The Habenula: Darkness, Disappointment, and Depression

Kaye, Alfred; Ross, David A.

doi:10.1016/j.biopsych.2016.12.004

Cited by 17 publications

(13 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When a reward is smaller than expected or the anticipated reward is unsatisfactory, the firing rate of the lateral habenula increases, leading to inhibition of dopamine release from midbrain dopaminergic neurons that project to the nucleus accumbens, highly involved in reward processing (2, 7, 12, 13). Therefore, the lateral habenula is implicated in encoding information about aversive signals or missing rewards.…”

Section: Introductionmentioning

confidence: 99%

“…Its firing rate increases in response to chronic stress, punishment, and stimuli that have been previously associated with negatively charged experiences (7, 11). Accordingly, the lateral habenula plays a key function in learning from painful experiences and in making decisions to avoid such aversive experiences in the future (12, 13). In contrast, if the expected reward meets or exceeds our expectations, the firing rate of the lateral habenula decreases, leading to activation of brainstem dopaminergic nuclei, which activate the nucleus accumbens (2, 12–14) that is critically important for mediating and experiencing reward.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

Gold

Kadriu

2019

Front. Psychiatry

View full text Add to dashboard Cite

Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role in the pathophysiology of depressive illness. Aberrant increases in neuronal activity in the lateral habenula, an anti-reward center, signals down-regulation of brainstem dopaminergic and serotonergic firing, leading to anhedonia, helplessness, excessive focus on negative experiences, and, hence, depressive symptomatology. The lateral habenula has distinctive regulatory adaptive role to stress regulation in part due to its bidirectional connectivity with the hypothalamic–pituitary–adrenal (HPA) axis. In addition, studies show that increased lateral habenula activity affects components of sleep regulation including slow wave activity and rapid eye movement (REM), both disrupted in depressive illness. Lack of perceived reward experienced during the adverse outcomes also precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. The ability to update expectations of the environment based on rewards and aversive stimuli reflects a potentially important survival mechanism relevant to the capacity to adapt to changing circumstances. What if one lives in a continuously aversive and invalidating environment or under the conditions of chronic stress? If there is a propensity of the habenula to release many burst discharges over time, an individual could habitually come to perceive the world as perpetually disappointing. Conceivably, the lateral habenula could learn to expect an adverse outcome systematically and communicate it more easily. Thus, if the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. Furthermore, postmortem studies reveal that the size of the lateral habenula and total number of neurons are decreased in patients who had depressive illness. Novel research in the field shows that ketamine induces rapid and sustained antidepressant effect. Intriguingly, recent preclinical animal models show that ketamine abolishes N -methyl- D -aspartate receptor (NMDAR)-dependent lateral habenula bursting activity, leading to rapid resolution of depressive symptoms.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

Gold

Kadriu

2019

Front. Psychiatry

View full text Add to dashboard Cite

show abstract

“…The habenula has been shown to be involved in aversive conditioning, reward pathways (Boulos et al, 2017 ) and in the pathophysiology of several psychiatric conditions (Fakhoury, 2017 ). The DCCS seems to be particularly relevant in negative reward prediction errors, or “disappointment”, where failure to receive an expected reward integrates cognitive and emotional inputs through the habenula to affect a depressive behavioral response (Kaye and Ross, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure

et al. 2018

View full text Add to dashboard Cite

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula’s principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment.

show abstract

“…The study of MOR function in aversion centers is only beginning. In particular, MOR is highly expressed in the medial part of the habenula (MHb) (86), a brain center that is particularly active in the anticipation of aversive outcomes (87)(88)(89) and is considered a key aversion center in addiction and depression research (90)(91)(92). In general, the habenula complex is important to regulate information flow from forebrain to midbrain (87,88,90).…”

Section: Mor Function In Oud-relevant Brain Circuitry and Neuronsmentioning

confidence: 99%

The Negative Affect of Protracted Opioid Abstinence: Progress and Perspectives From Rodent Models

Welsch¹,

Bailly²,

Darcq

et al. 2020

Biological Psychiatry

View full text Add to dashboard Cite

Opioid use disorder (OUD) is characterized by the development of a negative emotional state that develops after a history of long-term exposure to opioids. OUD represents a true challenge for treatment and relapse prevention. Human research has amply documented emotional disruption in individuals with an opioid substance use disorder, at both behavioral and brain activity levels; however, brain mechanisms underlying this particular facet of OUD are only partially understood. Animal research has been instrumental in elucidating genes and circuits that adapt to long-term opioid use or are modified by acute withdrawal, but research on long-term consequences of opioid exposure and their relevance to the negative affect of OUD remains scarce. In this article, we review the literature with a focus on two questions: 1) Do we have behavioral models in rodents, and what do they tell us? and 2) What do we know about the neuronal populations involved? Behavioral rodent models have successfully recapitulated behavioral signs of the OUD-related negative affect, and several neurotransmitter systems were identified (i.e., serotonin, dynorphin, corticotropin-releasing factor, oxytocin). Circuit mechanisms driving the negative mood of prolonged abstinence likely involve the 5 main reward-aversion brain centers (i.e., nucleus accumbens, bed nucleus of the stria terminalis, amygdala, habenula, and raphe nucleus), all of which express mu opioid receptors and directly respond to opioids. Future work will identify the nature of these mu opioid receptor-expressing neurons throughout reward-aversion networks, characterize their adapted phenotype in opioid abstinent animals, and hopefully position these primary events in the broader picture of mu opioid receptor-associated brain aversion networks.

show abstract

The Habenula: Darkness, Disappointment, and Depression

Cited by 17 publications

References 9 publications

A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure

The Negative Affect of Protracted Opioid Abstinence: Progress and Perspectives From Rodent Models

Contact Info

Product

Resources

About