Skara, V. | bioRxiv Science

bioRxiv2022

Sst+ GPi output neurons provide direct feedback to key nodes of the basal ganglia and drive behavioral flexibility.

The internal globus pallidus (GPi) is a basal ganglia output nucleus with separate projections to the thalamus and the lateral habenula (LHb). Here, we show a GPi subtype with projections to LHb (GPi-LHb), genetically defined based on glutamate/GABA co-transmission and somatostatin (Sst) expression, also projects back to key nodes in the basal ganglia: the external globus pallidus (GPe), the striatal striosomes, and dopamine neurons in the substantia nigra. We found that the Sst+ GPi population showed strong movement and direction-specific selectivity in a goal-directed choice task, but not during self-paced exploration, and did not signal prediction errors or outcome modulation. During goal-directed behavior, the Sst+ GPi activity slowly evolved with learning of correct choice actions and genetic silencing disrupted the ability to update choice behavior following a task rule reversal. In summary, we have found that Sst+ GPi neurons establish a wide feedback network in the basal ganglia and drive behavioral flexibility.

neuroscience↗

bioRxiv2022

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

How neurons in the CNS can maintain cellular identity over an entire lifespan remains largely unknown. Here we show that long-term maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2-component, Eed, in these neurons, resulted in global loss of H3K27me3, followed by a gradual activation of genes harbouring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was also lost at these PRC2-targets prior to gene activation. Neuronal survival was not compromised, instead there was a reduction in subtype specific gene expression as well as a progressive impairment of dopaminergic or serotonergic neuronal function leading to behavioural deficits characteristic of Parkinsons disease (PD) or mood disorders, respectively. Single cell analysis revealed an unexpected subtype specific vulnerability to loss of PRC2-repression in dopamine neurons of the substantia nigra, the neurons primarily affected in PD. Taken together, our study reveals that a PRC2-dependent non-permissive chromatin state is essential to maintain subtype identity and function of dopaminergic and serotonergic neurons.

neuroscience↗