Networks of habenula-projecting cortical neurons regulate cocaine seeking
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ABSTRACT:
SUBMITTER: Mathis V
PROVIDER: S-EPMC8570600 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The lateral habenula (LHb) is a brain structure receiving inputs from limbic forebrain areas and innervating major midbrain monoaminergic nuclei. Evidence indicates LHb involvement in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in the lack of control over drug seeking. Here we examine the effects of LHb inactivation in control over drug seeking in several cocaine self-administration (SA) paradigms in rats. We find that inhibition of the LHb with GABAergic agonists did not alter cocaine SA under progressive ratio or seeking/taking chained reinforcement schedules, or during punishment-induced suppression of cocaine-reinforced responding. In contrast, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect of LHb inhibition was selective for cocaine, as it did not impair responding for sucrose reinforcement. The effect of LHb injection of GABA agonists was mimicked by intra-LHb muscarinic cholinergic (mACh) antagonist injection, and activation of mACh receptors excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction.
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Project description:Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.
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Project description:After exposure to drugs of abuse, the reward circuit can experience persistent changes that are thought to underlie relapse behavior. These changes can be epigenetic in nature, and here we identify an epigenetic regulator of memory processes, nuclear orphan receptor subfamily4 groupA member2 (NR4A2 aka NURR1), as necessary for relapse to cocaine-seeking behavior. Nr4a2 is an epigenetically regulated immediate early gene and transcription factor that is highly expressed in the medial habenula (MHb). Despite the well-studied contributions of the MHb to nicotine-associated behaviors, the MHb is not classically included in reward circuits. Therefore, the role of MHb NR4A2 in cocaine-seeking and relapse behavior remains largely unknown. This is a key open question as NR4A2 is a powerful regulator of memory processes dependent on epigenetic mechanisms. In this study, we examined the role of MHb NR4A2 in cued reinstatement of cocaine self-administration in mice, and found that over-expressing a dominant negative form of Nr4a2 (Nurr2c) in the MHb results in a near complete block of relapse-like behavior. We used single-nucleus transcriptomics to characterize the molecular cascade following the manipulation of Nr4a2, revealing changes in transcriptional networks related to addiction, neuroplasticity, and glutamatergic signaling. Together, these results place the MHb in the reward circuit as a pivotal regulator of relapse behavior and demonstrate the importance of NR4A2 as a key mechanism driving relapse behavior in the MHb.
2024-03-01 | GSE208081 | GEO
Project description:The lateral habenula (LHb) is critical for modulation of negative reinforcement, punishment and aversive responses. In light of the success of deep-brain-stimulation (DBS) in the treatment of neurological disorders, we explored the use of LHb DBS as a method of intervention in cocaine self-administration, extinction, and reinstatement in rats. An electrode was implanted into the LHb and rats were trained to self-administer cocaine (21 days; 0.25-1 mg/kg) until they achieved at least three days of stable performance (as measured by daily recordings of active lever presses in self-administration cages). Thereafter, rats received DBS in the presence or absence of cocaine. DBS reduced cocaine seeking behavior during both self-administration and extinction training. DBS also attenuated the rats' lever presses following cocaine reinstatement (5-20 mg/kg) in comparison to sham-operated rats. These results were also controlled by the assessment of physical performance as measured by water self-administration and an open field test, and by evaluation of depressive-like manifestations as measured by the swim and two-bottles-choice tests. In contrast, LHb lesioned rats demonstrated increased cocaine seeking behavior as demonstrated by a delayed extinction response. In the ventral tegmental area, cocaine self-administration elevated glutamatergic receptor subunits NR1 and GluR1 and scaffolding protein PSD95, but not GABA(A)?, protein levels. Following DBS treatment, levels of these subunits returned to control values. We postulate that the effect of both LHb modulation and LHb DBS on cocaine reinforcement may be via attenuation of the cocaine-induced increase in glutaminergic input to the VTA.
| S-EPMC2946513 | biostudies-literature
Project description:The lateral hypothalamic area (LHA) regulates feeding- and reward-related behavior, but because of its molecular and anatomical heterogeneity, the functions of defined neuronal populations are largely unclear. Glutamatergic neurons within the LHA (LHAVglut2) negatively regulate feeding and appetitive behavior. However, this population comprises transcriptionally distinct and functionally diverse neurons that project to diverse brain regions, including the lateral habenula (LHb) and ventral tegmental area (VTA). To resolve the function of distinct LHAVglut2 populations, we systematically compared projections to the LHb and VTA using viral tracing, single-cell sequencing, electrophysiology, and in vivo calcium imaging. LHAVglut2 neurons projecting to the LHb or VTA are anatomically, transcriptionally, electrophysiologically, and functionally distinct. While both populations encode appetitive and aversive stimuli, LHb projecting neurons are especially sensitive to satiety state and feeding hormones. These data illuminate the functional heterogeneity of LHAVglut2 neurons, suggesting that reward and aversion are differentially processed in divergent efferent pathways.
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Project description:Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.
2024-05-01 | GSE227980 | GEO
Project description:Pyramidal tract neurons (PTs) represent the major output cell type of the mammalian neocortex. Here, we report the origins of the PTs' ability to respond to a broad range of stimuli with onset latencies that rival or even precede those of their intracortical input neurons. We find that neurons with extensive horizontally projecting axons cluster around the deep-layer terminal fields of primary thalamocortical axons. The strategic location of these corticocortical neurons results in high convergence of thalamocortical inputs, which drive reliable sensory-evoked responses that precede those in other excitatory cell types. The resultant fast and horizontal stream of excitation provides PTs throughout the cortical area with input that acts to amplify additional inputs from thalamocortical and other intracortical populations. The fast onsets and broadly tuned characteristics of PT responses hence reflect a gating mechanism in the deep layers, which assures that sensory-evoked input can be reliably transformed into cortical output.
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Project description:Cholinergic neurons in the medial habenula (MHb) modulate anxiety during nicotine withdrawal although the molecular neuroadaptation(s) within the MHb that induce affective behaviors during nicotine cessation is largely unknown. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their behavioral role as autoreceptors in these neurons has not been described. To test the hypothesis that nAChR signaling in MHb cholinergic neurons could modulate anxiety, we expressed novel "gain of function" nAChR subunits selectively in MHb cholinergic neurons of adult mice. Mice expressing these mutant nAChRs exhibited increased anxiety-like behavior that was alleviated by blockade with a nAChR antagonist. To test the hypothesis that anxiety induced by nicotine withdrawal may be mediated by increased MHb nicotinic receptor signaling, we infused nAChR subtype selective antagonists into the MHb of nicotine naïve and withdrawn mice. While antagonists had little effect on nicotine naïve mice, blocking ?4?2 or ?6?2, but not ?3?4 nAChRs in the MHb alleviated anxiety in mice undergoing nicotine withdrawal. Consistent with behavioral results, there was increased functional expression of nAChRs containing the ?6 subunit in MHb neurons that also expressed the ?4 subunit. Together, these data indicate that MHb cholinergic neurons regulate nicotine withdrawal-induced anxiety via increased signaling through nicotinic receptors containing the ?6 subunit and point toward nAChRs in MHb cholinergic neurons as molecular targets for smoking cessation therapeutics.
| S-EPMC4982553 | biostudies-literature
Project description:Stress facilitates reinstatement of addictive drug seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTPGABA), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTPGABA. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTPGABA. Using a kappa receptor antagonist as a selective tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.
| S-EPMC3632376 | biostudies-literature
Project description:BACKGROUND:The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking. METHODS:Using neurochemical, genetic, and electrophysiological approaches, we characterized glutamatergic VP neurons (n = 4-8 mice/group). We performed patch clamp and in vivo electrophysiology recordings in the lateral habenula, rostromedial tegmental nucleus, and ventral tegmental area to determine the effect of glutamatergic VP neuron activation in these target regions (n = 6-10 mice/group). Finally, we selectively optogenetically stimulated glutamatergic VP neurons in a real-time place preference task and ablated these neurons using a virally expressed caspase to determine their necessity for reward seeking. RESULTS:Glutamatergic VP neurons exhibit little overlap with cholinergic or gamma-aminobutyric acidergic markers, the canonical VP subtypes, and exhibit distinct membrane properties. Glutamatergic VP neurons innervate and increase firing activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons. While nonselective optogenetic stimulation of the VP induced a robust place preference, selective activation of glutamatergic VP neurons induced a place avoidance. Viral ablation of glutamatergic VP neurons increased reward responding and abolished taste aversion to sucrose. CONCLUSIONS:Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking.
| S-EPMC5972062 | biostudies-literature