Mapping the Inputs onto Neocortical Chandelier Cells

将输入映射到新皮质枝形吊灯细胞上

• 批准号: 8732703
• 负责人: Jason M Tucciarone
• 金额: $ 2.48万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2015-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732703
• 关键词: Action Potentials; Affect; American; Area; Autistic Disorder; Axon; Behavioral; Bipolar Disorder; Birth; Brain; Brain Diseases; Brain region; Cell Nucleus; Cells; Contralateral; Data; Data Set; Dendrites; Development; Disease; Distal; Embryo; Employee Strikes; Equilibrium; Functional disorder; Gene Expression; Generations; Genetic; Golgi Apparatus; Health Care Costs; In Vitro; Interneurons; Knowledge; Label; Laboratories; Lead; Learning; Light; Location; Maps; Medial; Mediating; Mental disorders; Methods; Morphology; Motor; Mus; Names; Neocortex; Neurons; Output; Parvalbumins; Pathology; Pathway interactions; Patients; Pattern; Physiological; Prefrontal Cortex; Pyramidal Cells; Rabies; Rabies virus; Recruitment Activity; Regulation; Research; Rhodopsin; Role; Schizophrenia; Signal Transduction; Site; Somatosensory Cortex; Source; Specificity; Staging; Staining method; Stains; Synapses; Thalamic structure; Time; Tracer; United States; Virus Receptors; base; brain cell; cell type; cognitive function; disability; effective therapy; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; homeodomain; inhibitory neuron; insight; mouse model; neocortical; nerve supply; neural circuit; neuronal cell body; neuropsychiatry; optogenetics; postsynaptic; presynaptic; promoter; public health relevance; relating to nervous system; sensory cortex; stereotypy; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): GABAergic interneurons are crucial in the spatial-temporal regulation of neuronal firing and ensemble activity in cortical circuits. Chandelier cells (ChCs) are a unique class of interneuron with striking features in their innervation: they specifically inhibit pyramidal neurons and specifically at axon initial segments (AIS) - the site o action potential generation. Further, a single ChC innervates hundreds of pyramidal cells in cortex. Therefore, ChCs are poised to powerfully control pyramidal cell firing and ensembles that support motor and cognitive functions. Knowledge on the source and pattern of inputs to ChCs is the basis for understanding how they are recruited and regulated to exert powerful control over pyramidal cell networks under relevant physiological and behavioral contexts. However, the location and identity of presynaptic cells that control ChCs activity is almost entirely unknown. Altered GABAergic markers in prefrontal cortex ChCs is one of the most consistent pathology in post mortem brain of schizophrenic patients. These changes are hypothesized to result from reduced inputs (e.g. local excitatory drive or modulatory pathway, but no direct evidence has been provided. My proposal aims will provide the first set of data on inputs to ChCs and can be applied to mouse models of mental disorders. As such, my proposal will attempt to label the local presynaptic inputs to layer 2 (L2) and L5 ChCs in the medial prefrontal cortex (mPFC). Preliminary data from our lab identified at least two subtypes of ChCs confined to L2 and L5. Additionally, I will label the long range subcortical and contralateral inputs to L2 and L5 ChCs. Finally, in order to assess whether this presynaptic connectivity is conserved across brain regions, I will label the local and long range inputs to L2 and L5 ChCs in the somatosensory cortex to compare with the data from mPFC. To accomplish these aims, I will employ a pseudotyped monosynaptic rabies tracer that was shown to isolate the first order inputs in a cell type specific manner based on Cre expression. [To validate the functional connectivity of inputs to ChCs, Channel Rhodopsin Assisted Circuit Mapping (CRACM) will be used to map the long range presynaptic cells in areas such the contralateral cortex, thalamus and neurmodulatory nuclei.] Preliminary data has established rabies tracing in a Parvalbumin-ires- Cre mouse line, and an inducible Cre line under the promoter of transcription factor Nkx2.1. We have found that induction of Nkx2.1-CreER at a late embryonic stage was found to label ChCs. The project will provide the first mapping of input on ChCs. Because ChCs are implicated in mental disorders such as schizophrenia, their connectivity and function could shed light into the pathophysiology and suggest new treatment strategies.

描述（由申请人提供）：GABA能中神经元对于皮质回路中神经元放电和合奏活动的空间调节至关重要。吊灯细胞 （CHC）是一类独特的中间神经元中具有惊人特征的中间神经元：它们特别抑制了锥体神经元，特别是在轴突初始段（AIS）（AIS） - 位点O动作电位生成。此外，单个CHC在皮质中支配了数百个锥体细胞。因此，CHC有望强大地控制锥体细胞的射击和支持运动和认知功能的合奏。关于CHC的投入的来源和模式的知识是了解它们如何被招募和监管的基础，以在相关的生理和行为环境下对锥体细胞网络产生强大的控制。但是，控制CHCS活性的突触前细胞的位置和身份几乎完全未知。前额叶皮层CHC中的GABA能标记改变是精神分裂症患者验尸大脑中最一致的病理之一。 These changes are hypothesized to result from reduced inputs (e.g. local excitatory drive or modulatory pathway, but no direct evidence has been provided. My proposal aims will provide the first set of data on inputs to ChCs and can be applied to mouse models of mental disorders. As such, my proposal will attempt to label the local presynaptic inputs to layer 2 (L2) and L5 ChCs in the medial prefrontal cortex （MPFC）。我们实验室的初步数据至少限制在L2和L5的CHC中，我将标记远距离皮层下和对侧输入L2和L5 CHC。与MPFC的数据进行比较，我将采用伪型的单突触狂犬病示踪剂，以基于CRE表达方式以特定于CRE的方式分离出一阶输入。 [为了验证输入到CHC的功能连通性，通道视紫红质辅助电路映射（CRACM）将用于绘制诸如对侧皮层，丘脑和神经模型核的区域的远程突触前细胞。转录因子NKX2.1。我们发现，发现在胚胎阶段的晚期诱导NKX2.1-creer标记CHC。该项目将在CHC上提供第一个输入的映射。由于CHC与精神分裂症等精神疾病有关，因此它们的连通性和功能可能会阐明病理生理学并提出新的治疗策略。