The cortico-basal ganglia system is a complex neural network involved in motivation and reward. Dysfunction of this circuitry has been implicated in many neuropsychiatric disorders, including drug addiction. The striatum acts as the principal interface of this circuit, and guides behavioral output primarily through two pathways, the direct and the indirect. These striatal pathways have been shown to play important, but distinct roles, in addiction-related behaviors. In addition, plasticity at striatal neurons, which promotes the selection of appropriate actions based on prior experience and is profoundly altered by exposure to drugs of abuse, is regulated by glutamatergic signaling from the cortex. However, how corticostriatal afferents targeting specific striatal cell populations regulate the behavioral and neurobiological impact of drugs has never been isolated. Furthermore, these corticostriatal pyramidal neurons can be subdivided into two major types with distinct projections targets, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts and minimal h-currents project intratelencephalically to striatum and contralateral cortex (IT-type) whereas cortical neurons that have thick apical tufts and prominent h-currents send their main axon into the pyramidal tract with collateral projections to striatum (PT-type). Although some evidence suggests that IT-type neurons preferentially target direct pathway striatal neurons and PT-type neurons target indirect pathway striatal neurons, this idea remains of debate. Cortical processing is crucial for the patterning of addiction- related behavior, so understanding which types of cortical cells target populations of striatal neurons as well as how discrete sets of cortical inputs produce adaptations within the direct and indirect striatal pathways will be critical for unraveling the circuitry underlying reward and motivated behavior. Thus, the overall goal of this proposal is to develop novel molecular targeting approaches to assess the phenotype of cortical neurons that target direct and indirect pathway striatal neurons as well as to define the role of sets of cortical afferents that target these two striatal pathwaysin one form of drug-induced behavioral plasticity, psychomotor sensitization. Through modeling how loss of top-down control from cortical inputs into the basal ganglia contribute to behaviors that are related to addiction, we will gain a better understanding of the intricacies of this circutry, which is likely to have a big impact on the development and application of treatments for addicts.
Drug abuse and addiction are tremendously costly public health problems that have profound medical consequences to individuals, as well as serious social and economic impacts on our society. The research in this application will develop and characterize novel tools in order to map afferent connections to striatum and to better understand how afferent activity to specific striatal cell populations contributes to the development of addiction. In doing so, this research may provide avenues for new therapeutic interventions in order to mitigate this serious public health crisis.