Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

Bernard G Schreurs

Committee Co-Chair

Albert S Berrebi

Committee Member

Adrienne K Salm

Committee Member

Maxim Sokolov

Committee Member

George A Spirou

Abstract

The main goal of this dissertation was to identify eyeblink projection neurons of the anterior interpositus nucleus (AIN) and to examine learning-specific changes in excitatory and inhibitory somatic synapses after eyeblink conditioning (EBC). In order to identify the specific subset of AIN neurons involved in EBC, a retrograde transneuronal viral tracer was injected into the eyelid (orbicularis oculi muscle) of the rabbit to reveal hierarchical chains of synaptically connected neurons involved in the eyeblink response. Experiment 1 was designed to provide a complete delineation of the rabbit eyeblink premotor pathway and to characterize the multiple neuronal types in the AIN that are involved in EBC and their possible interactions. Relevant structures involved in the generation or modulation of the rabbit eyeblink response were identified and possible sites of plasticity were revealed. First-order eyeblink motoneurons were found ipsilaterally in the dorsolateral facial nucleus. Second-order premotor neurons were found in the contralateral red nucleus and in different reticular, trigeminal, auditory, and vestibular nuclei. Third-order eyeblink premotor neurons were found in the pons, midbrain, and in the cerebellum, including dorsolateral AIN and rostral fastigial nucleus. Fourth-order neurons were found in Purkinje cells of the cerebellar cortex in lobule HVI and in lobule I. Eyeblink premotor neurons of the AIN were further characterized based on their neurotransmitter immunoreactivity which showed that glutamatergic eyeblink projection neurons are modulated by three different types of inhibitory interneurons that form a functional eyeblink microcomplex. Experiment 2 was designed to examine the effect of EBC on the number of excitatory and inhibitory somatic synapses in eyeblink projection neurons of the AIN. A coordinated increase in the number of excitatory and inhibitory Purkinje cell somatic synapses was observed in subjects in the experimental group that received paired delay EBC. These results support a parallel and correlated mechanism of cerebellar learning mediated by excitatory inputs presumably from mossy fibers and inhibitory inputs from Purkinje cells. In contrast, control subjects that received unpaired stimulus presentations showed an increase in the number of inhibitory somatic synapses originating from local interneurons, suggesting a possible role of feedback inhibition that may also explain the detrimental effect of unpaired exposure on subsequent learning. Another important finding was an increase in the somatic surface area of eyeblink projection neurons as a function of learning that was highly correlated with the number of somatic synapses; suggesting that synaptic remodeling is a bidirectional process that entails proportional structural alterations on the postsynaptic neuron. To our knowledge, this is the first time that the identity and function of specific nuclear neurons and their associated synaptic changes during learning can be linked to a behavior.

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