Striatal pathways are essential to the regulation of diverse behaviors relevant to a wide array of neuropsychiatric disorders. Important roles for the STR in hedonic processes are relevant to depressive disorders, anxiety disorders, substance abuse disorders and alcoholism. Whereas much attention has focused on the functional significance of the dopaminergic innervation of the STR, much less is known about the regulation of STR function by serotonin systems. The importance of this issue is highlighted by the known, yet poorly understood impact of serotonin system manipulations on both STR function and hedonic processes. This is in part attributable to the complexity of serotonergic neurotransmission; the actions of serotonin are mediated by at least 14 distinct serotonin receptor subtypes. Multiple lines of evidence indicate that the 5- HT2C receptor (5HT2CR) subtype plays a particularly prominent role in mediating the serotonergic regulation of both hedonic states and STR function. Accordingly, we had found that a line of mutant mice lacking functional 5HT2CRs displayed diverse neurochemical, physiological and behavioral phenotypes indicative of perturbed STR function and alterations in motivated behavior. Despite the acknowledged prominence of 5HT2CRs in the serotonergic modulation of STR function, it has been very difficult to discern those neural circuits most responsible for these effects. Progress i this area has been hindered by the widespread expression of 5HT2CRs in multiple cell types in multiple basal ganglia structures, and by limitations in the specificity of pharmacological probes of 5HT2CR function. To address this challenge, we will combine methods for the induction of cell type-specific genetic manipulations with high-resolution behavioral assessment technology to determine the contribution of dorsal raphe striatal projections to the serotonergic regulation o hedonic states. We will determine the functional significance of 5HT2CRs expressed in two principal striatal circuits: the direct and indirect pathways.
The collection of brain nuclei known as the basal ganglia are implicated in a wide variety of physiological and behavioral processes relevant to clinical conditions such as schizophrenia, major depression, substance abuse, obsessive-compulsive disorder, autism spectrum disorders, Huntington's Disease and Parkinson's Disease. Although brain serotonin systems have been strongly implicated in the modulation of basal ganglia function in health, disease, and pharmacotherapy, it has been difficult to discern precisely how this modulation occurs. To gain insights that can lead to new treatment strategies, we propose a novel approach to this problem that combines new methods for the selective control of neural circuits and for the detailed analysis of complex behavioral patterns relevant to neuropsychiatric disease.
