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Elucidation of the mediodorsal thalamic regulation of prefrontal function

阐明丘脑内侧对前额叶功能的调节

基本信息

批准号：
9194587
负责人：
Brielle Ferguson
金额：
$ 4.36万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-23 至 2018-08-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9194587
关键词：
Address Adult Affect Animals Anterior Attention Autistic Disorder Bathing Behavior Behavioral Clinical Clozapine Cognition Cognitive Cognitive deficits Disease Down-Regulation Drug Targeting Electrophysiology (science)Equilibrium Glutamates Impaired cognition Impairment Interneurons Lead Lesion Ligands Link Medial Mediating Membrane Methodology Neurons Operative Surgical Procedures Output Oxides Parvalbumins Performance Pharmacogenetics Physiological Play Population Prefrontal Cortex Property Pyramidal Cells Rattus Regulation Rescue Work Role Schizophrenia Sensory Short-Term Memory Slice Structure Synaptic Transmission Techniques Thalamic structure Time Whole-Cell Recordings base behavior influence cingulate cortex designer receptors exclusively activated by designer drugs executive function flexibility gamma-Aminobutyric Acid hippocampal pyramidal neuron inhibitory neuron nerve supply neurotransmission novel positive allosteric modulator receptor therapeutic development tool

项目摘要

PROJECT SUMMARY/ABSTRACT The mediodorsal thalamus (MD) is suggested to play a critical role in cognition through its extensive glutamatergic innervation of the medial prefrontal cortex (mPFC). These MD terminals provide AMPA-mediated excitation to both excitatory pyramidal neurons and gamma-aminobutyric (GABA)-ergic inhibitory interneurons. GABAergic interneurons, particularly the parvalbumin (PV)-expressing fast-spiking subtype, are fundamental in regulating the output of their neighboring pyramidal neurons, maintaining the excitation/inhibition (E/I) balance, and coordinating synchronous activity in populations of neurons. Interestingly, this neuronal subtype receives MD inputs, and their activity has been linked to working memory, attention, and executive functions associated with the PFC. However, how inhibitory interneurons are modulated by MD thalamocortical input remains unknown. We hypothesize that MD afferents drive mPFC inhibitory activity, aiding in the regulation of local circuit activity and thus optimizing performance on mPFC dependent tasks. This is based on feedforward inhibition observed not only in primary thalamic relays, but also recent evidence of this phenomenon in the anterior cingulate cortex. Given this, we propose that downregulation of MD activity will impair GABAergic activity in the prelimbic mPFC, causing dysregulation of local circuit activity, and cognitive deficits. To explore this possibility, we utilize Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that allow us to selectively target glutamatergic MD neurons, and transiently inhibit their activity in adult rats by expression of the inhibitory hM4D receptor. Using pharmacogenetics, we can evaluate the consequences of MD inhibition by two primary methodologies. With the designer ligand, Clozapine-N-Oxide (CNO), we will treat animals systemically and explore the effects of MD inhibition on mPFC-dependent behaviors using a working memory and cognitive flexibility task. We will also take slices containing the mPFC and MD afferents, bath apply CNO, and determine resultant changes in the circuitry using whole cell-recordings. Thus far, we have successfully demonstrated that MD inhibition resulted in a significant decrease of GABAAR-mediated IPSCs in PFC pyramidal neurons. This loss in IPSCs appears to be greater at α1- GABAARs. Further, these decreases of GABA activity in the PFC are associated with cognitive dysfunction in our MD-inhibited animals. Using a T- maze delayed-alternation task, we have shown that MD inhibition impairs working memory performance, which can be rescued by treatment with the GABAergic α1-positive allosteric modulator, indiplon. These findings raise intriguing questions of how MD inhibition mechanistically influences mPFC local circuitry, and whether the MD regulates the mPFC through PV interneurons to impact cognition. We will further address these questions using a combination of surgical, electrophysiological, behavioral, and pharmacogenetic techniques.

项目总结/文摘