RESUMO
Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.
Assuntos
Encéfalo/fisiologia , Depressão/patologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Estimulação Elétrica , Eletrodos Implantados , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Ketamina/farmacologia , Aprendizado de Máquina , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Estresse PsicológicoRESUMO
Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and -susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend upon paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible vs resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience.SIGNIFICANCE STATEMENTThis manuscript contributes to the complex factors that influence the paternal transmission of stress phenotypes. By leveraging the segregation of males exposed to chronic social defeat stress into either resilient or susceptible categories we were able to identify the phenotypic differences in the paternal transmission of stress phenotypes across generations between the two lineages. Importantly, this work also alludes to the significance of both long noncoding RNAs and protein coding genes mediating the paternal transmission of stress. The knowledge gained from these data is of particular interest in understanding the risk for the development of psychiatric disorders such as anxiety and depression.
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The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.
Assuntos
Cocaína/farmacologia , Neurônios/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Recompensa , Análise de Variância , Animais , Cocaína/administração & dosagem , Sinais (Psicologia) , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Imuno-Histoquímica , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimagem/métodos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type- and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc)-a key limbic brain reward region-in the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stress-associated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.
Assuntos
Transtorno Depressivo/fisiopatologia , Histonas/metabolismo , Núcleo Accumbens/fisiopatologia , Estresse Psicológico/fisiopatologia , Adulto , Idoso , Animais , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Núcleo Accumbens/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estresse Psicológico/genéticaRESUMO
Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.
Assuntos
Transtornos de Ansiedade/fisiopatologia , Colecistocinina/fisiologia , Transtorno Depressivo/fisiopatologia , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/fisiologia , Receptor de Colecistocinina B/fisiologia , Animais , Ansiolíticos/farmacologia , Transtornos de Ansiedade/patologia , Mapeamento Encefálico , Doença Crônica , Transtorno Depressivo/patologia , Indóis/farmacologia , Sistema Límbico/citologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiologia , Masculino , Meglumina/análogos & derivados , Meglumina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Receptor de Colecistocinina B/antagonistas & inibidores , Receptor de Colecistocinina B/genética , Predomínio Social , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologiaRESUMO
Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring. Preliminary genome-wide analyses of gene transcription and DNA methylation of the molecular basis for such maternal effects suggested differences in the epigenetic state and transcriptional activity of the Grm1 gene in the rat as a function of maternal care. Grm1 encodes the type I metabotropic glutamate receptor (mGluR1), and we found increased mGluR1 mRNA and protein in hippocampus from the adult offspring of mothers showing an increased frequency of pup licking/grooming (i.e., high-LG mothers) that was associated with a decrease in the methylation of Grm1. ChIP assays showed increased levels of histone 3 lysine 9 acetylation and histone 3 lysine 4 trimethylation of Grm1 in hippocampus from the adult offspring of high-LG compared with low-LG mothers. These histone posttranslational modifications were highly correlated, and both associate inversely with DNA methylation and positively with transcription. Studies of mGluR1 function showed increased hippocampal mGluR1-induced long-term depression in the adult offspring of high-LG compared with low-LG mothers, as well as increased paired-pulse depression (PPD). PPD is an inhibitory feedback mechanism that prevents excessive glutamate release during high-frequency stimulation. The maternal effects on both long-term depression and PPD were eliminated by treatment with an mGluR1-selective antagonist. These findings suggest that variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes implicated in glutamatergic synaptic signaling.
Assuntos
Hipocampo/fisiologia , Comportamento Materno/fisiologia , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Sequência de Bases , Comportamento Animal/fisiologia , DNA/genética , Metilação de DNA , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Potenciação de Longa Duração , Depressão Sináptica de Longo Prazo , Masculino , Dados de Sequência Molecular , Gravidez , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inibidoresRESUMO
The transcription factor, ΔFosB, is robustly and persistently induced in striatum by several chronic stimuli, such as drugs of abuse, antipsychotic drugs, natural rewards, and stress. However, very few studies have examined the degree of ΔFosB induction in the two striatal medium spiny neuron (MSN) subtypes. We make use of fluorescent reporter BAC transgenic mice to evaluate induction of ΔFosB in dopamine receptor 1 (D1) enriched and dopamine receptor 2 (D2) enriched MSNs in ventral striatum, nucleus accumbens (NAc) shell and core, and in dorsal striatum (dStr) after chronic exposure to several drugs of abuse including cocaine, ethanol, Δ(9)-tetrahydrocannabinol, and opiates; the antipsychotic drug, haloperidol; juvenile enrichment; sucrose drinking; calorie restriction; the serotonin selective reuptake inhibitor antidepressant, fluoxetine; and social defeat stress. Our findings demonstrate that chronic exposure to many stimuli induces ΔFosB in an MSN-subtype selective pattern across all three striatal regions. To explore the circuit-mediated induction of ΔFosB in striatum, we use optogenetics to enhance activity in limbic brain regions that send synaptic inputs to NAc; these regions include the ventral tegmental area and several glutamatergic afferent regions: medial prefrontal cortex, amygdala, and ventral hippocampus. These optogenetic conditions lead to highly distinct patterns of ΔFosB induction in MSN subtypes in NAc core and shell. Together, these findings establish selective patterns of ΔFosB induction in striatal MSN subtypes in response to chronic stimuli and provide novel insight into the circuit-level mechanisms of ΔFosB induction in striatum.
Assuntos
Corpo Estriado/citologia , Dopaminérgicos/farmacologia , Emoções/efeitos dos fármacos , Optogenética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Antidepressivos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Meio Ambiente , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/classificação , Neurônios/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genéticaRESUMO
Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.
Assuntos
Hipocampo/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Memória/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Fenóis/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Subunidades Proteicas , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/classificação , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologiaRESUMO
Interest in the therapeutic potential of serotonergic psychedelic compounds including psilocybin has surged in recent years. While human clinical research suggests psilocybin holds promise as a rapid and long-lasting antidepressant, little is known about how its acute mechanisms of action mediate enduring alterations in cognition and behavior. Human neuroimaging studies point to both acute and sustained modulation of functional connectivity in key cortically dependent brain networks. Emerging evidence in preclinical models highlights the importance of psilocybin-induced neuroplasticity and alterations in the prefrontal cortex (PFC). Overviewing research in both humans and preclinical models suggests avenues to increase crosstalk between fields. We review how acute modulation of PFC circuits may contribute to long-term structural and functional alterations to mediate antidepressant effects. We highlight the potential for preclinical circuit and behavioral neuroscience approaches to provide basic mechanistic insight into how psilocybin modulates cognitive and affective neural circuits to support further development of psilocybin as a promising new treatment for depression.
Assuntos
Alucinógenos , Psilocibina , Animais , Humanos , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Encéfalo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos AnimaisRESUMO
Making decisions is fundamental to how we navigate, survive, and thrive in our environment. The quality of information used to support decisions is rarely perfect. Many decisions are made under conditions of uncertainty, arising from ambiguous or conflicting information. Conflict and ambiguity, though conceptually distinct, both generate uncertainty, a commonality that has led to overlapping and inconsistent terminology in the literature. Evidence from human and animal research suggests a behavioral dissociation in responding to conflict and ambiguity. This dissociation can be studied through the implementation of spatial or operant tasks in rodents which find close parallels in gambling tasks in humans. Pharmacological manipulations in rodents and fMRI studies in humans further suggest a dissociation in the neural processing of conflict and ambiguity such that fronto-striato-parietal circuits may be most important for interpreting ambiguous information, while the ventral striatum and ventral hippocampus are critical for resolving conflicting information. Overall, the neural representation and resolution of conflict and ambiguity remain relatively understudied despite the fundamental importance of these processes to understanding decision-making. We highlight the need for further research to differentiate these related yet distinct processes through implementation of carefully designed behavioral tasks with neural circuit-dissection techniques and the potential to pursue translational research between rodents and humans. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Jogo de Azar , Estriado Ventral , Tomada de Decisões , Humanos , Assunção de Riscos , IncertezaRESUMO
BACKGROUND: Sex differences in addiction have been described in humans and animal models. A key factor that influences addiction in both males and females is adolescent experience. Adolescence is associated with higher vulnerability to substance use disorders, and male rodents subjected to adolescent social isolation (SI) stress form stronger preferences for drugs of abuse in adulthood. However, little is known about how females respond to SI, and few studies have investigated the transcriptional changes induced by SI in the brain's reward circuitry. METHODS: We tested the hypothesis that SI alters the transcriptome in a persistent and sex-specific manner in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Mice were isolated or group housed from postnatal day P22 to P42, then group housed until â¼P90. Transcriptome-wide changes were investigated by RNA sequencing after acute or chronic cocaine or saline administration. RESULTS: We found that SI disrupts sex-specific transcriptional responses to cocaine and reduces sex differences in gene expression across all three brain regions. Furthermore, SI induces gene expression profiles in males that more closely resemble group-housed females, suggesting that SI "feminizes" the male transcriptome. Coexpression analysis reveals that such disruption of sex differences in gene expression alters sex-specific gene networks and identifies potential sex-specific key drivers of these transcriptional changes. CONCLUSIONS: Together, these data show that SI has region-specific effects on sex-specific transcriptional responses to cocaine and provide a better understanding of reward-associated transcription that differs in males and females.
Assuntos
Cocaína , Recompensa , Animais , Encéfalo , Feminino , Masculino , Camundongos , Núcleo Accumbens , TranscriptomaRESUMO
BACKGROUND: Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse. METHODS: We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward. RESULTS: We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI. CONCLUSIONS: These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity.
Assuntos
Cocaína , Animais , Masculino , Feminino , Camundongos , Cocaína/farmacologia , Cocaína/metabolismo , Cristalinas mu , Recompensa , Neurônios/metabolismo , Tonsila do Cerebelo/metabolismoRESUMO
Parenting and the early environment influence the risk for various psychopathologies. Studies in the rat suggest that variations in maternal care stably influence DNA methylation, gene expression, and neural function in the offspring. Maternal care affects neural development, including the GABAergic system, the function of which is linked to the pathophysiology of diseases including schizophrenia and depression. Postmortem studies of human schizophrenic brains have revealed decreased forebrain expression of glutamic acid decarboxylase 1 (GAD1) accompanied by increased methylation of a GAD1 promoter. We examined whether maternal care affects GAD1 promoter methylation in the hippocampus of adult male offspring of high and low pup licking/grooming (high-LG and low-LG) mothers. Compared with the offspring of low-LG mothers, those reared by high-LG dams showed enhanced hippocampal GAD1 mRNA expression, decreased cytosine methylation, and increased histone 3-lysine 9 acetylation (H3K9ac) of the GAD1 promoter. DNA methyltransferase 1 expression was significantly higher in the offspring of low- compared with high-LG mothers. Pup LG increases hippocampal serotonin (5-HT) and nerve growth factor-inducible factor A (NGFI-A) expression. Chromatin immunoprecipitation assays revealed enhanced NGFI-A association with and H3K9ac of the GAD1 promoter in the hippocampus of high-LG pups after a nursing bout. Treatment of hippocampal neuronal cultures with either 5-HT or an NGFI-A expression plasmid significantly increased GAD1 mRNA levels. The effect of 5-HT was blocked by a short interfering RNA targeting NGFI-A. These results suggest that maternal care influences the development of the GABA system by altering GAD1 promoter methylation levels through the maternally induced activation of NGFI-A and its association with the GAD1 promoter.
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Metilação de DNA/genética , Glutamato Descarboxilase/genética , Hipocampo/metabolismo , Comportamento Materno/fisiologia , Animais , Células Cultivadas , Epigênese Genética , Glutamato Descarboxilase/biossíntese , Glutamato Descarboxilase/metabolismo , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Masculino , Regiões Promotoras Genéticas/genética , Ratos , Ratos Long-Evans , Receptores de Glucocorticoides/genética , Ácido gama-Aminobutírico/fisiologiaRESUMO
Women are twice as likely to experience depression than men, yet until recently, preclinical studies in rodents have focused almost exclusively on males. As interest in sex differences and sex-specific mechanisms of stress susceptibility increases, chronic stress models for inducing depression-relevant behavioral and physiological changes in male rodents are being applied to females, and several new models have emerged to include both males and females, yet not all models have been systematically validated in females. An increasing number of researchers seek to include female rodents in their experimental designs, asking the question "what is the ideal chronic stress model for depression in females?" We review criteria for assessing female model validity in light of key research questions and the fundamental distinction between studying sex differences and studying both sexes. In overviewing current models, we explore challenges inherent to establishing an ideal female chronic stress model, with particular emphasis on the need for standardization and adoption of validated behavioral tests sensitive to stress effects in females. Taken together, these considerations will empower female chronic stress models to provide a better understanding of stress susceptibility and allow the development of efficient sex-specific treatments.
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Roedores , Estresse Psicológico , Animais , Depressão , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Caracteres SexuaisRESUMO
Wang et al. (2021) characterize the molecular, cellular, and circuit-level role of Oligophrenin-1 in prefrontal parvalbumin interneurons, demonstrating that loss of Ophn1 function in these neurons is a mechanism for increased susceptibility to stress in intellectual disability caused by OPHN1 mutations.
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Deficiência Intelectual , Proteínas do Citoesqueleto/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Deficiência Intelectual/genética , Interneurônios/metabolismo , Proteínas Nucleares/metabolismo , Parvalbuminas , Córtex Pré-Frontal/metabolismoRESUMO
BACKGROUND: Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear. METHODS: We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing. RESULTS: Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation. CONCLUSIONS: Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.
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Comportamento Animal , Efeitos Tardios da Exposição Pré-Natal , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Neuroimagem , Poli I-C , GravidezRESUMO
BACKGROUND: Reinforcement learning (RL) and win stay/lose shift model accounts of decision making are both widely used to describe how individuals learn about and interact with rewarding environments. Though mutually informative, these accounts are often conceptualized as independent processes and so the potential relationships between win stay/lose shift tendencies and RL parameters have not been explored. NEW METHOD: We introduce a methodology to directly relate RL parameters to behavioral strategy. Specifically, by calculating a truncated multivariate normal distribution of RL parameters given win stay/lose shift tendencies from simulating these tendencies across the parameter space, we maximize the normal distribution for a given set of win stay/lose shift tendencies to approximate reinforcement learning parameters. RESULTS: We demonstrate novel relationships between win stay/lose shift tendencies and RL parameters that challenge conventional interpretations of lose shift as a metric of loss sensitivity. Further, we demonstrate in both simulated and empirical data that this method of parameter approximation yields reliable parameter recovery. COMPARISON WITH EXISTING METHOD: We compare this method against the conventionally used maximum likelihood estimation method for parameter approximation in simulated noisy and empirical data. For simulated noisy data, we show that this method performs similarly to maximum likelihood estimation. For empirical data, however, this method provides a more reliable approximation of reinforcement learning parameters than maximum likelihood estimation. CONCLUSIONS: We demonstrate the existence of relationships between win stay/lose shift tendencies and RL parameters and introduce a method that leverages these relationships to enable recovery of RL parameters exclusively from win stay/lose shift tendencies.
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Reforço Psicológico , Recompensa , Comportamento de Escolha , Humanos , AprendizagemRESUMO
BACKGROUND: Stress is a major risk factor for depression, but not everyone responds to stress in the same way. Identifying why certain individuals are more susceptible is essential for targeted treatment and prevention. In rodents, nucleus accumbens (NAc) afferents from the ventral hippocampus (vHIP) are implicated in stress-induced susceptibility, but little is known about how this pathway might encode future vulnerability or specific behavioral phenotypes. METHODS: We used fiber photometry to record in vivo activity in vHIP-NAc afferents during tests of depressive- and anxiety-like behavior in male and female mice, both before and after a sex-specific chronic variable stress protocol, to probe relationships between prestress neural activity and behavior and potential predictors of poststress behavioral adaptation. Furthermore, we examined chronic variable stress-induced alterations in vHIP-NAc activity in vivo and used ex vivo slice electrophysiology to identify the mechanism of this change. RESULTS: We identified behavioral specificity of the vHIP-NAc pathway to anxiety-like and social interaction behavior. We also showed that this activity is broadly predictive of stress-induced susceptibility in both sexes, while prestress behavior is predictive only of anxiety-like behavior. We observed a stress-induced increase in in vivo vHIP-NAc activity coincident with an increase in spontaneous excitatory postsynaptic current frequency. CONCLUSIONS: We implicate vHIP-NAc in social interaction and anxiety-like behavior and identify markers of vulnerability in this neural signal, with elevated prestress vHIP-NAc activity predicting increased susceptibility across behavioral domains. Our findings indicate that individual differences in neural activity and behavior play a role in predetermining susceptibility to later stress, providing insight into mechanisms of vulnerability.
Assuntos
Hipocampo , Núcleo Accumbens , Animais , Ansiedade , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social , Estresse PsicológicoRESUMO
Maternal licking and grooming (LG) in infancy influences stress responsiveness and cognitive performance in the offspring. We examined the effects of variation in the frequency of pup LG on morphological, electrophysiological, and behavioral aspects of hippocampal synaptic plasticity under basal and stress-like conditions. We found shorter dendritic branch length and lower spine density in CA1 cells from the adult offspring of low compared with high LG offspring. We also observed dramatic effects on long-term potentiation (LTP) depending on corticosterone treatment. Low LG offspring, in contrast to those of high LG mothers, displayed significantly impaired LTP under basal conditions but surprisingly a significantly enhanced LTP in response to high corticosterone in vitro. This enhanced plasticity under conditions that mimic those of a stressful event was apparent in vivo. Adult low LG offspring displayed enhanced memory relative to high LG offspring when tested in a hippocampal-dependent, contextual fear-conditioning paradigm. Hippocampal levels of glucocorticoid and mineralocorticoid receptors were reduced in low compared with high LG offspring. Such effects, as well as the differences in dendritic morphology, likely contribute to LTP differences under resting conditions, as well as to the maternal effects on synaptic plasticity and behavior in response to elevated corticosterone levels. These results suggest that maternal effects may modulate optimal cognitive functioning in environments varying in demand in later life, with offspring of high and low LG mothers showing enhanced learning under contexts of low and high stress, respectively.
Assuntos
Glucocorticoides/farmacologia , Hipocampo/fisiologia , Comportamento Materno/fisiologia , Plasticidade Neuronal/fisiologia , Estresse Psicológico/patologia , Sinapses/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Comportamento Materno/psicologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Long-Evans , Estresse Psicológico/psicologia , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
Maternal care in the rat influences hippocampal development, synaptic plasticity and cognition. Previous studies, however, have examined animals under minimally stressful conditions. Here we tested the hypothesis that maternal care influences hippocampal function differently when this structure is exposed to corticosteroid and noradrenergic hormones, which are elevated during the early phase of a stress response. In the adult male offspring of Long-Evans dams characterised as high or low in maternal care (high LG and low LG) we (1) examined basal dendritic morphology in the dentate gyrus by Golgi staining; (2) investigated rapid modulation of in vitro long term-potentiation (LTP) in the dentate gyrus by glucocorticoid and beta-adrenergic stimulation; (3) examined hippocampal and amygdala-dependent learning under stress using contextual and cued fear conditioning. We found differences in hippocampal dentate gyrus morphology in adult offspring of high and low LG mothers, with less dendritic complexity in low LG offspring. Under basal conditions LTP was lower in slices from low compared with high LG offspring. Hippocampal LTP was rapidly increased by either corticosterone (100 nM) or isoproterenol (1.0 microM) in low LG offspring, suggesting improved dentate plasticity during stress. This was mirrored in hippocampal but not amygdala-dependent learning, as low LG offspring showed enhanced contextual but not cued fear conditioning. We suggest that decreased pup LG during postnatal life may be adaptive in high-threat environments, potentially enhancing hippocampal function in the offspring under conditions of adversity.