Habenula

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Okihide Hikosaka (2007), Scholarpedia, 2(6):2703. doi:10.4249/scholarpedia.2703 revision #91335 [link to/cite this article]
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1.00 - Okihide Hikosaka

Figure 1: The habenula in the rhesus monkey. Top: The monkey’s brain viewed from the mesial side. The location of the habenula is indicated by a red circle. C: caudate nucleus, Th: Thalamus, SC: superior colliculus, IC: inferior colliculus. Scale: 5 mm x 2. Bottom: A coronal histological section showing the habenula (red circle). The medially located dark region corresponds to the medial habenula (MHb), while the lateral part corresponds to the lateral habenula (LHb). The vertical extent of this section corresponds to a violet line in the top figure. MD: mediodorsal nucleus of the thalamus, Pul: pulvinar, PT: pretectum, N3: oculomotor nucleus, hc: habenular commissure, pc: posterior commissure. Scale: 1 mm x 5.

The habenula is a pair of small nuclei located above the thalamus at its posterior end close to the midline (Figure 1). Habenula originally denoted the stalk of the pineal gland (or pineal body), as it sits just in front of the pineal body. Extending anteriorly from the habenula is the stria medullaris which is visible as a pair of streaks at the dorsal surface of the thalamus and consists of axons projecting to the habenula. It is regarded as part of the epithalamus which includes the pineal body and the habenula. The habenula is a phylogenetically well-preserved structure (Butler and Hodos, 2005). It is thought to have evolved in close relation to the pineal body. A striking feature of the habenula is that in many vertebrates it is markedly asymmetric, one side larger than the other, unlike most of the brain structures (Concha and Wilson, 2001). In mammals the asymmetry is minimal or absent. In many vertebrates, the habenula is divided into the medial habenula and the lateral habenula. They are connected with different brain areas and appear to have different functions.

Contents

Connections with other brain areas

The habenula receives inputs from the basal ganglia and the limbic system and sends outputs to midbrain and forebrain structures which contain dopaminergic and serotonergic neurons (Figure 2).

Figure 2: Afferent and efferent connections of the habenula. The medial habenula (MHb), lateral habenulas (LHb), and pineal body (PB) are collectively called the epithalamus. The medial habenula receives inputs mainly from the limbic system and sends outputs to the interpeduncular nucleus (IP). The lateral habenula receives inputs mainly from the basal ganglia and sends outputs to the brain structures containing dopaminergic neurons and serotonergic neurons. Green and blue lines indicate the axonal connections associated with the medial and lateral habenulae, respectively; black lines are associated with both. The thickness of the line implies the strength of the connection. Many other connections are not shown, including reverse connections (e.g., from DR/VTA to LHb). SNc: substantia nigra pars compacta, VTA: ventral tegmental area, DR: dorsal raphe, MR: medial raphe, S: septum, DBB: nucleus of diagonal band of Broca, LPO: lateral preoptic area, LH: lateral hypothalamus, GPi: globus pallidus internal segment, CPu: caudate and putamen, sm: stria medullaris, fr: fasciculus retroflexus.

Inputs

The habenula receives inputs from various limbic and basal ganglia structures (Herkenham and Nauta, 1977). The main inputs to the medial habenula originate from the septum. The main inputs to the lateral habenula, especially its lateral part, originate from the internal segment of the globus pallidus and the lateral hypothalamus. This pathway contains many GABAergic axons (Araki et al., 1984) and some cholinergic axons (Moriizumi and Hattori, 1992) . Pallidal neurons projecting to the lateral habenula are largely separate from pallidal neurons projecting to the motor part of the thalamus (Parent et al., 2001). There is some evidence that the dorsal striatum has polysynaptic connections to the habenula, presumably through the habenula-projecting pallidal neurons (Saleem et al., 2002). Other inputs to the lateral habenula originate from the nuclei of the diagonal band, basal nucleus of stria terminalis, substantia innominata, lateral preoptic area, ventral tegmental area, and mesencephalic raphe nuclei. Most of these inputs run within the stria medullaris before reaching the habenula; minor part of the inputs, such as from the ventral tegmental area, runs within the fasciculus retroflexus (or habenulo-interpeduncular tract). Direct projections from the cerebral cortex have also been reported (Greatrex and Phillipson, 1982).

Outputs

The medial habenula projects mainly to the interpeduncular nucleus (Herkenham and Nauta, 1979). Acetylcholine and substance P may be used as transmitters in this projection, but by different groups of neurons in the medial habenula (Eckenrode et al., 1987). The lateral habenula projects to the ventral tegmental area (VTA) and the substantia nigra pars compacta where dopaminergic neurons are located, and the dorsal and median raphe nuclei where serotonergic neurons are located. Neurons in the lateral habenula may be glutamatergic (Kalen et al., 1986), but they exert strong inhibitory influences over dopaminergic neurons (Christoph et al., 1986) as well as serotonergic neurons (Wang and Aghajanian, 1977; Park, 1987) , probably through inhibitory interneurons. The lateral habenula also projects to hypothalamic structures (Kiss et al., 2002). The habenula efferents form the fasciculus retroflexus, its core part from the medial habenula and its mantle part from the lateral habenula.

Functions of the habenula

Circadian control of behavior

It is thought that circadian rhythm in mammals is controlled mainly by the suprachiasmatic nucleus in the hypothalamus. There is some evidence that the habenula is involved in the behavioral expression of circadian rhythm originating from the suprachiasmatic nucleus. Many neurons in the lateral habenulae are tonically activated or suppressed by retinal illumination. The spontaneous firing rates of both the lateral and medial habenulae are higher during the day than during the night (Zhao and Rusak, 2005). This circadian rhythm is maintained even in vitro where there is no light input (Zhao and Rusak, 2005). If rodents are maintained in constant illumination for months, their circadian rhythm may split into two independent rhythms. Asymmetric neural activation (detected by c-FOS immunoreaction) correlated with locomotor activity following the split circadian rhythms is found in the suprachiasmatic nucleus and the lateral habenula (Tavakoli-Nezhad and Schwartz, 2006), suggesting that the lateral habenula may play an instrumental role in the circadian locomotor rhythm.

As described above, the habenula evolved in close connection with the pineal body. In many non-mammalian vertebrates the pineal body is directly photosensitive, which is called ‘epiphysis’, ‘pineal eye’, or ‘medial eye’ (Butler and Hodos, 2005), and plays a dominant role in the control of circadian rhythm. The axonal connection from the medial habenula to the pineal body is also present in the rat (Ronnekleiv and Moller, 1979). Although the pineal body seems to have lost the direct photosensitivity in mammals, a group of retinal ganglion cells that are directly photosensitive and contain a photopigment called melanopsin (Dacey et al., 2005) project to the lateral habenula in addition to the suprachiasmatic nucleus, pretectum, lateral geniculate nucleus, and other light-sensitive areas (Hattar et al., 2006). This direct retinal input might underlie the photosensitivity of habenula neurons and serve the formation of the intrinsic circadian rhythm in the habenula described above.

Control of body movements

  • Inhibitory control of motor behaviors

Lesions of the lateral habenula in the rat increases exploratory behavior including locomotor activity (Nielson and McIver, 1966). This is largely due to augmented responses to novelty and environmental stimuli rather than general motor hyperactivity (Thornton and Evans, 1984). In operant procedures, habenula-lesioned rats show a marked increase in premature responding. These effects appear to be mediated by increased activity of dopaminergic neurons (Sasaki et al., 1990).

  • Inhibitory control of dopamine neurons by the habenula

An important role of dopaminergic neurons in the substantia nigra in motor control is evident in Parkinson’s disease which is caused by degeneration of the midbrain dopaminergic neurons and is associated with various movement disorders. One of the major targets of the lateral habenula is the dopamine-rich midbrain areas including the ventral tegmental area and the substantia nigra pars compacta (Herkenham and Nauta, 1979). The net effect of these connections is likely to be inhibitory. First, electrical stimulation of the lateral habenula induces inhibitions in the midbrain dopamine neurons (Christoph et al., 1986). Second, lesions of the habenula lead to activation of dopaminergic neurons (Lisoprawski et al., 1980). In rats with unilateral habenular lesions, systemic injections of apomorphine (dopamine agonist) induce contralateral turning, probably due to an elevated dopaminergic activity on the lesioned side (Wickens and Thornton, 1996). The inhibition of dopaminergic neurons may be mediated by GABAergic interneurons in the ventral tegmental area which receives excitatory inputs from the lateral habenula (Kalen et al., 1986). Conversely, the lateral habenula, especially its lateral part, is under dopaminergic control (Wirtshafter et al., 1994), receiving inputs from the ventral tegmental area.

Midbrain dopaminergic neurons carry signals that are crucial for initiation and learning of body movements. First, they encode reward prediction error signals which act as a teaching signal for motor behavior that would maximize the gain of reward (Schultz, 1998). Second, they encode novel environmental events which would cause immediate changes in motor behavior (Redgrave and Gurney, 2006). An important source of the reward-related signal, especially its negative component, is the lateral habenula. The lateral habenula is one of few brain regions that are inhibited by positive hedonic stimuli (Gallistel et al., 1985). In human subjects performing a motion prediction task, negative feedback indicating task failure activates the habenula in addition to the anterior cingulate cortex and insula (Ullsperger and von Cramon, 2003). Such activation does not occur in schizophrenic subjects (Shepard et al., 2006). In monkeys performing eye movement tasks many neurons in the lateral habenula are excited by a visual target indicating that there will be no reward after the saccade and inhibited by another visual target indicating that there will be a reward. Dopaminergic neurons in the substantia nigra pars compacta exhibit the opposite pattern of activity. Furthermore, weak electrical stimulation of the lateral habenula elicited strong inhibitions in dopamine neurons (Matsumoto and Hikosaka, in press). These results suggest that the lateral habenula suppresses less rewarding motor behaviors by inhibiting dopamine neurons (Figure 3).

Figure 3: How the lateral habenula (LHb) might contribute to the reward-dependent modulation of motor behaviors – a hypothesis. LHb neurons are excited by the omission of reward or the sensory stimulus that indicates the absence of reward. This leads to a suppression of tonic activity of dopaminergic neurons in the substantia nigra pars compacta (SNc). Since the dopaminergic neurons are thought to modulate the synaptic effects of cortical inputs on projection neurons in the caudate/putamen (CPu), the LHb-induced inhibition of dopaminergic activity may lead to the suppression of body movements when rewards are not expected. Excitatory and inhibitory connections are indicated by (+) and (-), respectively. It is unknown whether habenula neurons themselves are inhibitory. Other indirect circuits in the basal ganglia are not shown. The basal ganglia control body movements through their connections to either the brainstem motor networks (e.g., saccadic eye movements, locomotion) or the thalamus and then to the cerebral motor cortices (e.g., skilled hand-finger movements). SNr: substantia nigra pars reticulata, GPi: globus pallidus internal segment.

Control of emotional and social behaviors

  • Relation to pain, stress and anxiety

The lateral habenula may be involved in behaviors associated with negative emotions. Lateral habenula neurons are excited by nociceptive stimulation (Dafny and Qiao, 1990; Gao et al., 1996). Neural activity assessed by c-FOS induction increases after stress, selectively in the medial region of the lateral habenula (Wirtshafter et al., 1994). Lesions, electrical stimulations, or morphine microinjections in the habenula change the animal’s sensitivity to pain (Mahieux and Benabid, 1987). Habenula lesions also change the state of anxiety (Murphy et al., 1996) and prevent learned helplessness due to inescapable shocks. In congenitally helpless rats, metabolism (presumably reflecting neural activity) is increased in the habenula (Shumake et al., 2003). Animals with habenular lesions have difficulty in learning conditioned avoidance responses (motor responses to avoid aversive stimulation) (Rausch and Long, 1974). This effect is clearer if stress levels are increased by raising the intensity of aversive stimulation or making the motor response more demanding (Thornton and Bradbury, 1989). In a classical conditioning to aversive stimulation, extinction, not learning, is accelerated in habenula-lesioned rats (Brady and Nauta, 1955).

  • Relation to social behavior

Habenular lesions disrupt female sexual behaviors (Modianos et al., 1974) and maternal behaviors (Matthews-Felton et al., 1995). These effects may be caused by changes in arginine-vasopression levels originating from the bed nucleus of stria terminalis (Fink et al., 1996).

  • Control of serotonin neurons by the habenula

These effects on emotional and social behaviors may be mediated by serotonergic neurons in the dorsal and median raphe (Amat et al., 2001), a main target of the lateral habenula (Sakai et al., 1977). The effect of this connection is also inhibitory. Electrical stimulation of the habenula suppresses activity of serotonergic neurons (Wang and Aghajanian, 1977) and decreases serotonin release in the caudate nucleus and the substantia nigra (Reisine et al., 1982). However, more recent data seem at odds with these results. For example, electrical stimulation of the lateral habenula induces an increase in serotonin release (Kalen et al., 1989). Habenula lesions eliminated the increase in serotonin release in the dorsal raphe in response to inescapable shocks (Amat et al., 2001). In patients with depression the habenula and the dorsal raphe are co-activated (Morris et al., 1999).

Cognitive functions

Spatial cognitive performance, as assessed in the Morris water maze task, is impaired in rats with habenular lesions (Lecourtier et al., 2004). In a sequential motor task habenula-lesioned rats showed a marked increase in premature responding and it may be mediated by increased dopaminergic activity (Lecourtier and Kelly, 2005). These deficits may be related to changes in synaptic plasticity in the connection from the hippocampus to the nucleus accumbens which occurs after habenular lesions (Lecourtier et al., 2006). This effect may be mediated by dopaminergic neurons projecting to the nucleus accumbens. There may be other mechanisms with which the lateral habenula influences the hippocampus. For example, stimulation of the lateral habenula increases release of noradrenaline (Kalen et al., 1989) and acetylcholine (Nilsson et al., 1990) in the hippocampus. The lateral habenula may also influence the hippocampus through the dorsal raphe and the supramammillary nucleus (Kiss et al., 2002).

Function of medial habenula

The medial habenula receives inputs mainly from the septal nuclei (Herkenham and Nauta, 1977) and sends axons to the interpeduncular nucleus (Herkenham and Nauta, 1979). Since the interpeduncular nucleus projects to the areas including the ventral tegmental area and the dorsal raphe, the medial habenula may perform functions similar to the lateral habenula, but indirectly. There have also been some suggestions that the medial habenula is involved in neuroendocrine and immunological responses to various kinds of stress. The medial habenula may contribute to the regulation of salt and water balance through its effects on the adrenal cortex (Lengvari et al., 1970) and exert an inhibitory control over the thyroid gland (Ford, 1968). After defeat stress or a period of courtship, the number of mast cells, one of immunocytes trafficking through the brain, increased markedly in the medial habenula (Silver et al., 1996). Interleukin-18, which is a pro-inflammatory cytokine acting as a modulator of immune functions, is found in the brain in the interpeduncular nucleus, ependymal cells and also in the medial habenula where restraint stress increases its release (Sugama et al., 2002). Stress-activated protein kinases are localized in the endopiriform nucleus and medial habenula (Carboni et al., 1998).

Dysfunctions of habenula: implication in psychosis

Dysfunctions of the habenula have been implicated in psychosis including depression, schizophrenia, and drug-induced psychosis (Sandyk, 1991; Scheibel, 1997). In rat models of depression the regional glucose metabolism is elevated in the lateral habenula more consistently than any other brain area (Caldecott-Hazard et al., 1988). Congenitally helpless rats show markedly elevated metabolism in the habenula (Shumake et al., 2003). Transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), are associated with correlated increases in activity in the habenula and the dorsal raphe as the rating of depressed mood increases (Morris et al., 1999). In patients with chronic schizophrenia calcification of the habenula occurs much more frequently than in age-matched control subjects (Sandyk, 1992; Caputo et al., 1998). Influenza virus, which increases the risk of schizophrenia if experienced prenatally, selectively damages the habenula when introduced into the brain via the olfactory bulb (Mori et al., 1999). A variety of addictive drugs induce degeneration of axons in the fasciculus retroflexus which originate in the habenula (Ellison, 1994, 2002). Drugs that predominantly potentiate dopamine, including D-amphetamine, methamphetamine, MDMA, cocaine, and cathinone, all induce degeneration in axons from the lateral habenula, while continuous nicotine selectively induces degeneration in axons from the medial habenula. Continuous cocaine exposure has selective neurotoxic effects on the habenula of the developing fetus similar to cocaine's effects in the adult (Murphy et al., 1999). It should be noted that these psychiatric disorders are associated with impairments in emotional, social, cognitive, and motor behaviors, all of which seem to be normally supported by the habenula.

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Internal references

See also

Thalamus, Basal Ganglia, Models of Basal Ganglia, Reward, Reward Signals, Reinforcement, Reinforcement Learning

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