Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.

The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (A‐kinase activity reporter 3) to record protein kinase A signals and by analyzing the distribution of dopamine D1R‐ and D2R‐SPNs in the TS, we characterized three subterritories: a D2R/A2aR‐lacking, a D1R/D2R‐intermingled and a D1R/D2R‐SPNs‐enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R‐ and D2R‐SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal‐regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety, or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R‐SPNs of the intermingled and D2R/A2aR‐lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d‐amphetamine, cocaine, 3,4‐methyl enedioxy methamphetamine, or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli. Cover Image for this issue: doi: . Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/

The nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here, we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult male mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA Ͼ PFC ϭ vHipp) while PFC inputs dominate D2 MSNs (PFC Ͼ vHipp Ͼ BLA). We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway-and cell-specific plasticity. Thus, whereas CB1 receptors (CB1R) uniformly depress excitatory pathways regardless of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show that the interplay of TRPV1R/CB1R shapes plasticity at BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity.

Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso-ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a prostaglandin E2 (PGE2) receptors agonist, decreased the excitability of D2 striatal projection neurons in slices and diminished their activity in vivo during novel environment exploration. We found that it also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.

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All custom-made materials will be shared upon reasonable request. Running title: ERK, dopamine and the caudal striatumKeywords: striatum, dopamine, ERK, D1R, D2R, psychostimulants ERK, dopamine and the caudal striatum 2 AbstractThe caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive.Taking advantage of genetically encoded biosensors (A-kinase activity reporter 3, AKAR3) to record PKA signals and by analyzing the distribution of dopamine D1Rand D2R-SPNs in the TS, we characterized three subterritories: a D2R/A2aR-lacking, a D1R/D2R-intermingled and a D1R/D2R-SPNs-enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R-and D2R-SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal-regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R-SPNs of the intermingled and D2R/A2aR-lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d-amphetamine, cocaine, MDMA or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli.ERK, dopamine and the caudal striatum 3

Parental care, one of the most sexually dimorphic behaviour in mammals, was long thought to be driven mostly, if not exclusively, by gonadal hormones. Over the past two decades, very few studies have challenged this view, highlighting the direct influence of the sex chromosome complement (XX vs XY). The African pygmy mouse, Mus minutoides , is a wild mouse species with a naturally occurring sex reversal due to a third, feminizing X* chromosome, leading to three female genotypes: XX, XX* and X*Y. Here, we show that the sex reversal in X*Y females shapes a divergent maternal care strategy from both XX and XX* females, rather than altering care quality. In addition, the sex reversal is likely to impact the dopaminergic system in the anteroventral periventricular nucleus of the hypothalamus, consistent with one component of maternal care: pup retrieval. Combining neurobiology and behavioural ecology in a wild mouse species subject to natural selection, we evaluate here the neural basis of maternal behaviours and strengthen the underestimated role of the sex chromosome in shaping sex differences in brain and behaviours. Furthermore, we highlight the emergence of a third sexual phenotype, challenging the binary view of sexes.

Learning causal relationships relies on understanding how often one event precedes another. To gain an understanding of how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Two cues were paired with distinct food rewards, one of which was also delivered in the absence of either cue. Conditioned approach was attenuated for the cue-reward contingency that was degraded. Dopamine neuron activity in the midbrain and dopamine release in the ventral striatum showed a profile of changes in cue- and reward-evoked responding that was not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture evoked dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.