The basal ganglia are critical for the learning and subsequent selection of motor programs. In health, adaptive plasticity in the basal ganglia enables easy execution of complex motor tasks through formation of habits. Conversely, in disease, repetitive behaviors, addictions and compulsions are thought to derive from maladaptive plasticity involving basal ganglia circuitry. The efficacy of medications and deep brain stimulation targeting the basal ganglia to treat Parkinson disease offer examples of the benefits to be gained by understanding the mechanisms by which this circuitry modulates behavior. However, major gaps in our understanding of the functional principles of the basal ganglia limit more widespread and more effective targeting of this circuitry to alleviate other ailments deriving from dysfunction of this circuitry, such as addictions, compulsions, and dystonia. Historically, there have been wide gaps in the levels of analysis of brain plasticity mechanisms, typically involving isolated study of particular candidate synapses ex vivo and regional activity in awake behaving animals. However, emerging technologies to image and selectively manipulate brain circuitry now provide several key opportunities to bridge these levels of analysis. These opportunities can reveal how plasticity is organized across the local microcircuitry and enable finer levels of monitoring and perturbing activity in the awake behaving animal. In this mentored career award, an accomplished investigator in the field of synaptic plasticity and the basal ganglia, Dr. Calakos, proposes to undertake career enhancement activities to acquire new expertise in in vivo physiology and familiarity with the latest cutting-edge opportunities to evaluate and manipulate activity in vivo. In collaboration with key mentors, the research objectives will be to develop an approach to simultaneously image both classes of striatal projection neurons in vivo and to use that approach to evaluate the novel variable of relative latency to fire between the two neuronal classes of striatal projection neurons as a driver of habitual behavior.
The basal ganglia circuitry modulates motor behavior and is a therapeutic target of medications and deep brain stimulation for a number of diseases, such as Parkinson?s, that carry a major toll on the health of our population. Although these therapies are effective, major gaps in our understanding of the functional principles of the basal ganglia limit more widespread and more effective targeting of this circuitry to alleviate ailments deriving from dysfunction of this circuitry that exist in a much broader range of neurological and neuropsychiatric diseases. Basal ganglia circuit dysfunction plays a prominent role in the symptomatology of several devastating neurological and neuropsychiatric disorders, such as addictions, substance abuse, Tourette?s syndrome, Obsessive Compulsive Disorder, Huntington disease, autism, Parkinson disease, dystonia, and Lesch-Nyhan disease. The knowledge and methodology gained from the proposed studies will enable the identification of new mechanisms and therapeutic targets to alleviate some of the disabling movement and neuropsychiatric symptoms in these disorders.