Evaluation of acute alcohol intoxication as a model of cerebellar disease

The cerebellum is one of the most sensible regions to alcohol effect, since ethanol directly interacts with the functioning of synapses in the cerebellar cortex. Cerebellar patients manifest deficits of cerebellar functions comparable, although stronger, to those experienced by alcohol-intoxicated subjects. Based on such similarities, my work aimed at exploiting the transient cerebellar impairment caused by alcohol in order to model cerebellar diseases, and get new insights on its role in motor control. To achieve this goal, the research activity described in this thesis has concerned the study of the effects induced by alcohol on the control of eye movements in humans and zebrafish, focusing on the gaze-holding mechanism. The gaze-holding mechanism is fundamental and is “implemented” in our CNS by means of two actors: the neural integrator and the cerebellum. Both cerebellar patients and alcohol-intoxicated subjects manifest a typical clinical ocular motor sign called gaze-evoked nystagmus (GEN): an abnormal centripetal eye drift with centrifugal correcting saccades while at eccentric gaze. Despite GEN has been extensively investigated in cerebellar patients, a detailed analysis of the influence of alcohol on gaze-dependent eye drift is still missing. Thus, as a first aim of my research, we examined gaze-holding in two groups of healthy human subjects recorded before and 30 minutes after intake of the estimated alcohol amount needed to reach a blood alcohol content (BAC) of 0.06 and 0.10%, respectively. The results presented here showed that alcohol intoxication caused a linear increase of drift velocity for all gaze eccentricities. A secondary effect, instead, was found in a subgroup of subjects, which showed an additional nonlinear increase of drift velocity at large gaze angles. Considering that similar linear and nonlinear transformations were described in patients affected by cerebellar degenerations, our results suggest that alcohol-induced GEN could provide a model of GEN in cerebellar pathology. The second part of my research aimed at understanding whether the results found in alcohol intoxicated human subjects, could be generalized to zebrafish, which has been frequently considered as potential candidate for modeling cerebellar diseases in the scientific literature. To pursue such aim, we exploited the advantages of using a simpler vertebrate as a model organism and the analogies between alcohol-induced and cerebellar-induced ocular motor abnormalities. Despite the zebrafish cerebellum shares relevant functions with the human one, the involvement of the cerebellum in the gaze-holding mechanism of the fish has not been explicitly tested yet. Thus, my study was designed to face two purposes: quantifying ethanol effects on the zebrafish ocular motor system for the first time, and elucidating the role of the cerebellum on the gaze-holding mechanism at two developmental stages, i.e. larval and juvenile.The study on larvae did not reveal any macroscopic effect on their ocular motor system, showing only a nonhomogeneous effect of ethanol on their eye movements. In juvenile zebrafish, instead, ethanol-dependent abnormalities were induced both in gaze-holding and in the saccadic system. In the former system, a nonlinear a transformation of the position-drift velocity relationship was observed, although any reduction in the time constant of the neural integrator was not statistically significant. In the latter, instead, only a reduction of saccade peak velocity and amplitude was found. Despite the observed saccadic abnormalities are partially comparable to those documented in intoxicated humans, the dissimilar alteration found in gaze-holding system after alcohol exposure suggests that cerebellar involvement in eye movement control may be limited in zebrafish. Such limitation pointed out that zebrafish may not be a suitable model organism for cerebellar diseases, although it is widely used in ophthalmic research.