Deciphering cell- and circuit-specific behavioral correlates following cholesterol-based Precision Nanomedicine in early Huntington’s disease

Novel nanocarriers have become available that cross the blood-brain barrier (BBB) and deliver therapeutic molecules to the brain in a non-invasive way. One of these molecules of therapeutic interest is cholesterol (Chol) which is essential for brain function. Its in-brain synthesis is reduced in Huntington disease (HD), a genetic neurodegenerative disorder characterized by the loss of the spiny projection neurons (SPN) of the striatum. Since nearly all brain Chol is produced locally, its exogenous supplementation is emerging as a potential therapeutic option in HD. Recently, a comprehensive set of preclinical data were obtained on the ability of the most advanced formulation of Chol-loaded nanoparticles (Chol-NPs) to restore cognitive and motor dysfunctions in HD mice. This project aims to decipher the specific cell- and circuit-based signals associated with the early behavioral recovery observed in HD mice upon brain cholesterol supplementation. The rationale of the study stands on the evidence of reduced brain Chol biosynthesis in HD mouse models, which occurs early in the striatum. This dysfunction is mirrored in HD patients through reduced plasma levels of the brain-specific Chol catabolite, 24-hydroxy-Chol, even at presymptomatic stages. Studies conducted by members of this consortium show that reduced brain cholesterol biosynthesis affects the integrity of the HD synapse and its remodeling, and replenishment of cholesterol – via osmotic mini-pumps or intraperitoneal injection of brain-permeable Chol-NPs – normalizes synaptic transmission, prevents cognitive decline, and ameliorates motor defects in HD mice. Taking advantage of the recent findings obtained in the heterozygous Q175 knock-in HD mouse model for validating Chol-NPs as preclinical candidate for HD, here we set two main goals. By using optogenetic tools, we will first interrogate specific circuits and individual striatal neurons to identify which are more associated with early behavioral defects in HD mice; by using biochemical and immunofluorescence assays, we will also explore synaptic properties associated with these changes (Aim 1). Then, we will explore how selective striatal neurons and their relevant synaptic changes (identified in aim 1) are modulated in wt and HD mice following systemic administration of Chol-NPs to decipher the circuit- and synaptic-based mechanisms through which exogenous Chol exerts its behavioral benefits (Aim 2). Collectively, these studies should provide first insights into the causative role of specific circuits in giving rise to early behavioral defects in HD mice, and in their modulation following Chol brain delivery. Moreover, a deeper understanding of specific circuit components implicated will help to reinforce the therapeutic potential of Cholesterol-based Nanomedicine in HD.