Myelin plasticity in the ventral tegmental area is required for opioid reward.

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.

Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens.

It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors.

Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement.

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (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 drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, 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.

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types.

The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.

Maintaining body temperature is calorically expensive for endothermic animals1. Mammals eat more in the cold to compensate for energy expenditure2, but the neural mechanism underlying this coupling is not well understood. Through behavioural and metabolic analyses, we found that mice dynamically switch between energy-conservation and food-seeking states in the cold, the latter of which are primarily driven by energy expenditure rather than the sensation of cold. To identify the neural mechanisms underlying cold-induced food seeking, we used whole-brain c-Fos mapping and found that the xiphoid (Xi), a small nucleus in the midline thalamus, was selectively activated by prolonged cold associated with elevated energy expenditure but not with acute cold exposure. In vivo calcium imaging showed that Xi activity correlates with food-seeking episodes under cold conditions. Using activity-dependent viral strategies, we found that optogenetic and chemogenetic stimulation of cold-activated Xi neurons selectively recapitulated food seeking under cold conditions whereas their inhibition suppressed it. Mechanistically, Xi encodes a context-dependent valence switch that promotes food-seeking behaviours under cold but not warm conditions. Furthermore, these behaviours are mediated by a Xi-to-nucleus accumbens projection. Our results establish Xi as a key region in the control of cold-induced feeding, which is an important mechanism in the maintenance of energy homeostasis in endothermic animals.

Threat and Bidirectional Valence Signaling in the Nucleus Accumbens Core.

Appropriate responding to threat and reward is essential to survival. The nucleus accumbens core (NAcc) is known to support and organize reward behavior. The NAcc is also necessary to fully discriminate threat and safety cues. To directly reveal NAcc threat firing, we recorded single-unit activity from seven female rats undergoing pavlovian fear discrimination. Rats fully discriminated danger, uncertainty, and safety cues, and most NAcc neurons showed the greatest firing change to danger and uncertainty. Heterogeneity in cue and reward firing led us to identify distinct functional populations. One NAcc population signaled threat, specifically decreasing firing to danger and uncertainty cues. A separate population signaled Bidirectional Valence, decreasing firing to the danger cue (negative valence), but increasing firing to reward (positive valence). The results reveal the NAcc to be a source of threat information and a more general valence hub.SIGNIFICANCE STATEMENT The nucleus accumbens core (NAcc) is synonymous with reward. Yet, anatomy, neurotoxic lesions, and optogenetic manipulation implicate the NAcc in threat. Here, we directly revealed NAcc threat firing by recording single-unit activity during multicue fear discrimination. Most cue-responsive NAcc neurons markedly altered firing to threat cues. Finer analyses revealed a NAcc population signaling threat, specifically decreasing firing to danger and uncertainty cues; and a NAcc population signaling Bidirectional Valence, increasing firing to reward but decreasing firing to the danger cue. The results reveal the NAcc to be a source of threat information and a valence hub.

Contribution of analog signaling to neurotransmitter interactions and behavior: Role of transporter-mediated nonquantal dopamine release.

Neuronal networks cause changes in behaviorally important information processing through the vesicular release of neurotransmitters governed by the rate and timing of action potentials (APs). Herein, we provide evidence that dopamine (DA), nonquantally released from the cytoplasm, may exert similar effects in vivo. In mouse slice preparations, (+/-)-3,4-methylenedioxy-methamphetamine (MDMA, or ecstasy) and ß-phenylethylamine (ß-PEA)-induced DA release in the striatum and nucleus accumbens (NAc), two regions of the brain involved in reward-driven and social behavior and inhibited the axonal stimulation-induced release of tritiated acetylcholine ([3 H]ACh) in the striatum. The DA transporter (DAT) inhibitor (GBR-12909) prevented MDMA and ß-PEA from causing DA release. GBR-12909 could also restore some of the stimulated acetylcholine release reduced by MDMA or ß-PEA in the striatum confirming the fundamental role of DAT. In addition, hypothermia could prevent the ß-PEA-induced release in the striatum and in the NAc. Sulpiride, a D2 receptor antagonist, also prevented the inhibitory effects of MDMA or ß-PEA on stimulated ACh release, suggesting they act indirectly via binding of DA. Reflecting the neurochemical interactions in brain slices at higher system level, MDMA altered the social behavior of rats by preferentially enhancing passive social behavior. Similar to the in vitro effects, GBR-12909 treatment reversed specific elements of the MDMA-induced changes in behavior, such as passive social behavior, while left others including social play unchanged. The changes in behavior by the high level of extracellular DA-- a significant amount originating from cytoplasmic release--suggest that in addition to digital computation through synapses, the brain also uses analog communication, such as DA signaling, to mediate some elements of complex behaviors, but in a much longer time scale.

GABAB receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice.

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

dCA1-NAc shell glutamatergic projection mediates context-induced memory recall of morphine.

Opioid relapse is generally caused by the recurrence of context-induced memory reinstatement of reward. However, the internal mechanisms that facilitate and modify these processes remain unknown. One of the key regions of the reward is the nucleus accumbens (NAc) which receives glutamatergic projections from the dorsal hippocampus CA1 (dCA1). It is not yet known whether the dCA1 projection to the NAc shell regulates the context-induced memory recall of morphine. Here, we used a common model of addiction-related behavior conditioned place preference paradigm, combined with immunofluorescence, chemogenetics, optogenetics, and electrophysiology techniques to characterize the projection of the dCA1 to the NAc shell, in context-induced relapse memory to morphine. We found that glutamatergic neurons of the dCA1 and gamma aminobutyric acidergic (GABA) neurons of the NAc shell are the key brain areas and neurons involved in the context-induced reinstatement of morphine memory. The dCA1-NAc shell glutamatergic input pathway and the excitatory synaptic transmission of the dCA1-NAc shell were enhanced via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) when mice were re-exposed to environmental cues previously associated with drug intake. Furthermore, chemogenetic and optogenetic inactivation of the dCA1-NAc shell pathway decreased the recurrence of long- and short-term morphine-paired context memory in mice. These results provided evidence that the dCA1-NAc shell glutamatergic projections mediated the context-induced memory recall of morphine.

Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding.

Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

Dopamine D1 Receptor in the Nucleus Accumbens Modulates the Emergence from Propofol Anesthesia in Rat.

It has been reported that systemic activation of D1 receptors promotes emergence from isoflurane-induced unconsciousness, suggesting that the central dopaminergic system is involved in the process of recovering from general anesthesia. The nucleus accumbens (NAc) contains abundant GABAergic medium spiny neurons (MSNs) expressing the D1 receptor (D1R), which plays a key role in sleep-wake behavior. However, the role of NAc D1 receptors in the process of emergence from general anesthesia has not been identified. Here, using real-time in vivo fiber photometry, we found that neuronal activity in the NAc was markedly disinhibited during recovery from propofol anesthesia. Subsequently, microinjection of a D1R selective agonist (chloro-APB hydrobromide) into the NAc notably reduced the time to emerge from propofol anesthesia with a decrease in δ-band power and an increase in ß-band power evident in the cortical electroencephalogram. These effects were prevented by pretreatment with a D1R antagonist (SCH-23390). Whole-cell patch clamp recordings were performed to further explore the cellular mechanism underlying the modulation of D1 receptors on MSNs under propofol anesthesia. Our data primarily demonstrated that propofol increased the frequency and prolonged the decay time of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature IPSCs (mIPSCs) of MSNs expressing D1 receptors. A D1R agonist attenuated the effect of propofol on the frequency of sIPSCs and mIPSCs, and the effects of the agonist were eliminated by preapplication of SCH-23390. Collectively, these results indicate that modulation of the D1 receptor on the activity of NAc MSNs is vital for emergence from propofol-induced unconsciousness.

HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner.

Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in gene expression and synaptic plasticity following cocaine exposure, despite having no effects on cocaine-induced behaviors. In further assessing HDAC3's role within the NAc, we observed that chronic cocaine increases Hdac3 expression in Drd1 but not Drd2-cells of the NAc. Moreover, we discovered that HDAC3 acts selectively within D1R cell-types to regulate cocaine-associated memory formation and cocaine-seeking. Overall, these results suggest that cocaine induces cell-type-specific changes in epigenetic mechanisms to promote plasticity important for driving cocaine-related behaviors.SIGNIFICANCE STATEMENT Drugs of abuse alter molecular mechanisms throughout the reward circuitry that can lead to persistent drug-associated behaviors. Epigenetic regulators are critical drivers of drug-induced changes in gene expression. Here, we demonstrate that the activity of an epigenetic enzyme promotes neuroplasticity within the nucleus accumbens (NAc) critical to cocaine action. In addition, we demonstrate that these changes in epigenetic activity drive cocaine-seeking behaviors in a cell-type-specific manner. These findings are key in understanding and targeting cocaine's impact of neural circuitry and behavior.

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging.

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor-receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson's disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.

The contribution of medium spiny neuron subtypes in the nucleus accumbens core to compulsive-like ethanol drinking.

Compulsive alcohol use, or drinking that persists despite negative or aversive consequences, is a defining characteristic of alcohol use disorder. Here, chemogenetic technology (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) was used to inhibit or excite the NAc core or selectively inhibit D1-or D2 receptor-expressing neurons in the NAc core to understand the role of the NAc core and how these subpopulations of neurons may influence compulsive-like ethanol (EtOH) drinking using C57BL/6J, Drd1-cre, and Drd2-cre male and female mice. Compulsive-like EtOH drinking was modeled with a two-bottle choice, drinking in the dark paradigm. The major finding of this study was that mice decreased compulsive-like EtOH intake when the NAc core was inhibited and there was no change of EtOH + quinine intake when the NAc core was excited. Interestingly, inhibition of D1-or D2 receptor-expressing neurons did not alter compulsive-like EtOH intake. Control experiments showed that NAc core excitation and selective inhibition of D1-or D2-receptor-expressing neurons had no effect on baseline EtOH drinking, intake of water, or intake of quinine-adulterated water. CNO reduced amphetamine-induced locomotion in the D1-CRE+ (but not the D2CRE+) group in a control experiment. Finally, pharmacological antagonism of D1 and D2 receptors together, but not separately, reduced quinine-resistant EtOH drinking. These results suggest that the NAc core is a critical region involved in compulsive-like EtOH consumption, and that both D1-and D2 receptor-expressing medium spiny neurons participate in controlling this behavior.

The ethanol metabolite acetic acid activates mouse nucleus accumbens shell medium spiny neurons.

Although ethanol consumption leads to an array of neurophysiological alterations involving the neural circuits for reward, the underlying mechanisms remain unclear. Acetic acid is a major metabolite of ethanol with high bioactivity and potentially significant pharmacological importance in regulating brain function. Yet, the impact of acetic acid on reward circuit function has not been well explored. Given the rewarding properties associated with ethanol consumption, we investigated the acute effects of ethanol and/or acetic acid on the neurophysiological function of medium spiny neurons of the nucleus accumbens shell, a key node in the mammalian reward circuit. We find that acetic acid, but not ethanol, provided a rapid and robust boost in neuronal excitability at physiologically relevant concentrations, whereas both compounds enhanced glutamatergic synaptic activity. These effects were consistent across both sexes in C57BL/6J mice. Overall, our data suggest acetic acid is a promising candidate mediator for ethanol effects on mood and motivation that deserves further investigation.NEW & NOTEWORTHY Ethanol consumption disrupts many neurophysiological processes leading to alterations in behavior and physiological function. The possible involvement of acetic acid, produced via ethanol metabolism, has been insufficiently explored. Here, we demonstrate that acetic acid contributes to rapid neurophysiological alterations in the accumbens shell. These findings raise the interesting possibility that ethanol may serve as a prodrug-generating acetic acid as a metabolite-that may influence ethanol consumption-associated behaviors and physiological responses by altering neurophysiological function.

Cell-type-specific asynchronous modulation of PKA by dopamine in learning.

Reinforcement learning models postulate that neurons that release dopamine encode information about action and action outcome, and provide a teaching signal to striatal spiny projection neurons in the form of dopamine release1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron2. However, the real-time relationship between dopamine and PKA in spiny projection neurons remains untested in behaving animals. Here we monitor the activity of dopamine-releasing neurons, extracellular levels of dopamine and net PKA activity in spiny projection neurons in the nucleus accumbens of mice during learning. We find positive and negative modulation of dopamine that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in the PKA activity of spiny projection neurons. Modulations of PKA in spiny projection neurons that express type-1 and type-2 dopamine receptors are dichotomous, such that these neurons are selectively sensitive to increases and decreases, respectively, in dopamine that occur at different phases of learning. Thus, PKA-dependent pathways in each class of spiny projection neuron are asynchronously engaged by positive or negative dopamine signals during learning.

The tubular striatum and nucleus accumbens distinctly represent reward-taking and reward-seeking.

The ventral striatum regulates motivated behaviors that are essential for survival. The ventral striatum contains both the nucleus accumbens (NAc), which is well established to contribute to motivated behavior, and the adjacent tubular striatum (TuS), which is poorly understood in this context. We reasoned that these ventral striatal subregions may be uniquely specialized in their neural representation of goal-directed behavior. To test this, we simultaneously examined TuS and NAc single-unit activity as male mice engaged in a sucrose self-administration task, which included extinction and cue-induced reinstatement sessions. Although background levels of activity were comparable between regions, more TuS neurons were recruited upon reward-taking, and among recruited neurons, TuS neurons displayed greater changes in their firing during reward-taking and extinction than those in the NAc. Conversely, NAc neurons displayed greater changes in their firing during cue-reinstated reward-seeking. Interestingly, at least in the context of this behavioral paradigm, TuS neural activity predicted reward-seeking, whereas NAc activity did not. Together, by directly comparing their dynamics in several behavioral contexts, this work reveals that the NAc and TuS ventral striatum subregions distinctly represent reward-taking and reward-seeking.NEW & NOTEWORTHY The ventral striatum, considered the reward circuitry "hub," is composed of two regions: the NAc, which is well established for its role in reward processing, and the TuS, which has been largely excluded from such studies. This study provides a first step in directly contextualizing the TuS's activity in relation to that in the NAc and, by doing so, establishes a critical framework for future research seeking to better understand the brain basis for drug addiction.

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding.

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA-pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA-pPVT-NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.

Activity-Based Anorexia Dynamically Dysregulates the Glutamatergic Synapse in the Nucleus Accumbens of Female Adolescent Rats.

Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN.