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1.
Nat Commun ; 15(1): 5042, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871707

RESUMO

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.


Assuntos
Antidepressivos , Transtorno Depressivo Maior , Núcleo Dorsal da Rafe , Histonas , Estresse Psicológico , Animais , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Histonas/metabolismo , Masculino , Feminino , Estresse Psicológico/metabolismo , Humanos , Antidepressivos/farmacologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/tratamento farmacológico , Camundongos , Serotonina/metabolismo , Camundongos Endogâmicos C57BL , Epigênese Genética/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Derrota Social
2.
bioRxiv ; 2023 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-37205414

RESUMO

Background: Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

3.
Psychopharmacology (Berl) ; 239(10): 3287-3296, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35974246

RESUMO

RATIONALE: The attraction to alcohol can be greatly increased when it is consumed in a social context. While pro-social interactions can potentiate voluntary alcohol drinking under some conditions, aversive social experience (i.e., social stress) can similarly intensify alcohol consumption. OBJECTIVE: We sought to determine how exposure to different types of chronic social stress (i.e., intermittent episodes of social defeat or continuous social stress) influences alcohol consumption and the reinforcing effects of alcohol in mice with a history of drinking. METHODS: Separate cohorts of male C57BL/6J mice were exposed to either 10 days of continuous or intermittent social defeat stress. In experiment 1, mice were assigned to 20% w/v alcohol consumption in a two-bottle choice protocol both prior to and after exposure to social defeat stress. In a second experiment, mice engaged in an operant response sequence to gain access to alcohol wherein completion of a fixed interval (FI; 5 min) schedule was reinforced with continuous access to alcohol (fixed ratio; FR1) for up to 1.8 g/kg. Alcohol-reinforced responding and subsequent alcohol consumption were assessed daily for 4 weeks prior to the 10-day social stress exposure and for 6-week post-stress. Machine learning was implemented to standardize the analysis of defeat behaviors exhibited by the intruder mouse during confrontation with an attacking resident. RESULTS: In mice with a prior history of alcohol drinking, intermittent episodes of social defeat stress produced a significant increase in 20% EtOH consumption in preference over concurrently available water. This increased intake persisted for at least 6 weeks after the final social stress experience. Intermittently stressed mice also accelerated their anticipatory responding during the fixed interval component of the operant response chain that was reinforced by alcohol. Neither unstressed controls nor mice exposed to continuous social stress exhibited significant increases in alcohol consumption and alcohol reinforcement. DISCUSSION: Episodic social defeat stress promotes the seeking and consumption of alcohol, extending earlier work to alcohol-experienced mice. We hypothesize that intermittent access to alcohol and intermittent episodes of social stress are additive and share common sensitizing neural mechanisms that engender excessive alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas , Etanol , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico , Água
4.
Psychopharmacology (Berl) ; 239(10): 3249-3261, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35951078

RESUMO

RATIONALE: Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC). OBJECTIVE: In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male. While deciding to engage in aggressive vs. sociosexual behavior, corresponding neural activation was assessed via c-Fos immunoreactivity in cortical, amygdaloid and tegmental regions of interest. A further objective was to investigate how self-administered alcohol impacted social choice. METHODS: During repeated confrontations with an intruder male in their home cage, experimental mice engaged in species-specific sequence of pursuit, threat, and attack behavior within < 2 min. Mice were then conditioned to respond at one of two separate illuminated operanda in an experimental chamber (octagon) attached to their home cage; completion of 10 responses (fixed ratio 10; FR10) was reinforced by access to either a female or a male intruder which were presented in the resident's home cage. Brains were harvested following choice between the concurrently available aggressive and sociosexual options and processed for c-Fos immunoreactivity across 10 brain regions. In two separate groups, mice were trained to rapidly self-administer ethanol prior to a social choice trial in order to examine the effects of alcohol on social choice, sociosexual, aggressive acts and postures, and concurrent c-Fos activity in the mPFC and limbic regions. RESULTS AND DISCUSSION: Eight out of 65 mice consistently chose to engage in aggressive behavior in preference to sociosexual contact with a female when each outcome was concurrently available. Self-administered alcohol (experiment 1: 1.2 ± 0.02 g/kg; experiment 2: 0, 1.0, 1.5, and 1.8 g/kg) increased responding for the aggressive option in mice that previously opted predominantly for access to sociosexual interactions with the female. When choosing the aggressive, but not the sociosexual option, the prelimbic area of the mPFC revealed increased c-Fos activity, guiding future detailed inquiry into the neural mechanisms for aggressive choice.


Assuntos
Agressão , Consumo de Bebidas Alcoólicas , Animais , Modelos Animais de Doenças , Etanol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos
5.
Curr Top Behav Neurosci ; 54: 245-281, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34964935

RESUMO

The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption. Increasingly discrete regions and connections within the prefrontal cortex, the ventral and dorsal striatum, thalamic and hypothalamic nuclei, tegmental areas as well as brain stem structures begin to be identified as critical for reacting to and coping with social stress while seeking and consuming alcohol. Several candidate molecules that modulate signals within these neural connections have been targeted in order to reduce excessive drinking and relapse. In spite of some early clinical failures, neuropeptides such as CRF, opioids, or oxytocin continue to be examined for their role in attenuating stress-escalated drinking. Recent work has focused on neural sites of action for peptides and steroids, most likely in neuroinflammatory processes as a result of interactive effects of episodic social stress and excessive alcohol seeking and drinking.


Assuntos
Receptores de Hormônio Liberador da Corticotropina , Estresse Psicológico , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Etanol , Córtex Pré-Frontal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismo
6.
Biol Psychiatry ; 90(8): 563-574, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34281710

RESUMO

BACKGROUND: Comorbid stress-induced mood and alcohol use disorders are increasingly prevalent among female patients. Stress exposure can disrupt salience processing and goal-directed decision making, contributing to persistent maladaptive behavioral patterns; these and other stress-sensitive cognitive and behavioral processes rely on dynamic and coordinated signaling by midline and intralaminar thalamic nuclei. Considering the role of social trauma in the trajectory of these debilitating psychopathologies, identifying vulnerable thalamic cells may provide guidance for targeting persistent stress-induced symptoms. METHODS: A novel behavioral protocol traced the progression from social trauma to the development of social defensiveness and chronically escalated alcohol consumption in female mice. Recent cell activation-measured as cFos-was quantified in thalamic cells after safe social interactions, revealing stress-sensitive corticotropin-releasing hormone-expressing (Crh+) anterior central medial thalamic (aCMT) cells. These cells were optogenetically stimulated during stress-induced social defensiveness and abstinence-escalated binge drinking. RESULTS: Crh+ aCMT neurons exhibited substantial activation after social interactions in stress-naïve but not in stressed female mice. Photoactivating Crh+ aCMT cells dampened stress-induced social deficits, whereas inhibiting these cells increased social defensiveness in stress-naïve mice. Optogenetically activating Crh+ aCMT cells diminished abstinence-escalated binge alcohol drinking in female mice, regardless of stress history. CONCLUSIONS: This work uncovers a role for Crh+ aCMT neurons in maladaptive stress-induced social interactions and in binge drinking after forced abstinence in female mice. This molecularly defined thalamic cell population may serve as a critical stress-sensitive hub for social deficits caused by exposure to social trauma and for patterns of excessive alcohol drinking in female populations.


Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas , Animais , Hormônio Liberador da Corticotropina , Etanol , Feminino , Humanos , Camundongos , Receptores de Hormônio Liberador da Corticotropina , Estresse Psicológico
7.
Curr Biol ; 31(11): R716-R718, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34102118

RESUMO

Violent behavior is the product of a diverse network of neural structures. A new study shows that the anterior cingulate cortex is important for helping to restrain overly aggressive acts, even within a fight, to ensure animals match their behavioral intensity with the challenge posed by their opponents.


Assuntos
Agressão , Giro do Cíngulo , Animais
8.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31281636

RESUMO

Aggression is a phylogenetically stable behavior, and attacks on conspecifics are observed in most animal species. In this review, we discuss translational models as they relate to pathological forms of offensive aggression and the brain mechanisms that underlie these behaviors. Quantifiable escalations in attack or the development of an atypical sequence of attacks and threats is useful for characterizing abnormal variations in aggression across species. Aggression that serves as a reinforcer can be excessive, and certain schedules of reinforcement that allow aggression rewards also allow for examining brain and behavior during the anticipation of a fight. Ethological attempts to capture and measure offensive aggression point to two prominent hypotheses for the neural basis of violence. First, pathological aggression may be due to an exaggeration of activity in subcortical circuits that mediate adaptive aggressive behaviors as they are triggered by environmental or endogenous cues at vulnerable time points. Indeed, repeated fighting experiences occur with plasticity in brain areas once considered hardwired. Alternatively, a separate "violence network" may converge on aggression circuitry that disinhibits pathological aggression (for example, via disrupted cortical inhibition). Advancing animal models that capture the motivation to commit pathological aggression remains important to fully distinguish the neural architecture of violence as it differs from adaptive competition among conspecifics.


Assuntos
Agressão , Encéfalo , Violência , Agressão/fisiologia , Animais , Encéfalo/fisiologia , Motivação
9.
Biol Psychiatry ; 86(9): 657-668, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255250

RESUMO

BACKGROUND: Despite the twofold higher prevalence of major depressive and posttraumatic stress disorders in women compared with men, most clinical and preclinical studies have focused on male subjects. We used an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression. METHODS: Intact Swiss Webster (CFW) female resident mice were housed with castrated male mice and tested for aggression toward female intruders. For 10 days, aggressive CFW female residents defeated C57BL/6J (B6) female intruders during 5-minute encounters. Measures of corticosterone, c-Fos activation in hypothalamic and limbic structures, and species-typical behaviors were collected from defeated and control females. Ketamine (20 mg/kg) was tested for its potential to reverse stress-induced social deficits. RESULTS: Housed with a castrated male mouse, most intact resident CFW females readily attacked unfamiliar B6 female intruders, inflicting >40 bites in a 5-minute encounter. Compared with controls, defeated B6 females exhibited elevated plasma corticosterone and increased c-Fos activation in the medial amygdala, ventral lateral septum, ventromedial hypothalamus, and hypothalamic paraventricular nucleus. Chronically defeated females also showed vigilance-like behavior and deficits in social interactions, novel object investigation, and nesting. The duration of social interactions increased 24 hours after chronically defeated female mice received a systemic dose of ketamine. CONCLUSIONS: These findings demonstrate that CFW female mice living with male conspecifics can be used as aggressive residents in an ethological model of female social defeat stress. These novel behavioral methods will encourage further studies of sex-specific neural, physiological, and behavioral adaptations to chronic stress and the biological bases for interfemale aggression.


Assuntos
Agressão , Comportamento Animal , Encéfalo/fisiologia , Genes fos , Estresse Psicológico , Animais , Corticosterona/sangue , Modelos Animais de Doenças , Feminino , Genes Precoces , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais , Comportamento Social
10.
Psychopharmacology (Berl) ; 236(7): 2027-2037, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30798402

RESUMO

RATIONALE: Stressful life experiences can persistently increase the motivation for, and consumption of, intensely rewarding stimuli, like cocaine, over time. In rodents, intermittent versus continuous exposure to social stress engenders opposing changes to reward-related behavior, as measured by consumption of sucrose and cocaine. OBJECTIVE: The present study examines if the effects of intermittent versus continuous social stress on cocaine self-administration in mice parallel those seen in rats. METHODS: Both forms of social stress involve a brief daily physical confrontation with an aggressive resident for 10 consecutive days. Continuous social stress involves constant visual and olfactory exposure to an aggressive resident via habitation in a protected portion of the resident's home cage, while exposure to an aggressive resident during intermittent social stress is limited to a single, physical encounter per day. Implementing a femoral vein catheterization method for the first time in mice, we determined divergent changes to intravenous cocaine self-administration. RESULTS: Modestly increased cocaine self-administration after intermittent social stress was confirmed. In a subset of animals, continuous social stress in mice substantially increased cocaine self-administration and sucrose intake. By stark contrast, another subpopulation had substantial attenuation of cocaine self-administration and sucrose intake after continuous social stress. CONCLUSIONS: Bimodal divergence in responding for rewarding stimuli including cocaine after social stress experience likely reflects two opposing forms of coping to continuous social stress that promote either a sensitization or attenuation of reward-seeking.


Assuntos
Agressão/psicologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Relações Interpessoais , Estresse Psicológico/psicologia , Agressão/efeitos dos fármacos , Agressão/fisiologia , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Feminino , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Autoadministração , Sacarose/administração & dosagem
11.
Front Behav Neurosci ; 12: 206, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271332

RESUMO

Alcohol drinking, in some individuals, culminates in pathologically aggressive and violent behaviors. Alcohol can escalate the urge to fight, despite causing disruptions in fighting performance. When orally administered under several dosing conditions the current study examined in a mouse model if repeated alcohol escalates the motivation to fight, the execution of fighting performance, or both. Specifically, seven daily administrations of alcohol (0, 1.8, or 2.2 g/kg) determined if changes in the motivation to initiate aggressive acts occur with, or without, shifts in the severity of fighting behavior. Responding under the control of a fixed interval (FI) schedule for aggression reinforcements across the initial daily sessions indicated the development of tolerance to alcohol's sedative effect. By day 7, alcohol augmented FI response rates for aggression rewards. While alcohol escalated the motivation to fight, fighting performance remained suppressed across the entire 7 days. Augmented FI responding for aggression rewards in response to a low dose of alcohol (1.0 g/kg) proved to be persistent, as we observed sensitized rates of responding for more than a month after alcohol pretreatment. In addition, this sensitization of motivated aggression did not occur with a general enhancement of motor activity. Antagonism of NMDA or AMPA receptors with ketamine, dizocilpine, or NBQX during later challenges with alcohol were largely serenic without having any notable impact on the expression of alcohol-escalated rates of FI responding. The current dissociation of appetitive and performance measures indicates that discrete neural mechanisms controlling aggressive arousal can be distinctly sensitized by alcohol.

12.
Behav Brain Res ; 346: 96-104, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29203334

RESUMO

Olfactory signals, including the scent of urine, are thought to be processed by specific brain regions, such as the medial amygdala (Me), and regulate sexual behavior in a sex-dependent manner. We aimed to reveal the sex-specific neural circuit from the accessory olfactory bulb (AOB) to Me by using a transgenic mouse. We quantified the long-lasting green fluorescent protein (GFP) expression profile, which was controlled by the c-fos promotor in a sex-dependent manner by the scent of urine. Female urine predominantly activated neurons of the posterodorsal medial amygdala (MePD) in male mice and the posteroventral medial amygdala (MePV) in female mice. Male urine, in contrast, generated the opposite pattern of activation in the Me. Secondary, the selective artificial activation of these circuits was used to examine their specific behavioral function, by using a dual Cre-loxP viral infection. AAV-hSyn-FLEX-hM3Dq-EGFP-the designer receptor exclusively activated by a designer drug-was infused into the AOB after infection with trans-synaptic AAV(DJ)-CMV-mCherry-2A-Cre-TTC into either the MePD or the MePV. Double virus-transfected mice were injected with hM3Dq activator and their sexual behavior was monitored. However, selective activation of sex-dependent circuits, i.e., the AOB-MePD or AOB-MePV, did not significantly alter mounting or attack behavior in male mice. There were clear sex differences in the pheromone conveying circuits in the AOB-Me of mice. The sex-dependent functional activation of the Me, however, no effect on behavior. This suggests that a diverse number of nuclei and brain areas are likely to function in concert to successfully facilitate sexual and aggressive behaviors.


Assuntos
Tonsila do Cerebelo/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Caracteres Sexuais , Percepção Social , Tonsila do Cerebelo/citologia , Animais , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Condutos Olfatórios/citologia , Condutos Olfatórios/fisiologia , Comportamento Social , Urina
14.
J Neurosci ; 33(3): 1116-29, 2013 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-23325249

RESUMO

Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.


Assuntos
Afeto/fisiologia , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Córtex Cerebral/fisiologia , Rede Nervosa/fisiologia , Animais , Masculino , Camundongos , Neurônios/fisiologia
15.
Ann N Y Acad Sci ; 1265: 36-45, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22823549

RESUMO

Major depressive disorder (MDD) is a central nervous system disorder characterized by the culmination of profound disturbances in mood and affective regulation. Animal models serve as a powerful tool for investigating the neurobiological mechanisms underlying this disorder; however, little standardization exists across the wide range of available modeling approaches most often employed. This review will illustrate some of the most challenging obstacles faced by investigators attempting to associate depressive-like behaviors in rodents with symptoms expressed in MDD. Furthermore, a novel series of depressive-like criteria based on correlating behavioral endophenotypes, novel in vivo neurophysiological measurements, and molecular/cellular analyses within multiple brain are proposed as a potential solution to overcoming this barrier. Ultimately, linking the neurophysiological and cellular/biochemical actions that contribute to the expression of a defined MDD-like syndrome will dramatically extend the translational value of the most valid animal models of MDD.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/fisiopatologia , Modelos Animais de Doenças , Animais , Ansiedade/diagnóstico , Ansiedade/fisiopatologia , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/parasitologia , Depressão/fisiopatologia , Transtorno Depressivo Maior/psicologia , Humanos , Camundongos , Reprodutibilidade dos Testes
16.
Biol Psychiatry ; 71(12): 1068-74, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22322104

RESUMO

Novel antidepressants are needed to enhance the health and quality of life of the hundreds of millions of depressed individuals worldwide who remain inadequately treated with today's approaches. In reality, no new class of antidepressant medication has been introduced in over 50 years. This insufficiency of current drug treatments is evident to those eager to pursue invasive experimental options like that of deep brain stimulation. Encouragingly, human brain imaging studies and animal work implicate strong relationships between depressive symptoms and patterns of brain activity, which are now open to more empirical assessments using optogenetics. Recent advances in optogenetics permit control over specific subtypes of neurons or their afferent or efferent projections and can greatly further our understanding of the neural mechanisms involved in depression and the mechanism of action of deep brain stimulation and perhaps chemical antidepressants. Here, we discuss how optogenetic tools are being used to answer a broad range of molecular, cellular, and circuit-level questions pertaining to depression that, up until now, have been resistant to other experimental approaches. The emergence of optogenetic technology, when combined with the best-validated animal models of depression, will dramatically increase knowledge about the basic neurobiology of depression, as well as facilitate the development of more effective antidepressant treatments.


Assuntos
Antidepressivos/farmacocinética , Estimulação Encefálica Profunda , Depressão/fisiopatologia , Marcação de Genes/métodos , Vias Neurais/fisiologia , Estimulação Luminosa/métodos , Animais , Depressão/terapia , Modelos Animais de Doenças , Hipocampo/fisiologia , Humanos , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/fisiologia
17.
Neuron ; 71(4): 656-70, 2011 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-21867882

RESUMO

Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Histonas/metabolismo , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/fisiopatologia , Inibidores da Captação de Dopamina/farmacologia , Humanos , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Receptor trkB/metabolismo , Transdução de Sinais/fisiologia , Comportamento Social
18.
J Neurosci ; 31(27): 9848-57, 2011 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-21734276

RESUMO

The neural link between ostensibly aversive stress experiences and intensely rewarding drug taking remains to be delineated. Epidemiological data associate stress and the abuse of various drugs, and experimental data identify the conditions that determine how episodic social stress intensifies the motivation for cocaine and the actual self-administration of cocaine. Two types of social stress have been the focus of experimental study in Long-Evans rats, since they engender divergent changes in drug- or sugar-rewarded behavior and in neuroadaptation. Episodic social defeat stress consists of four brief confrontations between the experimental rat and an aggressive resident rat of the Long-Evans strain over the course of 10 d. Subordination stress involves the continuous exposure to an aggressive resident for 5 weeks, while living in a protective cage within the resident's home cage with brief daily confrontations. These stress experiences result in (1) increased intravenous cocaine self-administration under a fixed ratio schedule with prolonged binge-like access in episodically defeated intruder rats but suppressed cocaine intake by continuously subordinate rats; (2) deteriorated sugar preference and intake and decreased exploratory behavior in subordinate, but not intermittently defeated, rats; and (3) a sensitized dopamine (DA) response in the nucleus accumbens via in vivo microdialysis and increased tegmental brain-derived neural growth factor (BDNF) in episodically defeated rats, whereas the continuously subordinate rats show suppression of the DA and BDNF responses. These divergent neuroadaptations to social stress may represent the substrates for the intensification of cocaine "bingeing" relative to the anhedonia-like deterioration of reward processes during subordination stress.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Área Tegmentar Ventral/metabolismo , Análise de Variância , Animais , Peso Corporal/fisiologia , Condicionamento Operante/fisiologia , Eletroquímica/métodos , Manipulação de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Microdiálise/métodos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Proteínas Oncogênicas v-fos/metabolismo , Ratos , Ratos Long-Evans , Esquema de Reforço , Autoadministração , Sacarose/administração & dosagem , Fatores de Tempo , Área Tegmentar Ventral/efeitos dos fármacos
19.
Nat Protoc ; 6(8): 1183-91, 2011 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-21799487

RESUMO

A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion.


Assuntos
Comportamento Animal , Modelos Psicológicos , Predomínio Social , Estresse Psicológico , Adaptação Psicológica , Agressão , Animais , Depressão/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social
20.
J Neurosci ; 31(25): 9084-92, 2011 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-21697359

RESUMO

Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. Other DVL isoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3ß (glycogen synthase kinase-3ß), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression-like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3ß in the NAc, while overexpressing a dominant-negative mutant of GSK3ß promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3ß reflects an increase in GSK3ß activity. These studies reveal a novel role for the DVL-GSK3ß signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/metabolismo , Núcleo Accumbens/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Animais , Depressão/etiologia , Proteínas Desgrenhadas , Dominação-Subordinação , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo
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