Functional Striatal Microcircuits in vivo and in vitro

体内和体外功能性纹状体微电路

基本信息

批准号：
8632129
负责人：
James M Tepper
金额：
$ 52.7万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-02-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8632129
关键词：
Action Potentials Address Affect Afferent Neurons Attention Auditory Basal Ganglia Behavior Behavioral Brain Brain Part Cells Corpus striatum structure Cues DRD2 gene Data Development Disease Dopamine D1 Receptor Dopamine D2 Receptor Exhibits Experimental Designs Genetic Techniques Goals Housing Imagery In Vitro Interneurons Learning Maps Mediating Methods Molecular Genetics Motor Mus Neostriatum Neurologic Neurons Optics Output Pathway interactions Performance Phase Physiological Play Population Psychological reinforcement Reaction Time Research Design Rewards Role Series Specificity Stimulus Structure Synapses System Testing Text Thalamic structure Therapeutic Intervention Tomatoes Training Transgenes Transgenic Mice Transgenic Organisms Tyrosine 3-Monooxygenase Viral Whole-Cell Recordings base behavior measurement behavior prediction cell type cholinergic cholinergic neuron cognitive function disability extracellular in vivo insight interest motor control nerve supply neural circuit neuropsychiatry novel optogenetics postsynaptic presynaptic promoter public health relevance recombinase research study response tool

项目摘要

DESCRIPTION (provided by applicant): The neostriatum is the main input structure of the basal ganglia, a system that is crucial not only for voluntary motor control, but also for reinforcement-mediated learning and higher cognitive functions. The importance of understanding the functioning of the nesotriatum is dramatically illustrated by the severe disability associated with numerous neurological and neuropsychiatric conditions that affect this brain structure. Developments in transgenic methods that allow visualization and targeting of genetically and functionally distinct types of neurons has recently led to the discovery of an unexpectedly large diversity of GABAergic interneurons in the neostriatum. As a result the striatum is now known to contain at least 7 types of GABAergic interneurons that include, in addition to the previously known fast spiking (FS) and the NPY expressing NPY-PLTS interneurons, 4 distinct classes of tyrosine hydroxylase (TH) containing interneurons and a new class of NPY expressing interneuron. We hypothesize, based on preliminary data and earlier studies, that the newly discovered TH and NPY interneurons are integral and important constituents of a highly organized intrastriatal synaptic circuitry and play essential roles in determining the activity and computational function of the neostriatum. The goal of the proposed studies is to understand the synaptic organization of this circuitry and to assess the functional significance of the newly discovered interneuron classes in determining the activity of other constituent neurons, in particular, the activity of functionally distinct types of projection neuros. The circuit organization of TH and NPY interneurons will be mapped in in vitro optogenetic experiments using a series of double transgenic mice in which expression of Cre-recombinase and EGFP in distinct types of neurons will allow high-throughput bidirectional analysis of the connectivity among TH, NPY, and FS interneurons and projection neurons of the direct and indirect pathways. The functional impact of TH and NPY interneurons will be assessed in in vivo optogenetic recording experiments in mice trained to perform operant tasks. First, we will examine how the firing rate of these interneurons varies in relation to distinct phases of the operant tasks. Next, we will examine how optogenetic manipulation (silencing or activation) of the activity of TH and NPY interneurons affects the firing rate of projection neurons, cholinergic and FS interneurons, how these manipulations affect local field potential oscillations, and how qualitative or quantitative measures of behavioral performance are affected. These experiments are expected to yield important new insights into the functioning of the neostriatum and may help to identify new cellular substrates for therapeutic interventions in a variety of neurological and neuropsychiatric disorders.

描述（由申请人提供）：新纹状体是基底神经节的主要输入结构，该系统不仅对于自主运动控制至关重要，而且对于强化介导的学习和高级认知功能也至关重要。与影响大脑结构的众多神经系统和神经精神疾病相关的严重残疾，极大地说明了了解新视脑功能的重要性。转基因方法的发展允许可视化和靶向遗传和功能上不同类型的神经元，最近导致在新纹状体中发现了意想不到的大量 GABA 能中间神经元的多样性。因此，现在已知纹状体含有至少 7 种类型的 GABA 能中间神经元，其中除了先前已知的快速尖峰 (FS) 和表达 NPY 的 NPY-PLTS 中间神经元外，还包括 4 种不同类别的酪氨酸羟化酶 (TH)，其中包含中间神经元和一类新的表达 NPY 的中间神经元。根据初步数据和早期研究，我们假设新发现的 TH 和 NPY 中间神经元是高度组织的纹状体内突触回路的组成部分，并且在确定新纹状体的活动和计算功能方面发挥着重要作用。拟议研究的目标是了解该电路的突触组织，并评估新发现的中间神经元类别在确定其他组成神经元的活动中的功能意义，特别是功能上不同类型的投射神经元的活动。 TH 和 NPY 中间神经元的电路组织将在体外光遗传学实验中使用一系列双转基因小鼠进行绘制，其中不同类型神经元中 Cre 重组酶和 EGFP 的表达将允许对 TH、NPY 之间的连接进行高通量双向分析。 NPY、FS 中间神经元和直接和间接通路的投射神经元。 TH 和 NPY 中间神经元的功能影响将在经过训练的小鼠体内光遗传学记录实验中进行评估。首先，我们将研究这些中间神经元的放电率如何随着操作任务的不同阶段而变化。接下来，我们将研究 TH 和 NPY 中间神经元活性的光遗传学操作（沉默或激活）如何影响投射神经元、胆碱能神经元的放电率和 FS 中间神经元，这些操作如何影响局部场电位振荡，以及行为表现的定性或定量测量如何受到影响。这些实验有望对新纹状体的功能产生重要的新见解，并可能有助于确定用于各种神经系统治疗干预的新细胞基质。和神经精神疾病。