A novel circuit underlying amotivation in a mouse model of 22q11DS - PROJECT SUMMARY (See instructions): The work proposed in the R00 phase of this project will be completed at the University of Tennessee Health Science Center in Memphis, TN. Schizophrenia is a multifaceted neurodevelopmental disorder characterized by positive, cognitive, and negative symptom categories. One particular negative symptom, amotivation, generates a major impact on public health, yet the treatment options for this symptom remain sparse. This proposal seeks to investigate a novel circuit underlying the amotivation phenotype in a mouse model of 22q11 deletion syndrome (22q11DS), one of the most robust genetic contributors to schizophrenia. Data derived from this study stand to provide novel treatment options aimed at rectifying amotivation. Despite being implicated in motivational states, the dorsal striatum is largely overlooked when studying motivated behavior. Moreover, disruptions in thalamic nuclei are involved in all facets of schizophrenia symptomology, but the role of the thalamus in amotivation remains unknown. My preliminary results demonstrate amotivation in 22q11DS mice, as well as a deficit in synaptic transmission in the thalamostriatal pathway. Information flow through this circuit is modulated by intra-striatal cholinergic interneurons. In 22q11DS mice, I find that there is an increase in the number of spontaneously active cholinergic interneurons and that blocking cholinergic transmission rescues the thalamostriatal synaptic deficit. These findings are the first to implicate the thalamostriatal circuit and cholinergic signaling in motivated behaviors. To study this further, I propose to use cutting-edge approaches in three aims of investigation: 1) to determine the role of striatal cholinergic interneuron activity in amotivation, 2) to elucidate the cholinergic mechanism underlying weakened thalamostriatal synaptic transmission, and 3) to identify the contribution of distinct striatal microcircuits in amotivation. The results of this study stand to significantly enhance our understanding of the neural circuits underlying motivated behaviors and provide important insight into the disruption of motivation that occurs in neuropsychiatric disorders such as schizophrenia, depression, and addiction.
