Wednesday, May 21, 2025
5/21/2025
Neuron-Glial Interactions in Basal Ganglia Circuitry - Recent studies show that striatal astrocytes can affect and be affected by the ambient dopamine in the striatum. Electrophysiological studies show that striosomes also have reciprocal effects on dopamine, with powerful direct projections onto the dopamine-containing neurons in the substantia nigra pars compacta (SNpc) such that they can shut down dopamine neuron activity and then evoke a rebound excitation, likely playing a critical role in state transitions of behavior. In accordance with these data, we have found preliminary evidence that the striatal astrocyte activity and striatal dopamine activity are correlated tightly with each other while mice perform decision- making tasks. Large transients of astrocytic activity, with timescales on the order of seconds, occur around the transition of behavioral states from task engagement to non-engagement or vice versa. Prompted by these findings, we propose here to investigate whether striatal astrocytes, in cooperation with the striosomes of the striatum, exert a facilitative role in state transitions by modulating dopamine signals in the striato-nigro-striatal loop. We will ask whether astrocyte activity causally affects learning, state transitions of behavior, from engagement to non-engagement, from strategy shifting to judging cost-benefit options, and whether astrocytes track changes associated with striatal dopamine release and activities of striatal projection neurons in millisecond and second timescales. We propose here to seek the possible role of striatal astrocytes in transitions of behavioral states via modulation of the dopamine signals transmitted along the striato-nigro-striatal loops. The striatum is one of the core brain regions to implement reinforcement learning and make transitions from an exploratory/learning phase to an exploitation/habitual phase of behavior. The striosomes, which are neurochemically specialized striatal compartments, have been shown to be specifically involved in the development of habitual behavior and recently in switches between unengaged and engaged states of behavior. This then poses the question “how can striosomes make a transition in a behavioral state?”. We will also approach the issues of whether these astrocytic modulations are exerted locally in the striatum as well as, our main focus, through the striato-nigro-striatal loop, by modulating activities of strioSPNs and dopamine-containing neurons in SNpc. We will, for this work, combine many advanced state-of-the-art methods including optogenetics, chemogenetics, intersectional viral and transgenic mouse line approaches, novel enhancer-based cell-targeting methods combined with photometric imaging and the use of chemosensors for registering dopamine release. This work is novel and at the front edge of new concepts of neuromodulatory mechanisms in controlling cognitive processing in the brain. Thus, the proposed work is crucial for and aligns with the goals outlined in the Notice of Special Interest (NIMH) regarding neuro-glial interactions by directly addressing profound issues about key dopamine-related astrocyte involvement in functions affected by mental health disorders.
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