Table 1. Functions mediated by habenula in rodents and human.

This table summarizes main preclinical and human studies discussed in this review. Reports for rodents and humans are categorized based on studies in area of pain and analgesia, depression, addiction and in schizophrenia (top to bottom). These studies address the medial habenula (MHb), lateral habenula (LHb) or both. Some of the studies are also reviewed in (10) for pain and analgesia, in (12) for mood and depression, in (13) for drug dependence and in (14) for schizophrenia. The parallel between rodent and human findings show promises for effective translation of preclinical research to human psychiatry.

Humans	Functions
Pain and Analgesia MHb and LhB	fMRI: Noxious Heat activates Hb (108)
	Rs-fMRI: Pediatric patients with chronic pain exhibit a reduced Hb rsFC to the rest of the brain and specifically with forebrain area (105)
	Post-mortem histological study (23) and structural MRI studies (21, 44) show decreased volumes of Hb in MDD and BD patients
Mood and Depression MHb and LhB	PET study shows enhanced coupling between Hb and raphe activities in volunteer patients experiencing transient depressive relapse upon tryptophan depletion (41)
Mood and Depression LhB	DBS of the stria medullaris thalami, the major LHb afferent bundle, reduces symptoms of treatment-resistant depression (50, 52)
Drug Dependence MHb	Genetic meta-analyses found association between α5-α3-β4 cluster and cigarettes smoked per day. Only the MHb shows co-expression of all three subunits (73)
Drug Dependence & Schizophrenia LHb	Computed tomographic study on post-mortem brain slices shows increased calcification in the Hb of schizophrenic patients (78)
Schizophrenia MHb and LhB	fMRI study shows that patients with schizophrenia lack appropriate modulation of Hb activity in adaptive response to feedback and errors (80).
Rodents	Functions
Pain and Analgesia MHb	Gene Knock down: Medical habenular RSK2 contributes to morphine analgesia (107)
Pain and Analgesia MHb and LHb	Electrical stimulation of the Hb induces analgesia (109, 110)
	Hb: integrative hub for pain control and regulating nociceptive processes (111)
Mood and Depression LHb	Activation of LHb 5-HT2C receptors increases depressive-like behaviors (32)
	LHb lesion studies (30, 31) or pharmacological inhibition (33, 34) reduces depressive- like behaviors
	DBS of LHb reduces depressive-like behavior (36, 37) by suppressing synaptic drive onto VTA-projecting LHb neurons (36) and increases monoamine concentrations (37)
	Optogenetic stimulations of GABA and Glu neurons projecting to the LHb demonstrate that LHb activity is regulated by corelease of both neurotransmitters (40)
Mood and Depression MHb and LHb	18FDG-PET live imaging study shows increased activity of Hb that correlates with subsequent learned helplessness behavior (41)
Drug Dependence LHb	A cocaine conditioned place preference study shows increased neuronal activation in the LHb of mice undergoing cocaine-primed reinstatement (53)
	Electrophysiological studies show that cocaine induces synaptic potentiation of LHb neurons (54, 55)
Drug Dependence MHb	Optogenetic silencing of MHb input to the IPN or pharmacological blockade of CRF1 receptors in the IPN reduce nicotine withdrawal-induced anxiety (61)
Drug Dependence & Schizophrenia MHb	Pharmacological Blockade of α3β4 nicotinic receptors in MHb and IPN attenuates sensitization of the dopamine response to repeated morphine administration (112).
	Chronic exposure to morphine enhances cholinergic signaling in the MHb (62).
Drug Dependence & Schizophrenia LHb	Retrograde labeling shows dose-dependent degeneration of the fasciculus retroflexus after extinction and reinstatement of cocaine self-administration (64)
	DBS of LHb reduces cocaine intake and seeking (63, 64)
	Relevant to schizophrenia: LHb stimulation prior to choice redirects the selection of action away from the preferred or rewarded outcome (14).
Schizophrenia LHb	LHb lesions in the rat induce memory (81, 113)) and attentional (81) deficits analogous to cognitive impairments in schizophrenic patients.

Abbreviations: rsFC: resting-state functional connectivity; MDD: major depression disorder; BD: bipolar disorder; VTA: ventral tegmental area; GABA: γ-Aminobutyric acid; Glu: glutamate; DBS: deep brain stimulation.