Cortico-Striatal Cross-Frequency Coupling and Gamma Genesis Disruptions in Huntington’s Disease Mouse and Computational Models

Abstract

Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s disease (HD) in both patients and animal models, but neither the origin nor the functional relevance of this phenotype is well understood. Here, we analyzed local field potential (LFP) activity in freely behaving, symptomatic R6/2 and Q175 mouse models and corresponding wild-type (WT) controls. We focused on periods of quiet rest, which show strong γ activity in HD mice. Simultaneous recording from motor cortex and its target area in dorsal striatum in the R6/2 model revealed exaggerated functional coupling over that observed in WT between the phase of delta frequencies (1–4 Hz) in cortex and striatum and striatal amplitude modulation of low γ frequencies (25–55 Hz; i.e., phase-amplitude coupling, PAC), but no evidence that abnormal cortical activity alone can account for the increase in striatal γ power. Both HD mouse models had stronger coupling of γ amplitude to δ phase and more unimodal phase distributions than their WT counterparts. To assess the possible role of striatal fast-spiking interneurons (FSIs) in these phenomena, we developed a computational model based on additional striatal recordings from Q175 mice. Changes in peak γ frequency and power ratio were readily reproduced by our computational model, accounting for several experimental findings reported in the literature. Our results suggest that HD is characterized by both a reorganization of cortico-striatal drive and specific population changes related to intrastriatal synaptic coupling.

Multiscale dynamics and information flow in a data-driven model of the primary motor cortex microcircuit

“…More generally, these physiological oscillations are considered to be fundamental to the relation of brain structure and function 20 . Phase-amplitude coupling of delta/beta and theta/gamma oscillations has also been reported in motor and somatosensory cortices of rodents 94,59,144,4 and primates 118,32,90 . Cross-frequency coupling may help integrate information across temporal scales and across networks 21 .…”

Cortical and Striatal Circuits in Huntington’s Disease

“…In vivo electrophysiological studies in freely behaving mice also analyzed local field potentials (LFPs), transient extracellular signals generated by large populations of neurons. These recordings uncovered altered synchrony between the cortical and striatal networks in HD Naze et al, 2018). However, it is still unknown how cortical activity shapes firing patterns in the striatum.…”

A biophysical model of striatal microcircuits suggests gamma and beta oscillations interleaved at delta/theta frequencies mediate periodicity in motor control

“…It is the primary target of dopaminergic (DAergic) neurons in the brain, and its activity is strongly modulated by DAergic tone. Disorders of the DA and motor systems, such as Parkinson's, Huntington's, Tourette's, and many others, result in abnormal network activity within striatum [1][2][3][4][5][6][7][8][9]. Rhythmic activity is observed in both striatal spiking and local field potential, and oscillations in the striatum are correlated with voluntary movement, reward, and decision-making in healthy individuals [10][11][12][13][14][15][16][17][18], while disruptions of these rhythms are biomarkers of mental and neurological disorders [1,2,[19][20][21][22][23][24][25][26][27].…”