Effects of thymus size and involution on the contribution of recent thymic emigrants to the peripheral T cell pool

The contribution of recent thymic emigrants (RTEs) to the peripheral naïve T cell population is necessary to maintain diversity of the T cell receptor (TCR) repertoire and produce immune responses against newly encountered antigens. The thymus involutes with age, after irradiation or chemotherapy, and due to severe viral infections. Thymus involution results in decreased thymopoiesis and RTE output leading to a reduced diversity of peripheral T cells. This increases susceptibility to disease and impairs immune responsiveness to vaccines. Therefore, studies aimed at maintaining or regenerating thymic function are integral for maintaining and restoring peripheral TCR diversity. Mice that express a K5.CyclinD1 transgene expression have a severely hyperplastic thymus that fails to undergo involution. Both thymocyte and TEC development appear normal in these mice. We have used the K5.CyclinD1 transgenic model to test the hypothesis that preventing thymus involution will sustain RTE output and incorporation into the peripheral T cell pool to prevent naïve T cell depletion with age. The K5.CyclinD1 transgene was crossed to the RAG2p-GFP transgenic model so that RTEs could be tracked by the intensity of the GFP signal. The frequency and number of RTEs in naïve CD4 splenic T cells was analyzed at monthly intervals to 5 months of age. Using this double transgenic approach, we determined that preventing thymus involution does maintain or enhance the number of RTEs in the peripheral T cell pool before and after thymus involution.

Learning in the cerebellar nucleus is necessary for acquisition of Pavlovian eyelid conditioning

The cumulative work presented here supports the hypothesis that plasticity in the cerebellar cortex and cerebellar nuclei mediates a simple associative form of motor teaming-Pavlovian eyelid conditioning. It was previously demonstrated that focal ablative lesions of cerebellar anterior lobe or pharmacological block of the cerebellar cortex output disrupted the timing of the conditioned eyeblink response, unmasking a response with a relatively fixed and very short latency to onset. The results of this thesis demonstrate that the short-latency responses are due to associative learning. Unpaired training does not support the acquisition of short-latency responses while the rate of acquisition of short-latency responses during paired training is approximately the same as that of timed conditioned responses. The acquisition of short-latency responses is dependent on an intact cerebellar cortex. Both ablative lesions of the cerebellar cortex and inactivation of cerebellar cortex output with picrotoxin block the acquisition of short-latency responses. However, once the short-latency responses are acquired neither disconnection of cerebellar cortex nor inactivation of the cerebellar nucleus block reacquisition. The results are consistent with the proposal that plasticity in the cerebellar cortex is necessary for learning the timing of conditioned responses, plasticity in the interpositus nucleus mediates the short latency responses, and cerebellar cortical output and mossy fiber input are necessary for the acquisition of short latency responses. ^