RESUMEN

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

Asunto(s)

Precursor de Proteína beta-Amiloide , Giro Dentado , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-fos , Convulsiones , Animales , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Neuroprotección/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Convulsiones/genética , Convulsiones/metabolismo

RESUMEN

To mitigate potential mental health crises within a Community Mental Health Team (CMHT) the psychology department implemented a short-term, rapid access, crisis telephone support service for clients during the COVID-19 pandemic. We aimed to evaluate the feasibility and acceptability. Data was collected on who the service was offered to and whom engaged. Demographic information, referral and crisis support call information was collected from the service's electronic database. Forty-four participants were referred to the service. Seventy seven percent of participants engaged in one or more telephone sessions. Participants rated the service as highly useful, with simply 'talking to someone' seen as the most important aspect of the calls. A number of age differences were noted regarding the content that was discussed in sessions. The psychological crisis telephone support service was feasible and acceptable to service users during the COVID-19 pandemic.

Asunto(s)

COVID-19 , Humanos , COVID-19/epidemiología , Salud Mental , Pandemias , Consejo

RESUMEN

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Asunto(s)

Trastornos del Conocimiento , Síndrome de Down , Ratones , Animales , Síndrome de Down/genética , Síndrome de Down/metabolismo , Variaciones en el Número de Copia de ADN/genética , Modelos Animales de Enfermedad , Trastornos del Conocimiento/genética , Cromatina/genética , Ratones Transgénicos

RESUMEN

The lateral hypothalamic area (LHA) is essential for ingestive behavior but has primarily been studied in modulating feeding, with comparatively scant attention on drinking. This is partly because most LHA neurons simultaneously promote feeding and drinking, suggesting that ingestive behaviors track together. A notable exception are LHA neurons expressing neurotensin (LHANts neurons): activating these neurons promotes water intake but modestly restrains feeding. Here we investigated the connectivity of LHANts neurons, their necessity and sufficiency for drinking and feeding, and how timing and resource availability influence their modulation of these behaviors. LHANts neurons project broadly throughout the brain, including to the lateral preoptic area (LPO), a brain region implicated in modulating drinking behavior. LHANts neurons also receive inputs from brain regions implicated in sensing hydration and energy status. While activation of LHANts neurons is not required to maintain homeostatic water or food intake, it selectively promotes drinking during the light cycle, when ingestive drive is low. Activating LHANts neurons during this period also increases willingness to work for water or palatable fluids, regardless of their caloric content. By contrast, LHANts neuronal activation during the dark cycle does not promote drinking, but suppresses feeding during this time. Finally, we demonstrate that the activation of the LHANts â†’ LPO projection is sufficient to mediate drinking behavior, but does not suppress feeding as observed after generally activating all LHANts neurons. Overall, our work suggests how and when LHANts neurons oppositely modulate ingestive behaviors.

Asunto(s)

Área Hipotalámica Lateral , Neurotensina , Alimentos , Área Hipotalámica Lateral/metabolismo , Neuronas/metabolismo , Neurotensina/metabolismo , Agua

Asunto(s)

Trastornos Mentales , Salud Mental , Femenino , Humanos , Trastornos Mentales/terapia , Parto , Embarazo

RESUMEN

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

Asunto(s)

Conducta Animal , Área Hipotalámica Lateral/fisiopatología , Nocicepción , Dolor/fisiopatología , Dolor/psicología , Analgésicos Opioides/uso terapéutico , Animales , Animales Modificados Genéticamente , Conducta Animal/efectos de los fármacos , Señalización del Calcio , Modelos Animales de Enfermedad , Tolerancia a Medicamentos , Femenino , Neuronas GABAérgicas/metabolismo , Ácido Glutámico/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Área Hipotalámica Lateral/metabolismo , Masculino , Ratones Endogámicos C57BL , Microscopía Fluorescente , Morfina/farmacología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Técnicas de Trazados de Vías Neuroanatómicas , Nocicepción/efectos de los fármacos , Optogenética , Dolor/metabolismo , Dolor/prevención & control , Parvalbúminas/genética , Parvalbúminas/metabolismo

RESUMEN

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.

Asunto(s)

Agresión , Derrota Social , Animales , Conducta Animal , Individualidad , Masculino , Ratones , Estándares de Referencia , Conducta Social , Estrés Psicológico

RESUMEN

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.

Asunto(s)

Cocaína , Área Tegmental Ventral , Cocaína/farmacología , Condicionamiento Clásico , Neuronas Dopaminérgicas , Glucocorticoides

RESUMEN

The Akt family of kinases exerts many of its cellular effects via the activation of the mammalian target of rapamycin (mTOR) kinase through a series of intermediary proteins. Multiple lines of evidence have identified Akt-family kinases as candidate schizophrenia and bipolar disorder genes. Although dysfunction of the prefrontal cortex (PFC) is a key feature of both schizophrenia and bipolar disorder, no studies have comprehensively assessed potential alterations in Akt-mTOR pathway activity in the PFC of either disorder. Here, we examined the activity and expression profile of key proteins in the Akt-mTOR pathway in bipolar disorder and schizophrenia homogenates from two different PFC subregions. Our findings identify reduced Akt-mTOR PFC signaling in a subset of bipolar disorder subjects. Using a reverse-translational approach, we demonstrated that Akt hypofunction in the PFC is sufficient to give rise to key cognitive phenotypes that are paralleled by alterations in synaptic connectivity and function.

Asunto(s)

Trastorno Bipolar/metabolismo , Disfunción Cognitiva/metabolismo , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Trastorno Bipolar/patología , Trastorno Bipolar/fisiopatología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Femenino , Humanos , Masculino , Neuronas/patología , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología

RESUMEN

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.

Asunto(s)

Reacción de Prevención/fisiología , Hipocampo/fisiología , Proteínas Proto-Oncogénicas c-fos/fisiología , Animales , Ansiedad/metabolismo , Conducta Animal/fisiología , Técnicas de Inactivación de Genes , Silenciador del Gen , Hipocampo/anatomía & histología , Hipocampo/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/deficiencia , Proteínas Proto-Oncogénicas c-fos/genética , Conducta Social , Estrés Psicológico

RESUMEN

BACKGROUND: Depression affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Preclinical studies in male mice suggest that activity of ventral hippocampus (vHPC) neurons projecting to the nucleus accumbens (NAc) regulates mood-related behavioral responses to stress. We sought to characterize this circuit in both sexes and to investigate its role in potential sex differences in models of depression. METHODS: We used male and female adult C57BL/6J mice in the subchronic variable stress model to precipitate female-specific reduction in sucrose preference and performed gonadectomies to test the contributions of gonadal hormones to this stress response. In addition, ex vivo slice electrophysiology of transgenic Cre-inducible Rosa-eGFP-L10a mice in combination with retrograde viral tracing to identify circuits was used to test contributions of gonadal hormones to sex differences in vHPC afferents. Finally, we used an intersecting viral DREADD (designer receptor exclusively activated by designer drugs) strategy to manipulate vHPC-NAc excitability directly in awake behaving mice. RESULTS: We show a testosterone-dependent lower excitability in male versus female vHPC-NAc neurons and corresponding testosterone-dependent male resilience to reduced sucrose preference after subchronic variable stress. Importantly, we show that long-term DREADD stimulation of vHPC-NAc neurons causes decreased sucrose preference in male mice after subchronic variable stress, whereas DREADD inhibition of this circuit prevents this effect in female mice. CONCLUSIONS: We demonstrate a circuit-specific sex difference in vHPC-NAc neurons that is dependent on testosterone and causes susceptibility to stress in female mice. These data provide a substantive mechanism linking gonadal hormones to cellular excitability and anhedonia-a key feature in depressive states.

Asunto(s)

Andrógenos , Núcleo Accumbens , Animales , Femenino , Hipocampo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos

RESUMEN

Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ΔFosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ΔFosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ΔFosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ΔFosB was subregion-specific, and that ΔFosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause ΔFosB induction critical for cocaine-related learning.SIGNIFICANCE STATEMENT Although cocaine addiction is driven in part by the formation of indelible associations between the drug and the environment, paraphernalia, and circumstances of use, and although this type of associative learning is dependent upon changes in gene expression in a brain region called the hippocampus, the mechanisms by which cocaine alters hippocampal gene expression to drive formation of these associations is poorly understood. Here, we demonstrate that chronic cocaine engages locus-specific changes in the epigenetic profile of the FosB gene in the hippocampus, and that these alterations are required for cocaine-dependent gene expression and cocaine-environment associations. This work provides novel insight into addiction etiology and potential inroads for therapeutic intervention in cocaine addiction.

Asunto(s)

Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Epigénesis Genética/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Hipocampo/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

Neural proliferation in the dentate gyrus (DG) is closely linked with learning and memory, but the transcriptional programming that drives adult proliferation remains incompletely understood. Our lab previously elucidated the critical role of the transcription factor ΔFosB in the dorsal hippocampus (dHPC) in learning and memory, and the FosB gene has been suggested to play a role in neuronal proliferation. However, the subregion-specific and potentially cell-autonomous role of dHPC ΔFosB in neurogenesis-dependent learning has not been studied. Here, we crossed neurotensin receptor-2 (NtsR2) Cre mice, which express Cre within the subgranular zone (SGZ) of dHPC DG, with floxed FosB mice to show that knockout of ΔFosB in hippocampal SGZ neurons reduces antidepressant-induced neurogenesis and impedes hippocampus-dependent learning in the novel object recognition task. Taken together, these data indicate that FosB gene expression in SGZ is necessary for both hippocampal neurogenesis and memory formation.

Asunto(s)

Hipocampo/metabolismo , Aprendizaje por Laberinto/fisiología , Neurogénesis/fisiología , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Animales , Femenino , Hipocampo/citología , Aprendizaje/fisiología , Masculino , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-fos/genética

RESUMEN

Pregnancy, birth and adjusting to a new baby is a potentially stressful time that can negatively affect the health of women. There is some evidence that expressive writing can have positive effects on psychological and physical health, particularly during stressful periods. The current study aimed to evaluate whether expressive writing would improve women's postpartum health. A randomized controlled trial was conducted with three conditions: expressive writing (n = 188), a control writing task (n = 213), or normal care (n = 163). Measures of psychological health, physical health and quality of life were measured at baseline (6-12 weeks postpartum), 1 and 6 months later. Ratings of stress were taken before and after the expressive writing task. Intent-to-treat analyses showed no significant differences between women in the expressive writing, control writing and normal care groups on measures of physical health, anxiety, depression, mood or quality of life at 1 and 6 months. Uptake and adherence to the writing tasks was low. However, women in the expressive writing group rated their stress as significantly reduced after completing the task. Cost analysis suggest women who did expressive writing had the lowest costs in terms of healthcare service use and lowest cost per unit of improvement in quality of life. Results suggest expressive writing is not effective as a universal intervention for all women 6-12 weeks postpartum. Future research should examine expressive writing as a targeted intervention for women in high-risk groups, such as those with mild or moderate depression, and further examine cost-effectiveness.Clinical trial registration number ISRCTN58399513 www.isrctn.com.

Asunto(s)

Depresión/prevención & control , Terapia Narrativa/métodos , Periodo Posparto/psicología , Calidad de Vida/psicología , Estrés Psicológico/prevención & control , Escritura , Adaptación Psicológica , Adulto , Teorema de Bayes , Depresión/psicología , Femenino , Humanos , Salud Mental , Embarazo , Reproducibilidad de los Resultados , Encuestas y Cuestionarios

Asunto(s)

Alcoholismo , Etanol , Glucógeno Sintasa Quinasa 3 beta , Humanos , Corteza Prefrontal , Factores de Riesgo

RESUMEN

Both the function of hippocampal neurons and hippocampus-dependent behaviors are dependent on changes in gene expression, but the specific mechanisms that regulate gene expression in hippocampus are not yet fully understood. The stable, activity-dependent transcription factor ΔFosB plays a role in various forms of hippocampal-dependent learning and in the structural plasticity of synapses onto CA1 neurons. The authors examined the consequences of viral-mediated overexpression or inhibition of ΔFosB on the function of adult mouse hippocampal CA1 neurons using ex vivo slice whole-cell physiology. We found that the overexpression of ΔFosB decreased the excitability of CA1 pyramidal neurons, while inhibition increased excitability. Interestingly, these manipulations did not affect resting membrane potential or spike frequency adaptation, but ΔFosB overexpression reduced hyperpolarization-activated current. Both ΔFosB overexpression and inhibition decreased spontaneous excitatory postsynaptic currents, while only ΔFosB inhibition affected the AMPA/NMDA ratio, which was mediated by decreased NMDA receptor current, suggesting complex effects on synaptic inputs to CA1 that may be driven by homeostatic cell-autonomous or network-driven adaptations to the changes in CA1 cell excitability. Because ΔFosB is induced in hippocampus by drugs of abuse, stress, or antidepressant treatment, these results suggest that ΔFosB-driven changes in hippocampal cell excitability may be critical for learning and, in maladaptive states, are key drivers of aberrant hippocampal function in diseases such as addiction and depression.

Asunto(s)

Región CA1 Hipocampal/fisiología , Expresión Génica/fisiología , Aprendizaje/fisiología , Potenciales de la Membrana/fisiología , Proteínas Proto-Oncogénicas c-fos/fisiología , Células Piramidales/fisiología , Animales , Región CA1 Hipocampal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células Piramidales/metabolismo

RESUMEN

BACKGROUND: Post-traumatic stress disorder (PTSD) affects men and women differently. Not only are women twice as likely as men to develop PTSD, they experience different symptoms and comorbidities associated with PTSD. Yet the dearth of preclinical research on females leaves a notable gap in understanding the underlying neuropathology of this sex difference. METHODS: Using two standard measures of PTSD-like responses in rats, the acoustic startle response (ASR) and dexamethasone suppression test (DST), we tested the effects of traumatic stress in adult male and female rats using two rodent models of PTSD, single prolonged stress and predator exposure. We then examined the neural correlates underlying these responses with cFos and glucocorticoid receptor immunohistochemistry in brain regions implicated in the traumatic stress response. RESULTS: We now report that adult male and female rats across two models of PTSD show consistent sex-specific responses that recapitulate fundamental differences of PTSD in men and women. Trauma-exposed males showed the well-established hyper-responsive phenotype of enhanced ASR and exaggerated negative feedback control of the hypothalamic-pituitary-adrenal axis, while the same traumatic event had little effect on these same measures in females. Dramatic sex differences in how trauma affected cFos and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of male and female rats is fundamentally different. CONCLUSIONS: Two standard measures, ASR and DST, might suggest that females are resilient to the effects of traumatic stress, but other measures make it clear that females are not resilient, but simply respond differently to trauma. The next important question to answer is why. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. The divergent effects of trauma in the brains of males and females begin to shed light on the neurobiological underpinnings of these sex differences, paving the way for improved diagnostics and therapeutics that effectively treat both men and women.

Asunto(s)

Caracteres Sexuales , Estrés Psicológico , Animales , Encéfalo/metabolismo , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflejo de Sobresalto , Trastornos por Estrés Postraumático , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología

RESUMEN

BACKGROUND: Our previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones? METHODS: For the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined. RESULTS: We now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females. CONCLUSIONS: We propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.

Asunto(s)

Hormonas Gonadales/fisiología , Caracteres Sexuales , Estrés Psicológico , Anhedonia , Animales , Encéfalo/metabolismo , Dexametasona/administración & dosificación , Éter/administración & dosificación , Femenino , Relaciones Interpersonales , Masculino , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Reflejo de Sobresalto , Restricción Física , Estrés Fisiológico , Natación

RESUMEN

Post-traumatic stress disorder (PTSD) is a common, costly, and often debilitating psychiatric condition. However, the biological mechanisms underlying this disease are still largely unknown or poorly understood. Considerable evidence indicates that PTSD results from dysfunction in highly-conserved brain systems involved in stress, anxiety, fear, and reward. Pre-clinical models of traumatic stress exposure are critical in defining the neurobiological mechanisms of PTSD, which will ultimately aid in the development of new treatments for PTSD. Single prolonged stress (SPS) is a pre-clinical model that displays behavioral, molecular, and physiological alterations that recapitulate many of the same alterations observed in PTSD, illustrating its validity and giving it utility as a model for investigating post-traumatic adaptations and pre-trauma risk and protective factors. In this manuscript, we review the present state of research using the SPS model, with the goals of (1) describing the utility of the SPS model as a tool for investigating post-trauma adaptations, (2) relating findings using the SPS model to findings in patients with PTSD, and (3) indicating research gaps and strategies to address them in order to improve our understanding of the pathophysiology of PTSD.

RESUMEN

BACKGROUND: Pregnancy, birth and adjusting to a new baby is a potentially stressful time that can negatively affect women's mental and physical health. Expressive writing, where people write about a stressful event for at least 15 min on three consecutive days, has been associated with improved health in some groups but it is not clear whether it is feasible and acceptable for use with postpartum women. This study therefore examined the feasibility and acceptability of expressive writing for postpartum women as part of a randomised controlled trial (RCT). METHODS: The Health After Birth Trial (HABiT) was an RCT evaluating expressive writing for postpartum women which included measures of feasibility and acceptability. At 6 to 12 weeks after birth 854 women were randomised to expressive writing, a control writing task or normal care, and outcome measures of health were measured at baseline, one month later and six months later. Feasibility was measured by recruitment, attrition, and adherence to the intervention. Quantitative and qualitative measures of acceptability of the materials and the task were completed six months after the intervention. RESULTS: Recruitment was low (10.7% of those invited to participate) and the recruited sample was from a restricted sociodemographic range. Attrition was high, increased as the study progressed (35.8% at baseline, 57.5% at one month, and 68.1% at six months) and was higher in the writing groups than in the normal care group. Women complied with instructions to write expressively or not, but adherence to the instruction to write for 15 min per day for three days was low (Expressive writing: 29.3%; Control writing: 23.5%). Acceptability measures showed that women who wrote expressively rated the materials/task both more positively and more negatively than those in the control writing group, and qualitative comments revealed that women enjoyed the writing and/or found it helpful even when it was upsetting. CONCLUSIONS: The feasibility of offering expressive writing as a universal self-help intervention to all postpartum women 6 to 12 weeks after birth in the HABiT trial was low, but the expressive writing intervention was acceptable to the majority of women who completed it. TRIAL REGISTRATION: ISRCTN58399513, 10/09/2013.

Asunto(s)

Aceptación de la Atención de Salud/psicología , Atención Posnatal/psicología , Periodo Posparto/psicología , Escritura , Adulto , Emociones , Estudios de Factibilidad , Femenino , Humanos , Atención Posnatal/métodos , Embarazo