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.

Synaptic modifications in nucleus accumbens (NAc) medium spiny neurons (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modification of NAc MSN synapses may occur in part via changes in the transcriptional potential of certain genes in a cell type-specific manner. The transcription factor ΔFosB is one of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. Here, we demonstrate that overexpression of ΔFosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor-expressing direct pathway MSNs in both the NAc shell and core. In contrast, ΔFosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor-expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ΔFosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. To determine the behavioral consequences of cell type-specific actions of ΔFosB, we selectively overexpressed ΔFosB in D1 direct or D2 indirect MSNs in NAc in vivo and found that direct (but not indirect) pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ΔFosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type-and subregion-specific fashion.T he nucleus accumbens (NAc) is a key substrate for integrating motivational information for the purpose of regulating goaldirected behavior. More than 90% of the cells within the NAc are medium spiny neurons (MSNs), which can be divided into two major subpopulations. Direct pathway MSNs, which predominantly express D1 dopamine receptors (D1 MSNs), project primarily to midbrain dopamine (DA) nuclei, whereas indirect pathway MSNs, which predominantly express D2 receptors (D2 MSNs), project mostly to the ventral pallidum, thereby indirectly influencing DA neurons (1, 2). The activity of NAc MSNs is driven chiefly by excitatory inputs from the prefrontal cortex, hippocampus, and amygdala. It has been suggested that pathological activity at NAc excitatory synapses induced by behavioral experiences such as exposure to drugs of abuse induces a reorganization of both transcriptional machinery and synapses on NAc MSNs, which in turn mediate long-lasting behavioral adaptations associated with addiction (1-3).Recent studies have demonstrated that D1 MSNs and D2 MSNs in the core subregion of NAc exhibit different electrophysiological and synaptic properties (4) and that the two subtypes of MSNs play distinct roles in addiction-related behavior (5). However, the molecular mechanisms underlying these differences remain poorly understood. Over the last two decades, increasing evidence has linked induction of ΔFosB, a Fos family transcription factor, ...

The bed nucleus of the stria terminalis (BNST) is a key component of the CNS stress and reward circuit. Synaptic plasticity in this region could in part underlie the persistent behavioral alterations in generalized anxiety and addiction. Group I metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction, and synaptic plasticity, but their roles in the BNST are unknown. We find that activation of group I mGluRs in the dorsal BNST induces depression of excitatory synaptic transmission through two distinct mechanisms. First, a combined activation of group I mGluRs (mGluR1 and mGluR5) induces a transient depression that is cannabinoid 1 receptor dependent. Second, as with endocannabinoid-independent group I mGluR long-term depression (LTD) in the adult hippocampus, we find that activation of mGluR5 induces an extracellular signal-regulated kinase (ERK)-dependent LTD. Surprisingly, our data demonstrate that this LTD requires the ERK1 rather than ERK2 isoform, establishing a key role for this isoform in the CNS. Finally, we find that this LTD is dramatically reduced after multiple exposures but not a single exposure to cocaine, suggesting a role for this form of plasticity in the actions of psychostimulants on anxiety and reward circuitries and their emergent control of animal behavior.

Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G q -linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero-and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G q -linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5-and α 1 -adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the α 1 -AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, α 1 -AR-but not mGluR5-dependent LTD is disrupted by restraint stress. α 1 -AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE-and glutamate-activated G q -linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.addiction | norepinephrine | metabotropic glutamate receptor | calcium-permeable AMPA receptor | ethanol A lterations in key amygdalar and reward circuitries have been proposed as potential mechanisms underlying interrelated anxiety disorders and addiction. The bed nucleus of the stria terminalis (BNST) is a nucleus within a series of structures known as the "extended amygdala," which receives a mix of glutamatergic inputs from cognitive and systemic brain centers and projects to key nuclei in both the reward and stress circuitries (1, 2). Consistent with this anatomy, a large literature indicates key roles of this region in anxiety-related behaviors, addiction, and other affective disorders (3).The BNST receives intense noradrenergic innervation through the ventral noradrenergic bundle (VNAB) (4). Disruption of the VNAB or noradrenergic signaling in the BNST alters responses to stressors, preference for opiates, and stress-induced reinstatement to drug seeking (5, 6). α 1 -Adrenergic receptors (ARs) are G qlinked G-protein-coupled receptors (GPCRs) that participate in shaping responses to stressors. Signaling through BNST α 1 -ARs within the BNST potently regulates the hypothalamic-pituitaryadrenal (HPA) stress axis and anxiety responses after stressors (7). The α 1 -AR antagonist prazosin has been shown to attenuate ethanol self-administration (SA) in ethanol-dependent rats (8) and reduces opiate SA (9). Furthermore, data from clinical trials have demonstrated that prazosin alleviates symptoms of posttraumatic stress disorder (PTSD) (10) and reduces alcohol drinking behavior in alcoholics (11).Like α 1 -ARs, group I metabotropic glutamat...

Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.