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Behavioral effects of igsf9b in the prefrontal cortex

igsf9b 对前额皮质的行为影响

基本信息

批准号：
10054717
负责人：
Wen-Jun Gao
金额：
$ 42.52万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054717
关键词：
Adhesions Affect Amygdaloid structure Anhedonia Animals Anxiety Area Behavior Behavior Control Behavioral Behavioral Mechanisms Bilateral Biological Brain Brain region CAV2 gene Cell Adhesion Molecules Cells Cholera Toxin Code Cognition Cognitive Coupling Dimensions Equilibrium Genes Glutamates Hippocampus (Brain)Hyperactive behavior Impairment In Vitro Inhibitory Synapse Injections Interneurons Knockout Mice Knowledge Label Link Locomotion Major Depressive Disorder Medial Memory Mental Depression Mental disorders Modeling Motivation Motor Cortex Mus Neocortex Neurons Nucleus Accumbens Pathway interactions Physiological Pilot Projects Prefrontal Cortex Property Prosencephalon Proteins RNA Interference Regulation Reporting Rewards Role Schizophrenia Short-Term Memory Signal Transduction Single Nucleotide Polymorphism Social Behavior Social Controls Structure Sucrose Symptoms Testing Tracer Viral Viral Vector Wild Type Mouse Withdrawal base behavioral impairment behavioral phenotyping biophysical properties cell type clinically relevant executive function flexibility gamma-Aminobutyric Acid genome wide association study genomic locus high risk hippocampal pyramidal neuron in vivo insight interest knock-down loss of function neural circuit neural network neuroligin 2 neuropsychiatric disorder novel object recognition preference protein function relating to nervous system risk variant small hairpin RNA social social deficits synaptic function transmission process young adult

项目摘要

Behavioral Effect of IgSF9b in the Prefrontal Cortex Abstract IgSF9b was recently identified as a high-risk gene strongly associated with negative symptoms of schizophrenia (SZ) and major depressive disorders (MDD). IgSF9b gene codes for adhesion protein IgSF9b, which is specifically expressed in the brain, especially in the forebrain region of the neocortex. In vitro studies indicate IgSF9b is primarily expressed in GABAergic interneurons and subset of pyramidal neurons, with coupling to neuroligin 2 to promote inhibitory signaling. However, whether and how IgSF9b deficiency affects cognitive and social behaviors, especially those related to social withdrawal and anhedonia, remains untested. We endeavored to explore the functional roles of protein IgSF9b in the medial prefrontal cortex (mPFC) in the regulation of motivational and social behaviors as this brain region is highly associated with executive function, cognition, and social behavior control, as well as deficits related to depression and SZ. Our studies aim to elucidate the fundamental physiological role of protein IgSF9b, at a cellular, circuit, and behavioral level. In our pilot study, we performed successful knockdown (KD) of protein IgSF9b in the young adult mouse mPFC, and interestingly, we found that IgSF9b KD significantly impairs both social preference and social memory. We hypothesize that selective KD of IgSF9b impairs behaviors associated with social withdrawal and anhedonia by reducing inhibition and affecting neurons projecting to subcortical areas related to social behavior such as nucleus accumbens (NAc). We will first evaluate the effects of IgSF9b KD in the mPFC on motivational and social withdrawal behaviors and then determine whether IgSF9b KD in the mPFC selectively affects the mPFC-NAc pathway to regulate social behaviors. IgSF9b is mainly expressed in the forebrain of the neocortex and is proposed to be highly associated with negative symptoms. Therefore, examining the effects of IgSF9b on mPFC-associated behaviors has the potential to elucidate unidentified mechanisms of behavioral deficits seen in neuropsychiatric diseases such as SZ.

前额叶皮质中IgSF 9 b的行为效应摘要 IgSF 9 b最近被鉴定为与以下疾病的阴性症状强烈相关的高危基因：精神分裂症（SZ）和重性抑郁症（MDD）。IgSF 9 b基因编码粘附蛋白IgSF 9 b，它在大脑中特别是在新皮层的前脑区域中表达。体外研究表明IgSF 9 b主要在GABA能中间神经元和锥体神经元亚群中表达，偶联至神经配素2以促进抑制性信号传导。然而，IgSF 9 b缺乏是否以及如何影响认知和社会行为，特别是那些与社交退缩和快感缺乏有关的行为，仍然没有得到测试。本研究旨在探讨IgSF 9 b蛋白在脑梗死患者内侧前额叶皮质（mPFC）中的功能作用。调节动机和社会行为，因为这个大脑区域与执行功能高度相关，认知和社会行为控制，以及与抑郁症和SZ相关的缺陷。我们的研究旨在阐明蛋白IgSF 9 b在细胞、电路和行为水平上的基本生理作用。在我们在初步研究中，我们在年轻的成年小鼠mPFC中成功敲低（KD）蛋白IgSF 9 b，有趣的是，我们发现IgSF 9 b KD显著损害社会偏好和社会记忆。我们假设IgSF 9 b选择性KD通过以下方式损害与社交退缩和快感缺乏相关的行为：减少抑制并影响投射到与社会行为相关的皮层下区域的神经元，丘脑核（NAc）。我们将首先评估mPFC中IgSF 9 b KD对动机和社交退缩行为，然后确定mPFC中的IgSF 9 b KD是否选择性地影响 mPFC-NAc通路调节社会行为。IgSF 9 b主要表达于新皮质的前脑并且被认为与阴性症状高度相关。因此，检查IgSF 9 b的作用对mPFC相关行为的研究有可能阐明行为缺陷的未识别机制在神经精神疾病如SZ中可见。