Cortical and Striatal Circuits in Huntington’s Disease

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

Human Fronto-Striatal Connectivity is Organized into Discrete Functional Subnetworks

“…The striatum works in close concert with the cortex-and especially the frontal cortex-via a series of parallel, partially segregated cortico-striato-thalamo-cortical circuits (Haber, 2003;Nakano et al, 2000). The integrity of cortico-striatal connectivity is critical for healthy brain function, as its disruption causes devastating neurological and psychiatric symptoms in disorders such as Parkinson's and Huntington's disease (Blumenstock and Dudanova, 2020;Bunner and Rebec, 2016). Even relatively minor alterations in cortico-striatal circuitry are thought to play a major role in symptoms observed in Tourette syndrome (Greene et al, 2017;Mink, 2001), schizophrenia (Simpson et al, 2010), obsessive-compulsive disorder (Harrison et al, 2009), depression (Borsini et al, 2020), and autism (Li and Pozzo-Miller, 2019).…”

Fronto-striatal circuits for cognitive flexibility in far from onset Huntington’s disease: evidence from the Young Adult Study

“…It is well established that the neurodegeneration in both HD and pre-HD is especially severe in the striatum in HD, 3 5–8 largely due to loss of GABAergic spiny projection neurons (medium spiny neurons). 9 In more advanced stages of the disease, neurodegeneration becomes more widespread in the cortex. 5 10 Indeed, fronto-striatal circuits are among the earliest to show degeneration in pre-HD.…”

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

“…While astrocyte dysfunction may directly affect local myelination and spinal cord circuits, deterioration of other brain regions or descending spinal tracts may also contribute to cord atrophy and motor impairment. Future studies to assess CNS connectivity and descending versus ascending tracts in spinal cord, brainstem and other brain regions in the rat model could potentially reveal how astrocyte pathology affects long range relays, local circuits, or central pattern generators in AxD (43)(44)(45)(46)(47)(48).…”