Wednesday, April 23, 2025
4/23/2025
Functional and anatomical characterization of the striosomal system - The striatum is critically important to health and well-being, and to our ability to adapt behaviorally to our environment. As the great input-output center of the basal ganglia, the striatum receives projections from all parts of the neocortex including mood-related areas connecting to specialized striatal zones called striosomes, and sensorimotor areas projecting to action control circuits, involving mainly the other compartment, the matrix. Crucially, the striatum is the main target of the tract input carrying dopamine (DA) from the substantia nigra pars compacta (SNc), which degenerates in Parkinson’s disease. Striosomes project back to the SNc, so as to form the nigro-striato-nigral loop famed in the clinic. The DA SNc cells not only modulate movement initiation, but also mood, vigor, learning and decision-making. The ‘return’ striatonigral tract mainly arises in striosomes. Thus striosomes are strategically wired to directly influence these DA neurons. Due to formidable technical hurdles, the functions of this critical part of the nigro-striato-nigral loop remain unclear. Yet, there are clues about the functions. Previous studies suggest that striosomes could process mood-related cortical information and send the resultant neural signals to DA neurons in SNc. Models suggest, among others, that striosomes could serve as critics in actor-critic reinforcement learning models. However, critically lacking is the understanding of the relationship between the striosome-matrix axis—striosomes (S) receiving limbic, and the surrounding matrix (M) receiving sensorimotor/associative cortical inputs—and the D1-D2 axis of the striatum—composed of direct (D1) movement-promoting striatal projection neurons (dSPNs) and indirect (D2) movement-suppressing iSPNs, due to the lack of experimental tools to dissociate the two axes. We have overcome some of the technical hurdles and propose to address these issues guided by our overarching hypotheses, that the cortico-striosomal circuit gates the state transitions of brain networks underlying mood, motivation, or vigor of action; that this circuit modulates learning processes through its powerful connections with DA-containing SNc neurons; and that striosome-dopamine circuits can adjust functional balance across distinct SPN subtypes with identities multiplexed across S-M compartments and D1-D2 pathways. We will use intersect methods in mice to dissect individual SPN subtypes according to their D1-D2 and S-M identities, DA sensors to measure DA release under the control of the striatonigral path, and chemogenetics to manipulate each component of the nigro-striato-nigral circuit so as to assess its causal role in behavior. Thus, we are fully equipped, standing on our groundworks that found that cost-benefit, approach-avoidance conflict recruit the cortico-striosomal circuit, that identified by snRNA-seq differential gene-expression patterns of individual SPN subtypes, and that have developed strategies for simultaneously recording and individually manipulating the SPN subtypes. This work is directly in line with the goals of the NIMH to advance human health and well-beings by directly addressing profoundly important gaps in knowledge about key functional circuits affected in a range of mental health disorders.
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