Synaptic regulation of affective behaviors

情感行为的突触调节

基本信息

批准号：
8720894
负责人：
Ipe Ninan
金额：
$ 6.42万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720894
关键词：
Affect Affective Affective Symptoms Animals Anxiety Anxiety Disorders Behavior Brain Brain region Brain-Derived Neurotrophic Factor Caucasians Caucasoid Race Diestrus Disease Electric Capacitance Estradiol Estrous Cycle Extinction (Psychology)Female Frequencies Fright Genes Genetic Polymorphism Genets Glutamates High Prevalence Hippocampus (Brain)Impaired cognition Knock-in Mouse Learning Measures Medial Membrane Membrane Potentials Mental Depression Modification Mood Disorders Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurobiology Neurons Physiologic pulse Play Population Prefrontal Cortex Prevalence Proestrus Property Psychiatry Regulation Resistance Rest Role Signal Transduction Single Nucleotide Polymorphism Synapses Synaptic Transmission Synaptic plasticity Testing Time Variant Wild Type Mouse Woman base behavior influence experience genetic risk factor hippocampal pyramidal neuron male meetings men neuropsychiatry neurotransmission receptor research study sex sexual dimorphism synaptic function transmission process

项目摘要

The neurobiological basis of the high prevalence of affective disorders in women is not well understood. One potential mechanism for sex-dependent modification of affective behaviors is an interaction with genetic risk factors. Brain-derived neurotrophic factor (BDNF) has been shown to exert sexually dimorphic effect on affective behaviors. We propose to explore the effect of a potential interaction between a common single nucleotide polymorphism in the BDNF gene, the Val66Met polymorphism, and sex on synaptic function in the infralimbic medial prefrontal cortex. The BDNF Val66Met polymorphism has been implicated in cognitive dysfunctions and several neuropsychiatric disorders including anxiety and depression. Also, this polymorphism is known to modify brain functions in a sex-dependent manner. BDNFMet/Met mice, a variant BDNF Val66Met knock-in mouse, showed anxiety-like behavior and deficit in fear extinction, a form of inhibitory learning that suppresses a previously learned fear. BDNFMet/Met mice also showed a sex-dependent modification of glutamatergic neurotransmission in the infralimbic medial prefrontal cortex. The BDNF Val66Met is known to interact with estradiol and alter brain function. Therefore, we hypothesize that the Val66Met polymorphism exacerbates deficits in IL-mPFC synaptic function by its interaction with estradiol. We will test this hypothesis by analyzing glutamatergic synaptic transmission in the IL-mPFC layer V pyramidal neurons from male and female [proestrus (high-estradiol), diestrus (low-estradiol) and ovariectomized] BDNFMet/Met and wild-type mice. In addition to the effect on synaptic function, the Val66Met could affect intrinsic properties of IL-mPFC neurons in a sex-specific fashion. Therefore, we will also study whether an interaction between Val66Met and estradiol modifies intrinsic properties of the IL-mPFC layer V pyramidal neurons. By undertaking this study, we expect to understand the interaction of BDNF Val66Met polymorphism and sex in the IL-mPFC and its involvement in sexual dimorphism in affective behaviors.

尚不清楚女性情感障碍高流行率的神经生物学基础。性别依赖性修饰情感行为的一种潜在机制是与遗传危险因素的相互作用。脑衍生的神经营养因子（BDNF）已显示出对情感行为的性二态效应。我们建议探索BDNF基因中常见的单核苷酸多态性，Val66met多态性与性别对突触功能的突触功能之间潜在相互作用的影响。 BDNF Val66met多态性与认知功能障碍和几种神经精神疾病有关，包括焦虑和抑郁。同样，已知这种多态性会以性别依赖性方式改变大脑功能。 BDNFMET/MET MICE是一种变体BDNF Val66met敲入小鼠，在恐惧消灭中表现出焦虑般的行为和缺陷，这是一种抑制性学习的形式，可抑制先前学到的恐惧。 BDNFMET/MET小鼠还显示了谷氨酸能神经传递性的性别依赖性修饰。已知BDNF Val66met与雌二醇相互作用并改变脑功能。因此，我们假设VAL66MET多态性通过与雌二醇的相互作用来加剧IL-MPFC突触功能的缺陷。我们将通过分析来自雄性和雌性的IL-MPFC层V锥体神经元中的谷氨酸能突触传播来检验这一假设，[雌性（高雌二醇），diestrus（低雌二醇）（低雌二醇）和卵巢肌切除术] bdnfmet/met/met/met和野生型小鼠。除了对突触函数的影响外，Val66met还可以以性别特定的方式影响IL-MPFC神经元的内在特性。因此，我们还将研究Val66met和雌二醇之间的相互作用是否修饰IL-MPFC层V锥体神经元的内在特性。通过进行这项研究，我们希望了解IL-MPFC中BDNF Val66met多态性和性别的相互作用及其参与情感行为中的性二态性。