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Journal of Anatomy 2001The epithalamus is a major subdivision of the diencephalon constituted by the habenular nuclei and pineal complex. Structural asymmetries in this region are widespread... (Review)
Review
The epithalamus is a major subdivision of the diencephalon constituted by the habenular nuclei and pineal complex. Structural asymmetries in this region are widespread amongst vertebrates and involve differences in size. neuronal organisation, neurochemistry and connectivity. In species that possess a photoreceptive parapineal organ, this structure projects asymmetrically to the left habenula, and in teleosts it is also situated on the left side of the brain. Asymmetries in size between the left and right sides of the habenula are often associated with asymmetries in neuronal organisation, although these two types of asymmetry follow different evolutionary courses. While the former is more conspicuous in fishes (with the exception of teleosts), asymmetries in neuronal organisation are more robust in amphibia and reptiles. Connectivity of the parapineal organ with the left habenula is not always coupled with asymmetries in habenular size and/or neuronal organisation suggesting that, at least in some species, assignment of parapineal and habenular asymmetries may be independent events. The evolutionary origins of epithalamic structures are uncertain but asymmetry in this region is likely to have existed at the origin of the vertebrate, perhaps even the chordate, lineage. In at least some extant vertebrate species, epithalamic asymmetries are established early in development, suggesting a genetic regulation of asymmetry. In some cases, epigenetic factors such as hormones also influence the development of sexually dimorphic habenular asymmetries. Although the genetic and developmental mechanisms by which neuroanatomical asymmetries are established remain obscure, some clues regarding the mechanisms underlying laterality decisions have recently come from studies in zebrafish. The Nodal signalling pathway regulates laterality by biasing an otherwise stochastic laterality decision to the left side of the epithalamus. This genetic mechanism ensures a consistency of epithalamic laterality within the population. Between species, the laterality of asymmetry is variable and a clear evolutionary picture is missing. We propose that epithalamic structural asymmetries per se and not the laterality of these asymmetries are important for the behaviour of individuals within a species. A consistency of the laterality within a population may play a role in social behaviours between individuals of the species.
Topics: Amphibians; Animals; Biological Evolution; Epithalamus; Fishes; Functional Laterality; Habenula; Hormones; Pineal Gland; Reptiles; Species Specificity; Vertebrates
PubMed: 11523830
DOI: 10.1046/j.1469-7580.2001.19910063.x -
Pharmacology, Biochemistry, and Behavior Nov 2017Over the past 20years, substantive research has firmly implicated the lateral habenula in myriad neural processes including addiction, depression, and sleep. More... (Review)
Review
Over the past 20years, substantive research has firmly implicated the lateral habenula in myriad neural processes including addiction, depression, and sleep. More recently, evidence has emerged suggesting that the lateral habenula is a component of the brain's intrinsic daily or circadian timekeeping system. This system centers on the master circadian pacemaker in the suprachiasmatic nuclei of the hypothalamus that is synchronized to the external world through environmental light information received directly from the eye. Rhythmic clock gene expression in suprachiasmatic neurons drives variation in their electrical activity enabling communication of temporal information, and the organization of circadian rhythms in downstream targets. Here, we review the evidence implicating the lateral habenula as part of an extended neural circadian system. We consider findings suggesting that the lateral habenula is a recipient of circadian signals from the suprachiasmatic nuclei as well as light information from the eye. Further we examine the proposition that the lateral habenula itself expresses intrinsic clock gene and neuronal rhythms. We then speculate on how circadian information communicated from the lateral habenula could influence activity and function in downstream targets such as the ventral tegmental area and raphe nuclei.
Topics: Animals; CLOCK Proteins; Circadian Rhythm; Habenula; Humans; Suprachiasmatic Nucleus Neurons
PubMed: 28624585
DOI: 10.1016/j.pbb.2017.06.007 -
Scientific Reports Oct 2021The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central...
The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder (ASD) is characterized by social communication deficits, restricted interests, repetitive behaviors, and is frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in ASD subjects compared to controls across the entire age range studied (6-30 years). No differences were observed between sexes. Furthermore, support-vector machine modeling classified ASD with 85% accuracy (model using habenula volume, age and sex) and 64% accuracy in cross validation. The Social Responsiveness Scale (SRS) significantly differed between groups, however, it was not related to individual habenula volume. The present study is the first to provide evidence in human subjects of an involvement of the habenula in the pathophysiology of ASD.
Topics: Adolescent; Adult; Autism Spectrum Disorder; Child; Female; Habenula; Humans; Magnetic Resonance Imaging; Male; Social Behavior; Support Vector Machine
PubMed: 34707133
DOI: 10.1038/s41598-021-00603-0 -
NeuroImage. Clinical 2022A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of...
BACKGROUND
A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD.
METHODS
35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons.
RESULTS
The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation.
CONCLUSIONS
This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.
Topics: Anhedonia; Case-Control Studies; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Habenula; Humans; Magnetic Resonance Imaging; Suicidal Ideation
PubMed: 35305499
DOI: 10.1016/j.nicl.2022.102990 -
The International Journal of... May 2021Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized... (Clinical Trial)
Clinical Trial
BACKGROUND
Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.
METHODS
Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.
RESULTS
A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.
CONCLUSIONS
These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.
Topics: Administration, Intravenous; Adult; Antidepressive Agents; Cerebral Cortex; Connectome; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Female; Habenula; Humans; Ketamine; Magnetic Resonance Imaging; Male; Middle Aged; Outcome Assessment, Health Care
PubMed: 33249434
DOI: 10.1093/ijnp/pyaa089 -
Current Opinion in Neurobiology Jun 2021The habenula is among the evolutionarily most conserved parts of the brain and has been known for its role in the control of behavior to cope with aversive stimuli.... (Review)
Review
The habenula is among the evolutionarily most conserved parts of the brain and has been known for its role in the control of behavior to cope with aversive stimuli. Recent studies in zebrafish have revealed the novel roles of the two parallel neural pathways from the dorsal habenula to its target, the interpeduncular nucleus, in the control of behavioral choice whether to behave dominantly or submissively in the social conflict. They are modifiable depending on the internal state of the fish such as hunger and play another important role in orientation of attention whether to direct it internally to oneself or externally to others. These studies, therefore, are revealing a novel role for the habenula as the integrated switchboard for concertedly controlling behavior either as a winner with self-centered (idiothetic) attention or a loser with others-oriented (allothetic) attention.
Topics: Animals; Attention; Habenula; Interpeduncular Nucleus; Neural Pathways; Zebrafish
PubMed: 33421772
DOI: 10.1016/j.conb.2020.12.005 -
Brain : a Journal of Neurology Jun 2023Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the...
Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the habenula is believed to play an important role in adaptive behavioural responses to punishment and underlie depressive symptoms and their alleviation with ketamine. However, its role in value-based decision-making in humans is poorly understood due to limitations with non-invasive imaging methods which measure metabolic, not neural, activity with poor temporal resolution. Here, we overcome these limitations to more closely bridge the gap between species by recording local field potentials directly from the habenula in 12 human patients receiving deep brain stimulation treatment for bipolar disorder (n = 4), chronic pain (n = 3), depression (n = 3) and schizophrenia (n = 2). This allowed us to record neural activity during value-based decision-making tasks involving monetary rewards and losses. High-frequency gamma (60-240 Hz) activity, a proxy for population-level spiking involved in cognitive computations, increased during the receipt of loss and decreased during receipt of reward. Furthermore, habenula high gamma also encoded risk during decision-making, being larger in amplitude for high compared to low risk. For both risk and aversion, differences between conditions peaked approximately between 400 and 750 ms after stimulus onset. The findings not only demonstrate homologies with the primate habenula but also extend its role to human decision-making, showing its temporal dynamics and suggesting revisions to current models. The findings suggest that habenula high gamma could be used to optimize real-time closed-loop deep brain stimulation treatment for mood disturbances and impulsivity in psychiatric disorders.
Topics: Animals; Humans; Habenula; Reward; Neurons; Punishment; Schizophrenia
PubMed: 36445730
DOI: 10.1093/brain/awac456 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... May 2019The habenula is a small and bilateral nucleus above dorsal thalamus, which contains several different types of neurons. The habenula has extensive connections with the... (Review)
Review
The habenula is a small and bilateral nucleus above dorsal thalamus, which contains several different types of neurons. The habenula has extensive connections with the forebrain, septum and monoaminergic nuclei in the midbrain and brainstem. Habenula is known as an 'anti-reward' nucleus, which can be activated by aversive stimulus and negative reward prediction errors. Accumulating researchs have implicated that the habenula is involved in several behaviors crucial to survival. Meanwhile, the roles of the habenula in neuropsychiatric diseases have received increasing attention. This review summaries the studies regarding the roles of habenula and the related circuits in neuropathic pain, depression, drug addiction and schizophrenia, and discusses the possibility to use the habenula as a treatment target.
Topics: Depressive Disorder; Habenula; Humans; Mental Disorders; Mesencephalon; Neurons; Reward
PubMed: 31496164
DOI: 10.3785/j.issn.1008-9292.2019.06.12 -
Molecular Brain Jun 2023Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The...
Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (Glu) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of Glu neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of Glu neurons was enhanced by chronic itch. Chemogenetic suppression of Glu neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by Glu neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.
Topics: Mice; Animals; Habenula; Histamine; Emotions; Sensation; Pruritus
PubMed: 37370111
DOI: 10.1186/s13041-023-01045-7 -
Philosophical Transactions of the Royal... Mar 2014The rise of zebrafish as a neuroscience research model organism, in conjunction with recent progress in single-cell resolution whole-brain imaging of larval zebrafish,... (Review)
Review
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.
Topics: Animals; Basal Ganglia; Behavior, Animal; Habenula; Larva; Mammals; Models, Animal; Models, Neurological; Neurotransmitter Agents; Prosencephalon; Species Specificity; Time Factors; Time Perception; Zebrafish
PubMed: 24446496
DOI: 10.1098/rstb.2012.0462