In the basal ganglia, focused rhythmicity is an important feature of network activity at certain stages of motor processing. In disease, however, the basal ganglia develop amplified rhythmicity. Here, we demonstrate how the cellular architecture and network dynamics of an inhibitory loop in the basal ganglia yield exaggerated synchrony and locking to ␤ oscillations, specifically in the dopamine-depleted state. A key component of this loop is the pallidostriatal pathway, a well-characterized anatomical projection whose function has long remained obscure. We present a synaptic characterization of this pathway in mice and incorporate these data into a computational model that we use to investigate its influence over striatal activity under simulated healthy and dopamine-depleted conditions. Our model predicts that the pallidostriatal pathway influences striatal output preferentially during periods of synchronized activity within GPe. We show that, under dopamine-depleted conditions, this effect becomes a key component of a positive feedback loop between the GPe and striatum that promotes synchronization and rhythmicity. Our results generate novel predictions about the role of the pallidostriatal pathway in shaping basal ganglia activity in health and disease.

The identification of distinct cell-types within the basal ganglia has played a critical role in our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has remained an untapped resource for therapeutic interventions. Here, we demonstrate that optogenetic interventions that dissociate the activity of two neuronal populations in the GPe – elevating the activity of PV-GPe neurons over that of Lhx6-GPe neurons – restores movement in dopamine depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine.

The ability to precisely monitor and manipulate neural circuits is essential to understand the brain. Advancements over the last decade in optical techniques such as calcium imaging and optogenetics have empowered researchers to gain insight into brain function by systematically manipulating or monitoring defined neural circuits. Combining these cutting-edge techniques enables a more direct mechanism for ascribing neural dynamics to behavior. Here, we developed a miniaturized integrated microscope that allows for simultaneous optogenetic manipulation and cellular-resolution calcium imaging within the same field of view in freely behaving mice. The integrated microscope has two LEDs, one filtered with a 435–460 nm excitation filter for imaging green calcium indicators, and a second LED filtered with a 590–650 nm excitation filter for optogenetic modulation of red-shifted opsins. We developed and tested this technology to minimize biological and optical crosstalk. We observed insignificant amounts of biological and optical crosstalk with regards to the optogenetic LED affecting calcium imaging. We observed some amounts of residual crosstalk of the imaging light on optogenetic manipulation. Despite residual crosstalk, we have demonstrated the utility of this technology by probing the causal relationship between basolateral amygdala (BLA) -to- nucleus accumbens (NAc) circuit function, behavior, and network dynamics. Using this integrated microscope we were able to observe both a significant behavioral and cellular calcium response of the optogenetic modulation on the BLA-to-NAc circuit. This integrated strategy will allow for routine investigation of the causality of circuit manipulation on cellular-resolution network dynamics and behavior.

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