Social trauma engages lateral septum circuitry to occlude social reward.

In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement.

Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio-economic burden. Both nicotine and alcohol perturb the brain's mesocorticolimbic system. Dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to multiple downstream structures, including the nucleus accumbens, prefrontal cortex, and amygdala, are highly involved in the maintenance of healthy brain function. VTA DA neurons play a crucial role in associative learning and reinforcement. Nicotine and alcohol usurp these functions, promoting reinforcement of drug taking behaviors. In this review, we will first describe how nicotine and alcohol individually affect VTA DA neurons by examining how drug exposure alters the heterogeneous VTA microcircuit and network-wide projections. We will also examine how coadministration or previous exposure to nicotine or alcohol may augment the reinforcing effects of the other. Additionally, this review briefly summarizes the role of VTA DA neurons in nicotine, alcohol, and their synergistic effects in reinforcement and also addresses the remaining questions related to the circuit-function specificity of the dopaminergic system in mediating nicotine/alcohol reinforcement and comorbidity.

Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny.

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically gene x chronic stress -here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J. Utilizing the chronic social defeat stress (CSDS) and chronic variable stress (CVS) paradigms, we first showed sexual dimorphism in the behavioral stress response between the mouse strains. Further, we observed an interaction between genetic background and vulnerability to prolonged exposure to non-social stressors. Finally, we found that DBA/2J and C57BL/6J mice pre-exposed to stress displayed differences in morphine sensitivity. Our results support the hypothesis that genetic variation in predisposition to stress responses influences morphine sensitivity and is likely to modulate the development of drug addiction.

Mesolimbic Neural Response Dynamics Predict Future Individual Alcohol Drinking in Mice.

BACKGROUND: Individual variability in response to rewarding stimuli is a striking but understudied phenomenon. The mesolimbic dopamine system is critical in encoding the reinforcing properties of both natural reward and alcohol; however, how innate or baseline differences in the response dynamics of this circuit define individual behavior and shape future vulnerability to alcohol remain unknown. METHODS: Using naturalistic behavioral assays, a voluntary alcohol drinking paradigm, in vivo fiber photometry, in vivo electrophysiology, and chemogenetics, we investigated how differences in mesolimbic neural circuit activity contribute to the individual variability seen in reward processing and, by proxy, alcohol drinking. RESULTS: We first characterized heterogeneous behavioral and neural responses to natural reward and defined how these baseline responses predicted future individual alcohol-drinking phenotypes in male mice. We then determined spontaneous ventral tegmental area dopamine neuron firing profiles associated with responses to natural reward that predicted alcohol drinking. Using a dual chemogenetic approach, we mimicked specific mesolimbic dopamine neuron firing activity before or during voluntary alcohol drinking to link unique neurophysiological profiles to individual phenotype. We show that hyperdopaminergic individuals exhibit a lower neuronal response to both natural reward and alcohol that predicts lower levels of alcohol consumption in the future. CONCLUSIONS: These findings reveal unique, circuit-specific neural signatures that predict future individual vulnerability or resistance to alcohol and expand the current knowledge base on how some individuals are able to titrate their alcohol consumption whereas others go on to engage in unhealthy alcohol-drinking behaviors.

HCN channel inhibitor induces ketamine-like rapid and sustained antidepressant effects in chronic social defeat stress model.

Repeated, long-term (weeks to months) exposure to standard antidepressant medications is required to achieve treatment efficacy. In contrast, acute ketamine quickly improves mood for an extended time. Recent work implicates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in mediating ketamine's antidepressant effects. In this study, we directly targeted HCN channels and achieved ketamine-like rapid and sustained antidepressant efficacy. Our in vitro electrophysiological recordings first showed that HCN inhibitor DK-AH 269 (also called cilobradine) decreased the pathological HCN-mediated current (Ih) and abnormal hyperactivity of ventral tegmental area (VTA) dopamine (DA) neurons in a depressive-like model produced by chronic social defeat stress (CSDS). Our in vivo studies further showed that acute intra-VTA or acute systemic administration of DK-AH 269 normalized social behavior and rescued sucrose preference in CSDS-susceptible mice. The single-dose of DK-AH 269, both by intra-VTA microinfusion and intraperitoneal (ip) approaches, could produce an extended 13-day duration of antidepressant-like efficacy. Animals treated with acute DK-AH 269 spent less time immobile than vehicle-treated mice during forced swim test. A social behavioral reversal lasted up to 13 days following the acute DK-AH 269 ip injection, and this rapid and sustained antidepressant-like response is paralleled with a single-dose treatment of ketamine. This study provides a novel ion channel target for acutely acting, long-lasting antidepressant-like effects.

Dopaminoceptive D1 and D2 neurons in ventral hippocampus arbitrate approach and avoidance in anxiety.

The hippocampus 1-7, as well as dopamine circuits 8-11, coordinate decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally-salient stimuli to inform appropriate resolution of approach versus avoidance conflicts. We here study dopaminoceptive neurons in mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioral selection. In turn, they mediate opposite approach/avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviors under contextual uncertainty, implicating dopaminoception in the complex computation engaged in vHipp to govern emotional states.

Chemokine receptor 5 signaling in PFC mediates stress susceptibility in female mice.

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors.

Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice.

Different adaptations of dopamine release in Nucleus Accumbens shell and core of individual alcohol drinking groups of mice.

Alcohol use disorder (AUD) places a tremendous burden on society, with approximately two billion alcohol users in the world. While most people drink alcohol recreationally, a subpopulation (3-5%) engages in reckless and compulsive drinking, leading to the development of AUD and alcohol dependence. The Ventral Tegmental Area (VTA)-Nucleus Accumbens (NAc) circuit has been shown to encode rewarding stimuli and drive individual alcohol drinking behavior. Our previous work successfully separated C57BL/6J isogenic mice into high or low alcohol drinking subgroups after a 12-day, two-bottle choice voluntary alcohol access paradigm. Electrophysiological studies revealed that low alcohol drinking mice exhibited elevated spontaneous and burst firing properties of their VTA dopamine (DA) neurons and specifically mimicking this pattern of activity in VTA-NAc neurons in high alcohol drinking mice using optogenetics decreased their alcohol preference. It is also known that VTA DA neurons encode the salience and rewarding properties of external stimuli while also regulating downstream dopamine concentrations. Here, as a follow-up to this study, we utilized Fast Scan Cyclic Voltammetry (FSCV) to examine dopamine release in the NAc shell and core between alcohol drinking groups. We observed dynamic changes of dopamine release in the core of high drinking mice, but failed to see widely significant differences of dopamine release in the shell of both groups, when compared with ethanol-naive controls. Overall, the present data suggest subregion-specific differences of evoked dopamine release in the NAc of low and high alcohol drinking mice, and may provide an anatomical substrate for individual alcohol drinking behavior. This article is part of the special issue on Stress, Addiction and Plasticity.

α1- and ß3-Adrenergic Receptor-Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice.

BACKGROUND: Homeostatic plasticity in mesolimbic dopamine (DA) neurons plays an essential role in mediating resilience to social stress. Recent evidence implicates an association between stress resilience and projections from the locus coeruleus (LC) to the ventral tegmental area (VTA) (LC→VTA) DA system. However, the precise circuitry and molecular mechanisms of the homeostatic plasticity in mesolimbic DA neurons mediated by the LC→VTA circuitry, and its role in conferring resilience to social defeat stress, have not been described. METHODS: In a well-established chronic social defeat stress model of depression, using projection-specific electrophysiological recordings and optogenetic, pharmacological, and molecular profiling techniques, we investigated the functional role and molecular basis of an LC→VTA circuit in conferring resilience to social defeat stress. RESULTS: We found that LC neurons projecting to the VTA exhibit enhanced firing activity in resilient, but not susceptible, mice. Optogenetically mimicking this firing adaptation in susceptible mice reverses their depression-related behaviors, and induces reversal of cellular hyperactivity and homeostatic plasticity in VTA DA neurons projecting to the nucleus accumbens. Circuit-specific molecular profiling studies reveal that α1- and ß3-adrenergic receptors are highly expressed in VTA→nucleus accumbens DA neurons. Pharmacologically activating these receptors induces similar proresilient effects at the ion channel and cellular and behavioral levels, whereas antagonizing these receptors blocks the proresilient effect of optogenetic activation of LC→VTA circuit neurons in susceptible mice. CONCLUSIONS: These findings reveal a key role of the LC→VTA circuit in mediating homeostatic plasticity in stress resilience and reveal α1- and ß3-adrenergic receptors as new molecular targets for therapeutically promoting resilience.

A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats.

Tobacco addiction is a chronic and relapsing disorder with an important genetic component that represents a major public health issue. Meta-analysis of large-scale human genome-wide association studies (GWASs) identified a frequent non-synonymous SNP in the gene coding for the α5 subunit of nicotinic acetylcholine receptors (α5SNP), which significantly increases the risk for tobacco dependence and delays smoking cessation. To dissect the neuronal mechanisms underlying the vulnerability to nicotine addiction in carriers of the α5SNP, we created rats expressing this polymorphism using zinc finger nuclease technology and evaluated their behavior under the intravenous nicotine-self-administration paradigm. The electrophysiological responses of their neurons to nicotine were also evaluated. α5SNP rats self-administered more nicotine at high doses and exhibited higher nicotine-induced reinstatement of nicotine seeking than wild-type rats. Higher reinstatement was associated with altered neuronal activity in several discrete areas that are interconnected, including in the interpeduncular nucleus (IPN), a GABAergic structure that strongly expresses α5-containing nicotinic receptors. The altered reactivity of IPN neurons of α5SNP rats to nicotine was confirmed electrophysiologically. In conclusion, the α5SNP polymorphism is a major risk factor for nicotine intake at high doses and for relapse to nicotine seeking in rats, a dual effect that reflects the human condition. Our results also suggest an important role for the IPN in the higher relapse to nicotine seeking observed in α5SNP rats.

Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress.

Women are twice as likely to be diagnosed with major depressive disorder. However, fewer studies in rodent models of depression have used female animals, leading to a relative lack of understanding of the female brain's response to stress, especially at a neural circuit level. In this study, we utilized a 6-day subchronic variable stress (SCVS) mouse model and measured novelty suppressed feeding as behavioral criteria to evaluate susceptibility to SCVS in male and female mice. First, we showed that SCVS induced a decrease in latency to eat (susceptible phenotype) in female mice, but not in males (resilient phenotype). After determining behavioral phenotypes, we investigated the firing activities of dopamine (DA) neurons in the ventral tegmental area (VTA), as well as the neurons that project from lateral habenula (LHb) to the VTA and from locus coeruleus (LC) to the VTA. Utilizing retrograding lumafluor fluorescent tracers and electrophysiology techniques, we performed cell type- and circuit-specific measures of neuronal firing rates. Our data show that SCVS significantly increased the firing rate of LHb-VTA circuit neurons in female mice when compared to that of their female controls, an effect that was absent in SCVS-exposed males. Interestingly, SCVS did not induce significant firing alterations in VTA DA neurons and LC-VTA circuit neurons in either female mice or male mice when compared to their stress-naïve controls. Overall, our data show sex differences in the LHb-VTA circuit responses to SCVS, and implicates a potential role of this projection in mediating vulnerability of female mice to stress-induced depression.

Author Correction: Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article.

Nicotine enhances alcohol intake and dopaminergic responses through ß2* and ß4* nicotinic acetylcholine receptors.

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of ß4 * nAChRs, but not ß2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (ß2-/- and ß4-/- mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in ß2-/- and ß4-/- mice, suggesting that nicotine triggers ß2* and ß4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.

Dopaminergic dynamics underlying sex-specific cocaine reward.

Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.

Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.

Role of ß4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. ß4-containing (ß4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of ß4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive ß4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 µg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that ß4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of ß4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of ß4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that ß4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

A concurrent excitation and inhibition of dopaminergic subpopulations in response to nicotine.

Midbrain dopamine (DA) neurons are key players in motivation and reward processing. Increased DA release is thought to be central in the initiation of drug addiction. Whereas dopamine neurons are generally considered to be activated by drugs such as nicotine, we report here that nicotine not only induces excitation of ventral tegmental area (VTA) DA cells but also induces inhibition of a subset of VTA DA neurons that are anatomically segregated in the medial part of the VTA. These opposite responses do not correlate with the inhibition and excitation induced by noxious stimuli. We show that this inhibition requires D2 receptor (D2-R) activation, suggesting that a dopaminergic release is involved in the mechanism. Our findings suggest a principle of concurrent excitation and inhibition of VTA DA cells in response to nicotine. It promotes unexplored roles for DA release in addiction contrasting with the classical views of reinforcement and motivation, and give rise to a new interpretation of the mode of operation of the reward system.