Huntington’s disease (HD) is an inherited neurodegenerative disorder with symptomatic manifestations, including involuntary movements such as chorea, dystonia, poor motor coordination, psychiatric, and cognitive symptoms. HD is caused by a CAG repeat expansion in the huntingtin (Htt) gene that translates into a polyglutamine tract in the Htt protein. Mutant Htt (mHtt) is expressed throughout the brain and disrupts a wide range of molecular pathways and signaling cascades, yet HD pathology is most prominent in the basal ganglia circuitry.
The central hub of the basal ganglia is the striatum, which controls movements and behavior through a myriad of inputs and outputs (Calabresi et al., 2014; Freeze et al., 2013; Rothwell et al., 2015; Rueda-Orozco and Robbe, 2015; Tecuapetla et al., 2016). The striatum receives glutamatergic inputs from all neocortical areas and the thalamus (Bolam et al., 2000). Information flows from the cortex through the basal ganglia and it goes back to the cortex via the thalamus through two main pathways (direct and indirect), which orchestrate the proper execution of movement. Additionally, the specific origin of the cortical inputs to the striatum provides a substrate for information segregation in these circuits (Hintiryan et al., 2016; Wall et al., 2013).
In HD, motor symptoms emerge from dysregulated information flow through the basal ganglia circuits. Disturbances of the cortico-striatal communication have a leading role in HD network dysfunction, with alterations appearing in prodromal HD (Burgold et al., 2019; Dumas et al., 2013; Unschuld et al., 2012). Specifically, the caudate nucleus and the premotor cortex are predominantly affected (Unschuld et al., 2012). In HD mouse models, there is abundant evidence of a progressive disconnection between cortex and striatum (Cepeda et al., 2007; Veldman and Yang, 2018). Cortico-striatal dysfunction in HD is strongly supported by the impaired cortico-striatal-dependent motor functions (Hong et al., 2012; Puigdellívol et al., 2015), altered paired-pulse facilitation at cortico-striatal synapses (Milnerwood and Raymond, 2007), reduction of striatal excitatory postsynaptic currents with loss of cortico-striatal synapses (Cepeda et al., 2003; Deng et al., 2013); and altered glutamate release in the striatum of transgenic R6/1 mice (Nicniocaill et al., 2001). Moreover, reducing mHtt in the striatum is not sufficient to revert HD neurodegeneration, while reducing mHtt expression in both striatum and cortex ameliorates behavioral and neuropathological features of HD animals (Gu et al., 2005; Wang et al., 2014). Thus, a progressive disconnection of cortico-striatal pathways alters the information processing in basal ganglia circuitry, leading to motor disturbances. However, we do not know yet if specific cortico-striatal pathways are affected.
In this study, we aimed to further map cortico-striatal dysfunction in HD by using in vivo multimodal magnetic resonance imaging (MRI) techniques in the R6/1 HD mouse model. We took advantage of optogenetic tools (Zhang et al., 2010) and high-resolution cortico-striatal maps (Hintiryan et al., 2016) to modulate cortico-striatal function in HD mice. More specifically, we modulated the secondary motor (M2) cortex projection to dorsolateral striatum (DLS), whose structural alterations have been previously reported in HD (Hintiryan et al., 2016). Then, we used optogenetics coupled to in vivo microdialysis and to ex vivo multi-electrode arrays (MEAs) to characterize cortico-striatal dysfunction in symptomatic HD mice. With this knowledge, we aimed to test novel therapeutic interventions based on circuit restoration, an approach previously found successful for other basal ganglia disorders (Gradinaru et al., 2009; Kravitz et al., 2010).
Strikingly, selective optogenetic stimulation of the M2-DLS afferent pathway successfully rectified motor learning and coordination deficits in symptomatic HD mice. These effects were associated with improvements in synaptic plasticity such as induced long-term depression (LTD) and normalization of spine density within the striatum of HD mice. Our findings reveal that the function of the M2 cortex-DLS circuit is deeply impaired in the present HD mouse model, and indicate that selective stimulation of this pathway induces long-lasting plasticity effects that significantly ameliorate motor symptoms in HD.
