Mapping Global Brain Connectivity Mediated by DISC1 Gene in Adult-born Neurons

绘制成年神经元中 DISC1 基因介导的全球大脑连接图

• 批准号: 9069990
• 负责人: Wei Gao
• 金额: $ 22.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069990
• 关键词: Address; Adult; Affect; Affective; Animal Model; Animals; Autistic Disorder; Axon; Behavioral; Bipolar Disorder; Brain; Brain Diseases; Brain region; Cells; Chromosomal translocation; Chronic; Clinical; Cognition; Cognitive; Cytoplasmic Granules; DISC1 gene; Data; Data Analyses; Date of birth; Degenerative Disorder; Development; Disease; Embryo; Epilepsy; Equilibrium; Exhibits; Family; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Goals; Health; Hippocampus (Brain); Imaging Techniques; Impairment; Label; Lead; Learning; Life; Link; Major Depressive Disorder; Maps; Measures; Mediating; Memory; Mental disorders; Modification; Molecular; Molecular Profiling; Morphogenesis; Nature; Neurodegenerative Disorders; Neurons; Neurosciences; Newborn Infant; Patients; Physiological; Play; Population; Positioning Attribute; Predisposition; Process; Property; Quality of life; Recurrence; Retroviridae; Role; Scaffolding Protein; Schizophrenia; Social Functioning; Susceptibility Gene; Testing; adult neurogenesis; base; biological adaptation to stress; dentate gyrus; effective therapy; experience; genetic risk factor; granule cell; in vivo; knock-down; mood regulation; nerve supply; network dysfunction; neurogenesis; neuroimaging; neuron development; newborn neuron; novel therapeutics; optogenetics; relating to nervous system; synaptogenesis

 DESCRIPTION (provided by applicant): Mental disorders are chronic and disabling disorders in need of effective treatments. They affect a large portion of the world's population, with significant impairment in their social function and have devastating consequence on the quality of life. Significant progress has been made in recent years to identify genetic disruptions that increase susceptibility to mental disorders, but we have little understanding of the circuitry mechanisms linking these genetic risk factors to the widespread cognitive and affective deficits associated with these disorders. Accumulating evidence suggests that brain connectivity alteration plays an important role in the pathophysiology of mental disorders. More recently, functional imaging data garnered from patients with mental disorders and animal models of schizophrenia and autism have collectively pointed to the aberrant hippocampal activity as a central feature of pathophysiology. Together, these data suggest that aberrant hippocampal activity may be a critical factor that contributes to brain network abnormalities in mental disorders. Within the hippocampus, dentate gyrus continuously generates new neurons throughout life, therefore making significant modifications to the hippocampal circuitry activity. Cumulative evidence suggests that these adult- born neurons are involved in cognition, stress response and mood regulation; and aberrant adult neurogenesis contributes to brain disorders, such as epilepsy and mental disorders. The current project is built upon our recent discoveries, including (i) identification of critical roles of DISC1 in regulating morphogenesis, cell positionig, axon/dendritic development and synapse formation of newborn granule cells in the adult hippocampus; and (ii) DISC1 deficiency in adult-born dentate granule neurons causes cognitive and affective behavioral deficits. However, how dysregulation of adult-born neurons by genetic risk factor DISC1 leads to these behavioral deficits at the circuitry level is largely unknown. Th overall goal of this proposed project is to investigate whether aberrant adult neurogenesis mediated by DISC1 deficiency serves as a critical neural substrate for brain connectivity abnormalities associated with mental disorders. To test this hypothesis, we propose to utilize in vivo multi-channel recording to examine local hippocampal activity (Aim 1) and functional magnetic resonance imaging (fMRI) to measure global brain connectivity (Aim 2) with or without DISC1 deficiency in adult-born neurons at the baseline and upon activity stimulation of those neurons. Our proposed studies will address fundamental questions on how genetic risk factors lead to the clinical manifestation of many severe psychological disorders by focusing on adult neurogenesis as a promising but ill-defined substrate in mediating global brain connectivity. Adult neurogenesis correlates with many physiological and pathological states, such as learning and memory, epilepsy, neurodegenerative diseases and mental disorders. Therefore, targeting adult neurogenesis process could constitute a novel therapeutic strategy for treating these disorders.



项目成果

Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep.

• DOI: 10.1038/nature23663
• 发表时间: 2017-08-31
• 期刊: Nature
• 影响因子: 64.8
• 作者: Liu K;Kim J;Kim DW;Zhang YS;Bao H;Denaxa M;Lim SA;Kim E;Liu C;Wickersham IR;Pachnis V;Hattar S;Song J;Brown SP;Blackshaw S
• 通讯作者: Blackshaw S

Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses.

• DOI: 10.1038/s41380-018-0245-8
• 发表时间: 2019-05
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Chen YW;Das M;Oyarzabal EA;Cheng Q;Plummer NW;Smith KG;Jones GK;Malawsky D;Yakel JL;Shih YI;Jensen P
• 通讯作者: Jensen P

Corrigendum: Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep.

• DOI: 10.1038/nature24274
• 发表时间: 2017-10-26
• 期刊: Nature
• 影响因子: 64.8
• 作者: Liu K;Kim J;Kim DW;Stephanie Zhang Y;Bao H;Denaxa M;Lim SA;Kim E;Liu C;Wickersham IR;Pachnis V;Hattar S;Song J;Brown SP;Blackshaw S
• 通讯作者: Blackshaw S