We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at -opioid receptors) in NAc neurons, these findings raised the possibility that -receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the -antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at -receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar -antagonists: 5Ј-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5Ј-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the -antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the -agonist) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the -ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective -antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that -antagonists may have efficacy as antidepressants, but lack stimulant or rewardrelated effects.The neurobiology of depression is not understood. Because most antidepressants with clinical efficacy act upon monoamines [primarily norepinephrine (NE) and serotonin (5HT)], much research on depression has focused upon interactions between these neurotransmitters and their reuptake transporters and receptor proteins. However, recent research has become progressively focused upon the intracellular mechanisms of depression and antidepressant treatments (Manji et al., 2001;Duman, 2002;Nestler et al., 2002), with the goal of developing novel therapeutics that act faster, are more efficacious, and have fewer side effects. This approach has led to the study of brain circuits typically associated with reward-related processes, including the mesolimbic dopamine (DA) system Newton et al., 2002).The mesolimbic DA system projects from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc) of the basal forebrain, and is modulated directly and indirectly by noradrenergic and serotonergic inputs (Pasquier et al., 1977). This circuitry contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (Carlezon and Wise, 1996b;Kreek and Koob, 1998;Wise, 1998...

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

A single nucleotide polymorphism (SNP) in the human -opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to addiction and analgesia phenotypes, we derived a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. Mice harboring this SNP (A112G) demonstrated several phenotypic similarities to humans carrying the A118G SNP, including reduced mRNA expression and morphine-mediated antinociception. We found additional phenotypes associated with this SNP including significant reductions of receptor protein levels, morphine-mediated hyperactivity, and the development of locomotor sensitization in mice harboring the G112 allele. In addition, we found sex-specific reductions in the rewarding properties of morphine and the aversive components of naloxone-precipitated morphine withdrawal. Further cross-species analysis will allow us to investigate mechanisms and adaptations present in humans carrying this SNP.analgesia ͉ morphine ͉ -opioid receptor ͉ sex differences ͉ SNP M OPR (-opioid receptors) are integrally involved in the modulation of several pathways including pain, stress, and drug reward. Genetic mutations of the MOPR alter endogenous and exogenous opioidergic function, thus influencing behavior. A single nucleotide polymorphism (SNP) in exon 1 of the -opioid receptor gene (OPRM1), in which an adenine-toguanine substitution (A118G) exchanges an asparagine for an aspartic acid at a putative N-glycosylation site (N40D), is common in persons of European (15Ϫ30%) and Asian ancestry (49-60%), with lower prevalence in African American and Hispanic populations (1-3). The A118G SNP has been associated with an altered vulnerability to opioid addiction (4-6), a decreased response to opioid-induced analgesia (7,8), and an enhanced response to therapies for alcohol (9, 10) and nicotine addiction (7, 11). However, some association studies report divergent effects (12, 13), and sex-specific associations (14-16), underscoring the need to understand the functional significance of this SNP.Examination of the A118G variant in heterologous expression systems has yielded inconsistent results. Initial in vitro studies indicated that expression of the human G118 MOPR variant in AV-12 cells increases the binding affinity of ␤-endorphin to 3-fold higher than that of the human A118 MOPR and results in higher potency for activation of G protein-coupled potassium channels (17), suggesting a gain of function of the receptor. However, other studies report no differences in agonist binding, functional coupling, or desensitization (18). Using an allelic expression assay, Zhang and colleagues (19) found a 1.5-fold reduction in allele-specific mRNA expression in postmortem brain tissue and also a 10-fold reduction in protein levels in CHO cells expressi...

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Summary Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.

Summary Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social-defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions.

Endogenous opioids acting at μ-opioid receptors mediate many biological functions. Pharmacological intervention at these receptors has greatly aided in the treatment of acute and chronic pain, in addition to other uses. However, the development of tolerance and dependence has made it difficult to adequately prescribe these therapeutics. A common single nucleotide polymorphism (SNP), A118G, in the μ-opioid receptor gene can affect opioid function and, consequently, has been suggested to contribute to individual variability in pain management and drug addiction. Investigation into the role of A118G in human disease and treatment response has generated a large number of association studies across various disease states as well as physiological responses. However, characterizing the functional consequences of this SNP and establishing if it causes or contributes to disease phenotypes have been significant challenges. In this manuscript, we will review a number of association studies as well as investigations of the functional impact of this gene variant. In addition, we will describe a novel mouse model that was generated to recapitulate this SNP in mice. Evaluation of models that incorporate known human genetic variants into a tractable system, like the mouse, will facilitate the understanding of discrete contributions of SNPs to human disease.

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