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1.
Front Cell Neurosci ; 18: 1386715, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601025

RESUMO

Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessive-compulsive disorder, autism spectrum disorder, Huntington's disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuit-level, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes.

2.
Cell Rep ; 39(8): 110857, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35613587

RESUMO

Protocadherin-19 (PCDH19) is a synaptic cell-adhesion molecule encoded by X-linked PCDH19, a gene linked with epilepsy. Here, we report a synapse-to-nucleus signaling pathway through which PCDH19 bridges neuronal activity with gene expression. In particular, we describe the NMDA receptor (NMDAR)-dependent proteolytic cleavage of PCDH19, which leads to the generation of a PCDH19 C-terminal fragment (CTF) able to enter the nucleus. We demonstrate that PCDH19 CTF associates with chromatin and with the chromatin remodeler lysine-specific demethylase 1 (LSD1) and regulates expression of immediate-early genes (IEGs). Our results are consistent with a model whereby PCDH19 favors maintenance of neuronal homeostasis via negative feedback regulation of IEG expression and provide a key to interpreting PCDH19-related hyperexcitability.


Assuntos
Caderinas , Epilepsia , Genes Precoces , Protocaderinas , Caderinas/genética , Caderinas/metabolismo , Cromatina/genética , Cromatina/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Regulação da Expressão Gênica , Humanos , Protocaderinas/genética , Protocaderinas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais
3.
Int J Mol Sci ; 21(20)2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050350

RESUMO

Emotional and cognitive information processing represent higher-order brain functions. They require coordinated interaction of specialized brain areas via a complex spatial and temporal equilibrium among neuronal cell-autonomous, circuitry, and network mechanisms. The delicate balance can be corrupted by stressful experiences, increasing the risk of developing psychopathologies in vulnerable individuals. Neuropsychiatric disorders affect twenty percent of the western world population, but therapies are still not effective for some patients. Elusive knowledge of molecular pathomechanisms and scarcity of objective biomarkers in humans present complex challenges, while the adoption of rodent models helps to improve our understanding of disease correlate and aids the search for novel pharmacological targets. Stress administration represents a strategy to induce, trace, and modify molecular and behavioral endophenotypes of mood disorders in animals. However, a mouse or rat model will only display one or a few endophenotypes of a specific human psychopathology, which cannot be in any case recapitulated as a whole. To override this issue, shared criteria have been adopted to deconstruct neuropsychiatric disorders, i.e., depression, into specific behavioral aspects, and inherent neurobiological substrates, also recognizable in lower mammals. In this work, we provide a rationale for rodent models of stress administration. In particular, comparing each rodent model with a real-life human traumatic experience, we intend to suggest an introductive guide to better comprehend and interpret these paradigms.


Assuntos
Transtornos Mentais/etiologia , Estresse Fisiológico , Estresse Psicológico/complicações , Animais , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Meio Ambiente , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/terapia , Prognóstico , Pesquisa
4.
J Neurochem ; 155(1): 98-110, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32141088

RESUMO

Acute environmental stress rarely implies long-lasting neurophysiological and behavioral alterations. On the contrary, chronic stress exerts a potent toxic effect at the glutamatergic synapse whose altered physiology has been recognized as a core trait of neuropsychiatric disorders. The endocannabinoid system (ECS) plays an important role in the homeostatic response to acute stress. In particular, stress induces synthesis of endocannabinoid (eCB) 2-arachidonyl glycerol (2-AG). 2-AG stimulates presynaptic cannabinoid 1 (CB1) receptor contributing to stress response termination through inhibition of glutamate release, restraining thereafter anxiety arousal. We employ mouse models of stress response coupled to gene expression analyses, unravelling that in response to acute psychosocial stress in the mouse hippocampus, ECS-mediated synaptic modulation is enhanced via transcriptional repression of two enzymes involved in 2-AG degradation: α/ß-hydrolase domain containing 6 (ABHD6) and monoacylglycerol lipase (MAGL). Such a process is orchestrated by the epigenetic corepressor LSD1 who directly interacts with promoter regulatory regions of Abhd6 and Magl. Remarkably, negative transcriptional control of Abhd6 and Magl is lost in the hippocampus upon chronic psychosocial stress, possibly contributing to trauma-induced drift of synapse physiology toward uncontrolled glutamate transmission. We previously showed that in mice lysine-specific demethylase 1 (LSD1) increases its hippocampal expression in response to psychosocial stress preventing excessive consolidation of anxiety-related plasticity. In this work, we unravel a nodal epigenetic modulation of eCB turn over, shedding new light on the molecular substrate of converging stress-terminating effects displayed by ECS and LSD1.


Assuntos
Endocanabinoides/fisiologia , Histona Desmetilases/metabolismo , Transtornos de Estresse Traumático Agudo/fisiopatologia , Animais , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Repressão Epigenética , Regulação da Expressão Gênica , Glicerídeos/farmacologia , Hipocampo/metabolismo , Histona Desmetilases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monoacilglicerol Lipases/biossíntese , Monoacilglicerol Lipases/genética , Receptor CB1 de Canabinoide/agonistas , Meio Social , Estresse Psicológico
5.
Mol Neurobiol ; 57(1): 393-407, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31364026

RESUMO

Ten to 20% of western countries population suffers from major depression disorder (MDD). Stressful life events represent the main environmental risk factor contributing to the onset of MDD and other stress-related neuropsychiatric disorders. In this regard, investigating brain physiology of stress response underlying the remarkable individual variability in terms of behavioral outcome may uncover stress-vulnerability pathways as a source of candidate targets for conceptually new antidepressant treatments. Serum response factor (SRF) has been addressed as a stress transducer via promoting inherent experience-induced Immediate Early Genes (IEGs) expression in neurons. However, in resting conditions, SRF also represents a transcriptional repressor able to assemble the core LSD1/CoREST/HDAC2 corepressor complex, including demethylase and deacetylase activities. We here show that dominant negative SRF splicing isoform lacking most part of the transactivation domain, namely SRFΔ5, owes its transcriptional repressive behavior to the ability of assembling LSD1/CoREST/HDAC2 corepressor complex meanwhile losing its affinity for transcription-permissive cofactor ELK1. SRFΔ5 is highly expressed in the brain and developmentally regulated. In the light of its activity as negative modulator of dendritic spine density, SRFΔ5 increase along with brain maturation suggests a role in synaptic pruning. Upon acute psychosocial stress, SRFΔ5 isoform transiently increases its levels. Remarkably, when stress is chronically repeated, a different picture occurs where SRF protein becomes stably upregulated in vulnerable mice but not in resilient animals. These data suggest a role for SRFΔ5 that is restricted to acute stress response, while positive modulation of SRF during chronic stress matches the criteria for stress-vulnerability hallmark.


Assuntos
Processamento Alternativo/genética , Proteínas Correpressoras/metabolismo , Histona Desmetilases/metabolismo , Plasticidade Neuronal , Fator de Resposta Sérica/genética , Estresse Fisiológico , Animais , Forma Celular , Espinhas Dendríticas/metabolismo , Células HeLa , Hipocampo/metabolismo , Histona Desacetilase 2/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Fator de Resposta Sérica/metabolismo , Estresse Psicológico/patologia
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