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1.
Nat Rev Neurosci ; 22(11): 674-684, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34545241

RESUMO

Epidemiological sex differences in anxiety disorders and major depression are well characterized. Yet the circuits and mechanisms that contribute to these differences are understudied, because preclinical studies have historically excluded female rodents. This oversight is beginning to be addressed, and recent studies that include male and female rodents are identifying sex differences in neurobiological processes that underlie features of these disorders, including conflict anxiety, fear processing, arousal, social avoidance, learned helplessness and anhedonia. These findings allow us to conceptualize various types of sex differences in the brain, which in turn have broader implications for considering sex as a biological variable. Importantly, comparing the sexes could aid in the discovery of novel therapeutics.


Assuntos
Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Depressão/fisiopatologia , Rede Nervosa/fisiopatologia , Caracteres Sexuais , Animais , Ansiedade/diagnóstico , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , Masculino
2.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33593913

RESUMO

Experiencing some early life adversity can have an "inoculating" effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.


Assuntos
Comportamento Animal , Núcleo Accumbens/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Resiliência Psicológica , Estresse Psicológico , Transcriptoma , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica , Masculino , Núcleo Accumbens/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/metabolismo , Fenótipo , Ratos , Ratos Long-Evans , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores Sexuais
3.
Eur J Neurosci ; 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37118907

RESUMO

Deficits in hippocampus-dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic-pituitary-adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress-related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response.

4.
Eur J Neurosci ; 52(1): 2664-2680, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31660665

RESUMO

Early life adversity is a risk factor for psychiatric disorders, yet the mechanisms by which adversity increases this risk are still being delineated. Here, we used a limited bedding and nesting (LBN) manipulation in rats that models a low resource environment to examine effects on growth, developmental milestones, and endocrine endpoints. In LBN, dams and pups, from pups' postnatal days 2-9, are exposed to an environment where dams lack proper materials to build a nest. This manipulation is compared to control housing conditions, where rat dams have access to ample nesting materials and enrichment throughout pups' development. We found that the LBN condition altered maternal care, increasing pup-directed behaviors while reducing self-care. This, perhaps compensatory, increase in nursing and attention to pups did not mitigate against changes in metabolism, as LBN reduced weight gain in both sexes and this effect persisted into adulthood. Although adult stress hormone levels in both sexes and vaginal opening and estrous cycle length in females were not disrupted, there was other evidence of endocrine dysregulation. Compared to controls, LBN rats of both sexes had shortened anogenital distances, indicating reduced androgen exposure. LBN males also had higher plasma estradiol levels in adulthood. This combination of results suggests that LBN causes a demasculinizing effect in males that could contribute to lasting changes in the brain and behavior. Importantly, alterations in metabolic and endocrine systems due to early life adversity could be one mechanism by which stress early in life increases risk for later disease.


Assuntos
Esteroides , Estresse Psicológico , Animais , Feminino , Masculino , Ratos , Animais Recém-Nascidos , Hormônios
5.
Addict Biol ; 25(3): e12769, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31099135

RESUMO

Adolescence represents increased susceptibility to stress that increases risk for nicotine dependence. The present study examined the interactive effects of brief exposure to stress (shipping/transportation or experimentally induced) and chronic nicotine during adolescence on cognitive function and stress reactivity in adulthood. Adolescent (P31), but not young adult (P47), C57BL/6J mice had higher levels of corticosterone after shipping vs mice bred onsite. Shipped preadolescent (P23) and adolescent (P38) mice, but not those bred onsite, exposed to nicotine showed deficits in contextual fear learning when tested in adulthood. Adult learning deficits were replicated in adolescent mice bred onsite, exposed to experimentally induced stress, and administered chronic nicotine. Stress and nicotine during adolescence resulted in higher expression of hippocampal glucocorticoid receptors and corticotropin-releasing factor receptors and blunted restraint induced CORT release in adulthood. Importantly, studies examining adolescent behavior in mice should consider stress influences outcomes.


Assuntos
Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estresse Psicológico/fisiopatologia , Animais , Cognição/fisiologia , Corticosterona/metabolismo , Medo , Hipocampo/fisiopatologia , Aprendizagem/fisiologia , Camundongos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo
6.
J Neurosci ; 38(44): 9423-9432, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30381434

RESUMO

Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Emoções/fisiologia , Motivação/fisiologia , Resiliência Psicológica , Caracteres Sexuais , Estresse Psicológico/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Transtornos Mentais/psicologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fatores de Risco , Estresse Psicológico/patologia , Estresse Psicológico/psicologia
7.
Horm Behav ; 111: 46-59, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30708031

RESUMO

Early life exposure to a low security setting, characterized by a scarcity of resources and limited food access, increases the risk for psychiatric illness and metabolic dysfunction. We utilized a translational rat model to mimic a low security environment and determined how this manipulation affected offspring behavior, metabolism, and puberty. Because food insecurity in humans is associated with reduced access to healthy food options the "low security" rat manipulation combined a Western diet with exposure to a limited bedding and nesting manipulation (WD-LB). In this setting, dams were provided with limited nesting materials during the pups' early life (P2-P10). This manipulation was contrasted with standard rodent caging (SD) and environmental enrichment (EE), to model "medium security" and "high security" environments, respectively. To determine if transitioning from a low to high security environment improved outcomes, some juvenile WD-LB offspring were exposed to EE. Maternal care was impacted by these environments such that EE dams engaged in high quality care when on the nest, but spent less time on the nest than SD dams. Although WD-LB dams excessively chased their tails, they were very attentive to their pups, perhaps to compensate for limited resources. Offspring exposed to WD-LB only displayed subtle changes in behavior. However, WD-LB exposure resulted in significant metabolic dysfunction characterized by increased body weight, precocious puberty and alterations in the hypothalamic kisspeptin system. These negative effects of WD-LB on puberty and weight regulation were mitigated by EE exposure. Collectively, these studies suggest that both compensatory maternal care and juvenile enrichment can reduce the impact of a low security environment. Moreover, they highlight how utilizing diverse models of resource (in)stability can reveal mechanisms that confer vulnerability and resilience to early life stress.


Assuntos
Abrigo para Animais , Comportamento Materno/fisiologia , Maturidade Sexual/fisiologia , Meio Social , Estresse Psicológico/complicações , Animais , Peso Corporal/fisiologia , Modelos Animais de Doenças , Feminino , Hipotálamo/metabolismo , Masculino , Comportamento Materno/psicologia , Estimulação Física/métodos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/psicologia
8.
Horm Behav ; 97: 145-153, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29037972

RESUMO

Women are more likely than men to suffer from psychiatric disorders characterized by corticotropin releasing factor (CRF) hypersecretion, suggesting sex differences in CRF sensitivity. In rodents, sex differences in the sensitivity of specific brain regions to CRF have been identified. However, regions do not work in isolation, but rather form circuits to coordinate distinct responses to stressful events. Here we examined whether CRF activates different circuits in male and female rats. Following central administration of CRF or artificial cerebrospinal fluid (aCSF), neuronal activation in stress-related areas was assessed using cFOS. Functional connectivity was gauged by correlating the number of cFOS-positive cells between regions and then identifying differences within each sex in correlations for aCSF-treated and CRF-treated groups. This analysis revealed that CRF altered different circuits in males and females. As an example, CRF altered correlations involving the dorsal raphe in males and the bed nucleus of the stria terminalis in females, suggesting sex differences in stress-activated circuits controlling mood and anxiety. Next, plasma estradiol and progesterone levels were correlated with cFOS counts in females. Negative correlations between estradiol and neuronal activation in the regions within the extended amygdala were found in CRF-treated, but not aCSF-treated females. This result suggests that estrogens and CRF together modulate the fear and anxiety responses mediated by these regions. Collectively, these studies reveal sex differences in the way brain regions work together in response to CRF. These differences could drive different stress coping strategies in males and females, perhaps contributing to sex biases in psychopathology.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Caracteres Sexuais , Tonsila do Cerebelo/metabolismo , Animais , Núcleo Dorsal da Rafe/metabolismo , Estradiol/sangue , Feminino , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Neurônios/metabolismo , Progesterona/sangue , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos
9.
J Neurosci Res ; 95(1-2): 75-82, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27870416

RESUMO

Posttraumatic stress disorder and major depression share stress as an etiological contributor and are more common in women than in men. Traditionally, preclinical studies investigating the neurobiological underpinnings of stress vulnerability have used only male rodents; however, recent studies that include females are finding sex-specific mechanisms for responding to stress. This Mini-Review examines recent literature using a framework developed by McCarthy and colleagues (2012; J Neurosci 32:2241-2247) that highlights different types of sex differences. First, we detail how learned fear responses in rats are sexually dimorphic. Then, we contrast this finding with fear extinction, which is similar in males and females at the behavioral level but at the circuitry level is associated with sex-specific cellular changes and, thus, exemplifies a sex convergence. Next, sex differences in stress hormones are detailed. Finally, the effects of stress on learning, attention, and arousal are used to highlight the concept of a sex divergence in which the behavior of males and females is similar at baseline but diverges following stressor exposure. We argue that appreciating and investigating the diversity of sex differences in stress response systems will improve our understanding of vulnerability and resilience to stress-related psychiatric disorders and likely lead to the development of novel therapeutics for better treatment of these disorders in both men and women. © 2016 Wiley Periodicals, Inc.


Assuntos
Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/psicologia
10.
J Youth Adolesc ; 46(1): 91-103, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26923989

RESUMO

Major Depressive Disorder is a common mental illness with rates increasing during adolescence. This has led researchers to examine developmental antecedents of depression. This study examined the association between depressive symptoms and the interaction between two empirically supported risk factors for depression: poor recovery of the biological stress system as measured through heart rate and cortisol, and cognitive vulnerabilities as indexed by rumination and a negative cognitive style. Adolescents (n = 127; 49 % female) completed questionnaires and a social stress task to elicit a stress response measured with neuroendocrine (cortisol) and autonomic nervous system (heart rate) endpoints. The findings indicated that higher depressive symptoms were associated with the combination of higher cognitive vulnerabilities and lower cortisol and heart rate recovery. These findings can enhance our understanding of stress responses, lead to personalized treatment, and provide a nuanced understanding of depression in adolescence.


Assuntos
Depressão/psicologia , Estresse Fisiológico/fisiologia , Adolescente , Sistema Nervoso Autônomo/fisiologia , Depressão/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Personalidade , Fatores de Risco , Estresse Psicológico/psicologia , Inquéritos e Questionários
11.
Front Neuroendocrinol ; 35(3): 303-19, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24726661

RESUMO

Stress is associated with the onset and severity of several psychiatric disorders that occur more frequently in women than men, including posttraumatic stress disorder (PTSD) and depression. Patients with these disorders present with dysregulation of several stress response systems, including the neuroendocrine response to stress, corticolimbic responses to negatively valenced stimuli, and hyperarousal. Thus, sex differences within their underlying circuitry may explain sex biases in disease prevalence. This review describes clinical studies that identify sex differences within the activity of these circuits, as well as preclinical studies that demonstrate cellular and molecular sex differences in stress responses systems. These studies reveal sex differences from the molecular to the systems level that increase endocrine, emotional, and arousal responses to stress in females. Exploring these sex differences is critical because this research can reveal the neurobiological underpinnings of vulnerability to stress-related psychiatric disorders and guide the development of novel pharmacotherapies.


Assuntos
Transtornos Mentais , Estresse Psicológico , Animais , Nível de Alerta/fisiologia , Encéfalo , Hormônio Liberador da Corticotropina/metabolismo , Humanos , Caracteres Sexuais
12.
Horm Behav ; 76: 125-35, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25888454

RESUMO

This article is part of a Special Issue "SBN 2014". Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF's ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described.


Assuntos
Transtornos Cognitivos/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Animais , Humanos
13.
Neurochem Int ; 176: 105739, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38604443

RESUMO

Corticoptropin releasing factor (CRF) is implicated in stress-related physiological and behavioral changes. The septohippocampal pathway regulates hippocampal-dependent mnemonic processes, which are affected in stress-related disorders, and given the abundance of CRF receptors in the medial septum (MS), this pathway is influenced by CRF. Moreover, there are sex differences in the MS sensitivity to CRF and its impact on hippocampal function. However, the mechanisms underlying these associations remain elusive. In the present study, we utilized an in vivo biosensor-based electrochemistry approach to examine the impact of MS CRF infusions on hippocampal cholinergic signaling dynamics in male and female rats. Our results show increased amplitudes of depolarization-evoked phasic cholinergic signals in the hippocampus following MS infusion of CRF at the 3 ng dose as compared to the infusion involving artificial cerebrospinal fluid (aCSF). Moreover, a trend for a sex × infusion interaction indicated larger cholinergic transients in females. On the contrary, intraseptal infusion of a physiologically high dose (100 ng) of CRF produced a subsequent reduction in phasic cholinergic transients in both males and females. The assessment of tonic cholinergic activity over 30 min post-infusion revealed no changes at the 3 ng CRF dose in either sex, but a significant infusion × sex interaction indicated a reduction in females at the 100 ng dose of CRF as compared to the aCSF. Taken together, our results show differential, dose-dependent modulatory effects of MS CRF on the dynamics of phasic and tonic modes of cholinergic signaling in the hippocampus of male and female rats. These cholinergic signaling modes are critical for memory encoding and maintaining arousal states, and may underlie sex differences in cognitive vulnerability to stress and stress-related psychiatric disorders.


Assuntos
Hormônio Liberador da Corticotropina , Hipocampo , Animais , Feminino , Masculino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ratos , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/administração & dosagem , Ratos Sprague-Dawley , Núcleos Septais/metabolismo , Núcleos Septais/efeitos dos fármacos , Caracteres Sexuais , Acetilcolina/metabolismo
14.
Neurobiol Stress ; 29: 100607, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38304302

RESUMO

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN augments maternal behaviors and promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

15.
bioRxiv ; 2023 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-37425737

RESUMO

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

16.
J Neurosci ; 31(40): 14436-49, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21976528

RESUMO

Because overactivation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer's disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood, and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both ß-amyloid (Aß) and tau pathology remain unclear. Therefore, we first established a model of chronic stress, which exacerbates Aß accumulation in Tg2576 mice and then extended this stress paradigm to a tau transgenic mouse model with the P301S mutation (PS19) that displays tau hyperphosphorylation, insoluble tau inclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, 1 month of restraint/isolation (RI) stress increased Aß levels, suppressed microglial activation, and worsened spatial and fear memory compared with nonstressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration, and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF(1)) antagonist. The role for a CRF(1)-dependent mechanism was further supported by the finding that mice overexpressing CRF had increased hyperphosphorylated tau compared with wild-type littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aß and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD.


Assuntos
Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Degeneração Neural/patologia , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Estresse Psicológico/patologia , Tauopatias/patologia , Animais , Doença Crônica , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Tauopatias/etiologia , Tauopatias/metabolismo , Proteínas tau/biossíntese
17.
Cell Mol Neurobiol ; 32(5): 709-23, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22488525

RESUMO

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.


Assuntos
Caracteres Sexuais , Transdução de Sinais , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Humanos , Locus Cerúleo/metabolismo , Masculino , Receptores de Hormônio Liberador da Corticotropina/metabolismo
18.
Neurosci Biobehav Rev ; 137: 104638, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35341796

RESUMO

Elevated impulsivity is a symptom shared by various psychiatric disorders such as substance use disorder, bipolar disorder, and attention-deficit/hyperactivity disorder. However, impulsivity is not a unitary construct and impulsive behaviors fall into two subcategories: impulsive action and impulsive choice. Impulsive choice refers to the tendency to prefer immediate, small rewards over delayed, large rewards, whereas impulsive action involves difficulty inhibiting rash, premature, or mistimed behaviors. These behaviors are mediated by the mesocorticolimbic dopamine (DA) system, which consists of projections from the ventral tegmental area to the nucleus accumbens and prefrontal cortex. Early life stress (ELS) alters both impulsive choice and impulsive action in rodents. ELS also changes DA receptor expression, transmission, and activity within the mesocorticolimbic system. This review integrates the dopamine, impulsivity, and ELS literature to provide evidence that ELS alters impulsivity via inducing changes in the mesocorticolimbic DA system. Understanding how ELS affects brain circuits associated with impulsivity can help advance treatments aimed towards reducing impulsivity symptoms in a variety of psychiatric disorders.


Assuntos
Experiências Adversas da Infância , Dopamina , Comportamento de Escolha , Dopamina/metabolismo , Humanos , Comportamento Impulsivo , Núcleo Accumbens , Área Tegmentar Ventral/metabolismo
19.
Psychopharmacology (Berl) ; 239(12): 3929-3937, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36301314

RESUMO

RATIONALE: Early life adversity impacts reward-related behaviors, including reward seeking for drugs of abuse. However, the effects of early stress on natural rewards, such as food and social rewards, which have strong implications for symptoms of psychiatric conditions such as major depressive disorder (MDD), are understudied. To fill this gap, we used the limited bedding and nesting (LBN) procedure to assess the impact of early resource scarcity on motivational drive for both food and social rewards in rats. METHODS: Male and female Long Evans rats were reared in either an LBN environment, with limited nesting materials and no enrichment, from their postnatal day 2-9 or control environment with ample nesting materials and enrichment. As adults, they were tested for reward-seeking behavior on progressive ratio operant tasks: food reward (sucrose) or social reward (access to a same-sex/age conspecific). RESULTS: We observed sex differences in the impact of LBN on motivation for natural rewards. In males, LBN increased motivation for both a sucrose and social reward. In females, LBN reduced motivation for sucrose but had no effect on social reward. CONCLUSIONS: These results suggest that the effects of LBN on motivation for natural rewards are both sex- and reinforcer-dependent, with males and females showing differential motivation for food and social rewards following early scarcity. Our previous data revealed an LBN-driven reduction in motivation for morphine in males and no effect in females, highlighting the reinforcer-dependent impact of early resource scarcity on motivated behavior more widely.


Assuntos
Transtorno Depressivo Maior , Motivação , Feminino , Masculino , Ratos , Animais , Ratos Long-Evans , Recompensa , Sacarose/farmacologia
20.
Neuropsychopharmacology ; 47(6): 1231-1239, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35102257

RESUMO

Early life adversity can alter reproductive development in humans, changing the timing of pubertal onset and sexual activity. One common form of early adversity is limited access to resources. This adversity can be modeled in rats using the limited bedding/nesting model (LBN), in which dams and pups are placed in a low resource environment from pups' postnatal days 2-9. Our laboratory previously found that adult male rats raised in LBN conditions have elevated levels of plasma estradiol compared to control males. In females, LBN had no effect on plasma hormone levels, pubertal timing, or estrous cycle duration. Estradiol mediates male reproductive behaviors. Thus, here we compared reproductive behaviors in adult males exposed to LBN vs. control housing. LBN males acquired the suite of reproductive behaviors (mounts, intromissions, and ejaculations) more quickly than their control counterparts over 3 weeks of testing. However, there was no effect of LBN in males on puberty onset or masculinization of certain brain regions, suggesting LBN effects on estradiol and reproductive behaviors manifest after puberty. In male and female rats, we next used RNA sequencing to characterize LBN-induced transcriptional changes in the medial preoptic area (mPOA), which underlies male reproductive behaviors. LBN produced sex-specific alterations in gene expression, with many transcripts showing changes in opposite directions. Numerous transcripts altered by LBN in males are regulated by estradiol, linking hormonal changes to molecular changes in the mPOA. Pathway analysis revealed that LBN induced changes in neurosignaling and immune signaling in males and females, respectively. Collectively, these studies reveal novel neurobiological mechanisms by which early life adversity can alter reproductive strategies.


Assuntos
Área Pré-Óptica , Comportamento Reprodutivo , Estresse Psicológico , Transcriptoma , Animais , Feminino , Masculino , Ratos , Estradiol/farmacologia , Comportamento Sexual Animal
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