molecules used to trace dopamine. We review the small molecules, nanoparticles, and protein sensors used with fluorescent microscopy/photometry, MRI, and PET that shape dopamine research today. None of these tools observe dopamine itself, but instead harness the biology of the dopamine system-its synthetic and metabolic pathways, synaptic vesicle cycle, and receptors-in elegant ways. Their advantages and weaknesses are covered here, along with recent examples and the chemistry and biology that allow them to function.
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Affiliation(s)
- Michael R Post
- Department of Psychiatry, Columbia University Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
| | - David Sulzer
- Departments of Psychiatry, Neurology, and Pharmacology, Columbia University Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
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50
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Muir J, Bagot RC. Mechanisms of Stress-Induced Sleep Disturbance Give New Insight Into Stress Vulnerability. Biol Psychiatry 2021; 89:1108-1110. [PMID: 34082885 DOI: 10.1016/j.biopsych.2021.03.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Affiliation(s)
- Jessie Muir
- Integrated Program in Neuroscience, McGill University, Montréal, Canada.
| | - Rosemary C Bagot
- Department of Psychology, McGill University, Montréal, Quebec, Canada; Ludmer Centre for Neuroinformatics and Mental Health, Montréal, Quebec, Canada
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