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Cerebellum & Alcohol

Kim Light, Abdallah Hayar, Xiong Lin, Dwight Pierce

Neuronal circuit interactions in a rat model of Fetal Alcohol Spectrum Disorder  

   Purkinje cells (PCs) in the cerebellum are particularly vulnerable to damage caused by alcohol exposure during early brain development. It is unknown how neuronal circuit interactions are altered during alcohol exposure and how neurons that survive the insult of alcohol manage to compensate for the loss of a significant number of PCs. In order to investigate the damage on cerebellar circuits caused by developmental alcohol exposure, we will use a rat model of fetal alcohol spectrum disorder (FASD), which mimics the deleterious effects on the fetus caused by alcohol ingested by a pregnant mother during the third trimester.

   Because PCs are the sole output of the cerebellar cortex, we hypothesize that a disruption in coordinated activity among PCs is the leading cause of cerebellar dysfunction in the FASD model. This hypothesis is being tested using a combination of sophisticated electrophysiological and imaging techniques where it is possible to record multiple neurons simultaneously and characterize the spatiotemporal propagation of their activity. Our main goal is to elucidate the impact of alcohol exposure on cerebellar network processing in the FASD model.

   We will test the hypothesis that the PC synchronized activity is impaired in the FASD model. In particular, we will test whether PCs which survive the alcohol treatment exhibit an altered synchronized activity caused by a change in GABAergic synaptic transmission and the delayed hyperpolarization-activated current (Ih). These experiments will be performed using multiunit extracellular loose-patch and intracellular whole-cell patch clamp recordings. The mechanisms and degree of synchronized activity will be analyzed as a function of distance between PCs.

   We will also test whether the spatiotemporal population activity of PCs is altered in the FASD model by performing neuronal population recordings using ultrafast imaging of cerebellar slices that have been labeled with voltage- and calcium- sensitive dyes. Moreover, we will test the hypothesis that disruption in neuro-plasticity at the level of the synapses is altered in the FASD model. For these experiments, we are using another combination of techniques such as immunofluorescence, confocal microscopy and 3D-reconstruction for quantitative analysis in fixed tissues, as well as dynamic visualization of axons and spines in live cerebellar slices.

   The results of this study are expected to provide a break-through in our understanding of the functioning of homeostatic neuronal circuits altered by alcohol exposure. This knowledge is necessary to conceptualize and identify appropriate interventions to alleviate the brain damage induced by developmental alcohol exposure. This project is very important for public health because it will enhance our understanding of the fundamental mechanisms of developmental alcohol effects on cerebellar control of motor movement. It also raises the awareness of the general population about the detrimental effects of alcohol and drugs of addiction on brain networks.

1.       Pierce DR, Hayar A, Wiley CA, Light KE. Rat Purkinje cells that survive postnatal ethanol exposure are altered morphologically and physiologically. (32nd Annual Meeting of the Research Society on Alcoholism, San Diego, June 2009). Alcoholism-Clinical and Experimental Research, Volume: 33 Issue: 6 Special Issue: Sp. Iss. S1   Pages: 168A-168A.

2.       Hayar AM, Light KE, Pierce DR. Coincident inhibitory inputs induce synchronized pauses in the firing of Purkinje cells (39th Annual Meeting of the Society for Neuroscience, Chicago, October 2009, Abstract). Program # 622.3, Poster # F4.


Recently submitted grants

RC1AA019098-01: (submitted on 4/24/2009) PI: Hayar, 6.0 calendar, NIH/NIAAA, Title: “Neuronal circuit interactions in a rat model of Fetal Alcohol Spectrum Disorder”, 10/01/2009-09/30/2011, Direct costs: $583,793, Total costs: $846,499/2 years.

RC1AA019238-01: (submitted on 4/24/2009) PI: Kim Light, Role, co-I, 2.4 calendar, NIH/NIAAA, Title: “Dynamic Visual Analysis of Purkinje Neuron Spine Plasticity in a Rat FASD Model”, 10/01/2009-09/30/2011, Direct costs: $ 530,173, Total costs: $ 652,300/2 years

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