Acute and long-term ethanol (EtOH) exposure produces cerebellar dysfunction, leading to alterations in gait, balance and coordination that are responsible for a large number of injuries and deaths in the United States. Recent evidence indicates that EtOH affects executive functions and this could be a consequence of disruptions in frontocerebellar circuitry. However, our understanding of the mechanism of action of EtOH in the cerebellum is still in its infancy. Excitatory input from the brain stem and spinal cord enters the cerebellar cortex at the granule cells via the mossy fibers. These neurons also receive inhibitory input from the Golgi cells, which are the major granule cell layer interneuronal subtype. Golgi cells, in turn, receive feedforward excitatory input from mossy fibers, feedback excitatory input from granule cell axons and inhibitory input from molecular layer interneurons. Our overarching hypothesis is that acute EtOH exposure impairs the normal functioning of granule layer circuitry by decreasing glutamatergic and increasing GABAergic transmission at both granule and Golgi cells.
Specific Aim #1 is to characterize the effect of EtOH on glutamatergic transmission at granule cells. During the previous funding period, we determined that EtOH increases tonic and phasic GABAergic input to granule cells without affecting spontaneous glutamatergic transmission mediated by AMPA receptors. Using the acute cerebellar slice preparation and patch-clamp electrophysiological techniques, we will now study the effect of EtOH on NMDA receptor function and long- term potentiation at mossy fiber-to-granule cell synapses. We will investigate its effects on granule cell activation by sensory-like patters of mossy fiber activation;for these studies, single-neuron recordings will be complemented by autofluorescence optical imaging of [the mossy fiber area of activation].
Specific Aim #2 is to further characterize the effects of EtOH on Golgi cells. During the previous funding period, we demonstrated that EtOH increases Golgi cell firing and propose to characterize the mechanism responsible for this effect. [Based on a combination of computer modeling and experimental studies, we propose to characterize IA, Na+/K+ pump and persistent Na+ currents as potential mediators of EtOH's effect]. We will also investigate EtOH's effect on GABAergic and/or glutamatergic input to Golgi cells. These studies with acute slices will be complemented with in vivo electrophysiological experiments of the acute effects of EtOH on the function of these neurons.
In Specific Aim #3, we will investigate the effect of EtOH on network activity in the granule cell layer as a whole using a data-driven computational neuroscience approach. These multidisciplinary studies will significantly increase our understanding of the acute effects of EtOH on the cerebellar granule cell layer, forming the basis for the identification of new targets for therapeutic interventions against EtOH-induced cerebellar dysfunction.

Public Health Relevance

The cerebellum is a portion of the brain that controls gait, balance, coordination and certain internal mental processes such as attention and planning. Ingestion of alcohol profoundly affects normal cerebellar functioning and our understanding of the mechanisms responsible for these effects of alcohol is very limited. The goal of this project is to characterize the effect of alcohol on communication between cerebellar neurons, forming the basis for the development of novel treatments that may aid in the recovery of alcoholic patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AA014973-10
Application #
8692610
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Diaz, Marvin R; Valenzuela, C Fernando (2016) Sensitivity of GABAergic Tonic Currents to Acute Ethanol in Cerebellar Granule Neurons is Not Age- or δ Subunit-Dependent in Developing Rats. Alcohol Clin Exp Res 40:83-92
Nirgudkar, Pranita; Taylor, Devin H; Yanagawa, Yuchio et al. (2016) Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis. Neurosci Lett 632:86-91
Jotty, Karick; Shuttleworth, C William; Valenzuela, C Fernando (2015) Characterization of activity-dependent changes in flavoprotein fluorescence in cerebellar slices from juvenile rats. Neurosci Lett 584:17-22
Valenzuela, C Fernando; Jotty, Karick (2015) Mini-Review: Effects of Ethanol on GABAA Receptor-Mediated Neurotransmission in the Cerebellar Cortex--Recent Advances. Cerebellum 14:438-46
Diaz, Marvin R; Vollmer, Cyndel C; Zamudio-Bulcock, Paula A et al. (2014) Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABA(A) receptor δ subunit in cerebellar granule neurons and delays motor development in rats. Neuropharmacology 79:262-74
Huang, Jian-Jia; Yen, Cheng-Tung; Tsao, Hen-Wai et al. (2014) Neuronal oscillations in Golgi cells and Purkinje cells are accompanied by decreases in Shannon information entropy. Cerebellum 13:97-108
Botta, Paolo; Zucca, Aya; Valenzuela, C Fernando (2014) Acute ethanol exposure inhibits silencing of cerebellar Golgi cell firing induced by granule cell axon input. Front Integr Neurosci 8:10
Zamudio-Bulcock, Paula A; Morton, Russell A; Valenzuela, C Fernando (2014) Third trimester-equivalent ethanol exposure does not alter complex spikes and climbing fiber long-term depression in cerebellar Purkinje neurons from juvenile rats. Alcohol Clin Exp Res 38:1293-300
Morton, Russell A; Diaz, Marvin R; Topper, Lauren A et al. (2014) Construction of vapor chambers used to expose mice to alcohol during the equivalent of all three trimesters of human development. J Vis Exp :
Brady, Megan L; Diaz, Marvin R; Iuso, Anthony et al. (2013) Moderate prenatal alcohol exposure reduces plasticity and alters NMDA receptor subunit composition in the dentate gyrus. J Neurosci 33:1062-7

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