Cerebellar neurons are among the most sensitive targets of alcohol in the nervous system. At concentrations just above the legal limit for driving in the United States (>17mM BAC), alcohol causes cerebellar dysfunction, leading to impairments in gait, balance and motor coordination that are responsible for thousands of injuries and deaths every year. There is also evidence from electrophysiology experiments in cerebellar slices that at lower concentrations (<10mM), alcohol alters the function of multiple neurons in the cerebellum. However, our understanding of the action of low doses of alcohol in the cerebellum is still in its infancy. A critical barrier to progress in the field has been to understand how the effects of low dose alcohol observed in vitro translate to the unanesthetized animal and lead to impaired function during cerebellar-driven behaviors. The goal of this proposal is to overcome this prior limitation, by being the first to measure the impact of low doses of alcohol in the cerebellum of behaving mice. Mice will be trained in cerebellum-dependent eyeblink conditioning because our preliminary data indicates that low doses of alcohol (<5mM BAC) impair performance in this task. Our general strategy is to search for cell-specific targets of low dose alcohol during eyeblink conditioning, by recording and manipulating the activity of cerebellar circuits at three different stages of processing: the output stage, processed by neurons of the interpositus nucleus (specific aim 1), the intermediate stage, processed by Purkinje cells (specific aim 2), and the input stage, processed by granule cells (specific aim 3). The proposed experiments will break new ground and advance the field substantially: By combining the simplicity of eyeblink conditioning with new technologies for optogenetics, electrophysiology, and two-photon calcium imaging, this project will provide a first look at the mechanistic links between low dose alcohol, the cerebellum, and behavior.

Public Health Relevance

Alcohol impairs certain aspects of cognitive function and behavior, even at low doses that can be achieved by 1-3 drinks. The goal of this research is to document the effects of low doses of alcohol on motor performance, and to identify which subpopulations of neurons are responsible for the behavioral impairments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA025572-02
Application #
9337320
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Liu, Qi-Ying
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Raymond, Jennifer L; Medina, Javier F (2018) Computational Principles of Supervised Learning in the Cerebellum. Annu Rev Neurosci 41:233-253
Giovannucci, Andrea; Badura, Aleksandra; Deverett, Ben et al. (2017) Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning. Nat Neurosci 20:727-734
Ten Brinke, Michiel M; Heiney, Shane A; Wang, Xiaolu et al. (2017) Dynamic modulation of activity in cerebellar nuclei neurons during pavlovian eyeblink conditioning in mice. Elife 6: