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In mammals, the ability to optimize and select behavioral strategies is a cardinal and conserved psychophysiological feature for maximizing the chances of survival. However, the neural circuits and underlying mechanisms regulating this flexible feature remain yet unsolved. Here, we demonstrate that such optimization relies on dopamine D2 receptors (D2R) within a subcircuit spanning across the extended amygdala (EA) and the tail of the striatum (TS). Using a mouse model carrying a temporally controlled deletion of D2R within a subcircuit defined by WFS1 neurons, we found that intact EA D2R signaling is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice as well as active avoidance learning and innate escape responses in males. Altogether, these findings identify EA and TS D2R signaling as a novel hub through which dopamine optimizes appetitive behaviors and regulates the switch from passive to active defensive behaviors, regardless of learned or innate threats.

International audience; Psychostimulant drugs, such as cocaine, d-amphetamine and methylphenidate, alter a wide range of behaviors including locomotor activity and somatosensory perception. These altered behaviors are accompanied by the activation of specific neuronal populations within reward-, emotion- and locomotion-related circuits. However, whether such regulation occurs at the level of the spinal cord, a key node for neural circuits integrating and coordinating sensory and motor functions has never been addressed. By evaluating the temporal and spatial expression pattern of the phosphorylated form of the immediate early gene cFos at Ser32 (pS32-cFos), used as a proxy of neuronal activation, we demonstrate that, in adult male mice, d-amphetamine increases pS32-cFos expression in both inhibitory and excitatory neurons in dorsal and ventral horns at the lumbar spinal cord level. Interestingly, a fraction of neurons activated by a first exposure to d-amphetamine can be re-activated following d-amphetamine re-exposure. Similar expression patterns were observed in response to cocaine and methylphenidate, but not following morphine and dozilcipine administration. Finally, the blockade of dopamine reuptake was sufficient to recapitulate the increase in pS32-cFos expression induced by psychostimulant drugs. Our work provides evidence that cFos expression can be activated in lumbar spinal cord in response to acute psychostimulants administration. Running title: Psychostimulant-evoked neuronal ensembles in spinal cord.

Upon threatening situations, animals exhibit a broad range of behavioral and autonomic responses necessary for survival. Under such conditions, a crucial adaptive response is the inhibition of pain responses that would otherwise interfere with behavioral defensive responses. Whereas the structures and mechanisms involved in fear and pain behavior are well documented, little is known about the precise neuronal mechanisms mediating the emotional regulation of endogenous pain-suppression. Here we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to show that somatostatin-expressing cells in the ventrolateral periaqueductal gray matter (SST+ vlPAG cells) control the analgesia induced by a negative emotional state. Our data indicate that the optogenetic inhibition of SST+ vlPAG cells promotes analgesia. Conversely, the optogenetic activation of long-range SST+ vlPAG cells that project to the RVM abolishes the analgesia mediated by a negative emotional state without impacting fear behavior. Together these results identify a novel brainstem circuit mechanism composed of long-range SST+ vlPAG cells projecting to the RVM that regulate analgesia elicited by negative emotional states.

Sexually dimorphic behaviours, such as parental care, have long been thought to be driven mostly, if not exclusively, by gonadal hormones. In the past two decades, a few studies have challenged this view, highlighting the direct influence of the sex chromosome complement (XX vs XY or ZZ vs ZW). The African pygmy mouse,Mus minutoides, is a wild mouse species with naturally occurring XY sex reversal induced by a third, feminizing X* chromosome, leading to three female genotypes: XX, XX* and X*Y. Here, we show that 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, we show that sex reversal may also impact the dopaminergic system in the anteroventral periventricular nucleus of the hypothalamus, consistent with one component of maternal care: pup retrieval. Combining behavioural ecology and neurobiology in a rodent subject to natural selection, we evaluate potential candidates for the neural basis of maternal behaviours and strengthen the underestimated role of the sex chromosomes in shaping sex differences in brain and behaviours. All things considered, we further highlight the emergence of a third sexual phenotype, challenging the binary view of phenotypic sexes.

In mammals, threat-related behavior is typically induced by a noxious physical stressor and is associated with a broad range of behavioral responses such as freezing and avoidance. These behavioral responses are associated with the regulation of pain responses allowing individuals to cope with noxious stimuli. Whereas the structures and mechanisms involved in pain behavior are well documented, little is known about the precise neuronal circuits mediating the emotional regulation of pain behavior. Here we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to show that somatostatin-expressing neurons in the ventrolateral periaqueductal gray matter (vlPAG SST cells) promote antinociceptive responses during the presentation of conditioned stimuli (CS) predicting footshocks. Whereas the optogenetic inhibition of vlPAG SST cells during CS presentation promoted analgesia, their optogenetic activation reduced analgesia by potentiating pain responses in the spinal cord through a relay in the rostral ventromedial medulla (RVM). Together these results identify a brainstem circuit composed of vlPAG SST cells specifically projecting to the RVM and mediating fear conditioned analgesia (FCA) to regulate pain responses during threatful situations.

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Prescription stimulants, such as d-amphetamine or methylphenidate are used to treat suffering from attention-deficit hyperactivity disorder (ADHD). They potently release dopamine (DA) and norepinephrine (NE) and cause phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the striatum. Whether other brain regions are also affected remains elusive. Here, we demonstrate that d-amphetamine and methylphenidate increase phosphorylation at Ser845 (pS845-GluA1) in the membrane fraction of mouse cerebellum homogenate. We identify Bergmann glial cells as the source of pS845-GluA1 and demonstrate a requirement for intact NE release. Consequently, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of DA D1 receptor had no effect. Together, these results indicate that NE regulates GluA1 phosphorylation in Bergmann glial cells in response to prescription stimulants., SCOPUS: ar.j, info:eu-repo/semantics/published

SummaryThe ability to efficiently switch from one defensive strategy to another maximizes an animal’s chance of survival. Here, we demonstrate that the selection of active defensive behaviors requires the coordinated activation of dopamine D2 receptor (D2R) signaling within the central extended amygdala (EA) comprising the nucleus accumbens, the oval bed nucleus stria terminals and the central amygdala. We find that discriminative learning between predictive and non-predictive threat auditory stimuli is unaltered in mice carrying a temporally-controlled deletion of D2R within output neurons of the EA. In contrast, intact EA D2R signaling is required for active avoidance learning and innate flight responses triggered by a visual threat stimulus (looming). Consequently, conditional D2R knockout mice biased defensive responses toward passive defensive strategies. Altogether, these findings identify EA D2R signaling as an important mechanism by which DA regulates the switch from passive to active defensive behaviors, regardless whether of learned or innate threat.

Forebrain dopaminoceptive neurons play a key role in movement, action selection, motivation, and working memory. Their activity is dysregulated in addiction, Parkinson’s disease and other conditions. To characterize the diverse dopamine target neuronal populations, we compare translating mRNAs in neurons of dorsal striatum and nucleus accumbens expressing D1 or D2 dopamine receptor and prefrontal cortex expressing D1 receptor. We identify D1/D2 and striatal dorso-ventral differences in the translational and splicing landscapes, which establish the characteristics of dopaminoceptive neurons. Expression differences and network analyses identify novel transcription factors with presumptive roles in these differences. Prostaglandin E2 appears as a candidate upstream regulator in the dorsal striatum, a hypothesis supported by converging functional evidence indicating its role in enhancing D2 dopamine receptor action. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns, and reveals the unforeseen role of prostaglandin E2 in the dorsal striatum.

Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.

The cerebellum, a primary brain structure involved in the control of sensorimotor tasks, also contributes to higher cognitive functions including reward, emotion and social interaction. Although the regulation of these behaviors has been largely ascribed to the monoaminergic system in limbic regions, the contribution of cerebellar dopamine signaling in the modulation of these functions remains largely unknown. By combining cell-type-specific transcriptomics, histological analyses, three-dimensional imaging and patch-clamp recordings, we demonstrate that cerebellar dopamine D2 receptors (D2Rs) in mice are preferentially expressed in Purkinje cells (PCs) and regulate synaptic efficacy onto PCs. Moreover, we found that changes in D2R levels in PCs of male mice during adulthood alter sociability and preference for social novelty without affecting motor functions. Altogether, these findings demonstrate novel roles for D2R in PC function and causally link cerebellar D2R levels of expression to social behaviors.

SummaryThe cerebellum, a primary center involved in the control of sensorimotor tasks, also contributes to higher cognitive functions including reward, emotion and social interaction. The regulation of these behaviors has been largely ascribed to the monoaminergic system in limbic regions. However, the contribution of cerebellar dopamine signaling in the modulation of these functions remains largely unknown due to the lack of precise characterization of cerebellar dopaminoceptive neurons. By combining cell type-specific transcriptomic and histological analyses, 3D imaging and electrophysiology we demonstrate that cerebellar dopamine D2 receptors (D2R) in mice are preferentially expressed in Purkinje cells (PCs). While activation of D2R regulate synaptic efficacy onto PCs, their deletion or overexpression in PCs bidirectionally controls preference for social novelty without affecting motor functions. Altogether, these findings demonstrate novel D2R’s roles in PC function and causally link cerebellar D2R levels of expression to social behaviors.

International audience; 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: 10.1111/jnc.14526. 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 > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > 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.SIGNIFICANCE STATEMENTWe examined the impact of connections from the ventral hippocampus (vHipp,) basolateral amygdala (BLA) and prefrontal cortex (PFC) onto identified medium spiny neurons (MSNs) in the adult accumbens core. We found BLA inputs were strongest at D1 MSNs while PFC inputs dominate D2 MSNs. Pathway- and cell-specific circuit control was also facilitated by endocannabinoids that endow bidirectional synaptic plasticity at identified BLA-NAc synapses. These data provide mechanistic insights on synapse and circuit specificity in the adult NAc core.

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.