Synaptic modifications in the nucleus accumbens (NAc) play a key role in adaptive and pathological reward-dependent learning. Medium spiny neurons (MSNs), the major cell type in the NAc, participate in two parallel circuits that subserve distinct behavioral functions yet little is known about differences in their electrophysiological and synaptic properties. Here we utilize bacterial artificial chromosome (BAC) transgenic mice to show that synaptic activation of group I metabotropic glutamate receptors (mGluRs) in indirect but not direct pathway NAc MSNs lead to production of endocannabinoids, which in addition to activating presynaptic CB1 receptors to trigger endocannabinoid-mediated long-term depression (eCB-LTD), activated postsynaptic TRPV1 channels that triggered a form of LTD due to endocytosis of AMPA receptors. These results reveal a novel action of TRPV1 channels and demonstrate that the postsynaptic generation of endocannabinoids can modulate synaptic strength in a cell type specific fashion via activation of distinct pre-and postsynaptic targets.

Chronic stress is a strong diathesis for depression in humans and is used to generate animal models of depression. It commonly leads to several major symptoms of depression including dysregulated feeding behavior, anhedonia, and behavioral despair. Although hypotheses defining the neural pathophysiology of depression have been proposed, the critical synaptic adaptations in key brain circuits that mediate stress-induced depressive symptoms remain poorly understood. Here we show that chronic stress decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons due to activation of melanocortin 4 receptors (MC4Rs). Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these MC4R-mediated synaptic changes in vivo . These results establish that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.

Summary A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11+/−). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2+) and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. Electrophysiological recordings of Drd2+ MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11+/− mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11+/− mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

Real-time imaging of transplanted stem cells is essential for understanding their interactions in vivo with host environments, for tracking cell fate and function and for successful delivery and safety monitoring in the clinical setting. In this study, we used bioluminescence (BLI) and magnetic resonance imaging (MRI) to visualize the fate of grafted human embryonic stem cell (hESC)-derived human neural stem cells (hNSCs) in stroke-damaged rat brain. The hNSCs were genetically engineered with a lentiviral vector carrying a double fusion (DF) reporter gene that stably expressed enhanced green fluorescence protein (eGFP) and firefly luciferase (fLuc) reporter genes. The hNSCs were self-renewable, multipotent, and expressed markers for neural stem cells. Cell survival was tracked noninvasively by MRI and BLI for 2 months after transplantation and confirmed histologically. Electrophysiological recording from grafted GFP(+) cells and immuno-electronmicroscopy demonstrated connectivity. Grafted hNSCs differentiated into neurons, into oligodendrocytes in stroke regions undergoing remyelination and into astrocytes extending processes toward stroke-damaged vasculatures. Our data suggest that the combination of BLI and MRI modalities provides reliable real-time monitoring of cell fate.