Newly generated striatal neurons rescue motor circuitry in a Huntington's disease mouse model

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by the selective loss of neostriatal medium spiny neurons (MSNs). We previously found that intraventricular delivery of viral vectors expressing brain-derived neurotrophic factor (BDNF) and Noggin induced heterotopic recruitment of new MSNs to the adult neostriatum and slowed disease progression in the R6/2 mouse model of HD. Nonetheless, the extent to which newly generated neurons integrate into adult striatal circuits has remained unclear. Here, using wild-type (WT) and R6/2 mice, we follow the fate of genetically tagged new neurons recruited to the striatum after intraventricular infusion of BDNF and Noggin. Using rabies tract tracing, optogenetics, and calcium imaging, we find that new neurons functionally assimilate into the cortico-striato-pallidal motor circuitry, and chemogenetic stimulation of these new neurons confirms their contribution to motor behavior. Together, these data indicate that induced neurogenesis may restore multi-synaptic circuits in the adult brain, offering a regenerative strategy for the treatment of HD.

Keywords: BDNF; CP: Cell biology; CP: Neuroscience; Huntington’s disease; adult neurogenesis; chemogenetics; gene therapy; neostriatum; neural stem cells; noggin; optogenetics; regenerative medicine.