Investigating tonic and synaptic excitatory signaling in the bed nucleus of the stria terminalis across models of alcohol exposure

研究酒精暴露模型中终纹床核的强直和突触兴奋信号传导

• 批准号: 10825889
• 负责人: Sara Yi-Ling Conley
• 金额: $ 3.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2025-11-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825889
• 关键词: AMPA Receptors; Acute; Affect; Affective Symptoms; Alcohol consumption; Alcohols; Anterolateral; Anxiety; Area; Attenuated; Brain; Brain region; Calcium; Cell Nucleus; Cells; Chronic; Coupled; Data; Dimensions; Dorsal; Electrophysiology (science); Ethanol; Event; Excitatory Postsynaptic Potentials; Exposure to; Family; Female; Fluorescent in Situ Hybridization; Functional disorder; Genetic; Genotype; Glutamate Receptor; Glutamates; Goals; Health; Image; In Situ Hybridization; Knock-out; Knockout Mice; Knowledge; Ligands; Link; Long-Term Depression; Macaca; Macaca mulatta; Mediating; Messenger RNA; Modeling; Mus; Neuronal Dysfunction; Neurons; Pattern; Permeability; Pharmaceutical Preparations; Phenotype; Population; Prosencephalon; Reporting; Research; Role; Self Administration; Sex Differences; Signal Transduction; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic plasticity; System; Testing; Withdrawal; Work; addiction; alcohol effect; alcohol exposure; alcohol relapse; alcohol seeking behavior; alcohol use disorder; clinical development; clinically relevant; effective therapy; experimental study; genome wide association study; glutamatergic signaling; in vivo calcium imaging; insight; interest; mRNA Expression; male; mouse model; negative affect; neuronal excitability; neuroregulation; nonhuman primate; novel; patch clamp; receptor; response; sex; species difference; targeted treatment; transmission process; vapor

Abstract/Project Summary While the effects of alcohol use disorder (AUD) on glutamatergic signaling have been widely reported, the role of delta glutamate receptors (GluD1 and GluD2) in AUD remains unknown. Although they are not involved in traditional excitatory synaptic responses to glutamate, the GluD family is known to mediate many subtler aspects of excitatory signaling which may contribute to the dysfunctions of neuronal activity observed in models of AUD. GluD1 has also been implicated in AUD by several genome-wide association studies. However, no research has been conducted directly evaluating the effect of alcohol exposure on GluD1 function. The bed nucleus of the stria terminalis (BNST) is a forebrain nucleus that has been heavily implicated as a critical hub for neuromodulation following alcohol exposure. Previous work has shown that alcohol exposure regulates synaptic glutamate in the BNST, but the exact mechanisms by which this happen remain unclear. Synaptic glutamatergic transmission is in part mediated by AMPA receptors, ~30% of which can pass calcium (calcium- permeable AMPARs, CP-AMPARs). Our preliminary data suggests that acute withdrawal from chronic intermittent ethanol vapor exposure (CIE) decreases both CP-AMPAR synaptic current and reduces a GluD1 mediated tonic excitatory current in the BNST. Although it has been observed before that GluD1 is expressed in the BNST, these are the first data to that they may be involved in regulating BNST signaling. These data also implicate GluD1 modulation as a possible novel target for neuromodulation following alcohol exposure. This proposal aims to further examine the role of CP-AMPARs and GluD1 in the BNST, how they may interact, and how they are affected by alcohol exposure using a combination of fluorescent in situ hybridization, patch-clamp electrophysiology, and ex vivo calcium imaging. Aim 1 will use GluD1 knockout (GluD1 KO) mice and wildtype (WT) littermates to establish a functional profile of GluD1 in the BNST, as well as its overlap with CP-AMPAR expressing BNST cells. Aim 2 will then evaluate the impact of CIE on BNST CP-AMPAR and GluD1 expression and signaling, neuronal excitability, and spontaneous calcium dynamics in these mouse models. Finally, Aim 3 will use these approaches to examine the translational relevance of BNST CP-AMPAR and GluD1 signaling across different models of AUD.

抽象/项目总结