Habenula

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Habenula
Epithalamus.png
Medial aspect of human brain showing location of the habenula in front of the pineal gland or body in the epithalamus shown in red The habenular commissure is labelled shown connecting the habenula.
Brainstem and thalamus ja ja 135.png
Habenula shown in blue just in front of the pineal gland shown in red
Identifiers
MeSH D019262
NeuroNames 294
NeuroLex ID birnlex_1611
TA98 A14.1.08.003
TA2 5662
FMA 62032
Anatomical terms of neuroanatomy

The habenula (diminutive of Latin habena meaning rein) is a small bilateral neuronal structure in the brain of vertebrates, that has also been called a microstructure since it is no bigger than a pea. The naming as little rein describes its elongated shape in the epithalamus, where it borders the third ventricle, and lies in front of the pineal gland. [1]

Contents

Although it is a microstructure each habenular nucleus is divided into two distinct regions of nuclei, a medial habenula (MHb), and a lateral habenula (LHb) both having different neuronal populations, inputs, and outputs. [2] [3] The medial habenula can be subdivided into five subnuclei, the lateral habenula into four subnuclei. [4] Research has shown morphological complexity in the MHb and LHb. Different inputs to the MHb are discriminated between the different subnuclei. [5] In the two regions of nuclei there is a difference in gene expression giving different functions to each. [6]

The habenula is a conserved structure across vertebrates. In mammals it is highly symmetric, and in fish, amphibians and reptiles it is highly asymmetric in size, molecular composition, and connections. [1] The habenular nuclei are a major component in the limbic system pathways. [1] The fasciculus retroflexus pathway between the habenula and the interpeduncular nucleus is one of the first major nerve tracts to form in the developing brain. [1]

The habenula is a central structure that connects forebrain regions to midbrain regions, and acts as a hub or node for the integration of emotional and sensory processing. [2] It integrates information from the limbic system, sensory and basal ganglia to guide appropriate and effective responses. [5] The habenula is involved in the regulation of monoamine neurotransmittters notably dopamine and serotonin. [2] [3] Both of these neurotransmitters are strongly associated with anxiety disorders, and avoidance behaviours. [2] The functions of the habenula are also involved in motivation, emotion, learning, and pain. [2] The MHb plays an important role in depression, stress, memory, and nicotine withdrawal, as well as a role in cocaine, methamphetamine and alcohol addiction. [6] The MHb shows a high level of nicotinic acetylcholine receptors (nAChRs), that are involved in many forms of addiction. Previously their expression was only noted in other structures associated with addiction. Their expression in the MHb has become a later focus of research. [6]

Anatomy

Each habenular nucleus has two divisions, a medial habenular nucleus (MHb), and a lateral habenular nucleus (LHb). Studies have shown that the medial habenula can be subdivided into five subnuclei, and the lateral habenula into four subnuclei. [4] The right and left habenular nuclei are connected to each other by the habenular commissure. The pineal gland is attached to the brain in this region. [7] The medial habenula (MHb) receives connections from posterior septum pellucidum and diagonal band of Broca; the lateral habenula receives afferents from the lateral hypothalamus, nucleus accumbens, internal globus pallidus, ventral pallidum, and diagonal band of Broca. [8] As a whole, this complexly interconnected region is part of the dorsal diencephalic conduction system (DDCS), responsible for relaying information from the limbic system to the midbrain, hindbrain, and medial forebrain. [9] [10]

Lateral habenula

The primary input regions to the lateral habenula (LHb) are the lateral preoptic area (bringing input from the hippocampus and lateral septum), the ventral pallidum (bringing input from the nucleus accumbens and mediodorsal nucleus of the thalamus), the lateral hypothalamus, the medial habenula, and the internal segment of the globus pallidus (bringing input from other basal ganglia structures). [8]

Neurons in the lateral habenula are 'reward-negative' as they are activated by stimuli associated with unpleasant events, the absence of the reward or the presence of punishment especially when this is unpredictable. [11] Reward information to the lateral habenula comes from the internal part of the globus pallidus. [12]

The outputs of the lateral habenula target dopaminergic regions (substantia nigra pars compacta and the ventral tegmental area), serotonergic regions (median raphe and dorsal raphe nuclei), and a cholinergic region (the laterodorsal tegmental nucleus). [8] This output inhibits dopamine neurons in substantia nigra pars compacta and the ventral tegmental area, with activation in the lateral habenula linking to deactivation in them, and vice versa, deactivation in the lateral habenula with their activation. [13] The lateral habenula functions to oppose the action of the laterodorsal tegmental nucleus in the acquisition of avoidance responses but not the processing of avoidance later on when it is a memory, motivation or its execution. [14] Research suggests that lateral habenula may play a crucial role in decision making. [15]

There has also shown to be an association with aberrant LHb activity and depression. [16]

Medial habenula

The medial habenula (MHb) receives connections from the posterior septum pellucidum and diagonal band of Broca. [8] Input to the medial habenula comes from a variety of regions and carries a number of different chemicals. Most neuronal projections to the MHb come from the septal area. [5] Input regions include septal nuclei (the nucleus fimbrialis septi and the nucleus triangularis septi); dopaminergic inputs from the interfascicular nucleus of the ventral tegmental area, noradrenergic inputs from the locus ceruleus, and GABAergic inputs from the diagonal band of Broca. The medial habenula sends outputs of glutamate, substance P and acetylcholine to the periaqueductal gray via the interpeduncular nucleus as well as to the pineal gland. [17] [18]

Asymmetry

Asymmetry in the habenula was first noted in 1883 by Nikolaus Goronowitsch. [7] Various species exhibit left-right asymmetric differentiation of habenular neurons. In many fishes and amphibians, the habenula on one side is significantly larger and better organized into distinct nuclei in the dorsal diencephalon than its smaller pair. The sidedness of such differentiation (whether the left or the right is more developed) varies with the species. In birds and mammals, however, both habenulae are more symmetrical (although not entirely) and consist of a medial and a lateral nucleus on each side which is in fish and amphibians equivalent to dorsal habenula and the ventral habenula, respectively. [19] [8] [20]

Olfactory coding

In some fish (lampreys and teleosts), mitral cell (principal olfactory neurons) axons project exclusively to the right hemisphere of the habenula in an asymmetric manner. It is reported that the dorsal habenula (DHb) are functionally asymmetric with predominantly odor responses in the right hemisphere. It was also shown that DHb neurons are spontaneously active even in the absence of olfactory stimulation. These spontaneously-active DHb neurons are organized into functional clusters which were proposed to govern olfactory responses. [21]

Functions

These nuclei are hypothesized to be involved in regulation of monoamines, such as dopamine and serotonin. [22] [23]

The habenular nuclei are involved in pain processing, reproductive behavior, nutrition, sleep-wake cycles, stress responses, and learning. Recent demonstrations using fMRI [24] and single unit electrophysiology [13] have closely linked the function of the lateral habenula with reward processing, in particular with regard to encoding negative feedback or negative rewards. Matsumoto and Hikosaka suggested in 2007 that this reward and reward-negative information in the brain might "be elaborated through the interplay among the lateral habenula, the basal ganglia, and monoaminergic (dopaminergic and serotonergic) systems" and that the lateral habenula may play a pivotal role in this "integrative function". [13] Then, Bromberg-Martin et al. (2011) highlighted that neurons in the lateral habenula signal positive and negative information-prediction errors in addition to positive and negative reward-prediction errors. [25]

Depression

Both the medial and lateral habenula show reduced volume in those with depression. Neuron cell numbers were also reduced on the right side. [26] Such changes are not seen in those with schizophrenia. [26] Deep brain stimulation of the major afferent bundle (i.e., stria medullaris thalami) of the lateral habenula has been used for treatment of depression where it is severe, protracted and therapy-resistant. [27] [28]

N-Methyl-D-aspartate (NMDA) receptor-dependent burst firing in the lateral habenula has been associated with depression in animal studies, [29] and it has been shown that the general anesthetic ketamine blocks this firing by acting as a receptor antagonist. [30] Ketamine has been the subject of numerous studies after having shown fast-acting antidepressant effects in humans (in a 0.5 mg/bw kg dose). [31]

Motivation and addiction

Recent exploration of the habenular nuclei has begun to associate the structure with an organism's current mood, feeling of motivation, and reward recognition. [32] Previously, the LHb has been identified as an "anti-reward" signal, but recent research suggests that the LHb helps identify preference, helping the brain to discriminate between potential actions and subsequent motivation decisions. [33] In a study using a Pavlovian conditioning model, results showed an increase in the habenula response. [34] This increase coincided with conditioned stimuli associated with more aversive punishments (i.e. electric shock). [34] Therefore, researchers speculate that inhibition or damage to the LHb resulting in a failure to process such information may lead to random motivation behavior. [33] [34]

LHb is especially important in understanding the reward and motivation relationship as it relates to addictive behaviors. [32] The LHb inhibits dopaminergic neurons, decreasing the release of dopamine. [35] It was determined by several animal studies that receiving a reward coincided with elevated dopamine levels, but once the learned association was learned by the animal, dopamine levels remain elevated, only decreasing when the reward is removed. [20] [23] [32] [35] Therefore, dopamine levels only increase with unpredicted rewards and with a "positive prediction error". [20] Moreover, it was determined that removal of an anticipated award activated LHb, inhibited dopamine levels. [20] This finding helps explain why addictive drugs are associated with elevated dopamine levels. [20]

Nicotine and nAChRs

According to the National Institute on Drug Abuse, one in five preventable deaths in the United States is caused by tobacco use. [36] Nicotine is the addictive drug found in most tobacco products and is easily absorbed by the bloodstream of the body. [36] Despite common misconceptions regarding the relaxing effects of tobacco and nicotine use, behavioral testing in animals has demonstrated nicotine to have an anxiogenic effect. [37] Nicotinic acetylcholine receptors (nAChRs) have been identified as the primary site for nicotine activity and regulate consequent cellular polarization. [38] nAChRs are made up a number of α and β subunits and are found in both the LHb and MHb, where research suggests they may play a key role in addiction and withdrawal behaviors. [38] [39]

History

The habenular is a well conserved structure that appeared in vertebrates more than 360 million years ago. [4] The habenular commissure was described for the first time in 1555 by Andreas Vesalius [40] and the habenula nuclei in 1872 by Theodor Hermann Meynert. [41]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Striatum</span> Nucleus in the basal ganglia of the brain

The striatum or corpus striatum is a nucleus in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.

<span class="mw-page-title-main">Basal ganglia</span> Group of subcortical nuclei involved in the motor and reward systems

The basal ganglia (BG) or basal nuclei are a group of subcortical nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into external and internal regions, and in the division of the striatum. Positioned at the base of the forebrain and the top of the midbrain, they have strong connections with the cerebral cortex, thalamus, brainstem and other brain areas. The basal ganglia are associated with a variety of functions, including regulating voluntary motor movements, procedural learning, habit formation, conditional learning, eye movements, cognition, and emotion.

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">Ventral tegmental area</span> Group of neurons on the floor of the midbrain

The ventral tegmental area (VTA), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.

<span class="mw-page-title-main">Reticular formation</span> Spinal trigeminal nucleus

The reticular formation is a set of interconnected nuclei that are located in the brainstem, hypothalamus, and other regions. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formation make up a complex set of networks in the core of the brainstem that extend from the upper part of the midbrain to the lower part of the medulla oblongata. The reticular formation includes ascending pathways to the cortex in the ascending reticular activating system (ARAS) and descending pathways to the spinal cord via the reticulospinal tracts.

<span class="mw-page-title-main">Septal area</span> Area in the lower, posterior part of the medial surface of the frontal lobe

The septal area, consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.

<span class="mw-page-title-main">Olfactory tubercle</span> Area at the bottom of the forebrain

The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to play a role in locomotor and attentional behaviors, particularly in relation to social and sensory responsiveness, and it may be necessary for behavioral flexibility. The OT is interconnected with numerous brain regions, especially the sensory, arousal, and reward centers, thus making it a potentially critical interface between processing of sensory information and the subsequent behavioral responses.

<span class="mw-page-title-main">Medial forebrain bundle</span>

The medial forebrain bundle (MFB) is a neural pathway containing fibers from the basal olfactory regions, the periamygdaloid region and the septal nuclei, as well as fibers from brainstem regions, including the ventral tegmental area and nigrostriatal pathway.

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.

The ventral pallidum (VP) is a structure within the basal ganglia of the brain. It is an output nucleus whose fibres project to thalamic nuclei, such as the ventral anterior nucleus, the ventral lateral nucleus, and the medial dorsal nucleus. The VP is a core component of the reward system which forms part of the limbic loop of the basal ganglia, a pathway involved in the regulation of motivational salience, behavior, and emotions. It is involved in addiction.

The interpeduncular nucleus (IPN) is an unpaired, ovoid cell group at the base of the midbrain tegmentum. It is located in the mesencephalon below the interpeduncular fossa. As the name suggests, the interpeduncular nucleus lies in between the cerebral peduncles.

Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

The parabrachial nuclei, also known as the parabrachial complex, are a group of nuclei in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. They are named from the Latin term for the superior cerebellar peduncle, the brachium conjunctivum. In the human brain, the expansion of the superior cerebellar peduncle expands the parabrachial nuclei, which form a thin strip of grey matter over most of the peduncle. The parabrachial nuclei are typically divided along the lines suggested by Baxter and Olszewski in humans, into a medial parabrachial nucleus and lateral parabrachial nucleus. These have in turn been subdivided into a dozen subnuclei: the superior, dorsal, ventral, internal, external and extreme lateral subnuclei; the lateral crescent and subparabrachial nucleus along the ventrolateral margin of the lateral parabrachial complex; and the medial and external medial subnuclei

The dorsal tegmental nucleus (DTN), also known as dorsal tegmental nucleus of Gudden (DTg), is a group of neurons located in the brain stem, which are involved in spatial navigation and orientation.

The fasciculus retroflexus (FR) also known as the habenulointerpeduncular tract is a bundle of fibers located at the base of the midbrain in vertebrates. Connected to the habenula (Hbn) and the interpeduncular nucleus (IPN), the fasciculus retroflexus is involved in a variety of bodily phenomena, some being sleep retention. and drug addiction. It acts as a channel through which messages are sent between the stria medullaris and the mid- and hindbrain. The fasciculus retroflexus, along with the stria medullaris, the habenula, and the medial forebrain bundle forms a unit for the transfer of neurological impulses. In this unit, the fasciculus retroflexus mediates the transfer of information for processes such as pain, pleasure, and motor control

References

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