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1.
Proc Natl Acad Sci U S A ; 121(1): e2308706120, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38147649

RESUMO

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.


Assuntos
Microbioma Gastrointestinal , Fobia Social , Humanos , Animais , Camundongos , Microbioma Gastrointestinal/fisiologia , Ocitocina , RNA Ribossômico 16S/genética , Medo , Ansiedade/psicologia
2.
Nat Rev Neurosci ; 20(11): 686-701, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31578460

RESUMO

Currently, over 300 million people worldwide have depression, and the socioeconomic burden of this debilitating disorder is anticipated to increase markedly over the coming decades against a background of increasing global turmoil. Despite this impending crisis, we are still waiting for improved therapeutic options for this disorder to emerge, which has led to increasing criticism of the role and value of preclinical models of depression. In this Review, we examine this landscape, focusing firstly on issues related to the terminology used in this context and the myriad of preclinical approaches to modelling and assaying aspects of depression in rodents. We discuss the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits. We then examine the technical strategies available to dissect these models and review emerging evidence for putative druggable disease mechanisms. Finally, we propose a brief framework for future research that makes optimal use of these models and will, we hope, accelerate the discovery of improved antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Pesquisa Biomédica/tendências , Depressão/genética , Depressão/psicologia , Modelos Animais de Doenças , Animais , Pesquisa Biomédica/métodos , Depressão/tratamento farmacológico , Previsões , Humanos , Roedores
3.
Brain Behav Immun ; 120: 315-326, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38852762

RESUMO

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.

4.
Mol Psychiatry ; 27(11): 4464-4473, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35948661

RESUMO

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.


Assuntos
Transtorno do Espectro Autista , Transtorno Depressivo Maior , Transtornos Mentais , Animais , Camundongos , Humanos , Transtorno do Espectro Autista/genética , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Camundongos Knockout , Fatores de Processamento de RNA/genética
5.
Mol Psychiatry ; 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035479

RESUMO

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.

6.
Front Neuroendocrinol ; 55: 100796, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31580837

RESUMO

Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don't model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.


Assuntos
Androgênios/metabolismo , Dendritos/fisiologia , Transtorno Depressivo , Estrogênios/metabolismo , Hipocampo , Neurogênese/fisiologia , Neuroesteroides/metabolismo , Progestinas/metabolismo , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico , Animais , Dendritos/metabolismo , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Feminino , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
7.
Front Neuroendocrinol ; 41: 114-28, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26828151

RESUMO

The peripartum period represents a time during which all mammalian species undergo substantial physiological and behavioural changes, which prepare the female for the demands of motherhood. In addition to behavioural and physiological alterations, numerous brain regions, such as the medial prefrontal cortex, olfactory bulb, medial amygdala and hippocampus are subject to substantial peripartum-associated neuronal, dendritic and synaptic plasticity. These changes, which are temporally- and spatially-distinct, are strongly influenced by gonadal and adrenal hormones, such as estrogen and cortisol/corticosterone, which undergo dramatic fluctuations across this period. In this review, we describe our current knowledge regarding these plasticity changes and describe how stress affects such normal adaptations. Finally, we discuss the mechanisms potentially underlying these neuronal, dendritic and synaptic changes and their functional relevance for the mother and her offspring.


Assuntos
Encéfalo/fisiologia , Comportamento Materno/fisiologia , Plasticidade Neuronal/fisiologia , Período Periparto/fisiologia , Estresse Psicológico , Animais , Encéfalo/metabolismo , Feminino , Período Periparto/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
8.
Stress ; 20(3): 303-311, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28460556

RESUMO

Increased basal glucocorticoid secretion and a reduced glucocorticoid response during acute stress, despite only minor changes in the secretion of the major secretagogue adrenocorticotropic hormone (ACTH), have been documented in the peripartum period in several species. We recently showed that the adrenal gland, the site of glucocorticoid synthesis, undergoes substantial postpartum-associated plasticity in the rat at mid-lactation. Here, we asked the question whether adrenal changes already take place around parturition in the rat and in another species, namely the mouse. After demonstrating that several components of the adrenal machinery mediating cholesterol supply for steroidogenesis, including protein levels of hormone-sensitive lipase, low-density lipoprotein receptor (LDLR) and scavenger receptor class-B type-1 (SRB1), are upregulated, while hydroxymethylglutaryl coenzyme A reductase (HMGCR) is downregulated in the lactating rat one day after delivery, as previously observed at mid-lactation, we demonstrated profound changes in the mouse. In detail, protein expression of LDLR, SRB1, HMGCR and adrenal lipid store density were increased in the mouse adrenal one day after parturition as tested via western blot analysis and oil-red lipid staining, respectively. Moreover, using in vitro culture techniques, we observed that isolated adrenal explants from lactating mice secreted higher levels of corticosterone under basal conditions, but showed impaired responsiveness to ACTH, mimicking the in vivo scenario. These results suggest that mechanisms of adaptation in the maternal adrenal after delivery, namely increased cholesterol availability and decreased ACTH sensitivity, are crucial for the basal increase in circulating glucocorticoids and maternal stress hyporesponsiveness that are typical of this period.


Assuntos
Glândulas Suprarrenais/metabolismo , Corticosterona/metabolismo , Lactação/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Colesterol/metabolismo , Feminino , Hidroximetilglutaril-CoA Redutases/metabolismo , Camundongos , Fosfoproteínas/metabolismo , Período Pós-Parto/metabolismo , Ratos , Receptores da Corticotropina/metabolismo , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/metabolismo , Esterol Esterase/metabolismo
9.
J Neurosci ; 35(35): 12248-60, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26338335

RESUMO

The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whether OT interferes with CRTC translocation and, thereby, Crf expression. OT (1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr(4) Gly(7)-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene. SIGNIFICANCE STATEMENT: The neuropeptide oxytocin has been proposed to reduce hypothalamic-pituitary-adrenal (HPA) axis activation during stress. The underlying mechanisms are, however, elusive. In this study we show that activation of the oxytocin receptor in the paraventricular nucleus delays transcription of the gene encoding corticotropin releasing factor (Crf), the main regulator of the stress response. It does so by sequestering the coactivator of the transcription factor CREB, CRTC3, in the cytosol, resulting in reduced binding of CRTC3 to the Crf gene promoter and subsequent Crf gene expression. This novel oxytocin receptor-mediated intracellular mechanism might provide a basis for the treatment of exaggerated stress responses in the future.


Assuntos
Proteína de Ligação a CREB/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Regulação da Expressão Gênica , Ocitocina/farmacologia , Estresse Psicológico/metabolismo , Tromboplastina/metabolismo , Animais , Células Cultivadas , Colforsina/farmacologia , Hormônio Liberador da Corticotropina/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ocitócicos/farmacologia , Ocitócicos/uso terapêutico , Ocitocina/análogos & derivados , Ocitocina/uso terapêutico , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Ratos , Ratos Wistar , Receptores de Ocitocina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
10.
J Neurosci ; 35(11): 4599-613, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25788677

RESUMO

Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.


Assuntos
Ansiedade/genética , Ansiedade/metabolismo , Cruzamento , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas G/genética , Estimulação Acústica/métodos , Animais , Ansiedade/psicologia , Cruzamento/métodos , Medo/fisiologia , Medo/psicologia , Células HEK293 , Humanos , Masculino , Camundongos , Ratos
11.
Acta Neuropsychiatr ; 28(1): 55-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26400016

RESUMO

OBJECTIVE: 11ß-dehydroxysteroid dehydrogenase (HSD) types 1 and 2, enzymes are involved in the activation and inactivation of glucocorticoids in vivo, respectively. Indirect evidence implicates two enzymes in the aetiology of depression but no study has directly assessed the potential role of 11 ß-HSD1 in animal tests. METHODS: We assessed 11 ß-HSD1 knockout mice in the forced swim test (FST), tail suspension test (TST) and for locomotor activity. RESULTS: Genetic ablation of the 11ß-HSD1 gene results in an antidepressant-like phenotype in the FST; the most widely utilised animal test of antidepressant activity, but not in the related TST. This may be related to the different biological substrates underlying these tests. The decreased FST immobility was not due to alterations in general activity. CONCLUSIONS: Taken together these results suggest that 11ß-HSD1 may play an important role in depression-related behaviours and further studies are necessary to fully characterise its role in such behaviour.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Transtorno Depressivo/enzimologia , Fenótipo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Corticosterona/metabolismo , Glucocorticoides/metabolismo , Elevação dos Membros Posteriores/fisiologia , Hidroxiesteroides/metabolismo , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Projetos Piloto , Natação/fisiologia
12.
Hippocampus ; 24(6): 673-83, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24615851

RESUMO

The peripartum period is a time of high susceptibility for mood and anxiety disorders, some of which have recently been associated with alterations in hippocampal neurogenesis. Several factors including stress, aging, and, perhaps unexpectedly, lactation have been shown to decrease hippocampal neurogenesis. Intriguingly, lactation is also a time of reduced stress responsivity suggesting that the effect of stress on neurogenic processes may differ during this period. Therefore, the aim of the present study was to assess the effect of repeated stress during lactation [2 h restraint stress from lactation day (LD) 2 to LD13] on brain weight, hippocampal volume, cell proliferation and survival, and on neuronal and astroglial differentiation. In addition to confirming the known lactation-associated decrease in cell proliferation and survival, we could reveal that stress reversed the lactation-induced decrease in cell proliferation, while it did not affect survival of newly born cells, nor the number of mature neurons , nor did it alter immature neuron production or the number of astroglial cells in lactation. Stress exposure increased relative brain weight and hippocampal volume mirroring the observed changes in neurogenesis. Interestingly, hippocampal volume and relative brain weight were lower in lactation as compared to nulliparous females under nonstressed conditions. This study assessed the effect of stress during lactation on hippocampal neurogenesis and indicates that stress interferes with important peripartum adaptations at the level of the hippocampus.


Assuntos
Hipocampo/fisiopatologia , Lactação/fisiologia , Neurogênese/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Contagem de Células , Proliferação de Células , Sobrevivência Celular , Corticosterona/sangue , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Feminino , Hipocampo/patologia , Células-Tronco Neurais/patologia , Células-Tronco Neurais/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Tamanho do Órgão , Paridade/fisiologia , Ratos Wistar , Restrição Física , Estresse Psicológico/patologia
13.
Sci Rep ; 14(1): 12252, 2024 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-38806649

RESUMO

Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.


Assuntos
Região CA2 Hipocampal , Espinhas Dendríticas , Ciclo Estral , Animais , Masculino , Feminino , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Camundongos , Ciclo Estral/fisiologia , Região CA2 Hipocampal/fisiologia , Região CA2 Hipocampal/metabolismo , Caracteres Sexuais , Neurônios/metabolismo
14.
Psychoneuroendocrinology ; 167: 107102, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38896988

RESUMO

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer's disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms.

15.
Hippocampus ; 23(6): 476-87, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23504963

RESUMO

Sex differences in basal as well as in stress-induced hippocampal neurogenesis processes have been reported in the literature. However, studies directly comparing sex differences on multiple neurogenesis processes under such conditions are lacking to date. Therefore, the aim of the present study was to directly compare cell proliferation and survival, neuronal and astroglial differentiation as well as stem cells quiescence in male and female Wistar rats under both basal and chronic stress conditions (12 days of 2 h restraint stress (RS)). In addition, corticosterone (CORT) levels and spatial working memory were assessed. Under baseline conditions, only the number of immature neurons within the hippocampal dentate gyrus was higher in males compared with females. In contrast, chronic stress resulted in a number of sex-specific alterations. Thus, stress exposure reduced cell proliferation in males with a concurrent increase in stem cell quiescence, while it did not alter either parameter in females but decreased cell survival. Analysis of astroglial and neuronal differentiation patterns revealed that chronic stress specifically diminished the number of mature neurons in females, with no effect in males. Despite the observed sex differences in adult hippocampal neurogenesis, spatial working memory was not altered by stress exposure in either sex. While basal CORT levels were higher, chronic stress exposure did not affect this parameter in either sex across the initial stress period. This study presents the first direct and detailed evaluation of sex-dependent and chronic stress-induced changes in adult hippocampal neurogenesis not only showing changes in cell proliferation and survival, but moreover immature neuron production, differentiation patterns, stem cell quiescence and therefore contributes to a better understanding of sex differences in neurogenesis processes.


Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Caracteres Sexuais , Estresse Psicológico/patologia , Animais , Proliferação de Células , Doença Crônica , Feminino , Masculino , Ratos , Ratos Wistar , Estresse Psicológico/psicologia
16.
Addict Biol ; 18(1): 66-77, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23126471

RESUMO

Chronic stress is known to enhance the susceptibility for addiction disorders including alcoholism. While these findings have been recapitulated in animal models, the majority of these studies have utilized non-social rather than social stress paradigms; the latter of which are believed to be more relevant to the human situation. Therefore, the major aim of this study was to investigate, if 14 days of chronic subordinate colony housing (CSC), a pre-clinically validated psychosocial stress paradigm relevant for human psychiatric and somatic disorders, enhances ethanol (EtOH) consumption in male mice. To assess this, we employed the well-established two-bottle free-choice paradigm where mice were given access to water and 2, 4, 6 and 8% EtOH solutions (with the concentrations increasing each fourth day) following termination of the stress procedure. After 14 days of CSC, stressed mice consumed significantly more EtOH at all concentrations tested and displayed increased EtOH preference at concentrations of 6 and 8%. This effect was not due to an altered taste preference in CSC mice as assessed by saccharine- and quinine-preference tests, but was accompanied by increased anxiety-related behavior. Systemic administration of baclofen (2.5 mg/kg) or oxytocin (OXT; 10 mg/kg) reduced the EtOH intake in single housed control (baclofen, OXT) and CSC (baclofen) mice, whereas intracerebroventricular OXT (0.5 µg/2 µl) was ineffective in both groups. Taken together, these results suggest that (i) chronic psychosocial stress enhances EtOH consumption, and (ii) baclofen and OXT differentially affect EtOH intake in mice.


Assuntos
Consumo de Bebidas Alcoólicas , Baclofeno/farmacologia , Etanol/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Ocitocina/farmacologia , Estresse Psicológico/psicologia , Adolescente , Alcoolismo/tratamento farmacológico , Alcoolismo/psicologia , Análise de Variância , Animais , Baclofeno/administração & dosagem , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido , Etanol/efeitos adversos , Preferências Alimentares , Agonistas dos Receptores de GABA-B/administração & dosagem , Abrigo para Animais , Humanos , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/administração & dosagem , Autoadministração
17.
Res Sq ; 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37461513

RESUMO

Maternal infections during pregnancy pose an increased risk for neurodevelopmental psychiatric disorders (NPDs) in the offspring. Here, we examined age- and sex-dependent dynamic changes of the hippocampal synaptic proteome after maternal immune activation (MIA) in embryonic and adult mice. Adult male and female MIA offspring exhibited social deficits and sex-specific depression-like behaviours, among others, validating the model. Furthermore, we observed dose-, age-, and sex-dependent synaptic proteome differences. Analysis of the embryonic synaptic proteome implicates sphingolipid and ketoacid metabolism pathway disruptions during neurodevelopment for NPD-pertinent sequelae. In the embryonic hippocampus, prenatal immune activation also led to changes in neuronal guidance, glycosphingolipid metabolism important for signalling and myelination, and post-translational modification of proteins that regulate intercellular interaction and developmental timing. In adulthood, the observed changes in synaptoneurosomes revealed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, and hormone-mediated metabolism. Importantly, 68 of the proteins with differential abundance in the embryonic brains of MIA offspring were also altered in adulthood, 75% of which retained their directionality. These proteins are involved in synaptic organisation, neurotransmitter receptor regulation, and the vesicle cycle. A cluster of persistently upregulated proteins, including AKT3, PAK1/3, PPP3CA, formed a functional network enriched in the embryonic brain that is involved in cellular responses to environmental stimuli. To infer a link between the overlapping protein alterations and cognitive and psychiatric traits, we probed human phenome-wise association study data for cognitive and psychiatric phenotypes and all, but PORCN were significantly associated with the investigated domains. Our data provide insights into the dynamic effects of an early prenatal immune activation on developing and mature hippocampi and highlights targets for early intervention in individuals exposed to such immune challenges.

18.
Eur Neuropsychopharmacol ; 67: 66-79, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36513018

RESUMO

The neuronal isoform of nitric oxide synthase (nNOS) and its interacting protein NOS1AP have been linked to several mental disorders including schizophrenia and depression. An increase in the interaction between nNOS and NOS1AP in the frontal cortex has been suggested to contribute to the emergence of these disorders. Here we aimed to uncover whether disruption of their interactions in the frontal cortex leads to mental disorder endophenotypes. Targeting the medial prefrontal cortex (mPFC), we stereotaxically injected wild-type C57BL/6J mice with recombinant adeno-associated virus (rAAV) expressing either full-length NOS1AP, the nNOS binding region of NOS1AP (i.e. NOS1AP396-503), or the nNOS amino-terminus (i.e. nNOS1-133), which was shown to disrupt the interaction of endogenous nNOS with PSD-95. We tested these mice in a comprehensive behavioural battery, assessing different endophenotypes related to mental disorders. We found no differences in anxiety-related and exploratory behaviours. Likewise, social interaction was comparable in all groups. However, social recognition was impaired in NOS1AP and NOS1AP396-503 mice. These mice, as well as mice overexpressing nNOS1-133 also displayed impaired spatial working memory (SWM) capacity, while spatial reference memory (SRM) remained intact. Finally, mice overexpressing NOS1AP and nNOS1-133, but not NOS1AP396-503, failed to habituate to the startling pulses in an acoustic startle response (ASR) paradigm, though we found no difference in overall startle intensity or prepulse inhibition (PPI) of the ASR. Our findings indicate a distinct role of NOS1AP/nNOS/PSD-95 interactions in the mPFC to contribute to specific endophenotypic changes observed in different mental disorders.


Assuntos
Memória de Curto Prazo , Reflexo de Sobressalto , Camundongos , Animais , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo I/genética , Reconhecimento Psicológico , Transtornos da Memória , Proteína 4 Homóloga a Disks-Large/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética
19.
Neurosci Biobehav Rev ; 155: 105435, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37913873

RESUMO

Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer's disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia - as a proxy of insulin-related metabolic dysfunctions - and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.


Assuntos
Doença de Alzheimer , Transtorno Obsessivo-Compulsivo , Humanos , Função Executiva , Insulina/metabolismo , Estudos Prospectivos
20.
World J Biol Psychiatry ; 24(7): 564-577, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36648064

RESUMO

OBJECTIVES: Kynurenine, kynurenic and quinolinic acid are important metabolites in tryptophan metabolism. Due to an involvement in glutamatergic neurotransmission and immune response, previous studies have investigated this pathway in mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). Tryptophan and kynurenine have been shown to be decreased across disorders, hinting at the missing link how inflammation causes neurotoxicity and psychiatric symptoms. The main aim of our study was to investigate if individual catabolites could serve as diagnostic biomarkers for MDD, BD and SCZ. METHODS: We measured plasma levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid and ratio of quinolinic acid/kynurenic acid using mass spectrometry in n = 175 participants with acute episodes and after remission, compared with controls. RESULTS: Decreased levels of all tryptophan catabolites were found in the whole patient group, driven by the difference between BD and HC. Manic and mixed phase BD individuals displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between disorders. Upon reaching remission, changes in catabolite levels partially normalised. CONCLUSIONS: Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD but disqualifying those metabolites as biomarkers for differential diagnosis.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Esquizofrenia , Humanos , Cinurenina , Triptofano , Esquizofrenia/diagnóstico , Ácido Cinurênico/metabolismo , Ácido Quinolínico/metabolismo , Biomarcadores
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