Striosomes Constrain Locomotor Vigor in Parkinson's disease and Other Movement Disorders

National Institute On Aging

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Abstract

To test for striosomal territories impact on behavior, we employed Sepw1-Cre BAC transgenic mice in all experiments. We bilaterally injected either AAV-DIO-taCaspase3 to create dorsal striatal striosome ablation (SA mice), or AAV-DIO-mCherry (controls), and tested whether assessment or response to naturalistic contrasts in valence relies on striosomes using a modified Light/Dark box (LDb). We found no evidence that striosomes impact valence perception. Instead, we found that striosomes control the speed with which mice navigate between high and low anxiety zones. A majority of Sepw1-Cre positive striosomes are dSPNs believed to promote locomotion, yet we found SA increased select, valence sensitive speed during LDb navigation. To investigate the relationship between striosomal activity, valence, and speed, we analyzed in vivo striosomal calcium transients with genetically encoded calcium indicator GCaMP6s in miniscope-mounted mice navigating the LDb. The calcium imaging study revealed that the striosome neuronal activity reflects zone, speed, and deceleration, and that more than half of light-and-speed related neurons possess a quadratic negative correlation with speed. In support of the negative relation between speed and a subset of striosome neurons, chemogenetic activation of strisosome neurons suppressed locomotion. Together, we provide the first evidence that striosomes regulate naturalistic motor behavior, and that in so doing, they enact implicit motivation to suit situational valence with speed. The present findings may be applied to interpret or predict striosomes contribution to disorders of attention, mood, and motor control, including PD. It will be important to continue to study striosomal modulation by diverse afferents, including the prefrontal cortex and anxiety nucleus BNST, and to parse striosomal impact through efferent pathways including striosome-dendron bouquets and the lateral habenula, in order to fully grasp striosomal importance in health and disease.