In
neuroanatomy
Neuroanatomy is the study of the structure and organization of the nervous system. In contrast to animals with radial symmetry, whose nervous system consists of a distributed network of cells, animals with bilateral symmetry have segregated, defi ...
, habenula (diminutive of Latin ''habena'' meaning
rein
Reins are items of horse tack, used to direct a horse or other animal used for riding. They are long straps that can be made of leather, nylon, metal, or other materials, and attach to a bridle via either its bit or its noseband.
Use f ...
) originally denoted the stalk of the
pineal gland (pineal habenula; pedunculus of pineal body), but gradually came to refer to a neighboring group of nerve cells with which the pineal gland was believed to be associated, the habenular nucleus. The habenular nucleus is a set of well-conserved structures in all
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
animals.
Currently, this term refers to this separate cell mass in the caudal portion of the dorsal
diencephalon, known as the
epithalamus
The epithalamus is a posterior (dorsal) segment of the diencephalon. The epithalamus includes the habenular nuclei and their interconnecting fibers, the habenular commissure, the stria medullaris and the pineal gland.
Functions
The function ...
, found in all vertebrates on both sides of the
third ventricle
The third ventricle is one of the four connected ventricles of the ventricular system within the mammalian brain. It is a slit-like cavity formed in the diencephalon between the two thalami, in the midline between the right and left lateral ...
.
It connects the
forebrain
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
and
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
within the
epithalamus
The epithalamus is a posterior (dorsal) segment of the diencephalon. The epithalamus includes the habenular nuclei and their interconnecting fibers, the habenular commissure, the stria medullaris and the pineal gland.
Functions
The function ...
.
It is embedded in the
posterior end of the
stria medullaris
The stria medullaris is a part of the epithalamus. It is a fiber bundle containing afferent fibers from the septal nuclei, lateral preoptico- hypothalamic region, and anterior thalamic nuclei to the habenula. It forms a horizontal ridge on the me ...
from which it receives most of its
afferent fibers. By way of the
fasciculus retroflexus
''Fasciculus vesanus'' is an extinct species of stem-group ctenophores known from the Burgess Shale of British Columbia, Canada. It is dated to and belongs to middle Cambrian strata.
The species is remarkable for its two sets of long and sho ...
(habenulointerpeduncular tract) it projects to the
interpeduncular nucleus
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'' t ...
and other paramedian cell groups of the
midbrain tegmentum
The midbrain is anatomically delineated into the tectum (roof) and the tegmentum (floor). The midbrain tegmentum extends from the substantia nigra to the cerebral aqueduct in a horizontal section of the midbrain. It forms the floor of the midbrain ...
.
Although they were predominantly studied for their demonstration of asymmetrical brain development and function, in recent years many scientists have begun to examine the habenular nuclei's role in motivation and behavior as it relates to an understanding of the physiology of addiction. Functionally, the habenula is involved in
nociception,
sleep-wake cycles
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
, reproductive behavioural, and mood (see section on
depression below). It is one of the few areas known to influence virtually all
monoaminergic
Monoaminergic means "working on monoamine neurotransmitters", which include serotonin, dopamine, norepinephrine, epinephrine, and histamine.
A monoaminergic, or monoaminergic drug, is a chemical, which functions to directly modulate the ser ...
systems in the
brainstem, such as
dopamine,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
, and
serotonin.
Anatomy
The habenula was traditionally divided into lateral (limbic) and medial (motor) parts. Detailed examination of the region in the cat, however, suggested that the lateral part should be further divided into ten distinct subnuclei and the medial into five distinct subnuclei.
Asymmetry
Various species exhibit left-right asymmetric differentiation of habenular neurons. In many
fish
Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of ...
es 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
bird
Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...
s 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.
The right and left habenular nuclei are connected to each other by the
habenular commissure
The habenular commissure, is a brain commissure (a band of nerve fibers) situated in front of the pineal gland that connects the habenular nuclei on both sides of the diencephalon.
The habenular commissure is part of the habenular trigone (a smal ...
. The
pineal gland is attached to the brain in this region. Habenula nuclear divisions:
* lateral habenular nucleus (, )
* medial habenular nucleus (, )
Lateral habenula
The primary input regions to the lateral habenula (LHb) are the lateral
preoptic area
The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular).
Functions
The preoptic area is responsible for ther ...
(bringing input from the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
and lateral septum), the ventral
pallidum
The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...
(bringing input from the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
and mediodorsal nucleus of the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
), the lateral
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, the medial habenula, and the internal segment of the
globus pallidus (bringing input from other
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
structures).
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. Reward information to the lateral habenula comes from the internal part of the globus pallidus.
The outputs of the lateral habenula target dopaminergic regions (
substantia nigra pars compacta
The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neuron ...
and the
ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), 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 th ...
), serotonergic regions (
median raphe and
dorsal raphe nuclei), and a cholinergic region (the
laterodorsal tegmental nucleus).
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.
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. New research suggests that lateral habenula may play a crucial role in decision making.
[
*]
Medial habenula
The medial habenula receives connections from posterior
septum pellucidum
The septum pellucidum (Latin for "translucent wall") is a thin, triangular, vertical double membrane separating the anterior horns of the left and right lateral ventricles of the brain. It runs as a sheet from the corpus callosum down to the f ...
and
diagonal band of Broca
The diagonal band of Broca is one of the basal forebrain structures that are derived from the ventral telencephalon during development. This structure forms the medial margin of the anterior perforated substance. This brain region was described b ...
; the lateral habenula receives afferents from the lateral
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for " nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypot ...
,
internal globus pallidus
The internal globus pallidus (GPi or medial globus pallidus; in rodents its homologue is known as the entopeduncular nucleus) and the external globus pallidus (GPe) make up the globus pallidus. The GPi is one of the output nuclei of the basal gang ...
,
ventral pallidum
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 ...
, and diagonal band of Broca.
As a whole, this complexly interconnected region is part of the
dorsal diencephalic conduction (DDC) system, responsible for relaying information from the limbic system to the
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
,
hindbrain
The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephal ...
, and
medial forebrain.
Input to the medial habenula (MHb) comes from a variety of regions and carries a number of different chemicals. Input regions include
septal nuclei
The septal area (medial olfactory 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.
The septal nuclei are loca ...
(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 diagonal band of Broca is one of the basal forebrain structures that are derived from the ventral telencephalon during development. This structure forms the medial margin of the anterior perforated substance. This brain region was described b ...
. The medial habenula sends outputs of
glutamate,
substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...
and
acetylcholine to the
periaqueductal gray
The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for d ...
via the
interpeduncular nucleus
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'' t ...
as well as to the pineal gland.
Olfactory coding in the habenula
In lower vertebrates (lampreys and teleost fishes), 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 habenulae (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. (Jetti, SK. et al 2014, Current Biology)
Functions
These nuclei are hypothesized to be involved in regulation of monoamines, such as
dopamine and
serotonin.
The habenular nuclei are involved in pain processing, reproductive behavior, nutrition,
sleep-wake cycles
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
, stress responses, and learning.
Recent demonstrations using
fMRI
Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area ...
and single unit electrophysiology
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".
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.
Depression
Both the medial and lateral habenula show reduced volume in those with
depression. Neuron cell numbers were also reduced on the right side.
Such changes are not seen in those with
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
.
Deep brain stimulation
Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleus ...
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.
N-Methyl-D-aspartate (NMDA) receptor-dependent
burst firing in the lateral habenula has been associated with depression in animal studies, and it has been shown that the general anesthetic
ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...
blocks this firing by acting as a
receptor antagonist.
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).
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.
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.
In a study using a
Pavlovian conditioning
Classical conditioning (also known as Pavlovian or respondent conditioning) is a behavioral procedure in which a biologically potent stimulus (e.g. food) is paired with a previously neutral stimulus (e.g. a triangle). It also refers to the learni ...
model, results showed an increase in the habenula response.
This increase coincided with conditioned stimuli associated with more aversive punishments (ie. electric shock).
Therefore, researchers speculate that inhibition or damage to the LHb resulting in a failure to process such information may lead to random motivation behavior.
LHb is especially important in understanding the reward and motivation relationship as it relates to addictive behaviors.
The LHb inhibits
dopaminergic neurons, decreasing the release of dopamine.
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.
Therefore, dopamine levels only increase with unpredicted rewards and with a "positive prediction error".
Moreover, it was determined that removal of an anticipated award activated LHb, inhibited dopamine levels.
This finding helps explain why addictive drugs are associated with elevated dopamine levels.
Nicotine and nAChRs
According to the
National Institute on Drug Abuse, 1 in 5
preventable deaths
Preventable causes of death are causes of death related to risk factors which could have been avoided. The World Health Organization has traditionally classified death according to the primary type of disease or injury. However, causes of deat ...
, in the United States, is caused by
tobacco
Tobacco is the common name of several plants in the genus '' Nicotiana'' of the family Solanaceae, and the general term for any product prepared from the cured leaves of these plants. More than 70 species of tobacco are known, but the ...
use.
Nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
is the addictive drug found in most tobacco products and is easily absorbed by the bloodstream of the body.
Despite common misconceptions regarding the relaxing effects of tobacco and nicotine use, behavioral testing in animals has demonstrated nicotine to have an anxiogenic effect.
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...
s (nAChRs) have been identified as the primary site for nicotine activity and regulate consequent cellular polarization.
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.
References
External links
*
NIF Search - Habenulavia the
Neuroscience Information Framework
The Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/genomic resources and provides many auth ...
Neuroanatomy lab sectional atlas
*
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