The habenula: from stress evasion to value-based decision-making

Hikosaka, Okihide

doi:10.1038/nrn2866

Cited by 829 publications

(891 citation statements)

References 114 publications

(139 reference statements)

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“…We also recently found prominent expression of RSK2 at the level of the habenular complex , a brain area that modulates many neural processes and is the subject of increasing attention (Lecourtier and Kelly, 2007;Hikosaka, 2010). Importantly, the habenula is a main site for mu opioid receptor expression, (Mansour et al, 1995;Kitchen et al, 1997) and therefore represents a possible brain substrate for functional interaction between mu opioid receptor and RKS2 signaling.…”

Section: Introductionmentioning

confidence: 99%

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Darcq

Befort

Koebel

et al. 2012

Neuropsychopharmacol

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It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.

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Section: Introductionmentioning

confidence: 99%

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Darcq

Befort

Koebel

et al. 2012

Neuropsychopharmacol

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“…Thus, as is the case for DA, 5-HT might have distinct effects in the ventral striatum, the amygdala, and the OFC (Clarke et al, 2008;Boulougouris and Robbins, 2010), or on functions associated with ventral versus dorsal frontostriatal circuitry (Tanaka et al, 2007). Crucial insights will also derive from an understanding of the neural mechanisms that control the activity of 5-HT neurons, such as the medial prefrontal cortex (Amat et al, 2005) and/or lateral habenula Hikosaka, 2010). ............................................................................................................................................................ …”

Section: Future Research Directionsmentioning

confidence: 99%

Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

Cools

Nakamura²,

Daw³

2010

Neuropsychopharmacol

409

369

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Serotonin, like dopamine (DA), has long been implicated in adaptive behavior, including decision making and reinforcement learning. However, although the two neuromodulators are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding about the mechanisms by which serotonin affects behavior. Here, we draw on recent work on computational models of dopaminergic function to suggest a framework by which many of the seemingly diverse functions associated with both DA and serotoninFcomprising both affective and activational ones, as well as a number of other functions not overtly related to eitherFcan be seen as consequences of a single root mechanism.

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“…The lateral habenula receives inputs from the BG (GPi) and projects to the midbrain ventral tegmental area, the locus coeruleus (LC), and the rostromedial tegmental nucleus [31][32][33]. Reflecting these complex connections, the proposed functions of the habenula are diverse and include value-based decision-making [34], anticipation of future events [35] and emotional regulation [36][37][38]. Although the habenula, especially the lateral habenula, is downstream of the BG and upstream of midbrain dopamine areas, both of which are critical for interval timing [3], it appears to be an overlooked brain region with respect to timing studies.…”

Section: (C) Habenula: the Dorsal Diencephalonmentioning

confidence: 99%

Zebrafish forebrain and temporal conditioning

Cheng

Jesuthasan

Penney

2014

Phil. Trans. R. Soc. B

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The rise of zebrafish as a neuroscience research model organism, in conjunction with recent progress in single-cell resolution whole-brain imaging of larval zebrafish, opens a new window of opportunity for research on interval timing. In this article, we review zebrafish neuroanatomy and neuromodulatory systems, with particular focus on identifying homologies between the zebrafish forebrain and the mammalian forebrain. The neuroanatomical and neurochemical basis of interval timing is summarized with emphasis on the potential of using zebrafish to reveal the neural circuits for interval timing. The behavioural repertoire of larval zebrafish is reviewed and we demonstrate that larval zebrafish are capable of expecting a stimulus at a precise time point with minimal training. In conclusion, we propose that interval timing research using zebrafish and whole-brain calcium imaging at single-cell resolution will contribute to our understanding of how timing and time perception originate in the vertebrate brain from the level of single cells to circuits.

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The habenula: from stress evasion to value-based decision-making

Cited by 829 publications

References 114 publications

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

Zebrafish forebrain and temporal conditioning

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