Molecular characterization of the subnuclei in rat habenula

Aizawa, Hidenori; Kobayashi, Megumi; Tanaka, Sayaka; Fukai, Tomoki; Okamoto, Hitoshi

doi:10.1002/cne.23230

Cited by 55 publications

(132 citation statements)

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“…2 A and Dataset S1, the TRAP samples show robust enrichment of known markers of MHb neurons, including Chrna3, Chrnb4, Tac2, and Gpr151, in agreement with other studies (14,17), whereas nonneuronal transcripts (e.g., glial genes) are depleted (red in Fig. 2A).…”

Section: Trap Analysis Of Cholinergic Mhb Neurons Reveals Enrichment Ofsupporting

confidence: 89%

“…A number of studies have begun to dissect the medial and lateral habenular nuclei in an effort to determine whether subpopulation differences in cytoarchitecture and connectivity could be correlated to molecular markers and electrophysiological properties (14)(15)(16)(17). For instance, the dorsal and ventral parts of the MHb can be clearly divided based on their respective enrichment in the neuropeptide Tachykinin 1, also known as substance P (SP), or the ACh synthesizing enzyme choline acetyltransferase (ChAT), and the segregation of their efferents to different parts of the IPN (18).…”

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confidence: 99%

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Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Görlich

Antolin-Fontes

Ables

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula-interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for α3, β4, and α5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2-10 Hz generated by hyperpolarization-activated cyclic nucleotidegated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, α3β4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse.nAChRs | TRAP profiling T he tobacco epidemic kills nearly six million smokers a year, primarily from lung cancer. The success rate for smoking cessation without pharmacological treatment is only 3-5% and less than 30% with nicotine-replacement therapies (1). Nicotine, the addictive component of tobacco, mediates its action by activating nicotinic acetylcholine receptors (nAChRs), which respond to the endogenous neurotransmitter acetylcholine (ACh). Like other drugs of abuse, chronic nicotine exposure promotes adaptations in neuronal circuits that sustain the use of cigarettes (2, 3). Upon nicotine cessation in humans, a withdrawal syndrome-characterized by negative somatic and affective symptoms such as irritability, anxiety, depressed mood, and loss of concentration-develops (2, 3) and contributes to the high probability of smoking relapse. In rodents that have been chronically treated with nicotine, withdrawal can be induced either by pharmacological precipitation or by cessation of nicotine administration. Somatic and affective signs of withdrawal differentially manifest in these two cases (3, 4). Additionally, studies in knockout mice have revealed a distinct contribution of various nAChR subtypes to somatic and affective withdrawal signs (5, 6), illustrating the molecular complexity of nicotine dependence, withdrawal, and relapse.Converging evidence from genome-wide association studies...

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Section: Trap Analysis Of Cholinergic Mhb Neurons Reveals Enrichment Ofsupporting

confidence: 89%

mentioning

confidence: 99%

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Görlich

Antolin-Fontes

Ables

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Although we selectively modulate cholinergic neurons of the MHb, this cell population has been previously shown to release glutamate and/or acetylcholine (Qin & Luo 2009;Ren et al 2011;Aizawa et al 2012). Therefore, it remains unclear which neurotransmitter system is responsible for driving the reinstatement phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…More specifically, the MHb may play a larger role in adaptive behaviors, where mounting evidence has demonstrated that loss of vMHb function leads to deficits in fear extinction and escape behaviors. Nevertheless, while the circuitry and cellular composition of the MHb has been well-characterized, the endogenous functions of the MHb remain relatively unknown and have recently become the focus of addiction neuroscience (Qin & Luo 2009;Aizawa et al 2012;Lima et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

et al. 2018

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Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

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“…Although both receptors are activated by either ligand, SP preferentially activates NK1 receptors and NKB preferentially activates NK3 receptors. In contrast to the expression of NKB, which is extremely dense and ubiquitous throughout the MHb (Lucas et al, 1992;Marksteiner et al, 1992;Lein et al, 2007), strong SP expression is confined to the dorsal one-third of the MHb (Lein et al, 2007;Aizawa et al, 2012). Both NK1 and NK3 receptors are strongly expressed in the cholinoceptive/cholinergic ventral two-thirds of the MHb (Langlois et al, 2001;Lein et al, 2007;Commons and Serock, 2009).…”

Section: Neuroadaptation During Chronic Nicotine Exposurementioning

confidence: 99%

Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling

et al. 2014

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The medial habenula (MHb) densely expresses nicotinic acetylcholine receptors (nAChRs) and participates in nicotine-related behaviors such as nicotine withdrawal and regulating nicotine intake. Although specific nAChR subunits are identified as being involved in withdrawal behavior, the cellular mechanisms through which nicotine acts to cause this aversive experience is unclear. Here, we demonstrate an interaction between the nicotinic and neurokinin signaling systems that may form the basis for some symptoms experienced during nicotine withdrawal. Using patch-clamp electrophysiology in mouse brain slices, we show that nicotine (1 M) increases intrinsic excitability in MHb neurons. This nicotine-induced phenomenon requires ␣5-containing nAChRs and depends on intact neurokinin signaling. The effect is blocked by preincubation with neurokinin 1 (NK1; L-732138, 10 M) and NK3 (SB222200, 2 M) antagonists and mimicked by NK1 (substance P, 100 nM) and NK3 (neurokinin B [NKB], 100 nM) agonists. Microinjections (1 l) of L-732138 (50 nM) and SB222200 (100 nM) into the MHb induces withdrawal behavior in chronic nicotine-treated (8.4 mg/kg/d, 2 weeks) mice. Conversely, withdrawal behavior is absent with analogous microinjections into the lateral habenula of nicotine-treated mice or in mice chronically treated with a vehicle solution. Further, chronic nicotine reduces nicotine's acute modulation of intrinsic excitability while sparing modulation by NKB. Our work elucidates the interplay between two neuromodulatory signaling systems in the brain through which nicotine acts to influence intrinsic excitability. More importantly, we document a neuroadaptation of this mechanism to chronic nicotine exposure and implicate these mechanisms collectively in the emergence of nicotine withdrawal behavior.

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Molecular characterization of the subnuclei in rat habenula

Cited by 55 publications

References 0 publications

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling

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