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Developmental Alcohol exposure and cerebro-cerebellar circuits

发育性酒精暴露和脑小脑回路

基本信息

批准号：
10573796
负责人：
Carlos Fernando Valenzuela
金额：
$ 21.92万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573796
关键词：
Affective Applications Grants Area Behavioral Biological Brain Brain region Cell Nucleus Cells Cerebellar Cortex Cerebellar Nuclei Cerebellum Cerebral cortex Clinical Research Cognition Cognitive Cognitive deficits Coupled Development Disease Electrophysiology (science)Emotions Equilibrium Executive Dysfunction Feedback Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Foundations Future Glutamates Goals Golgi Apparatus Health Human Impairment Individual Intervention Knowledge Label Lesion Limb structure Link Lobule Maps Mediating Motor Motor Skills Mus National Institute on Alcohol Abuse and Alcoholism Neocortex Neurodevelopmental Disorder Neurons Output Pontine structure Pregnancy Public Health Rattus Research Research Priority Rewards Rodent Role Schizophrenia Slice Synapses System Testing Thalamic structure Third Pregnancy Trimester Time United States Viral Work alcohol consequences alcohol effect alcohol exposure autism spectrum disorder cognitive function effective intervention effective therapy executive function granule cell high reward high risk improved in vivo innovation motor learning neocortical neurobehavioral neurobiological mechanism neuron apoptosis neuronal circuitry neuropsychiatric disorder novel novel therapeutic intervention optogenetics transmission process unborn child

项目摘要

Project Summary / Abstract Cognitive and executive function deficits are among the most devastating consequences of fetal alcohol exposure. Currently available treatments against these deficits have limited efficacy. Our long-term goal is to identify specific functional mechanisms underlying the cognitive deficits associated with FASD. Our objective is to use circuit tracing and slice electrophysiology to determine the long-term impact of third trimester-equivalent alcohol exposure (TTAE) on components of the cerebro-cerebellar system involved in executive function. Our working hypotheses are that 1) TTAE reduces glutamatergic input from the orbitrofrontal cortex—a brain region implicated in FASD-linked executive function deficits—to the cerebellar cortex via pontine nuclei neurons and 2) TTAE decreases glutamatergic output from the cerebellum to the orbitofrontal cortex via the deep cerebellar nuclei and the thalamus. Our rationale for using circuit mapping is to characterize the effects of TTAE on the function of reciprocal orbitofrontal cortex↔cerebellum connections. This proof-of-principle R21 proposal will establish a strong foundation for an R01 grant application to extend this work. In Aim 1, we will determine the effects of TTAE on the function of the cerebro-cerebellar system feed-forward limb. We will use anterograde transsynaptic labeling, slice electrophysiology, and optogenetics to test the hypothesis that TTAE persistently reduces glutamatergic transmission at synapses between pontine nuclei neurons (that receive input from the orbitofrontal cortex) and cerebellar granule cells (lobule VI) while also reducing feed-forward disynaptic inhibition at pontine nuclei neuron→Golgi cell→cerebellar granule cell synapses. In Aim 2, we will determine the effects of TTAE on the function of the cerebro-cerebellar system feedback limb. We will use an intersectional approach consisting of anterograde viral tracing coupled with retrobead labeling to test the hypothesis TTAE persistently reduces monosynaptic glutamatergic and disynaptic GABAergic transmission at synapses between deep cerebellar nuclei neurons—that receive input from lobule VI Purkinje neurons—and thalamic neurons that project to the orbitofrontal cortex. The research proposed in this application is innovative because it will systematically characterize, for the first time, the developmental effects of ethanol on interactions among key components of the cerebro-cerebellar network. The proposed research is significant because it will elucidate novel functional neurobiological mechanisms underlying fetal alcohol exposure-induced executive function deficits, and identify specific biological targets for interventions to ameliorate these deficits.

项目总结/摘要认知和执行功能缺陷是胎儿发育不良最具破坏性的后果之一。酒精暴露目前针对这些缺陷的可用治疗具有有限的功效。我们长期目标是确定认知缺陷背后的特定功能机制与FASD有关。我们的目标是使用电路跟踪和切片电生理学来确定第三个三个月相当的酒精暴露（TTAE）对成分的长期影响，参与执行功能的小脑系统。我们的工作假设是：1）TTAE 减少来自眶额皮质的神经元能输入，眶额皮质是与FASD相关的大脑区域。执行功能缺陷-通过脑桥核神经元和2）TTAE传递到小脑皮质减少从小脑经小脑深部到眶额皮质的交感神经能输出核和丘脑。我们使用电路标测的基本原理是描述TTAE的影响对眶额皮质参与小脑联系的功能的影响。这个原理证明R21 该提案将为R 01赠款申请扩展这项工作奠定坚实的基础。在目标1中，我们将确定TTAE对小脑-小脑系统前馈功能的影响四肢我们将使用顺行跨突触标记，切片电生理学和光遗传学来测试 TTAE持续减少突触间的突触能传递的假设脑桥核神经元（接受来自眶额皮质的输入）和小脑颗粒细胞（小叶VI）同时还减少脑桥核神经元→高尔基体的前馈反突触抑制细胞→小脑颗粒细胞突触在目标2中，我们将确定TTAE对功能的影响小脑-小脑系统的反馈肢。我们将使用交叉的方法，包括顺行病毒追踪结合逆转录微珠标记，以检验TTAE持续存在的假设减少突触间的单突触GABA能和双突触GABA能传递小脑深核神经元-接受来自第六小叶浦肯野神经元的输入-和丘脑投射到眶额皮质的神经元。本申请中提出的研究具有创新性因为它将首次系统地描述乙醇对发育的影响，小脑-小脑网络的关键组成部分之间的相互作用。拟议的研究是重要的是，它将阐明胎儿潜在的新的功能神经生物学机制，酒精诱导的执行功能缺陷，并确定特定的生物靶点，采取干预措施来改善这些缺陷。