Striato-Nigro-Striatal Circuits for Dopamine Disinhibition

Ambrosi, Priscilla

doi:https://doi.org/10.21985/n2-xbvd-kz31

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Striato-Nigro-Striatal Circuits for Dopamine Disinhibition

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The basal ganglia operate largely in closed parallel loops, including an associative circuit for goal-directed behavior originating from the dorsomedial striatum (DMS) and a somatosensory circuit important for habit formation originating from the dorsolateral striatum (DLS). An exception to this parallel circuit organization was proposed to explain how information is transferred between striatal subregions, for example from DMS to DLS during habit formation. The “ascending spiral hypothesis” proposes that DMS disinhibits dopamine signaling in DLS through an open loop involving substantia nigra pars reticulata (SNr) and compacta (SNc). Specifically, this hypothesis predicts the existence of a tri-synaptic striato-nigro-striatal circuit, DMS→SNr→SNc→DLS. Despite deeply influencing the habit and addiction literature, this hypothesis rests on weak anatomical evidence and lacks functional support. I tested the ascending spiral hypothesis using electrophysiology, optogenetics, and new tools available for circuit interrogation in mice. Using transsynaptic and intersectional genetic tools, I labeled SNr and SNc cells based on their inputs and outputs, respectively. Together, these tools allowed me to investigate both closed- and open-loop striato-nigro-striatal circuits ex vivo. I found strong evidence for closed loops (e.g., DLS→SNr→SNc→DLS), which would allow striatal subregions to self-regulate their dopamine signaling. I also found evidence for functional synapses in open loops, including a descending spiral (DLS→SNr→SNc→DMS). However, the synapses in open loops were unable to modulate dopamine neuron firing, questioning their ability to mediate crosstalk between striatal subregions through disinhibition of dopamine neurons. These findings challenge key predictions from the ascending spiral hypothesis and call for alternative mechanisms of habit formation.

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