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.

女性情感障碍高患病率的神经生物学基础尚不清楚。情感行为的性别依赖性改变的一种潜在机制是与遗传风险因素的相互作用。脑源性神经营养因子（BDNF）已被证明对情感行为产生性别二态性影响。我们建议探索 BDNF 基因中常见的单核苷酸多态性、Val66Met 多态性与性别之间潜在的相互作用对边缘下内侧前额叶皮层突触功能的影响。 BDNF Val66Met 多态性与认知功能障碍和包括焦虑和抑郁在内的多种神经精神疾病有关。此外，已知这种多态性会以性别依赖性方式改变大脑功能。 BDNFMet/Met 小鼠是 BDNF Val66Met 敲入小鼠的变体，表现出类似焦虑的行为和恐惧消退缺陷，这是一种抑制性学习形式，可以抑制先前习得的恐惧。 BDNFMet/Met 小鼠还表现出边缘下内侧前额皮质谷氨酸能神经传递的性别依赖性修饰。已知 BDNF Val66Met 会与雌二醇相互作用并改变大脑功能。因此，我们假设 Val66Met 多态性通过与雌二醇的相互作用加剧了 IL-mPFC 突触功能的缺陷。我们将通过分析雄性和雌性[发情前期（高雌二醇）、发情间期（低雌二醇）和卵巢切除]BDNFMet/Met 和野生型小鼠的 IL-mPFC 第 V 层锥体神经元中的谷氨酸突触传递来检验这一假设。除了对突触功能的影响外，Val66Met 还可以以性别特异性的方式影响 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会改变 IL-mPFC V 层锥体神经元的内在特性。通过开展这项研究，我们希望了解 BDNF Val66Met 多态性与 IL-mPFC 中性别的相互作用及其在情感行为中性别二态性中的作用。