BDNF-Endocannabinoid Interactions in the Cerebral Cortex

大脑皮层中的 BDNF-内源性大麻素相互作用

基本信息

批准号：
9054927
负责人：
Eric S Levine
金额：
$ 38.28万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054927
关键词：
2-arachidonylglycerol Antidepressive Agents Anxiety Biological Brain-Derived Neurotrophic Factor CNR1 gene Cannabinoids Cerebral cortex Coupled Development Diglycerides Disease Electrophysiology (science)Employee Strikes Endocannabinoids Enzymes Epilepsy Excitatory Synapse Functional disorder Glutamates Goals Inhibitory Synapse Knowledge Link Mediating Memory Mental Depression Mental disorders Molecular Monitor Mood Disorders Motor Motor Cortex Multiple Sclerosis Mus N-Methyl-D-Aspartate Receptors Nerve Growth Factor Receptors Neurologic Neuromodulator Neurotrophic Tyrosine Kinase Receptor Type 2 Perception Phospholipase C Play Process Production Pyramidal Cells RNA Interference Receptor Activation Regulation Role Schizophrenia Sensory Signal Pathway Signal Transduction Signaling Molecule Somatosensory Cortex Synapses Synaptic Potentials Synaptic plasticity System Work association cortex base cognitive ability endocannabinoid signaling endogenous cannabinoid system immunocytochemistry insight interest lipoprotein lipase neocortical nervous system disorder neuroregulation neurotrophic factor novel novel therapeutic intervention novel therapeutics painful neuropathy patch clamp postsynaptic presynaptic receptor research study response sensory cortex

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to explore previously-unknown interactions between brain-derived neurotrophic factor (BDNF) and the endocannabinoid system in the cerebral cortex. Both BDNF and endocannabinoids are highly expressed throughout the sensory, motor, and association cortices, and there is a striking overlap of expression of trkB neurotrophin receptors and type 1 cannabinoid (CB1) receptors across cortical layers, with highest levels of expression in cortical layers 2/3 and 5. Disruption f either of these neuromodulatory systems has been implicated in several neurologic and psychiatric diseases, including anxiety, depression, schizophrenia, and seizure disorders, and both systems are currently major targets for the development of novel therapeutics. We found that the effects of BDNF at inhibitory cortical synapses are mediated by the BDNF-induced mobilization of endocannabinoids acting at presynaptic CB1 receptors. The proposed studies will explore the signaling mechanisms underlying BDNF-evoked synthesis and release of endocannabinoids at inhibitory synapses using electrophysiological, molecular biological, and pharmacological approaches. The proposed studies will also extend these findings to examine BDNF-cannabinoid interactions at excitatory synapses, and explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. Knowledge gained from these studies will provide insights into the regulation and interdependence of BDNF and endocannabinoid signaling. New mechanistic insights regarding the interaction between these neuromodulators could provide the basis for novel therapeutic approaches to neurologic and psychiatric disease.

描述（由申请人提供）：该项目的目标是探索脑源性神经营养因子（BDNF）与大脑皮层内源性大麻素系统之间以前未知的相互作用。 BDNF 和内源性大麻素在整个感觉皮质、运动皮质和关联皮质中均高度表达，并且 trkB 神经营养蛋白受体和 1 型大麻素 (CB1) 受体在皮质各层的表达存在惊人的重叠，其中皮质层 2 的表达水平最高/3 和 5。这些神经调节系统中的任何一个的破坏都与多种神经系统和精神疾病有关，包括焦虑、抑郁、精神分裂症和癫痫症，这两个系统目前都是开发新疗法的主要目标。我们发现 BDNF 对抑制性皮质突触的作用是由 BDNF 诱导的作用于突触前 CB1 受体的内源性大麻素的动员介导的。拟议的研究将利用电生理学、分子生物学和药理学方法探索 BDNF 诱发的抑制性突触内源性大麻素合成和释放的信号传导机制。拟议的研究还将扩展这些发现，以检查兴奋性突触处的 BDNF-大麻素相互作用，并探索这些相互作用在调节活动依赖性突触可塑性方面的功能相关性。从这些研究中获得的知识将为 BDNF 和内源性大麻素信号传导的调节和相互依赖性提供见解。关于这些神经调节剂之间相互作用的新机制见解可以为神经系统和精神疾病的新治疗方法提供基础。