The differential role of cortical neuron types in motor behaviour and their alterations in disease

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The dysfunction of the brain in the neocortex and its target structure striatum is central to the development and progression of neurodegenerative movement disorders such as Huntington’s disease (HD). Previous studies have shown HD-related changes in excitatory neuron activity in the cortex, possibly related to a loss of inhibitory control through interneurons. Despite its relevance, the functional involvement of specific neuronal populations in HD remains largely unexplored. To characterize the contributions of 4 major cortical neuron subtypes, I performed chronic in vivo 2-photon calcium imaging in: 1. excitatory corticostriatal projection neurons (CSPN) as well as inhibitory 2. parvalbumin (PV), 3. somatostatin (SST) and 4. vasoactive intestinal peptide (VIP) populations in a HD mouse model. Behavioral abnormalities in HD mice were mirrored in aberrant activity of inhibitory neurons, with an overall reduction of VIP activity and an increase of SST activity. Similar to VIP neurons, CSPN activity was reduced, particularly at the onset of locomotion. My results indicate that HD affects cortical circuits in a cell-type specific manner, opening new possibilities for targeted therapeutic intervention. Using targeted optogenetic stimulation, preliminary results demonstrate a rescue of VIP activity. The consequences of this modulation on downstream communication within the brain and on behavior are open questions: - What consequences does activation of VIP neurons have on corticostriatal activity and mouse behavior? - Does the chronic inhibition of SST neuron activity rescue network changes and behavioral defects? - How are distinct cell types in the striatum functionally affected in HD mouse models? With an extension of my Walter Benjamin Fellowship, I intend to address these questions in collaboration with Prof. Takaki Komiyama at University of California San Diego (UCSD).