Medial Habenula Output Circuit Mediated by α5 Nicotinic Receptor-Expressing GABAergic Neurons in the Interpeduncular Nucleus

Hsu, Yun-Wei A.; Tempest, Lynne; Quina, Lely A.; Wei, Aguan; Zeng, Hongkui; Turner, Eric E.

doi:10.1523/jneurosci.2927-13.2013

Cited by 76 publications

(88 citation statements)

References 54 publications

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“…In short, both LHb and MHb may control motivation and emotion. This view may be supported by recent studies suggesting that the MHb also has substantial influences on DA and 5HT neurons 91, 92 , which are largely mediated by the IPN (Fig. 2).…”

Section: Lateral Habenula and Medial Habenulasupporting

confidence: 64%

Reward processing by the lateral habenula in normal and depressive behaviors

2014

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The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an important part of the reward circuit by providing ‘negative value’ signals to the dopaminergic and serotonergic systems. Studies also suggest that dysfunction of the lateral habenula is associated with psychiatric disorders including major depression. In this review, we first discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We next highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may play a role in depressive behaviors.

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Section: Lateral Habenula and Medial Habenulasupporting

confidence: 64%

Reward processing by the lateral habenula in normal and depressive behaviors

2014

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“…This is particularly important given that our pharmacological experiments suggest that nAChRs containing a6 subunits are a minority, although of high sensitivity, subtype in MHbVI. These results demonstrate the importance of considering MHb subregions independently when studying nAChRs and chronic nicotine, as several recent studies did not identify changes in the response of MHb neurons to nicotine when the MHb was analyzed without considering subregions (Gorlich et al, 2013;Hsu et al, 2013;Dao et al, 2014).…”

Section: Discussionmentioning

confidence: 57%

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

2015

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Nicotinic acetylcholine receptors (nAChRs) are the molecular target of nicotine. nAChRs in the medial habenula (MHb) have recently been shown to play a role in nicotine dependence, but it is not clear which nAChR subtypes or MHb neuron types are most important. To identify MHb nAChRs and/or cell types that play a role in nicotine dependence, we studied these receptors and cells with brain slice electrophysiology using both acute and chronic nicotine application. Cells in the ventroinferior (MHbVI) and ventrolateral MHb (MHbVL) subregions expressed functional nAChRs with different pharmacology. Further, application of nicotine to cells in these subregions led to different action potential firing patterns. The latter result was correlated with a differing ability of nicotine to induce nAChR desensitization. Chronic nicotine caused functional upregulation of nAChRs selectively in MHbVI cells, but did not change nAChR function in MHbVL. Importantly, firing responses were also differentially altered in these subregions following chronic nicotine. MHbVI neurons treated chronically with nicotine exhibited enhanced basal pacemaker firing but a blunted nicotine-induced firing response. MHbVL neurons did not change their firing properties in response to chronic nicotine. Together, these results suggest that acute and chronic nicotine differentially affect nAChR function and output of cells in MHb subregions. Because the MHb extensively innervates the interpeduncular nucleus, an area critical for both affective and somatic signs of withdrawal, these results could reflect some of the neurophysiological changes thought to occur in the MHb to the interpeduncular nucleus circuit in human smokers.

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“…Lentivirus-mediated gene delivery to the MHb restored β4 nAChR subunit expression on a β4KO background, forming putative a3β4* nAChRs in MHb soma and terminals innervating the IPN. MHb β4* nAChRs are required for nicotine-evoked excitatory responses (Dao et al, 2014;Görlich et al, 2013;Hsu et al, 2013), and β4* nAChRs on MHb terminals are required for nicotine-evoked acetylcholine release (Beiranvand et al, 2014;Grady et al, 2009). We found that partial re-expression of β4* nAChRs along the length of MHb neurons (mean: 26.0%) did not rescue nicotine IVSA.…”

Section: Discussionmentioning

confidence: 75%

“…The MHb receives input from the posterior septum (Yamaguchi et al, 2013), and sends neuronal efferents to co-release glutamate and acetylcholine onto GABAergic and serotonergic neurons of the IPN (Groenewegen et al, 1986;Ren et al, 2011). IPN neurons project to the raphe nucleus and dorsal tegmentum (Hsu et al, 2013), which provide neurological input to the ventral tegmental area (VTA) (Geisler and Zahm, 2005). Thus far, the MHb and IPN have been linked to anxiety, impulsivity, nicotine withdrawal, and primary reinforcement (Hsu et al, 2014;Kobayashi et al, 2013;Zhao-Shea et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

Harrington

Viñals

Herrera-Solís

et al. 2015

Neuropsychopharmacol

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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. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* 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 β4 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 β4KO 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 β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

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Medial Habenula Output Circuit Mediated by α5 Nicotinic Receptor-Expressing GABAergic Neurons in the Interpeduncular Nucleus

Cited by 76 publications

References 54 publications

Reward processing by the lateral habenula in normal and depressive behaviors

Reward processing by the lateral habenula in normal and depressive behaviors

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

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