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Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement 1 . Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement 2 , 3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs 4 . Among the opioid receptors, µ-opioid receptors have a key role 5 , yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation. Experiments using fentanyl treatment of mice show that µ-opioid receptors mediate positive reinforcement in the ventral tegmental area and negative reinforcement in central amygdala, thereby identifying the circuits that lead to opioid addiction.

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch–clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

Major depressive disorder is associated with both structural and functional alterations in the emotion regulation network of the central nervous system. The relation between structural and functional changes is largely unknown. Therefore, we sought to determine the relation between structural differences and functional alterations during the recognition of emotional facial expressions. We examined 13 medication-free patients with major depression and 15 healthy controls by use of structural T1-weighted high-resolution magnetic resonance imaging (MRI) and functional MRI during 1 session. We set the statistical threshold for the analysis of imaging data to p < 0.001 (uncorrected). As shown by voxel-based morphometry, depressed patients had reductions in orbitofrontal cortex volume and increases in cerebellar volume. Additionally, depressed patients showed increased activity during emotion recognition in the middle frontal cortex, caudate nucleus, precuneus and lingual gyrus. Within this cerebral network, the orbitofrontal volumes were negatively correlated in depressed patients but not in healthy controls with changes in blood oxygen level–dependent signal in the middle frontal gyrus, caudate nucleus, precuneus and supplementary motor area. Our results are limited by the relatively small sample size. This combined functional and structural MRI study provides evidence that the orbitofrontal cortex is a key area in major depression and that structural changes result in functional alterations within the emotional circuit. Whether these alterations in the orbitofrontal cortex are also related to persistent emotional dysfunction in remitted mental states and, therefore, are related to the risk of depression needs further exploration.