The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain’s reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXTneurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXTaxon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXTpromotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.

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SUMMARY Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.

Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors, although to date direct evidence to support this hypothesis is lacking. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next used novel multiple feature selection tools in Fmr1 KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are uniquely enriched in parvocellular oxytocin neurons. Taken together these results provide the first evidence that oxytocin pathway specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.

NMDA glutamate receptors play key roles in brain development, function, and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal and forebrain specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors, although to date direct evidence to support this hypothesis is lacking. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next used novel multiple feature selection tools in Fmr1 KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are uniquely enriched in parvocellular oxytocin neurons. Taken together these results provide the first evidence that oxytocin pathway specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.

25Recent studies showed that in the nervous system histone methyltransferase EZH2-mediated 26 trimethylation of histone H3 lysine 27 (H3K27me3) acts to regulate neural stem cell proliferation and fate 27 specificity through silencing different gene sets. Here we explored the function of EZH2 in early post-28 mitotic excitatory neurons by generating a neuronal specific Ezh2 conditional knockout mouse line. The 29 results showed that lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic 30 arborization, and significantly increased dendritic spine density. RNA-sequencing (RNA-seq) 31 experiments comparing control and Ezh2 knockout neurons revealed that neuronal EZH2 regulated genes 32 related to neuronal morphogenesis. In particular, Pak3 was identified as a target gene suppressed by EZH2 33 and H3K27me3, and expression of dominant negative PAK3 reversed Ezh2 knockout-induced higher 34 dendritic spine density. Lastly, lack of neuronal EZH2 resulted in impaired memory behaviors in adult 35 mice. Our results demonstrated that neuronal EZH2 played important roles in controlling multiple steps 36 of neuronal morphogenesis during development, which had long-lasting effects on cognitive function in 37 adult mice. 116To study the roles of EZH2 in post-mitotic neurons, we first performed immunostaining to examine 117 the presence of EZH2 and H3K27me3. The results showed that EZH2 and SUZ12, two major components 118 of the PRC2 complex, and H3K27me3 were all clearly presented in the nuclei of post-mitotic cortical 119 neurons ( Supplementary Fig. S1a). To delete EZH2 specifically in post-mitotic neurons, we generated 120 neuronal specific conditional EZH2 knockout mice by breeding Ezh2 floxed mice (Ezh2 f/f ) with Neurod6-121 Cre mice, which express the Cre recombinase mainly in early developing post-mitotic neurons and some 122 in intermediate progenitors (Goebbels et al., 2006). Previous studies (Goebbels et al., 2006; Wu et al., 123 2005) using Cre reporter mice showed that Neurod6-Cre-mediated recombination occurs in almost all 124 excitatory pyramidal neurons in the dorsal telencephalon staring at about embryonic day 11 (E11). Thus, 125 several recent studies used this mouse line to study gene functions specifically in post-mitotic neurons 126 during development (Hirayama et al., 2012; Kazdoba et al., 2012; Morgan-Smith et al., 2014; Schwab et 127 al. , 2000). In support, immunostaining of CRE in postnatal day 0 (P0) Neurod6-Cre mouse brain sections 128 showed wide spread CRE expression in cortex and hippocampus ( Supplementary Fig. S1b). 129Although both Ezh2 and Neurod6 are located in the chromosome 6, we were able to obtain a few 130 Neurod6-Cre/Ezh2 f/+ mice, which were then bred with Ezh2 f/f mice to obtain the conditional neuronal 131 EZH2 knockout mice, Neurod6-Cre/Ezh2 f/f mice (named Ezh2 D/D mice hereafter). The CRE-mediated 132 recombination was first verified by RT-PCR showing a CRE-generated band at 254 bp (Supplementary 133 Fig. S1c), the same as shown in a previous study in wh...

Prefrontal cortex (PFC) is a site of information convergence important for behaviors relevant to psychiatric disorders. Despite the importance of inhibitory GABAergic parvalbumin-expressing (PV+) interneurons to PFC circuit function and decades of interest in N-methyl-D-aspartate receptors (NMDARs) in these neurons, examples of defined circuit functions that depend on PV+ interneuron NMDARs have been elusive. Indeed, it remains controversial whether all PV+ interneurons contain functional NMDARs in adult PFC, which has major consequences for hypotheses of the pathogenesis of psychiatric disorders. Using a combination of fluorescent in situ hybridization, pathway-specific optogenetics, cell-type-specific gene ablation, and electrophysiological recordings from PV+ interneurons, here we resolve this controversy. We found that nearly 100% of PV+ interneurons in adult medial PFC (mPFC) express transcripts encoding GluN1 and GluN2B, and they have functional NMDARs. By optogenetically stimulating corticocortical and thalamocortical inputs to mPFC, we show that synaptic NMDAR contribution to PV+ interneuron EPSCs is pathway-specific, which likely explains earlier reports of PV+ interneurons without synaptic NMDAR currents. Lastly, we report a major contribution of NMDARs in PV+ interneurons to thalamus-mediated feedforward inhibition in adult mPFC circuits, suggesting molecular and circuit-based mechanisms for cognitive impairment under conditions of reduced NMDAR function. These findings represent an important conceptual advance that has major implications for hypotheses of the pathogenesis of psychiatric disorders.