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1.
Nat Commun ; 13(1): 4374, 2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902577

RESUMO

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.


Assuntos
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Animais , Extinção Psicológica , Medo/fisiologia , Feminino , Humanos , Hipotálamo/metabolismo , Camundongos , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo
2.
Mol Psychiatry ; 23(3): 658-665, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28093566

RESUMO

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.


Assuntos
Medo/fisiologia , Histona Desacetilases/metabolismo , Proteínas Repressoras/metabolismo , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Tonsila do Cerebelo/metabolismo , Animais , Condicionamento Clássico/fisiologia , Ilhas de CpG/genética , Metilação de DNA , Estradiol/análise , Estradiol/sangue , Estrogênios/metabolismo , Estrogênios/fisiologia , Medo/psicologia , Feminino , Histona Desacetilases/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reflexo de Sobressalto/fisiologia , Proteínas Repressoras/fisiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo
3.
Vitam Horm ; 103: 53-83, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28061976

RESUMO

Women are particularly vulnerable to the effects of psychological trauma and the development of trauma-, stressor-, and anxiety-related mental illnesses such as posttraumatic stress disorder (PTSD). In the current chapter, we examine the female hormonal systems that interact with psychobiological stress response systems to elicit maladaptive behavior and mental disease states in traumatized female populations. In addition, we provide a contemporary translational example of a stress vulnerability genomic profile (coding for pituitary adenylate cyclase-activating polypeptide) that may underlie the specific susceptibilities observed in women. Translational scientific investigations such as those described herein may lead to the identification of risk and resilience factors for PTSD as well as enhanced clinical interventions for treating excessive fear and anxiety.


Assuntos
Estrogênios/metabolismo , Sistemas Neurossecretores/fisiopatologia , Ovário/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Animais , Feminino , Predisposição Genética para Doença , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistemas Neurossecretores/fisiologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/sangue , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/agonistas , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Risco , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Testículo/metabolismo , Testosterona/metabolismo
5.
Psychol Med ; 42(3): 533-43, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21854700

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) develops in a minority of traumatized individuals. Attention biases to threat and abnormalities in fear learning and extinction are processes likely to play a critical role in the creation and/or maintenance of PTSD symptomatology. However, the relationship between these processes has not been established, particularly in highly traumatized populations; understanding their interaction can help inform neural network models and treatments for PTSD. METHOD: Attention biases were measured using a dot probe task modified for use with our population; task stimuli included photographs of angry facial expressions, which are emotionally salient threat signals. A fear-potentiated startle paradigm was employed to measure atypical physiological response during acquisition and extinction phases of fear learning. These measures were administered to a sample of 64 minority (largely African American), highly traumatized individuals with and without PTSD. RESULTS: Participants with PTSD demonstrated attention biases toward threat; this attentional style was associated with exaggerated startle response during fear learning and early and middle phases of extinction, even after accounting for the effects of trauma exposure. CONCLUSIONS: Our findings indicate that an attentional bias toward threat is associated with abnormalities in 'fear load' in PTSD, providing seminal evidence for an interaction between these two processes. Future research combining these behavioral and psychophysiological techniques with neuroimaging will be useful toward addressing how one process may modulate the other and understanding whether these phenomena are manifestations of dysfunction within a shared neural network. Ultimately, this may serve to inform PTSD treatments specifically designed to correct these atypical processes.


Assuntos
Atenção , Extinção Psicológica/fisiologia , Medo/fisiologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adolescente , Adulto , Negro ou Afro-Americano , Análise de Variância , Estudos de Casos e Controles , Criança , Condicionamento Clássico/fisiologia , Expressão Facial , Medo/psicologia , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-Idade , Rede Nervosa , Testes Neuropsicológicos , Estimulação Luminosa , Reflexo de Sobressalto/fisiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , População Urbana , Adulto Jovem
6.
Neuroscience ; 164(1): 272-87, 2009 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-19540311

RESUMO

Anxiety disorders are the most common psychiatric illnesses in the United States with approximately 30% of the population experiencing anxiety-related symptoms in their lifetime [Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593-60]. Notably, a variety of studies have demonstrated that 30-40% of the variance contributing to these disorders is heritable. In the present review, we discuss the latest findings regarding the genetic and environmental influences on the development and symptomatology of anxiety disorders. Specific emphasis is placed on posttraumatic stress disorder (PTSD) due to its uniqueness as an anxiety disorder; its diagnosis is dependent on a precipitating traumatic event and its development appears to be mediated by both genetic and environmental contributions. The co-morbidity of anxiety disorders and the potential re-classification of anxiety disorders as part of DSM-V are reviewed given the potential impact on the interpretation and design of genetic investigations. Lastly, several keys to future genetic studies are highlighted. Thorough analyses of the gene by environment (GxE) interactions that govern one's vulnerability to anxiety disorder(s), the effectiveness of individual treatment strategies, and the severity of symptoms may lead to more effective prophylactic (e.g. social support) and treatment strategies.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Transtornos de Ansiedade/diagnóstico , Medo , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico
7.
Neuroscience ; 116(1): 19-22, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12535933

RESUMO

Repeated exposure to cocaine produces an enduring increase in dendritic spine density in adult rat nucleus accumbens. It has been shown previously that chronic cocaine administration increases the expression of cyclin-dependent kinase-5 in this brain region and that this neuronal protein kinase regulates cocaine-induced locomotor activity. Moreover, cyclin-dependent kinase-5 has been implicated in neuronal function and synaptic plasticity. Therefore, we studied the involvement of this enzyme in cocaine's effect on dendritic spine density. Adult male rats, receiving intra-accumbens infusion of the cyclin-dependent kinase-5 inhibitor roscovitine or saline, were administered a 28-day cocaine treatment regimen. Animals were killed 24-48 h after the final cocaine injection and their brains removed and processed for Golgi-Cox impregnation. Our findings demonstrate that roscovitine attenuates cocaine-induced dendritic spine outgrowth in nucleus accumbens core and shell and such inhibition reduces spine density in nucleus accumbens shell of control animals. These data indicate that cyclin-dependent kinase-5 is involved in regulation of, as well as cocaine-induced changes in, dendritic spine density.


Assuntos
Cocaína/farmacologia , Quinases Ciclina-Dependentes/metabolismo , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/enzimologia , Animais , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Masculino , Microscopia Confocal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Roscovitina
8.
Synapse ; 42(3): 151-63, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11746712

RESUMO

Olfactory bulbectomy, neonatal clomipramine administration, and maternal deprivation have been employed as animal models of depression. Each model is unique with respect to the experimental manipulations required to produce "depressive" signs, expression and duration of these signs, and response to antidepressant treatments. Dendritic spines represent a possible anatomical substrate for the enduring changes seen with depression and we have previously shown that chronic antidepressant drug exposure alters the density of hippocampal dendritic spines in an enduring fashion. The purpose of the present study was to determine whether persistent alteration of hippocampal spine density is a common element in each of these different models of depression and whether such alterations could be reversed with chronic antidepressant treatment. The results show that olfactory bulbectomy reduced spine density in CA1, CA3, and dentate gyrus compared to sham-operated controls. Chronic treatment with amitriptyline, a tricyclic antidepressant, reversed the bulbectomy- induced reduction in dendritic spine density in CA1, CA3, and dentate gyrus, whereas treatment with mianserin, an atypical antidepressant, reversed this reduction only in dentate gyrus. On the other hand, neither neonatal clomipramine administration nor maternal deprivation affected hippocampal dendritic spine density. Repeated neonatal handling, however, as a control or as part of the maternal deprivation procedure, elevated spine density in dentate gyrus. These data suggest that long-lasting alterations in hippocampal dendritic spine density contribute to the neural mechanism underlying the olfactory bulbectomy model of depression, but not the neonatal clomipramine or maternal deprivation models.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Clomipramina/farmacologia , Dendritos/fisiologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Animais , Animais Recém-Nascidos , Dendritos/efeitos dos fármacos , Denervação , Modelos Animais de Doenças , Masculino , Privação Materna , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Bulbo Olfatório/cirurgia , Ratos , Ratos Sprague-Dawley
9.
Brain Res ; 883(2): 205-15, 2000 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-11074049

RESUMO

The density of dendritic spines, the postsynaptic sites of most excitatory synapses, increases during the first 2 postnatal months in rat hippocampus. Significant alterations in hippocampal levels of serotonin and norepinephrine impact synaptic development during this time period. In the present study, dendritic spine density was studied in the hippocampus (CA1) and dentate gyrus of juvenile rats acutely and chronically exposed to antidepressant drugs that act on serotonin and norepinephrine. One group of 21-day-old rats was given a single injection of a serotonin specific re-uptake inhibitor (fluoxetine or fluvoxamine), a norepinephrine-specific re-uptake inhibitor (desipramine), or saline and killed after 24 h. A second group of rats was injected daily, beginning on postnatal day (PN) 21, for 3 weeks. This group was further subdivided into rats that were killed 1 day or 21 days after the last injection. Golgi analysis showed that a single injection of fluvoxamine produced a significant increase in dendritic spine density in stratum radiatum of CA1 and in the dentate gyrus. Further, acute treatment with all three antidepressants increased the total length of secondary dendrites in CA1, with fluoxetine and desipramine increasing the number of secondary dendrites as well. In fluoxetine-treated animals killed on days 42 or 62 (1 or 21 days post-treatment, respectively), dendritic spine density remained at levels present in CA1 at 21 days. These results show that acute antidepressant treatment can impact dendritic length and spine density, and raise the possibility that chronic fluoxetine treatment arrests spine development into young adulthood.


Assuntos
Dendritos/efeitos dos fármacos , Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Hipocampo/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Contagem de Células , Dendritos/fisiologia , Desipramina/farmacologia , Hipocampo/citologia , Masculino , Células Piramidais/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley
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