NCK1 Regulates Amygdala Activity to Control Context-dependent Stress Responses and Anxiety in Male Mice.
Neuroscience
; 448: 107-125, 2020 11 10.
Article
em En
| MEDLINE
| ID: mdl-32946951
ABSTRACT
Anxiety disorder (AD) is characterized by the development of maladaptive neuronal circuits and changes to the excitatory/inhibitory (E/I) balance of the central nervous system. Although AD is considered to be heritable, specific genetic markers remain elusive. Recent genome-wide association studies (GWAS) studies have identified non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), a gene that codes for an intracellular adaptor protein involved in actin dynamics, as an important gene in the regulation of mood. Using a murine model in which NCK1 is inactivated, we show that male, but not female, mice display increased levels of context-dependent anxiety-like behaviors along with an increase in circulating serum corticosterone relative to control. Treatment of male NCK1 mutant mice with a positive allosteric modulator of the GABAA receptor rescued the anxiety-like behaviors implicating NCK1 in regulating neuronal excitability. These defects are not attributable to apparent defects in gross brain structure or in axon guidance. However, when challenged in an approach-avoidance conflict paradigm, male NCK1-deficient mice have decreased neuronal activation in the prefrontal cortex (PFC), as well as decreased activation of inhibitory interneurons in the basolateral amygdala (BLA). Finally, NCK1 deficiency results in loss of dendritic spine density in principal neurons of the BLA. Taken together, these data implicate NCK1 in the control of E/I balance in BLA. Our work identifies a novel role for NCK1 in the regulation of sex-specific neuronal circuitry necessary for controlling anxiety-like behaviors. Further, our work points to this animal model as a useful preclinical tool for the study of novel anxiolytics and its significance towards understanding sex differences in anxiolytic function.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estudo de Associação Genômica Ampla
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Complexo Nuclear Basolateral da Amígdala
Tipo de estudo:
Guideline
Limite:
Animals
Idioma:
En
Revista:
Neuroscience
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Canadá
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA