The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a “hit-and-run” adeno-associated virus–assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.

The ventral striatum, also called nucleus accumbens (NAc), has long been known to integrate information from cortical, thalamic, midbrain and limbic nuclei to mediate goal-directed behaviors. Until recently thalamic afferents have been overlooked when studying the functions and connectivity of the NAc. However, findings from recent studies have shed light on the importance and roles of precise Thalamus to NAc connections in motivated behaviors and in addiction. In this review, we summarize studies using techniques such as chemo- and optogenetics, electrophysiology and in vivo calcium imaging to elucidate the complex functioning of the thalamo-NAc afferents, with a particular highlight on the projections from the Paraventricular Thalamus (PVT) to the NAc. We will focus on the recent advances in the understanding of the roles of these neuronal connections in motivated behaviors, with a special emphasis on their implications in addiction, from cue-reward association to the mechanisms driving relapse.

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

The specific role of the striatum, especially its dorsolateral (DLS) and dorsomedial (DMS) parts, in male copulatory behavior is still debated. In order to clarify their contribution to male sexual behavior, we specifically ablated the major striatal neuronal subpopulations, direct and indirect medium spiny neurons (dMSNs and iMSNs) in DMS or DLS, and dMSNs, iMSNs and cholinergic interneurons in nucleus accumbens (NAc), The main results of this study can be summarized as follows: In DMS, dMSN ablation causes a reduction in the percent of mice that mount a receptive female, and a complex alteration in the parameters of the copulatory performance, that is largely opposite to the alterations induced by iMSN ablation. In DLS, dMSN ablation causes a widespread alteration in the copulatory behavior parameters, that tends to disappear at repetition of the test; iMSN ablation induces minor copulatory behavior alterations that are complementary to those observed after dMSN ablation. In NAc, dMSN ablation causes a marked reduction in the percent of mice that mount a receptive female and a disruption of copulatory behavior, while iMSN ablation induces minor copulatory behavior alterations that are opposite to those observed with dMSN ablation, and cholinergic neuron ablation induces a selective decrease in mount latency.

Background: Deficient social interactions are a hallmark of major neuropsychiatric disorders, and cumulating evidence point to altered social reward and motivation as key underlying mechanisms in these pathologies. In the present study, we aimed at assessing the role of the two striatal projecting neuronal (SPN) populations bearing either D1R or D2R dopamine receptors (D1R- and D2R-SPNs), in modulating social behavior and other behaviors often altered in neuropsychiatric disorders. Methods: We selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the Nucleus Accumbens (NAc) and pharmacological compounds repressing D2R-SPN. Results: Targeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated skill motor learning and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum (VP). In contrast, ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior, impaired motor skill learning, and decreased anxiety levels. Deletion of D2R-SPNs in the NAc also produced motor stereotypies but facilitated social behavior and impaired skill motor learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and evidenced a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. Conclusions: Repressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficit in neuropsychiatric disorders.