Claire Naon

Midbrain dopamine (DA)‐neurons are slow pacemakers that continuously fire action potentials, maintaining basal extracellular DA levels in target regions. The sodium leak channel NALCN has been identified as a key contributor in the pacemaker control of these neurons. However, the consequences of a disrupted DA pacemaker activity remain largely unexplored. By generating mice lacking NALCN selectively in midbrain DA‐neurons, we investigated the impact of this deletion on the activity of ventral tegmental area DA‐neurons, D2R‐mediated signalling, reactivity to cues predicting threat and psychostimulant responsiveness in both males and females. Selective deletion of NALCN in midbrain DA‐neurons dampens their tonic activity, without reducing the basal extracellular DA levels in the nucleus accumbens. Mice with a loss of NALCN in DA‐neurons exhibit no impairments of basal motor responses, unaltered reactivity to cues predicting threat and risk assessment, while the neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced and presynaptic D2R‐mediated signalling at DA terminals is altered. Together, our results emphasize the important role of NALCN conductance in controlling DA pacemaker activity, D2R‐mediated signalling and in modulating motor responses to psychostimulants. image Key points: The sodium leak channel NALCN is an important contributor to the spontaneous pacemaker activity in dopamine neurons, but the consequences of its loss in these neurons remain largely unknown. We investigated how selective deletion of NALCN in dopamine neurons affects neuronal activity, dopamine receptor signalling and behavioural responses in male and female mice. Loss of NALCN markedly reduced the spontaneous activity of dopamine neurons, yet basal motor function, reward‐related responses and reactivity to threat‐predicting cues remained largely preserved. In contrast, neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced, probably through an altered presynaptic D2R‐mediated signalling at DA terminals. NALCN emerges as a key regulator of dopamine neuron activity, with disrupted pacemaker firing selectively enhancing psychostimulant sensitivity.

Isolated dystonia can be caused by loss-of-function mutations in the GNAL gene (DYT-GNAL). This gene encodes the α _olf heterotrimeric G protein subunit, which, together with β ₂ γ ₇ subunits, mediates the stimulatory coupling of dopamine D1 and adenosine A2A receptors to adenylyl-cyclase. These receptors are expressed in distinct striatal projection neurons (SPNs) with complementary functions on motor behavior. To dissect the specific roles of Gα _olf in each subpopulation of SPNs, we generated and characterized mouse models in which Gnal was conditionally deleted in neurons expressing either D1 receptors (D1-SPNs) or A2A receptors (A2A-SPNs). Our results confirmed the critical role of Gα _olf in regulating adenylyl-cyclase 5 and its coupling with D1 and A2A receptors. Mice with a selective loss of Gα _olf in D1-SPNs showed nocturnal hyperactivity, deficits in motor performances, but no overt abnormal movements or generalized motor disability. Our experiments also revealed that Gα _olf in D1-SPNs is not systematically required for locomotor responses induced by D1 agonists or psychostimulants. Selective loss of Gα _olf in A2A-SPNs did not affect motor abilities nor learning. However, this loss strikingly increased spontaneous locomotor activity that was not further enhanced by psychostimulant drugs (cocaine, D-amphetamine, methylphenidate) or a selective A2 agonist, KW6002, and was paradoxically reduced by caffeine Our study identified specific roles of Gα _olf downstream of D1 and A2A receptors in the control of motor behavior and drug responses, highlighting their respective individual contribution in diseases associated with dysfunctional striatal signaling, including dystonia.

Parvalbumin (PV) interneurons in the dorsal striatum (DS) are fast-spiking GABAergic cells critical for feedforward inhibition and synaptic integration within basal ganglia circuits. Despite their well-characterized electrophysiological roles, their molecular identity remains incompletely defined. Using the Ribotag approach in Pvalb-Cre mice, we profiled the translatome of DS PV interneurons and identified over 2,700 transcripts significantly enriched (fold-change > 1.5) in this population. Our data validate established PV markers and reveal a distinct molecular signature of DS PV neurons compared to PV interneurons from the nucleus accumbens. Gene ontology analyses highlight prominent expression of genes related to extracellular matrix components, cell adhesion molecules, synaptic organization, ion channels, and neurotransmitter receptors, particularly those mediating glutamatergic and GABAergic signaling. Notably, perineuronal net markers were robustly expressed in DS PV interneurons and confirmed by immunofluorescence. Transcriptomic analysis of DS PV neurons following repeated d-amphetamine exposure identified Gm20683 as the only differentially expressed transcript between treated groups. Furthermore, RNAseq analysis of mice subjected to an operant behavior paradigm with two types of food reward (high-palatable diet or standard chow) identified over 1,000 and 100 genes enriched in DS PV neurons from standard and high-palatable masters, respectively. These findings provide a comprehensive molecular profile of DS PV interneurons, distinguishing them from other striatal PV populations, and reveal specific gene expression changes associated with psychostimulant exposure and reward-driven behaviors. Our findings deepen insight into the molecular mechanisms of PV interneuron activity in striatal circuits and their potential roles in neuropsychiatric, motor and reward-related disorders.

Summary: Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine (DA)-neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors (autoD2Rs), but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli. Using Drd2 ^Slc6a3 mice, in which Drd2 is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake. Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally, Drd2 ^Slc6a3 male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing. Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing.