Unexpected contributions of striatal projection neurons coexpressing dopamine D1 and D2 receptors in balancing motor control

Abstract

The central function of the striatum and its dopaminergic (DA) afference in motor control and integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptor- and D2 receptor (D1-SPNs and D2-SPNs), respectively, regardless of SPNs co-expressing these two receptors (D1/D2-SPNs). Here, after developing an approach that enables to target these hybrid SPNs, we demonstrated that, although these SPNs are rare, they play a major role in guiding the motor function of the other two main populations and convey a DA-mediated antagonistic motor brake. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 co-expressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops.One-Sentence SummaryD1/D2 striatal output promotes dopamine-induced motor inhibition

Integrative multi-dimensional characterization of striatal projection neuron heterogeneity in adult brain

“…Consistent with this, recent work found evidence of SPNs that co-express both receptors [23][24][25][26] . Yet, it remains unclear whether these co-expressing SPNs exhibit striatal distribution patterns distinct from those of SPNs that solely express single DA receptors.…”

“…In the context of drugs of abuse like cocaine and opioids, responses in D1R + and D2R + SPNs are heterogeneous, raising the possibility of unique subpopulations of striatal cells 22,81 . Indeed, SPNs that express multiple DA receptor subtypes are increasingly implicated in a variety of contexts, including reward-learning, decision-making, and goal-directed movement 22,82,83 .…”

Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons

“…Our data show that there are spontaneous calcium oscillations and spontaneous action potentials generated by a fraction of SPNs, an observation that applies to all four types of SPNs we were analyzing (strisosmal dSPNs, strisomal iSPNs, matrix dSPNs, matrix iSPNs). It should be noted that striatum contains a fraction of SPNs, co-expressing D1 receptor and D2 receptor (Bonnavion et al, 2023). D1R/D2R co-expressing cells accounted for 6-7% of all cells, and in our experiments, we will see these cells as dSPNs.…”

Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

“…Considering the dichotomic effect of D1-and D2-MSN manipulations on energy intake and activity-related energy expenditure, we then tested whether the concomitant manipulation of both neuronal subpopulations would potentiate the aforementioned effects, eventually leading to bidirectional disruption of the balance between food intake and activity-induced energy expenditure. We took advantage of a unique mouse model expressing the flippase recombinase in D1-expressing neurons (Bonnavion et al, 2022) and crossed this mouse line with the D2-cre line, thereby allowing the concomitant manipulation of both NAc MSN subpopulations (Figure 6A). Simultaneous activation of D1-MSNs together with inhibition of D2-MSNs strongly increased wheel running.…”