Development of the cortex is regulated by both intrinsic and extrinsic factors, including guidance molecules and neurotransmitters, that may be impacted by pharmacological or other environmental agents. The Eph receptors are members of the family of receptor tyrosine kinases which interact with ligand proteins, the ephrins, to mediate patterning of brain structures, in particular the axons that project from the thalamus to cortex, the thalamocortical afferents (TCAs). These molecules are good candidates for involvement in postnatal boundary formation and possibly in correcting errors induced in TCA patterns. Our previous results showed that TCA patterns are disrupted by excessive fiber outgrowth in neonate rats by elevated levels of the transmitter serotonin (5-HT), and yet these patterns become normalized during the second postnatal week, despite continued elevation of 5-HT. Moreover, there are spatial limits to TCA outgrowth induced by 5-HT. The existence of boundaries limiting abnormal growth and processes that remove axons from inappropriate regions may depend on repulsive molecular interactions, and expression of Eph/ephrin family molecules are consistent with their involvement with either or both of these mechanisms. The goal of the proposed research is to investigate the potential role of Ephs/ephrins in cortical boundary formation and to test whether these molecules redirect axons to normalize TCA patterns when these are perturbed, for example by drugs that alter cortical 5-HT levels (amphetamines, SSRIs).
The specific aims are: 1. Examine the distribution of Eph/ephrin protein and mRNA in and surrounding somatosensory cortex (S-l) and ventrobasal thalamus (VB). Expression patterns of these molecules will be visualized by immunohistochemistry and in situ hybridization. 2. Examine the influence of Eph/ephrin molecules on TCA patterns and arbors of individual TCA axons. Gain and loss of function experiments are used to test to test if TCAs are influenced by local changes in ephrin distributions.. 3. Determine the role of Eph/ephrin molecules in normalizing fused TCA patterns resultant from elevation of cortical 5-HT levels. Changes in Eph/ephrin distributions and function during the period of pattern normalization will be investigated. The knowledge gained by these studies will expand our understanding of how one class of endogenous guidance cues helps to define cortical boundaries and participates in early brain plasticity induced by the alteration of a cortical transmitter which is susceptible to widely utilized pharmaceutical agents..
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