Cortical Connectivity and Activity Changes in Motor Preparation and Execution in 6-OHDA-Lesioned Mice
Parkinsonian motor signs in rodents are frequently studied following dopamine depletion initiated by brain injections of the neurotoxin 6-hyroxydopamine. The dopamine loss leads to abnormal neuronal activity in elements of the basal ganglia-thalamocortical motor circuit. An important gap in our understanding of the consequences of dopamine depletion, however, is the lack of data concerning the neural processing in the parkinsonian condition in motor and premotor cortical areas. Investigations into this issue require a cell type-specific analysis of neural activity in cortex, as different subtypes of neurons engage differentially in parkinsonian activity patterns. In this project, we therefore leverage our ability to combine behavioral studies and mechanistic studies on the single-neuron level in mice to address the overall hypothesis that distinct classes of cortical neurons show different activity changes in response to the induction of the parkinsonian state.
Under aim 1, we will study the activity of neurons in the forelimb motor cortex that project to the spinal cord and/or to the subthalamic nucleus during locomotion and reaching movements. To assess parkinsonian network activity patterns, we use cell type-specific voltage imaging with genetically expressed voltage indicators. Further, we record the electrical activities of cortico-striatal and corticospinal projecting single cells in the rostral and caudal forelimb area of the cerebral cortex, using chronically implanted silicon probes.
In aim 2, we use computer modeling to arrive at a model describing how the motor cortex creates different output activity under parkinsonian and normal conditions. To this end, we are building a detailed computer model of cortical output neurons and plan to test its properties in processing network inputs under healthy or parkinsonian conditions. We will be guided by the hypothesis that parkinsonian output may be more bursty and exhibit oscillations in the beta frequency band.