Probes for INS

Stress-linked disorders are more prevalent in women than in men and differ in their clinical presentation. Thus, investigating sex differences in factors that promote susceptibility or resilience to stress outcomes, and the circuit elements that mediate their effects, is important. In male rats, instrumental control over stressors engages a corticostriatal system involving the prelimbic cortex (PL) and dorsomedial striatum (DMS) that prevent many of the sequelae of stress exposure. Interestingly, control does not buffer against stress outcomes in females, and here, we provide evidence that the instrumental controlling response in females is supported instead by the dorsolateral striatum (DLS). Additionally, we used in vivo microdialysis, fluorescent in situ hybridization, and receptor subtype pharmacology to examine the contribution of prefrontal dopamine (DA) to the differential impact of behavioral control. Although both sexes preferentially expressed D1 receptor mRNA in PL GABAergic neurons, there were robust sex differences in the dynamic properties of prefrontal DA during controllable stress. Behavioral control potently attenuated stress-induced DA efflux in males, but not females, who showed a sustained DA increase throughout the entire stress session. Importantly, PL D1 receptor blockade (SCH 23390) shifted the proportion of striatal activity from the DLS to the DMS in females and produced the protective effects of behavioral control. These findings suggest a sex-selective mechanism in which elevated DA in the PL biases instrumental responding towards prefrontal-independent striatal circuitry, thereby eliminating the protective impact of coping with stress.

The nucleus accumbens (NAc) is critical in mediating reward seeking and is also involved in negative emotion processing, but the cellular and circuitry mechanisms underlying such opposing behaviors remain elusive. Here, using the recently developed AAV1-mediated anterograde transsynaptic tagging technique in mice, we show that NAc neurons receiving basolateral amygdala inputs (NAcBLA) promote positive reinforcement via disinhibiting dopamine neurons in the ventral tegmental area (VTA). In contrast, NAc neurons receiving paraventricular thalamic inputs (NAcPVT) innervate GABAergic neurons in the lateral hypothalamus (LH) and mediate aversion. Silencing the synaptic output of NAcBLA neurons impairs reward seeking behavior, while silencing of NAcPVT or NAcPVT→LH pathway abolishes aversive symptoms of opiate withdrawal. Our results elucidate the afferent-specific circuit architecture of the NAc in controlling reward and aversion.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre-existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.