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[Preprint]. 2024 Jul 24:2024.07.24.604946. [Version 1] doi: 10.1101/2024.07.24.604946

Figure 1. Experimental design for presymptomatic targeted circuit manipulation in Huntington’s disease.

Figure 1.

(A) Firing patterns of cortical pyramidal neurons (green) and parvalbumin interneurons (purple) in normal compared to hyper- and hypo-active states in HD resulting in increased cortico-striatal drive. (B-C) Normalization of cortico-striatal drive through dampening of pyramidal neuronal activity by expressing an inhibitory luminopsin (LMO) (B) and through increasing parvalbumin interneuron activity by expressing an excitatory luminopsin (LMO) (C). (D) Validation of M1 coordinates in a 3-week-old mouse by Dil injection. (E-F) Neuronal subpopulation-specific targeting of LMOs in M1 cortex by transduction of AAV-Ef1a-DIO-NCS3-hGtACR1 in Emx-Cre × R6/2 mice (E) and AAV-Ef1a-DIO-NCS3-ChRmine in Pv-Cre × R6/2 mice (F). (G) Experimental timeline showing viral injection at week 3, baseline behavioral test at week 5, IP administration of hCTZ from weeks 6 – 8, and post-treatment behavioral tests at week 10.