The thalamic paraventricular nucleus (PVT) has generally been considered as one of the non-specific thalamic nuclei. More recent data indicate there is a high degree of specificity in the efferent projections of the PVT and argue against a non-specific role for the PVT. The PVT projects to several key sites linked to the pathophysiology of schizophrenia and drug abuse, including the prefrontal cortex (PFC), the shell of the nucleus accumbens (NAS), and the central and basolateral nuclei of the amygdala. The PVT also receives a dopamine (DA) innervation and PVT neurons express the D3 (but not other) DA receptor transcripts. We hypothesize that the PVT is both regulated by DA afferents and coordinately regulates DA function in mesocorticolimbic regions, including the NAS and PFC. Three related specific aims will explore the anatomical and functional organization of the PVT and test our hypotheses. 1)Tract-tracing--immunohistochemistry studies will determine the origins of the DA innervation of the PVT, examine the relationship of efferent projections to the extended amygdala and NAS, and characterize the phenotype of PVT neurons that innervate the NAS and other corticolimbic areas. 2)A series of studies will examine the regulation of the dopamine system of the PVT. These studies will determine the efferent targets of PVT neurons that are activated by clozapine and psychostimulants, determine if the Fos response of PVT neurons occurs in D3 receptor-expressing cells, and assess the regulation of D3 gene expression by chronic clozapine and psychostimulants. 3)The ability of the PVT to functionally regulate the DA innervations of mesocorticolimbic terminal fields, including the NAS and PFC, will be examined using in vivo microdialysis. These studies will assess the responsiveness of the NAS and PFC DA innervations to agents that evoke DA release (KC1 and amphetamine) and to excitatory amino acid agonists (NMDA and AMPA). These studies should reveal new aspects of thalamic regulation of mesocorticolimbic DA function that may be deranged in schizophrenia and drug abuse.
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