The habenula: from stress evasion to value-based decision-making
Open accessAbstract
Surviving in a world with hidden rewards and dangers requires choosing the appropriate behaviours. Recent discoveries indicate that the habenula plays a prominent part in such behavioural choice through its effects on neuromodulator systems, in particular the dopamine and serotonin systems. By inhibiting dopamine-releasing neurons, habenula activation leads to the suppression of motor behaviour when an animal fails to obtain a reward or anticipates an aversive outcome. Moreover, the habenula is involved in behavioural responses to pain, stress, anxiety, sleep and reward, and its dysfunction is associated with depression, schizophrenia and drug-induced psychosis. As a highly conserved structure in the brain, the habenula provides a fundamental mechanism for both survival and decision-making.
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LHb neurons are excited by omission of anticipated rewards or exposure to aversive stimuli.
“LHb neurons are excited by omission of anticipated rewards or exposure to aversive stimuli (Lecourtier and Kelly 2007;Matsumoto and Hikosaka 2009;Hikosaka 2010;Bromberg-Martin and Hikosaka 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Hikosaka 2010
The Avoidance of punishment section reports that LHb neurons are excited by aversive stimuli, and the Reward-based decision-making section reports excitation by cues predicting a small reward. The paper also describes LHb reward-prediction-error signals, but the passages do not establish excitation specifically when an anticipated reward is omitted; a cue predicting no reward is not the same as an unexpected omission. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe MHb projects almost exclusively to the IPN via the fasciculus retroflexus.
“Unlike LHb, the MHb projects almost exclusively to the interpeduncular nucleus (IPN) via the fasciculus retroflexus (Fr) (Lecourtier and Kelly 2007;Hikosaka 2010).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Hikosaka 2010
The Abstract (page unavailable) says that MHb neurons project to the IPN and identifies the fasciculus retroflexus as the habenula’s output tract. It contrasts this with LHb projections to other midbrain areas, but does not establish that MHb projections to the IPN are almost exclusive. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe lateral habenula may play a role in modulating motivated behavior and addiction by modulating dopamine neurotransmission via actions on dopamine neurons in the VTA.
“The lateral habenula may play a role in modulating motivated behavior and addiction by modulating dopamine neurotransmission via actions on dopamine neurons in the VTA (Hikosaka, 2010;Velasquez et al., 2014;Boulos et al., 2017).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Hikosaka, 2010
The Reward-based decision-making section says the lateral habenula inhibits dopamine neurons in the VTA, and Towards a unified theory of habenula function links that inhibition to reduced motivation. The paper discusses nicotine addiction, but attributes the withdrawal-related mechanism to the medial habenula and interpeduncular nucleus; it does not support the claim that the lateral habenula modulates addiction through VTA dopamine neurons. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSignificant evidence has emerged for a role for the lateral habenula-VTA circuit in driving aversive responses to the loss of reward and mediating and encoding aversive states.
“Significant evidence has also emerged for a role for the lateral habenula-VTA circuit in driving aversive responses to the loss of reward and mediating and encoding aversive states (Hikosaka, 2010).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Hikosaka, 2010
In “Avoidance of punishment” (page unavailable), the review says the lateral habenula signals negative stimulus value to dopamine neurons in the VTA and may contribute to suppressing movements leading to aversive outcomes. “Reward-based decision-making” describes responses to smaller-than-expected rewards. These passages support a role in encoding negative outcomes and responding to aversive stimuli, but the claim that the circuit *drives* aversive responses to reward loss states the proposed behavioral role more firmly than the source does. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe lateral habenula plays a key role in mediating and encoding aversive states.
“The lateral habenula plays a key role in mediating and encoding aversive states.”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [79]
The habenula is a diencephalic structure on the dorsomedial surface of the caudal thalamus, segregated into medial and lateral domains.
“The habenula is a diencephalic structure located on the dorsomedial surface of the caudal thalamus that is segregated into medial (MHb) and lateral (LHb) domains (Lecourtier and Kelly 2007;Hikosaka 2010).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Hikosaka 2010
The lateral habenula projects to the VTA and its activation decreases VTA dopamine neuron activity.
“The lateral habenula projects to the VTA, and its activation is known to decrease activity in VTA dopamine neurons (Hikosaka, 2010; see the Within-System Neuroadaptations section above).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Hikosaka, 2010
Altered activity in the habenula might explain the reduced motivation to compete and reduced sensitivity to social reward by exerting a powerful inhibition on dopamine neurons.
“Further, an altered activity in the habenula (a structure located at the most caudal and dorsal part of the thalamus) might explain the reduced motivation to compete and reduced sensitivity to social reward by exerting a powerful inhibition on dopamine neurons (Hikosaka, 2010).”
From Social functioning in major depressive disorder (2016) · cites this paper as Hikosaka, 2010
The habenula, particularly the MHb, opposes the behavioral processes mediated through the VTA.
“A number of studies have focused on the ability of the habenula, particularly the MHb to oppose the behavioral processes mediated through the VTA (for reviews, see (Fowler and Kenny, 2012; Hikosaka, 2010)).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Hikosaka, 2010
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“Whereas the MHb receives inputs primarily from the limbic system and sends outputs mainly to the IPN, the LHb receives inputs primarily from the basal ganglia and sends outputs mainly to dopaminergic and serotonergic neurons (Hikosaka 2010).”
BackgroundGABA/glutamate co-release controls habenula output and is modified by antidepressant treatment
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Transcriptional and spatial resolution of cell types in the mammalian habenula
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“…such as comparison—at least in the domain of reward and appetitive learning—is the reward-prediction-error mechanism that may be implemented by mesodiencephalic dopaminergic neurons projecting to striatum and prefrontal cortex [125], while the habenula has been implied in aversive learning [126].”
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“Dysfunction of the habenula has been implicated in psychiatric disorders, such as depression, schizophrenia, and drug-induced psychosis (Hikosaka, 2010).”
BackgroundA neural mechanism for conserved value computations integrating information and rewards
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Trier, H. A., Khalighinejad, N., Hamilton, S., Harbison, C., Priestley, L., Laubach, M., Klein-Flügge, M., Scholl, J., & Rushworth, M. F. S. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2410955121 · Cited by 12 · see citing works
Activity in human dorsal raphe nucleus signals changes in behavioural policy
Priestley, L., Mahmoodi, A., Reith, W. D., Khalighinejad, N., & Rushworth, M. F. S. (2026) · Nature Communications · doi:10.1038/s41467-026-68349-9 · Cited by 3 · see citing works
From psychache to neuroplasticity: A unified rescue-repair model of Ketamine’s anti-suicidal action
Domany, Y., & Solomon-Shashua, A. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106804 · Cited by 2 · see citing works
D’Ambrogio, S., Grohn, J., Khalighinejad, N., Mattar, M. G., Hunt, L., & Rushworth, M. F. S. (2026) · Nature Neuroscience · doi:10.1038/s41593-026-02342-9 · Cited by 1 · see citing works
- Authors
- Hikosaka, O.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Hikosaka, Okihide
- ORCID
- Hikosaka, Okihide
- Venue
- Nature Reviews Neuroscience
- Published
- 2010-07
- Volume
- 11
- Issue
- 7
- Pages
- 503-513
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC3447364
- OpenAlex
- W1993417422
- Semantic Scholar
- 07c06af66cec3a942087780296c7033df4f8efdf
- Cited by
- 955
- References
- 118
- Citations by year
- 2026: 51 · 2025: 53 · 2024: 52 · 2023: 51 · 2022: 73 · 2021: 79 · 2020: 69 · 2019: 62 · 2018: 63 · 2017: 62 · 2016: 71 · 2015: 64 · 2014: 55 · 2013: 51 · 2012: 51
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (ZIAEY000415)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- habenula, value-based decision making, dopamine, serotonin, motor inhibition, stress response, anxiety, pain, reward, depression, schizophrenia, drug-induced psychosis, neuromodulation, choice behavior
- MeSH terms
- Animals, Avoidance Learning, Mental Disorders, Decision Making, Humans, Stress, Psychological, Habenula
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