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

• Applicant: Dr. Sonja Blumenstock
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468603871

• Final Report Year: 2023

Final Report Abstract

Huntington’s disease (HD) is an incurable movement disorder resulting from a genetic mutation in the Huntingtin gene, leading to severe neuron degeneration in the striatum and motor cortex. Studies on mice and humans suggest early motor cortex involvement in HD pathogenesis, impacting excitatory neuron activity and inhibitory control. Despite its relevance, specific neuronal population involvement in HD is largely unexplored. We used chronic in vivo 2-photon calcium imaging to assess four cortical neuron subtypes in an HD mouse model: excitatory corticostriatal projection neurons (CSPN) and parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) inhibitory interneurons. HD-related behavioral abnormalities correlated with altered inhibitory neuron activity, specifically reduced VIP and increased SST activity. CSPN activity, akin to VIP neurons, was reduced, particularly during locomotion onset. Optogenetic modulation of VIP interneurons at behavior onset restored their activity to normal levels, partially rescuing corticostriatal activity. These results indicate that HD affects cortical circuits in a cell-type specific manner, opening new possibilities for targeted therapeutic intervention.

Publications

• Balancing neuronal circuits. Science, 377(6613), 1383–1384.
  Blumenstock, Sonja & Dudanova, Irina