M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington’s disease

Abstract

Huntington’s disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.

RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

“…RTP801 downregulation did not induce significant changes in travelled distance, thigmotaxis, or parallel index ( Figure 2 b–d). No differences were found between genotypes, as expected [ 45 ] (Two-way ANOVA group effect for travelled distance F (3,32) = 1.767, p = 0.1732; genotype effect for percentage of distance in the center of the arena F (1, 33) = 3.517, p = 0.0696; and genotype effect for parallel index F (1, 33) = 3.712, p = 0.0627).…”

RTP801/REDD1 is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

“…RTP801 downregulation did not induce significant changes in travelled distance, thigmotaxis or parallel index (Figure 2b-d). No differences were found between genotypes, as expected [45] (Two-way ANOVA group effect for travelled distance F(3,32)=1.767, P=0.1732; genotype effect for percentage of distance in the center of the arena F(1,33)=3.517, P=0.0696; genotype effect for parallel index F(1,33)=3.712, P=0.0627).…”

Altered M2 Cortex - Superior Colliculus visual perception circuit in Huntington’s Disease

“…Furthermore, our results in HD mice suggest that the failure to engage M2 cortex activity may be the underlying mechanism to explain visual perception alterations. In this line, M2 cortex activation has been involved in many naturalistic behaviours such as rearing, grasping, eating, grooming etc, as seen by calcium imaging experiments using miniature microscopes (Tombaz et al, 2020) and to motor learning processes using two-photon imaging of Arc-GFP expression (Cao et al, 2015), and which behaviours are known to be altered in HD mice (Fernández-García et al, 2020; Pépin et al, 2016). A recent publication shows that inhibiting M2 terminals in the SC (using DREADDS) selectively impairs decision maintenance in a memory-dependent perceptual decision task, indicating an additional role of this circuit in motor planning (Duan et al, 2021).…”

“…In HD patients, the most affected structural and functional striatal connexions arise from cortical premotor areas, analogous to the secondary motor (M2) cortex in rodents. Notably, these affectations appear many years before the onset of motor symptoms in HD carriers (Estevez-Fraga et al, 2021; Johnson et al, 2021; Shaffer et al, 2017; Unschuld et al, 2012) and are profoundly impaired in animal models (Creus-Muncunill et al, 2019; Fernández-García et al, 2020; Hintiryan et al, 2016). However, it is unclear whether dysregulated information flow from the M2 cortex in HD affects only cortico-striatal functions or could have an additional impact in the remaining long-distance output nuclei.…”

“…Cortico-striatal circuits are required for motor learning processes (Cao et al, 2015; Costa et al, 2004; Kupferschmidt et al, 2017) and M2 cortex projection to the striatum has been associated to the motor learning deficits that characterize HD mice (Fernández-García et al, 2020). Furthermore, M2 cortex is involved in a variety of functions including not only motor learning processes (Cao et al, 2015) but also decision-making (Sul et al, 2011) and perceptual behaviour (Duan et al, 2021), as widely reviewed (Barthas and Kwan, 2017; Yang and Kwan, 2021).…”