The lateral habenula and the serotonergic system

Metzger, Martin; Bueno, Débora Siqueira; Lima, Leandro B.

doi:10.1016/j.pbb.2017.05.007

Cited by 70 publications

(57 citation statements)

References 125 publications

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“…Among them, nicotine affects 5-HT neurons and 5-HT-innervated brain areas [17,36]. For instance, the LHb receives a dense serotonergic innervation from the raphe nuclei [30], expresses several 5-HTR subtypes [30,31], the HT2A gene [37], and 5-HT 2A R protein, both on neurons and glial cells [34]. Here, in line with our previous study, we found that only a small population of LHb neurons (9-8%) was 5-HT 2A R-IR, independently from the nicotine treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the LHb can be directly activated by nicotine [26][27][28], and its lesion prevented nicotine-induce anxiety [29]. The LHb is heavily modulated by the serotonergic system and expresses several 5-HTR subtypes [30,31]. Of note, the 5-HT 2A R seems to be one of the most critical 5-HTRs in modulating LHb neuronal activity also in comparison to 5-HT 2C Rs.…”

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Bombardi

Delicata

Tagliavia

et al. 2020

IJMS

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Nicotine addiction is a serious public health problem causing millions of deaths worldwide. Serotonin (5-hydroxytryptamine; 5-HT) is involved in central nervous system (CNS) nicotine effects, and it has been suggested as a promising pharmacological target for smoking cessation. In this regard, what is particularly interesting are the 5-HT2A receptors (5-HT2ARs) and the lateral habenula (LHb), a central area in nicotine addiction that we showed to be under a strong 5-HT2AR-modulation. Single-cell extracellular recording of LHb neurons was used to study the 5-HT2AR function by intravenously administrating the potent agonist TCB-2. Acute nicotine (2 mg/kg, intraperitoneal, i.p.) and chronic nicotine (6 mg/kg/day for 14 days) differently affected both the 5-HT2AR-immuno reactive (IR) neuron number and the 5-HT2AR immunostaining area in the different brain areas studied. After acute nicotine, TCB-2 cumulative doses (5–640 µg/kg, intravenous, i.v.) bidirectionally affected the activity of 74% of LHb recorded neurons. After chronic nicotine treatment, TCB-2 was only capable of decreasing the LHb firing rate. The expression of 5-HT2AR under acute and chronic nicotine exposure was studied in the LHb and in other brain areas involved in nicotine effects in rats by using immunohistochemistry. These data reveal that acute and chronic nicotine differentially affect the 5-HT2AR function in different brain areas and this might be relevant in nicotine addiction and its treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Bombardi

Delicata

Tagliavia

et al. 2020

IJMS

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“…In their seminal studies about the afferent and efferent connections of the habenular nuclei, Herkenham and Nauta (, ) already described that LHb is reciprocally linked to LDTg. Based on a differential set of major in‐ and outputs, they also partitioned the LHb into two principal subdivisions, the LHbM and LHbL, considering LHbM as “limbic” and LHbL as “pallidal” parts of the LHb (Herkenham & Nauta, ; Herkenham & Nauta, ; Metzger, Bueno, & Lima, ; Zahm & Root, ). Here, we specified the LHb subdivisions and subnuclei, which give rise to LHb projections to LDTg, clarifying that more than 70% of these extensive projections arise from subnuclei belonging to the LHbM.…”

Section: Discussionmentioning

confidence: 99%

Connections of the laterodorsal tegmental nucleus with the habenular‐interpeduncular‐raphe system

Bueno

Lima

Souza

et al. 2019

J of Comparative Neurology

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The laterodorsal tegmental nucleus (LDTg) is a hindbrain cholinergic cell group thought to be involved in mechanisms of arousal and the control of midbrain dopamine cells. Nowadays, there is increasing evidence that LDTg is also engaged in mechanisms of anxiety/fear and promotion of emotional arousal under adverse conditions. Interestingly, LDTg appears to be connected with other regulators of aversive motivational states, including the lateral habenula (LHb), medial habenula (MHb), interpeduncular nucleus (IP), and median raphe nucleus (MnR). However, the circuitry between these structures has hitherto not been systematically investigated. Here, we placed injections of retrograde or anterograde tracers into LDTg, LHb, IP, and MnR.We also examined the transmitter phenotype of LDTg afferents to IP by combining retrograde tracing with immunofluorescence and in situ hybridization techniques.We found LHb inputs to LDTg mainly emerging from the medial division of the LHb (LHbM), which also receives axonal input from LDTg. The bidirectional connections between IP and LDTg displayed a lateralized organization, with LDTg inputs to IP being predominantly GABAergic or cholinergic and mainly directed to the contralateral IP. Moreover, we disclosed reciprocal LDTg connections with structures involved Abbreviations: 3V, third ventricle; 4V, fourth ventricle; 4n, trochlear nerve; A13, A13 dopamine cell group; ac, anterior commissure; AcbRP, nucleus accumbens, rostral pole; AD, anterodorsal thalamic nucleus; AID, agranular insular cortex, dorsal part; AIV, agranular insular cortex, ventral part; AM, anteromedial thalamic nucleus; BAC, bed nucleus of the anterior commissure; BST, bed nucleus of the stria terminalis; Cg1, cingulate cortex 1in the modulation of hippocampal theta rhythm including MnR, nucleus incertus, and supramammillary nucleus. Our findings indicate that the habenula is linked with LDTg either by direct reciprocal projections from/to LHbM or indirectly via the MHb-IP axis, supporting a functional role of LDTg in the regulation of aversive behaviors, and further characterizing LHb as a master controller of ascending brainstem state-setting modulatory projection systems.

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“…). It remains controversial how the habenula modulates the serotonin metabolism in the brain . Both MHb and LHb share the afferent (stria medullaris) and efferent pathways (fasciculus retroflexus) forming the dorsal diencephalic conduction system in contrast to the ventral counterpart with the medial forebrain bundle (thick gray arrow in Fig.…”

Section: Mediolateral Subregions Of the Habenulamentioning

confidence: 99%

Toward an understanding of the habenula's various roles in human depression

Aizawa

Zhu

2019

Psychiatry Clin Neurosci

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The habenula is an evolutionarily conserved structure in the vertebrate brain. Lesion and electrophysiological studies in animals have suggested that it is involved in the regulation of monoaminergic activity through projection to the brain stem nuclei. Since studies in animal models of depression and human functional imaging have indicated that increased activity of the habenula is associated with depressive phenotypes, this structure has attracted a surge of interest in neuroscience research. According to pathway‐ and cell‐type‐specific dissection of habenular function in animals, we have begun to understand how the heterogeneity of the habenula accounts for alteration of diverse physiological functions in depression. Indeed, recent studies have revealed that the subnuclei embedded in the habenula show a wide variety of molecular profiles not only in neurons but also in glial cells implementing the multifaceted regulatory mechanism for output from the habenula. In this review, we overview the known facts on mediolateral subdivision in the habenular structure, then discuss heterogeneity of the habenular structure from the anatomical and functional viewpoint to understand its emerging role in diverse neural functions relevant to depressive phenotypes. Despite the prevalent use of antidepressants acting on monoamine metabolisms, ~30% of patients with major depression are reported to be treatment‐resistant. Thus, cellular mechanisms deciphering such diversity in depressive symptoms would be a promising candidate for the development of new antidepressants.

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The lateral habenula and the serotonergic system

Cited by 70 publications

References 125 publications

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

Connections of the laterodorsal tegmental nucleus with the habenular‐interpeduncular‐raphe system

Toward an understanding of the habenula's various roles in human depression

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