Nerve fibers and terminals containing RLN3-LI were observed throughout brain regions identical to those known to receive afferents from the NI in the rat, including the septum, hippocampus, entorhinal cortex, lateral, dorsomedial and ventromedial hypothalamus, supramammillary and interpeduncular nuclei, anterodorsal, paraventricular and reuniens thalamic nuclei, lateral Habenula, central gray, and dorsal raphe, solitary tract, and ambiguus nuclei.  

Here we propose a mechanism for the mediation of lateralization by the nodal-lefty-pitx2 (NLP) pathway in flounders, in which pitx2, the final left-right determinant of the NLP pathway, is re-expressed in the left Habenula at pre-metamorphosis. After the initiation of left-sided pitx2 re-expression, the eye commences migration, when the Habenulae shift their position on the ventral diencephalon rightwards in sinistral flounder (Paralichthys olivaceus) and leftwards in dextral flounder (Verasper variegatus). In addition, the right Habenula increases in size relative to the left Habenula in both species. Loss of pitx2 re-expression induces randomization of eye-sidedness, manifesting as normal, reversed or bilateral symmetry, with laterality of the structural asymmetry of Habenulae being entirely inverted in reversed flounders compared with normal ones. Thus, flounder pitx2 appears to be re-expressed in the left Habenula at metamorphosis to direct eye-sidedness by lateralizing the morphological asymmetry of the Habenulae..  

The caudate-putamen and accumbens, comprising the basal ganglia input structures, and the hypothalamic supraoptic and paraventricular nuclei, lateral and medial Habenula, mesopontine rostromedial tegmental nucleus and anterior cingulate cortex exhibited Fos expression enhanced by acute self-administration of cocaine (SAC), but desensitized after repeated administrations.  

Descending projections from the lateral Habenula (LHb) play a central role in inhibiting DA cell activity in response to the absence of expected rewards.  

The Habenulae are part of an evolutionary conserved conduction system that connects the limbic forebrain areas with midbrain structures and is implicated in important functions such as feeding, mating, avoidance learning, and hormonal response to stress. Very early during zebrafish neurogenesis the parapineal organ migrates near to one Habenula, commonly the left, inducing wide left-right Habenular asymmetries in gene expression and connectivity. Significant differences between fish with opposite parapineal position were found in all laterality tests while the influence of asymmetry of the Habenulae on personality was more complex.  

In the Habenula VGLUT3 was also found within NK1 receptor immunolabeled neurons.  

BACKGROUND: The Habenular complex is composed of important relay nuclei linking the limbic forebrain to the midbrain and brain stem nuclei. However, evidence in favour of this hypothesis is still lacking because the human Habenular complex has rarely been studied with regard to mental illness.MethodWe examined Habenular volumes in post-mortem brains of 17 schizophrenia patients, 14 patients with depression (six patients with major depression and eight patients with bipolar depression) and 13 matched controls. We further determined the neuronal density, cell number and cell area of the medial Habenular nuclei of the same cohorts using a counting box and a computer-assisted instrument. RESULTS: Significantly reduced Habenular volumes of the medial and lateral Habenula were estimated in depressive patients in comparison to normal controls and schizophrenia patients. CONCLUSIONS: Our anatomical data argue against prominent structural alterations of the Habenular nuclei in schizophrenia but demonstrate robust alterations in depressive patients.  

Less conspicuous was the innervation of the olfactory bulbs, pallial regions, Habenula, dorsomedial and dorsolateral thalamic nuclei, torus semicircularis and spinal cord.  

Additionally, there was mild expression of c-Fos-ir cells in the hippocampus, thalamus, and Habenula regions.  

Neuronal expression of taste genes was detected in different nutrient-sensing forebrain regions, including the paraventricular and arcuate nuclei of the hypothalamus, the CA fields and dentate gyrus of the hippocampus, the Habenula, and cortex.  

The LES component comprised the septohippocampal system and functionally interrelated areas including nucleus accumbens, anterior cingulate cortex, lateral Habenula and supramammillary areas, but not the dorsolateral part of the bed nucleus of the stria terminalis. Analysis of the separate brain areas revealed significantly higher Fos-IR in LES relative to FPS in the anterior cingulate cortex, nucleus accumbens shell, lateral septum, lateral Habenula and area postrema.  

Epithalamic asymmetries are coupled to visceral asymmetry and include left-sided migration of a single midline structure (the parapineal organ) and asymmetric differentiation of paired bilateral nuclei (Habenulae). This event triggers the amplification of Habenular asymmetries and the subsequent organisation of lateralised circuits in the interpeduncular nucleus. This review will summarise our current understanding on these processes and propose a sequential modular organisation of the events controlling the development of asymmetry along the parapineal-Habenular-interpeduncular axis..  

We examined the effects of bilateral electric lesion of the Habenula (Hb) on the acquisition and maintenance of heroin self-administration.  

Following ATD, Habenula blood flow increased significantly in the rMDD subjects relative to the control subjects, and increasing amygdala blood flow was associated with more negative emotional bias score across both groups. CONCLUSIONS: These data provide evidence for elevated Habenula blood flow and alterations in the neural processing of emotional stimuli following ATD in rMDD subjects, even in the absence of overt mood change.  

In the brain, prominent immunoreactivity was apparent in components of the limbic system, including the isocortex, hippocampus, amygdala, Habenula, basal ganglia, and interpeduncular nucleus.  

Substance P (SP) modulates serotonin neurotransmission via neurokinin-1 receptors (NK1rs), and exerts regulatory effects on mood through Habenular afferents to the dorsal raphe nucleus (DRN). Lastly, a marked increase in the membrane (but not cytoplasmic) density of NK1rs was measured in serotonin dendrites after bilateral Habenular lesion.  

The Habenular nuclei, for example, have been shown to present striking neuroanatomical and/or neurochemical asymmetries in species ranging from jawless fish to mammals. Those teleosts that do have asymmetrical Habenular nuclei, show varying patterns of asymmetry in different species. Here we investigate the relationship between individual variation of asymmetry in the Habenula of a South American cichlid fish, Geophagus brasiliensis, and behaviour in a commonly used test for visual laterality in fish, the detour task. We show that the strength of asymmetry in the Habenula is correlated with strength of behavioural lateralization in the detour task. Both the strength and direction of Habenular asymmetry are correlated with individual differences in growth rate.  

Recent studies showed evidence that the lateral Habenula, a part of the structure called the epithalamus, is a good candidate for a source of reward-related signals in dopamine neurons. The lateral Habenula projects to midbrain structures such as the substantia nigra pars compacta and ventral tegmental area which contain dopamine neurons. Electrical stimulation of the lateral Habenula inhibits the activity of dopamine neurons. Neurons in the lateral Habenula also encode reward-related signals but in a manner opposite to that obeerved for dopamine neurons (i.e., lateral Habenula neurons are inhibited by reward and sensory stimuli predicting reward and excited by reward omission). These anatomical and physiological findings suggest that the lateral Habenula transmits reward-related signals to dopamine neurons by inhibiting them. Thereby, the lateral Habenula could contribute to reward-seeking behaviors through its projections to the dopaminergic systems..  

The lateral Habenular complex (LHb) of the epithalamus is part of a dorsal diencephalic conduction system connecting basal forebrain with regulatory midbrain nuclei. Therefore, the results support the hypothesis of a functional subnuclear organization of the rat Habenular complex..  

Tracing MC axons at single-cell resolution revealed that (1) individual MCs send axons to multiple target regions in the forebrain; (2) MCs innervating the same glomerulus do not necessarily display the same axon trajectory; (3) MCs innervating distinct glomerular clusters tend to project axons to different, but partly overlapping, target regions; (4) MCs innervating the medial glomerular cluster directly and asymmetrically send axons to the right Habenula. Moreover, our finding of asymmetric bulbo-Habenular projection renders the olfactory system an attractive model for the studies of brain asymmetry and lateralized behaviors..  

The Habenulae are evolutionarily conserved bilateral nuclei in the epithalamus that relay input from the forebrain to the ventral midbrain. In zebrafish, the Habenulae display left-right (L/R) asymmetries in gene expression and axonal projections. The elaboration of Habenular asymmetries requires the presence of a second asymmetric structure, the parapineal, the laterality of which is biased by unilateral Nodal signalling. Here we show that neurons are present earlier in the left Habenula than in the right, but, in contrast to other Habenular asymmetry phenotypes, this asymmetry in neurogenesis is not dependent on the parapineal.  

The medial Habenula (MHb) is a key bridge between limbic forebrain and midbrain monoaminergic centers.  

Separate studies have implicated the lateral Habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood.  

Since the beta4 subunit is highly expressed in the medial Habenula, we focused our studies on the medial Habenula and its primary target, the interpeduncular nucleus. In addition, in wild-type mice chronically treated with nicotine, mecamylamine precipitated withdrawal when microinjected into the Habenula or the interpeduncular nucleus, but not into the cortex, ventral tegmental area or hippocampus.  

SSBP/1 prions produced abundant deposits of the disease-causing PrP isoform, denoted PrP(Sc), in the cerebellum and pons of Tg(ElkPrP) mice, whereas PrP(Sc) accumulation in Tg mice inoculated with sheep-passaged BSE prions was confined to the deep cerebellar nuclei, Habenula and the brainstem.  

GPR3 is an orphan G protein-coupled receptor endowed with constitutive Gs signaling activity, which is expressed broadly in the central nervous system, with maximal expression in the Habenula.  

PACAP binding sites were widely expressed in the brain of these two species with particularly high densities in the septum, hypothalamus and Habenula.  

Numerous GHRH-LP-immunoreactive fibers (also labeled by both antisera) probably originate from the gustatory/visceral nucleus to innervate the ventral area of the telencephalon, preglomerular nuclei, torus lateralis and hypothalamic diffuse nucleus, Habenula, torus semicircularis, and dorsolateral funiculus of the spinal cord.  

Moreover, this line also labels the Habenular complex and the domain of GFP expression is larger in the left than in the right Habenula.  

Retrogradely labeled neurons were observed in the medial prefrontal cortex, the lateral septum, the ventral pallidum, the bed nucleus of the stria terminalis, the substantia innominata, the medial and lateral preoptic areas, the lateral and dorsal hypothalamic areas, the lateral Habenula, the intermediate layers of the superior colliculus, the dorsal raphe, the periaqueductal gray, and the mesencephalic and pontine reticular formation. Projections from the prefrontal cortex, the hypothalamus, and the lateral Habenula to the tVTA were also shown by using the anterograde tracer biotinylated dextran amine (BDA).  

Strong inputs to the RMTg arise in the lateral Habenula (LHb) and, to a lesser extent, the SN.  

In contrast, medaka prox1b was expressed asymmetrically in part of the central nervous system, especially strongly in the right side of the Habenula..  

We suggest that, in Habenular cholinergic neurons, the beta3 subunit may be important for transporting the alpha3beta4* subtype from the medial Habenula to the IPn.  

Furthermore, a path analysis indicated that a network comprising lateral Habenula to dorsal raphe to hippocampus was effectively uncoupled in 13-cis-RA treated animals.  

In zebrafish Brachydanio rerio, this asymmetry is linked with neuroanatomical asymmetry of the Habenular complex (enlarged left lateral and right medial Habenular nuclei): if Habenular asymmetry is reversed, reader response to releasers shifts to the right eye. A known disturbance of gene (nrp1a) expression causes rerouting of the outflow of the left lateral Habenula to the way station of the right medial Habenula, providing a possible explanation of shifts.  

In the present study, we investigated the synaptic modulation of morphine to regulate excitatory synaptic transmission, probably glutamatergic transmission, in Habenular nucleus (Hb) and centrolateral nucleus (CL) neurons in the rat thalamus.  

Nicotine, compared to saline, when administrated 2 mins before [ 1-(14)C]AA infusion, significantly decreased k(*) for AA in 26 regions, including cerebral cortex, thalamus, and Habenula-interpeduncular regions, by 13% to 45%.  

High frequency stimulation was successfully applied in several small samples of patients with treatment-resistant depression when the stimulation focused on different areas, e.g., nucleus accumbens, the lateral Habenula or cortical areas.  

The Habenular complex of the epithalamus connects the limbic basal forebrain with numerous neuromodulatory centers in the midbrain. The Habenula consists of the medial and lateral nuclei, each of which is speculated to contain multiple subdivisions. Such anatomical arrangements raise the possibility that the Habenula accounts for multiple channels of information flow from the limbic forebrain to the midbrain. For understanding whether and, if so, how the multiple streams are organized via the Habenula, knowledge of the precise input-output connectivity of each Habenular subdivision is essential. In the present study, biotinylated dextran amine and cholera toxin subunit B were used to delineate the differential outputs of various subregions of the medial and lateral nuclei of the Habenula in the rat. Both anterograde and retrograde tracing uncovered a heavy commissural connection between the two Habenulae on the ipsilateral and contralateral sides. These projections produce terminal fields centered in different areas of the targets, supporting the topographically organized descending projections from the Habenula. These data together support the organization of multiple channels in the Habenula that convey parallel streams of information to the contralateral Habenula, midbrain, and brainstem..  

Lateral Habenula regulates the activity of dopamine neurons in the midbrain. Lateral Habenula neurons are excited while the unpredictable reward exists, and the dopamine neurons are strongly inhibited. Habenula can independently perform the reward function. Therefore Habenula may also be one of the center in the brain of homeostatic regulation..  

Hyperintensities were also observed in the olfactory bulbs, pituitary gland, optic nerves and chiasma, pons, midbrain tegmentum, Habenula, lentiform and caudate nuclei, thalamus, chorioid plexus and cerebellar hemispheres.  

The dorsal diencephalon, or epithalamus, contains the bilaterally paired Habenular nuclei and the pineal complex. The Habenulae form part of the dorsal diencephalic conduction (DDC) system, a highly conserved pathway found in all vertebrates. In this review, we shall describe the neuroanatomy of the DDC, consider its physiology and behavioural involvement, and discuss examples of neural asymmetries within both Habenular circuitry and the pineal complex.  

We found that these species share a strikingly conserved overall pattern of asymmetry in the parapineal-Habenular-interpeduncular system. Neuroanatomical asymmetries consist of left-sided asymmetric positioning and connectivity of the parapineal organ, enlargement of neuropil in the left Habenula compared with the right Habenula and segregation of left-right Habenular efferents along the dorsoventral axis of the interpeduncular nucleus.  

We found that the population of lateral Habenula neurons was most strongly excited by a conditioned stimulus associated with the most unpleasant event in each context: the absence of the reward or the presence of the punishment. The population of lateral Habenula neurons was also excited by the punishment itself and inhibited by the reward itself, especially when they were less predictable. These results suggest that the lateral Habenula has the potential to adaptively control both reward-seeking and punishment-avoidance behaviors, presumably through its projections to dopaminergic and serotonergic systems..  

In the zebrafish a key asymmetry is that of the Habenulae.  

A less well known fact is that the GPi also projects to the lateral Habenula (LHb) which is often associated with the limbic system.  

In this issue of Neuron, Hong and Hikosaka report on a little known projection from the monkey GPi to the lateral Habenula that is modulated by reward.  

Further maturation continued through pro-metamorphosis with the appearance of cell groups in the diagonal band, amygdala, pre-optic nucleus, dorsal nucleus of the Habenula, anterior ventral and dorsal thalamus, suprachiasmatic nucleus, tuberculum posterior, tectum, torus semicircularis, inter-peduncular nucleus and median eminence. During the metamorphic climax and soon after, the relative abundance of NPY-ir fibres decreased in all hypothalamic areas and the staining intensity and number of NPY-ir cells in the pallium also decreased, whereas no cells were found in the striatum, dorsal nucleus of the Habenula and tectum.  

The Habenula is uniquely positioned both anatomically and functionally to participate in the circuit mediating some forms of emotive decision making. In the last few years there has been a surge of interest in this structure, especially the lateral Habenula (LHb).  

GHB (500 mg/kg), but not baclofen (10 mg/kg), induced significant Fos expression in the median raphe nucleus and lateral Habenula, while a higher dose of GHB (1000 mg/kg) induced additional Fos expression in the islands of Calleja, dentate gyrus (polymorphic layer) and arcuate nucleus, and in various regions implicated in rapid and non-rapid eye movement sleep (laterodorsal tegmental nucleus, tuberomammillary nucleus and the ventrolateral and anterodorsal preoptic nuclei).  

Furthermore, the sensitized behavioral response was related to changes in Fos expression in the lateral shell of the nucleus accumbens, central nucleus of the amygdala and anteromedial part of the lateral Habenula.  

Because high densities of alpha3beta4 nicotinic receptors occur in the medial Habenula and the interpeduncular nucleus and moderate densities occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, the present study was conducted to determine if 18-MC could act in these brain areas to modulate methamphetamine self-administration in rats. Local administration of 18-MC into either the medial Habenula, the interpeduncular area or the basolateral amygdala decreased methamphetamine self-administration. In contrast, local administration of 18-MC and the other antagonists decreased sucrose self-administration when administered into the dorsolateral tegmentum or basolateral amygdala but had no effect when infused into the medial Habenula, interpeduncular nucleus, or ventral tegmental area.  

In the brain of zebrafish and medaka, in situ hybridization and laser capture microdissection coupled with real-time PCR showed kiss1 mRNA expression in the ventromedial Habenula and the periventricular hypothalamic nucleus. These results suggest that the Habenular Kiss1 and the hypothalamic Kiss2 are potential regulators of reproduction including puberty and that Kiss2 is the predominant regulator of gonadotropin synthesis in fish..  

Transient serotonin-immunoreactive cells were noted in the pineal organ, Habenula, and pretectum.  

Exposure to short photoperiod induced a major reduction in the expression of vasopressin in BNST neurons, as well as in their target areas, the lateral septum (LS) and the lateral Habenula (LHb).  

The lateral Habenula (HbL) receives noxious inputs and has an inhibitory influence on the nigral dopaminergic neurons.  

Double-labeling experiments revealed nNOS/ChAT-positive cells in (1) the diencephalon: the preoptic and suprachiasmatic nuclei, the Habenula, the dorsal thalamus, and the nucleus of the medial longitudinal fasciculus; (2) the mesencephalon: the optic tectum, the mesencephalic portion of the trigeminal nucleus, the oculomotor and trochlear nuclei, and the Edinger-Westphal nucleus; and (3) the rhombencephalon: the secondary gustatory nucleus, the nucleus isthmi, the lateral lemniscus nucleus, the cerebellum, the reticular formation, different nuclei of the octaval column, the motor zone of the vagal lobe, and the trigeminal, facial, abducens, glosso-pharyngeal, vagal, and hypobranchial motor nuclei.  

The medial Habenula (MHb) exhibits exceptionally high levels of nicotinic acetylcholine receptors (nAChRs), but it remains unclear whether all expressed nAChR subunit mRNAs are translated to form functional receptors.  

We recently showed evidence that the lateral Habenula transmits reward-related signals to dopamine neurons, especially to inhibit dopamine neurons. This recent study suggested that the lateral Habenula suppresses less rewarding saccadic eye movements by inhibiting dopamine neurons. In the present review, we first summarize anatomical and functional aspects of the lateral Habenula. Finally, we will discuss how the lateral Habenula, as well as dopamine neurons, contributes to the reward-based control of saccadic eye movements..  

High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial Habenula. LGR8 was also detected throughout the medial Habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites.  

Errors also evoked greater activity in the cuneus, retrosplenial cortex, insula, and subcortical structures including the thalamus and the region of the epithalamus (the Habenula).  

This enhancement of the indirect mechanism may be caused by a punishment-predictive signal which originates from the lateral Habenula and is mediated by dopamine neurons..  

Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral Habenula.  

Recently obtained evidence points to the involvement of the lateral Habenular nuclei (LHb) in the mediation of coping defensive responses to threatening/stressful stimuli.  

Activation of P2X receptors induces fast excitatory postsynaptic currents in synapses located in various brain regions, including medial Habenula, hippocampus and cortex.  

This minireview examines the roles of various nicotinic receptors in the mechanisms of nicotine dependence, discusses the potential role of the Habenula-interpeduncular nucleus axis in nicotine withdrawal, and highlights nicotinic receptors containing the beta4 subunit as a potential pharmacological target for smoking cessation strategies..  

Nerve processes were also missing from the auditory epithelium, with the exception of infrequent looping nerve processes above the Habenula perforata.  

While all four SSRIs similarly reduced rCMRglc in a network of subcortical brain regions including the amygdala, locus coeruleus, basal ganglia and hypothalamic paraventricular nuclei, fluvoxamine, paroxetine and sertraline reduced rCMRglc also in the hippocampus and sertraline in the lateral Habenula.  

Our findings here, however, indicate that this increase may involve active removal of a tonic inhibitory control on dopamine neurons exerted by the lateral Habenula (LHb).  

RESULTS: In this study, we use focal electroporation to examine the morphology and connectivity of individual neurons of the lateralized Habenular nuclei. Habenular projection neurons on both sides of the brain share a stereotypical unipolar morphology and elaborate remarkable spiraling terminal arbors in their target interpeduncular nucleus, a morphology unlike that of any other class of neuron described to date. We show that these differences in cell type composition account for the gross connectional asymmetry displayed by the left and right Habenulae. Analysis of the morphology and projections of individual post-synaptic neurons suggests that the target nucleus has the capacity to either integrate left and right inputs or to handle them independently, potentially relaying information from the left and right Habenulae within distinct downstream pathways, thus preserving left-right coding. However, following parapineal ablation, left and right Habenular neurons continue to elaborate arbors with distinct, lateralized morphologies.  

Litter presence before testing affected Fos expression due to handling or elevated plus-maze exposure only in the ventral bed nucleus of the stria terminalis, dorsal and ventral preoptic area, ventromedial hypothalamus, lateral Habenula, and supramammillary nucleus.  

Expression of the Slc10a4 protein was detected in motor regions of the spinal cord and rhombencephalon, as well as in mesopontine cholinergic neurons, the medial Habenula, cholinergic areas of the forebrain, and the gut myenteric plexus.  

The lateral Habenular complex (LHb) constitutes an important link in the dorsal diencephalic conduction system conveying information from limbic forebrain structures to regulatory midbrain nuclei. In line with the considerable number of biological functions in which the Habenula is thought to be involved, a complex subnuclear organization of the LHb has been suggested. However, the precise connectivity of Habenular subnuclei remains to be identified. This is the first comprehensive study so far to show that projections from LPOA subfields individually target subnuclei in the lateral Habenular complex..  

The VI was also not fused to the pineal gland or Habenula commissure but simply covered these structures.  

Here, we identify intermediate targets and signaling components acting on zebrafish Habenula commissural axons. Live imaging establishes that axons pause at the medial Habenula before and after crossing the roof plate. esrom mutants axons fail to advance beyond the ipsilateral medial Habenula. Consistent with signaling properties changing outside the roof plate, EphB is surface localized on axon segments within a zone demarcated by the medial Habenula. wnt4a is expressed in the medial Habenula and morpholino knockdown causes loss of the commissure. Electroporation of truncated Ryk causes axons to reenter the midline after reaching the contralateral Habenula.  

The Habenular nucleus (Hb) is closely connected with the DRN both morphologically and functionally. We investigated the effects of lateral Habenular nucleus (LHb) lesions on the behavioral response and on the level of 5-HT in DRN in the depressed rats.  

After 6 days, Mn2+ was injected into the Habenular nucleus (FR origin) of all animals, and MEMRI was repeatedly performed at certain points in time over 48 h.  

Recent evidence suggests that the lateral Habenular complex (LHb) is a source of negative reward signals in midbrain dopaminergic neurons. LHb activity, in turn, is modulated by locally released dopamine, which is largely derived from the ventral tegmental area (VTA) via the mesoHabenular pathway. About 47% (162) of retrogradely labeled cells displayed tyrosine hydroxylase immunoreactivity, suggesting that almost half of the mesoHabenular neurons are dopaminergic. The majority of LHb neurons, however, does not project to the origin of the mesoHabenular pathway in the anterior VTA.  

In contrast, the activation in Habenular nuclei and the midbrain periaqueductal gray were markedly decreased in STZ rats.  

MATERIAL AND METHODS: The manganese-enhanced MRI (MEMRI) method with direct injection of manganese chloride into the entopeduncular (EP), substantia nigra (SN), and the Habenula nuclei in unilateral 6-OHDA (N = 22) and sham-operated (N = 16) rat groups was used. RESULTS: Manganese injection into the EP nucleus resulted with bihemispheric signal enhancements in the Habenular complex (Hab) at both groups with stronger enhancements in the 6-OHDA group. SN manganese injection caused enhanced anteroventral thalamic and Habenular nuclei signals in the 6-OHDA rat group. Manganese Habenula injection revealed enhanced interpeduncular (IP) and raphe nuclei signals of the 6-OHDA rat group.  

The present experiment used electrolytic lesions in combination with curve-shift scaling to study the functional relation between the Habenula and four different brain sites that support operant responding for brain stimulation reward. Rats were implanted with a monopolar stimulation electrode aimed at the lateral hypothalamus, ventral tegmental area, dorsal raphe or median raphe nuclei, and a lesioning electrode in the ipsilateral Habenula. Testing resumed 24h after lesioning the Habenula (100 muA anodal current, 20-25s) and continued for 3-4 weeks. In five of these, Habenular lesions clearly reduced the rewarding effectiveness of the stimulation; reward thresholds increased by approximately 30-245% (0.12-0.54 log10 units). These results strongly suggest that the Habenula constitutes an important component of the neural circuitry important for brain stimulation reward..  

In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial Habenula (pKB = 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB = 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 receptors.  

SHBG uptake was seen in specific parts of the choroid plexus and periventricular cells as well as into cells in the paraventricular nucleus, the medial forebrain bundle, and the Habenula.  

Beta(1)- and beta(2)-ARs were immunolocalized to sites overlapping apical and basal poles of the inner and outer hair cells, putatively neural in part, with immunoreactive nerve fibers observed passing through the Habenula perforata.  

In the diencephalon, the cells were found in some nuclei of the preoptic area and hypothalamus, Habenula, pretectum, and dorsal and ventral thalamic regions.  

By using gramicidin-perforated patch recording in rat brain slices, we show that cells of the medial Habenula of the epithalamus generate tonic firing in basal conditions.  

Recent studies suggesting that the lateral Habenula (LHb) may contribute to this type of signaling in humans prompted us to evaluate the effects of LHb stimulation on the activity of dopamine and non-dopamine neurons of the anesthetized rat.  

The structures evaluated consisted of (A) the pineal gland, (B) the choroid plexus, (C) the Habenula, (D) the basal ganglia, (E) the tentorium cerebelli, sagittal sinus and falx cerebri, (F) vessels and (G) lens and other structures which could be calcified. Of the 1569 subjects, 71.0% had pineal calcification, 66.2% had choroid plexus calcification, 20.1% had Habenular calcification, 7.3% had tentorium cerebelli, sagittal sinus or falx cerebri calcifications, 6.6% had vascular calcification, 0.8% had basal ganglia calcification and 0.9% had lens and other non-defined calcifications.  

The dorsal diencephalon or epithalamus consists of the asymmetric pineal complex and adjacent paired nuclei, the left and right medial Habenulae, which in zebrafish larvae, exhibit differences in their size, neuropil density and patterns of gene expression. In all vertebrates, axons from the medial Habenular nuclei project within a prominent fiber bundle, the fasciculus retroflexus, to a shared midbrain target, the interpeduncular nucleus of the ventral tegmentum. However, in zebrafish, projections from the left Habenula innervate the dorsal and ventral regions of the target nucleus, whereas right Habenular efferents project only to the ventral region. A similar dorsoventral difference in Habenular connectivity is found in another teleost species, the highly derived southern flounder, Paralichthys lethostima. In this flatfish, directional asymmetry of the Habenular projection appears to be independent of the left-right morphology and orientation that an individual adopts post-metamorphosis. Comparative anterograde labeling of the brains of salamanders, frogs and mice reveals that axons emanating from the left and right medial Habenulae do not project to different domains, but rather, they traverse the target nucleus in a complementary mirror image pattern.  

Thus, in addition to the SCN, a number of areas of the mammalian brain including the olfactory bulb, amygdala, lateral Habenula and a variety of nuclei in the hypothalamus, express circadian rhythms in core clock gene expression, hormone output and electrical activity.  

18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial Habenula and interpeduncular nucleus.  

Here we show that the primate lateral Habenula, part of the structure called the epithalamus, is a major candidate for a source of negative reward-related signals in dopamine neurons. We recorded the activity of Habenula neurons and dopamine neurons while rhesus monkeys were performing a visually guided saccade task with positionally biased reward outcomes. Many Habenula neurons were excited by a no-reward-predicting target and inhibited by a reward-predicting target. Each time the rewarded and unrewarded positions were reversed, both Habenula and dopamine neurons reversed their responses as the bias in saccade latency reversed. In unrewarded trials, the excitation of Habenula neurons started earlier than the inhibition of dopamine neurons. Furthermore, weak electrical stimulation of the lateral Habenula elicited strong inhibitions in dopamine neurons. These results suggest that the inhibitory input from the lateral Habenula plays an important role in determining the reward-related activity of dopamine neurons..  

Both nuclei represent relatively small brain regions and both are controlled to some extent by the Habenular complex. We propose the hypothesis of an overactivation of the Habenula in human major depressive episodes (MDE's). Increased activation of the lateral Habenular nucleus leads to the down regulation of the serotonergic, noradrenergic, dopaminergic systems and stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Functional inhibition of the lateral Habenula via deep brain stimulation (DBS) has antidepressive properties. The hypothesis is based on the findings of a clinical imaging study examining the Habenular after tryptophan depletion and on several animal studies which are discussed.  

While there are very low densities of alpha3beta4 nicotinic receptors in the mesolimbic pathway, these receptors are prominently localized in the medial Habenula (MHb) and in the interpeduncular nucleus (IPN).  

Strong labeling was observed in the whole olfactory system, cortical layer VII, hippocampus, hypothalamus, cerebellum, Habenula, fasciculus retroflexus, and interpeduncular nucleus in adults.  

The Habenular complex is a paired structure found in the diencephalon of all vertebrates, linking the forebrain and midbrain. Habenulae are asymmetrical and may contribute to lateralized behavior. Recent studies in zebrafish have characterized molecular pathways that give rise to the Habenular asymmetry and the distinct projections of the left and right Habenula to the midbrain. However, it is unclear whether there are asymmetries in Habenula afferents from the forebrain. By lipophilic dye tracing, we find that axons innervating the Habenula derive primarily from a region in the lateral diencephalon containing migrated neurons of the eminentia thalami (EmT). EmT neurons terminate in neuropils in both ipsilateral and contralateral Habenula. These axons, together with axons from migrated neurons of the posterior tuberculum and pallial neurons, cross the midline via the Habenular commissure. Subsets of pallial neurons terminate only in the medial right Habenula, regardless of which side of the brain they originate from. These include an unusual type of forebrain projection: axons that cross the midline twice, at both the anterior and Habenular commissures. Our data establish that there is asymmetric innervation of the Habenula from the telencephalon, suggesting a mechanism by which Habenula asymmetry might contribute to lateralized behavior..  

Influences of the Habenular complex on electrophysiological and neurochemical aspects of brain functioning are well known. The Habenular complex, composed of medial and lateral subdivisions, is a node linking the forebrain with midbrain and hindbrain structures. The lateral Habenula is the principal actor in this direct dialogue, while the medial Habenula mostly conveys information to the interpeduncular nucleus before this modulates further regions. Here we describe neuroanatomical and physiological aspects of the Habenular complex, and its role in cognitive processes, including new behavioral, electrophysiological and imaging findings. Habenular complex lesions result in deficits in learning, memory and attention, some of which decline during repeated testing, while others become worse, consistent with multiple roles in cognition. The Habenular complex is particularly responsive to feedback about errors. These studies thus reveal important roles of the Habenular complex in learning, memory and attention..  

The expression of PPT A mRNA significantly decreased at 10d in most of the brain regions of MSG-treated mice including the cerebral cortex (CC), hippocampal subregions of CA1, CA2 (CA1, CA2), Habenula nucleus (HAB), hypothalamic periventricular nucleus (PE), hypothalamic arcuate nucleus (AR), median eminence (ME), amygdala nucleus (AMY), endopiriform nucleus (EN), and hypothalamic ventromedial nucleus (VMH) and dorsomedial nucleus (DMH).  

Fos-positive neurons were counted in a 0.3-mm(2) area from 5 regions previously shown to express T-induced Fos: the posteromedial bed nucleus of the stria terminalis (BSTPM), posteromedial amygdala (MeP), lateral Habenula (LHb), ventral tegmental area, and lateral pontine nucleus.  

The RLi also sends substantial projections to the magnocellular preoptic nucleus, lateral hypothalamus, central division of the mediodorsal thalamic nucleus, lateral part of the lateral Habenula and supraoculomotor region, and light projections to the prefrontal cortex, basolateral amygdala, and dorsal raphe nucleus. Overall, the data suggest that the RLi is a distinct VTA component in that it projects primarily to pallidal regions of the olfactory tubercle and to their diencephalic targets, the central division of the mediodorsal thalamic nucleus and the lateral part of the lateral Habenula.  

The medial Habenular nuclei of the zebrafish diencephalon, which lie bilateral to the pineal complex, exhibit left-right differences in their neuroanatomy, gene expression profiles and axonal projections to the unpaired midbrain target--the interpeduncular nucleus (IPN). Efferents from the left Habenula terminate along the entire dorsoventral extent of the IPN, whereas axons from the right Habenula project only to the ventral IPN. Prior to IPN innervation, we find that only the left Habenula expresses the zebrafish homologue of Neuropilin1a (Nrp1a), a receptor for class III Semaphorins (Sema3s). Loss of Nrp1a, through parapineal ablation or depletion by antisense morpholinos, prevents left Habenular neurons from projecting to the dorsal IPN. Conversely, Sema3D overexpression results in left Habenular projections that extend to the dorsal IPN, as well as beyond the target.  

The Habenular neurons on both sides of the zebrafish diencephalon show an asymmetric (laterotopic) axonal projection pattern into the interpeduncular nucleus. We previously revealed that the Habenula could be subdivided into medial and lateral subnuclei, and a prominent left-right difference in the size ratio of these subnuclei accounts for the asymmetry in its neural connectivity. Genetic hyperactivation and repression of Notch signaling revealed that differential timing determines both specificity and asymmetry in the neurogenesis of neural precursors for the Habenular subnuclei..  

The neuronal labeling was high in the neocortex, striatum, hippocampus, brain stem nuclei, deep cerebellar nuclei, catecholaminergic neurons, and reticular nuclei, and particularly high in neurons of the mesencephalic trigeminal nucleus and medial Habenular nucleus.  

The fraction of inward current carried by Ca(2+) (FCa(2+)) through nicotinic acetylcholine receptors (nAChRs) on acutely isolated rat medial Habenula (MHb) neurons was calculated from experiments that simultaneously monitored agonist-induced membrane currents and intracellular [ Ca(2+)], measured with patch-clamp and indo-1 fluorescence, respectively.  

The relationship between the concentration of intracellular Ca2+ ([ Ca2+](i)) and recovery from desensitization of nicotinic acetylcholine receptors (nAChRs) in rat medial Habenula (MHb) neurons was investigated using the whole cell patch-clamp techniques in combination with microfluorescent [ Ca2+](i) measurements.  

In the developing brain, drg11 expression is mainly restricted to sensory neuron populations of the midbrain and hindbrain, in cranial sensory ganglia and in the Habenula.  

nAChR expression was analyzed in cortex, hippocampus, thalamus and medial Habenula from autoradiograms using computer assisted image analysis. No effect of chronic nicotine on receptor expression was detected in the medial Habenula, suggesting that nicotine's effect was mainly on alpha4beta2-type heteromeric nAChRs.  

The SCN regulates many physiological events in the body via a network of efferent connections to areas of the brain such as the Habenula (Hb) in the epithalamus, subparaventricular zone (SPVZ) of the hypothalamus and locus coeruleus of the brainstem-areas of the brain associated with arousal and behavioral activation.  

PKR2 mRNA is detected throughout the brain, with prominent expression in olfactory regions, cortex, thalamus and hypothalamus, septum and hippocampus, Habenula, amygdala, nucleus tractus solitarius, and circumventricular organs such as subfornical organ, median eminence, and area postrema.  

PMNPQ and rolipram elevated FLI in the locus coeruleus, Habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, Habenula and nucleus accumbens in the anti-depressant activity of such compounds..  

Compared with ad libitum levels, food restriction decreased, and 90 min of refeeding reinstated, GnRH-II mRNA levels in midbrain and GnRH-II peptide in several target areas including the medial Habenula and ventromedial nucleus.  

The Habenula, paraventricular nucleus, infundibular recess nucleus and hypothalamo-hypophyseal tract presented denser innervations.  

Bnip3 mRNA was localized by in situ hybridization in the neonatal cortex, hippocampus, Habenula and thalamus.  

TH-positive neurons expressing neither AADC nor VMAT2 are termed "dopaergic TH neurons." We identified these neurons in supraoptic, paraventricular and periventricular hypothalamic nuclei, thalamic paraventicular nucleus, Habenula, parabrachial nucleus, cerebral cortex and spinal cord.  

Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral Habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral Habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets.  

We present preliminary evidence that Habenula projections to the midbrain are capable of producing a transient, but nearly complete, inhibition of dopamine neurons at a population level similar to that observed in behaving primates following an unexpected negative outcome. Human functional imaging studies offer further evidence that the Habenula is activated following receipt of unexpected negative feedback or the absence of expected positive feedback. We present initial evidence that patients with schizophrenia lack appropriate modulation of Habenula activity in response to feedback. Collectively, these data suggest that the Habenula may play a critical role in mediating the feedback-processing deficits of schizophrenia..  

Both the Habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the Habenula produce disturbances of memory and attention in experimental animals. As the Habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral Habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in Habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by Habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the Habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the Habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the Habenula is reported to exhibit exaggerated calcification..  

Previous anatomical and physiological studies have implicated the lateral Habenula, and especially its medial division (LHbM), as a candidate component of the circadian timing system in rodents. We assayed lateral Habenula rhythmicity in rodents using c-FOS immunohistochemistry and found a robust rhythm in immunoreactive cell counts in the LHbM, with higher counts during the dark phase of a light-dark (LD) cycle and during subjective night in constant darkness. Locomotor activity rhythms appear to be regulated by the suprachiasmatic nucleus (SCN) via multiple output pathways, one of which might be diffusible while the other might be neural, involving the lateral Habenula..  

By using immunofluorescent staining, we observed that K(+)-Cl(-) cotransporter isoform 2, GABA type A receptor beta2/3 subunits and a presynaptically localized glutamic acid decarboxylase isoform, glutamic acid decarboxylase 65, were all absent in adult Sprague-Dawley rat medial Habenular nucleus, while immunopositive staining for glutamic acid decarboxylase 67, GABA and GABA type B receptor type 2 subunit were present in the medial Habenular nucleus. Consistent with the lack of GABA type A signaling as detected by immunohistochemistry, GABA (100 muM) evoked no measurable currents in the medial Habenular nucleus but induced bicuculline-sensitive currents in the lateral Habenular nucleus and in the CA1 area of hippocampus. We also failed to record miniature inhibitory postsynaptic currents in medial Habenular nucleus neurons. These results support the idea that GABAergic transmission in medial Habenular nucleus is probably not mediated by any of the most common GABA type A receptor subtypes. Further exploration for factors determining medial Habenular nucleus neural inhibition will lead to a more complete understanding of control of synaptic balance in the CNS..  

This paper presents an overview on the epithalamus of vertebrates, with particular reference to the pineal and to the asymmetrical organization of the Habenular nuclei in lower vertebrates. The relationship between the pineal and the Habenulae in the course of phylogenesis is here emphasized, taking data in the frog as example. Altogether the data support the hypothesis, put forward also in earlier studies, of a correlation of Habenular asymmetry in lower vertebrates with phylogenetic modification of the pineal complex. The present re-visitation was also stimulated by recent data on the asymmetrical expression of Nodal genes, which involves the pineal and Habenular structures in zebrafish. In addition, in mammals, including rodents, a remarkable complexity has evolved in the organization of the Habenulae and their functional interactions with the pineal gland.  

Adenosine triphosphate (ATP) acts as a fast excitatory transmitter in several regions of the central nervous system (CNS) including the medial Habenula, dorsal horn, locus coeruleus, hippocampus, and somatosensory cortex.  

The total number of neurons in the medial and lateral Habenular nuclei of the rat epithalamus was estimated using modern stereological counting methods and systematic random sampling techniques. It was found that the right medial Habenular nucleus consisted, on average, of 18,000 neurons (with a coefficient of variation of 0.18), while the right lateral Habenular nucleus had 13,000 neurons on average (0.14).  

In the diencephalon, intensive staining was found in the nucleus of Bellonci, the dorsal Habenula, the lateral and central thalamic nuclei, and the subependymal zone of the third ventricle.  

Administration of biotinylated dextran amine into the vitreous body resulted in nerve cell body labeling in several structures: the supraoptic and paraventricular nuclei, the hippocampus (CA1, CA3), the dentate gyrus, the indusium griseum, the olfactory tubercle, and the medial Habenula, all of them belong to the limbic system.  

Because alpha3beta4 nicotinic receptors in the brain are preferentially located in the medial Habenula and the interpeduncular nucleus, the present study was conducted to determine if 18-MC could act in these brain areas to modulate morphine self-administration in rats. Local administration of 18-MC into either the medial Habenula or the interpeduncular area decreased morphine self-administration while having no effect on responding for a non-drug reinforcer (sucrose).  

None of these was associated with substantial ipsilateral loss of NT-ir in the VTA, lateral hypothalamus or lateral Habenula.  

Six hours after intracerebroventricular microinjection of MnCl2, T1-weighted 3D MRI (2.35 T) at 117 mum isotropic resolution revealed a continuous pattern of anterograde labeling from the Habenula via the fasciculus retroflexus to the interpeduncular nucleus.  

Furthermore, immunochemical staining of mouse brain revealed that Neurensin-1 and -2 had a similar distribution in many regions such as the Diagonal band, hippocampus, amygdaloid nucleus, and Habenula nucleus, but differed in the intracellular localization as follows: Neurensin-1 was found mainly in neuritic processes, while Neurensin-2 was found in cell bodies.  

Similar specializations with pronounced coclustering of the Kv4.2 and 4.3 subunits were observed between nerve cells in the medial nucleus of the Habenula.  

A similar trend was observed in other areas such as the lateral Habenula, somatosensory cortex and hippocampal regions (percentage changes of 27-41%), but these did not reach significance.  

The expression of pcp4a characterizes the dorsocaudal telencephalon, dorsal Habenula, pretectal nuclei, preglomerular complex, mammillary bodies, and deep layers of the optic tectum and is a hallmark of a subpopulation of reticulospinal neurons.  

We found that progesterone decreased AVP-ir labelling within the BST and CMA, as well as in two of the projection sites of these cells, the lateral septum and lateral Habenula.  

The Habenula complex modulates the activity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between Habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between Habenula lesions and stress that produces long-lasting effects on behavior. Mice received control lesions or bilateral electrolytic lesions of the Habenula and were tested for fear-potentiated startle and freezing measures of conditioned fear. There were no detectable effects of Habenula lesions on fear conditioning and no effects on PPI in the absence of stress. However, following conditioned fear stress, Habenula-lesioned animals showed decreased PPI which normalized with clozapine. These data support the hypothesis that the Habenula may be normally involved in stress-dependent regulation of monoamine systems..  

Overall, GnRH-I mRNA expression was greatest in the nucleus commissurae pallii (nCPa) and around the organum vasculosum lamina terminalis (OVLT), with less expression observed in the nucleus septalis lateralis (SL), cortico-Habenula cortico-septum area, and within the nucleus preopticus medialis.  

In late larvae, proliferation becomes confined to a few ventricular areas (medial pallium, caudal Habenula, ventral preoptic recess near the optic nerve, and tuberal portion of the posterior hypothalamic recess). During metamorphosis there appears to be no proliferation, but in upstream adults a few PCNA-ir cells are observed in the most caudal Habenula.  

Using immunohistochemistry, we detected that CRF-ir cell bodies exist in different brain regions: medulla oblongata (MO), midbrain tegmentum, Habenula, nucleus preopticus (NPO), and in a ventral hypothalamic region corresponding to the nucleus lateralis tuberis (NLTP).  

In situ hybridization indicated that Eif2s3x mRNA was expressed preferentially in specific brain regions including the Habenula, anterodorsal thalamic nucleus, hippocampus, hypothalamus, and cerebellum. Females had significantly higher levels of Eif2s3x mRNA expression than males in cortex, hippocampus and paraventricular nucleus but not in the Habenula.  

They fall into eight general categories: humeral sensory-related (subfornical organ and median preoptic nucleus, involved in initiating drinking behavior and salt appetite), neuroendocrine system (magnocellular: oxytocin, vasopressin; parvicellular: gonadotropin-releasing hormone, somatostatin, thyrotropin-releasing hormone, corticotropin-releasing hormone), central autonomic control network (central amygdalar nucleus, BST anterolateral group, descending paraventricular hypothalamic nucleus, retrochiasmatic area, ventrolateral periaqueductal gray, Barrington's nucleus), hypothalamic visceromotor pattern-generator network (five of six known components), behavior control column (ingestive: descending paraventricular nucleus; reproductive: lateral medial preoptic nucleus; defensive: anterior hypothalamic nucleus; foraging: ventral tegmental area, along with interconnected nucleus accumbens and substantia innominata), orofacial motor control (retrorubral area), thalamocortical feedback loops (paraventricular, central medial, intermediodorsal, and medial mediodorsal nuclei; nucleus reuniens), and behavioral state control (subparaventricular zone, ventrolateral preoptic nucleus, tuberomammillary nucleus, supramammillary nucleus, lateral Habenula, and raphé nuclei).  

These areas included the caudate putamen, nucleus accumbens, claustrum, medial Habenula, dorsal endopiriform nucleus, basolateral nucleus of the amygdala, hypothalamus, thalamus and ventral tegmental area.  

In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial Habenula and interpeduncular nuclei. To test this possibility, 18-MC was locally administered into the medial Habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial Habenula attenuated teeth chattering, burying, and weight loss.  

This immunoreactivity was also observed in extra-ependymal areas: in the internal granular layer of the olfactory bulbs in Triturus carnifex and Rana esculenta; in the diencephalic nuclei of the Habenula in Podarcis sicula, in both Amphibians and in Carassius carassius; in the mesencephalic tectum in Podarcis sicula and in the two Amphibians.  

Outside the SCN, visual inspection revealed an obvious left-right asymmetry of c-Fos expression in the medial preoptic nucleus and subparaventricular zone of split hamsters killed during the inactive phase and in the medial division of the lateral Habenula during the active phase (when the hamsters were running in their wheels). Roles for the dorsolateral SCN and the mediolateral Habenula in circadian timekeeping are not yet understood..  

In the current work, light and electron microscopic studies of the medial Habenula of the dove brain revealed that mast cell-derived material can enter neurons in three ways: by direct fusion of the granule and plasma membranes (mast cell and neuron); by capture of insoluble granule remnants and, potentially, via receptor-mediated endocytosis of gonadotropin-releasing hormone, a soluble mediator derived from the mast cell.  

The former include inputs to anterior hypothalamic nucleus, dorsomedial part of the ventromedial nucleus, and ventral region of the dorsal premammillary nucleus (defensive behavior control system components), and to lateral Habenula and dorsal region of the dorsal premammillary nucleus (foraging behavior control system components).  

In the diencephalon, the medial Habenula was most reactive followed by the reticular nucleus of the thalamus.  

The zebrafish epithalamus, consisting of the pineal complex and flanking dorsal Habenular nuclei, provides a valuable model for exploring how left-right differences could arise in the vertebrate brain. The parapineal lies to the left of the pineal and the left Habenula is larger, has expanded dense neuropil, and distinct patterns of gene expression from the right Habenula. Under the influence of Nodal signaling, positioning of the parapineal sets the direction of Habenular asymmetry and thereby determines the left-right origin of Habenular projections onto the midbrain target, the interpeduncular nucleus (IPN). In zebrafish with parapineal reversal, neurons from the left Habenula project to a more limited ventral IPN region where right Habenular axons would normally project. Conversely, efferents from the right Habenula adopt a more extensive dorsoventral IPN projection pattern typical of left Habenular neurons. Three members of the leftover-related KCTD (potassium channel tetramerization domain containing) gene family are expressed differently by the left and right Habenula, in patterns that define asymmetric subnuclei. Molecular asymmetry extends to protein levels in Habenular efferents, providing additional evidence that left and right axons terminate within different dorsoventral regions of the midbrain target. Laser-mediated ablation of the parapineal disrupts Habenular asymmetry and consequently alters the dorsoventral distribution of innervating axons.  

Zebra fish Mahya orthologues are expressed in the olfactory bulb, telencephalon, Habenula, optic tectum, and cerebellum of the brain.  

In contrast, spinal cord injury (SCI) resulted in strain-specific changes in forebrain activation categorized by structures that showed significant increases in: (1) only LE SCI rats (posterior, ventrolateral, and ventroposterolateral thalamic nuclei); (2) only SD SCI rats (anterior-dorsal and medial thalamus, basolateral amygdala, cingulate and retrosplenial cortex, Habenula, interpeduncular nucleus, hypothalamic paraventricular nucleus, periaqueductal gray); or (3) both strains (arcuate nucleus, ventroposteromedial thalamus, SI and SII somatosensory cortex).  

We used a combination of anterograde and retrograde tracing methods to show that the dorsal part of the reticular formation and the medial Habenula (MHb) project to the Uva.  

Congruent distribution patterns of Tac2 mRNA and NKB were found in many nuclei of the thalamus and hypothalamus (Habenula, anterodorsal nucleus, preoptic area, arcuate nucleus, paraventricular nucleus).  

Testosterone infusion induced Fos above control in the posteromedial bed nucleus of the stria terminalis (BSTPM), posteromedial amygdala (MeP), lateral Habenula (LHb), median raphe (MnR), lateral pontine nucleus (Pn), and ventral tegmental area (VTA).  

Thus, in zebrafish, cholinergic cells are absent from the Habenula and the rhombencephalic reticular formation, where such neurons are present in most vertebrate species analyzed. absence of cholinergic cells in the Habenula and their presence in the descendent octaval nucleus).  

The Habenula and interpeduncular nucleus (IPN) are part of a dorsal diencephalic conduction system which receives input from cholinergic, striatal, and hypothalamic areas, and sends output to several, disparate midbrain regions. The Habenula and IPN also project to the dorsal and medial Raphe nuclei, thought to be involved in mood and behavioral state regulation. Here, cells in both the Habenula and IPN were recorded in freely moving rats while they foraged for food pellets. Third, about 10% of the cells in the lateral Habenula showed a strong correlation between rate and angular head motion. This last finding may be related to work which shows an influence of the Habenula on locomotor activity, and in relation to the protective effects of exercise in relation to stress, as mediated by the Raphe nuclei..  

In addition, the Habenula and fascicules retroflexus in the right cerebral hemisphere degenerated and became intensely immunostained with the anti-phosphacan antibody shortly after hypoxia.  

Expression of c-Fos was examined in the lateral Habenula (LHb), a region important for conveying information between the limbic forebrain and midbrain.  

Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral Habenula, CA1 subfield of the hippocampus and median forebrain bundle.  

Placement into the novel environments also induced Fos expression in the Habenula and the paraventricular thalamic nucleus, but the response at these sites did not appear to be sensitive to cholinergic blockade.  

Moderate-dose ethanol also significantly lowered LCGU rates in the medial prefrontal cortex as well as in the Habenula of NP rats.  

However, there are also differences in the expression patterns, for example, high expression of MCHR1 was detected in the lateral Habenula, but no expression of MIZIP.  

Chronic administration of high doses of nicotine results in axonal degeneration in the central core of the fasciculus retroflexus, a fiber tract connecting the Habenulae (Hb) to the interpeduncular nucleus (IPN).  

NPY-ir cells were found in various locations including the TN, the medial zone of the area dorsalis telencephali, the ventral nucleus of the area ventralis telencephali, the Habenula, the dorsal posterior nucleus, the periventricular nucleus of the hypothalamus, the posterior tubercle, the optic tectum, and the lateral part of the tegmentum.  

In the midbrain, the epithalamus comprises the Habenular nuclei and the pineal gland. Recently, we showed that bilateral Habenula lesions in the rat induced some schizophrenia-like behavioural changes, namely memory and attention impairments, but unaltered social interaction in a brief encounter and prepulse inhibition (PPI) of the startle reflex. In the second, they were examined in rats with combined lesion of Habenula plus pinealectomy compared to sham-operated controls, to examine whether pinealectomy induced further deficits when combined with Habenula damage. Lesions of Habenula were confirmed histologically and neurochemically by reduction of choline acetyltransferase in the interpeduncular nucleus. Pinealectomy induced no deficits in any test, while combined lesions led to the same pattern of deficits as previously observed after Habenula lesion, i.e. Thus, loss of pineal function causes no deficits in these behaviours and does not alter the qualitative pattern of deficits resulting from Habenula damage..  

AChE-labeled cholinergic axons from dorsal lateral pontine tegmentum and from spinal cord sometimes formed this pattern, while axons from the Habenula failed to extend into the dentate gyrus.  

PTZ kindled animals mainly showed increased Fos IR in limbic regions, whereas Fos IR in nicotine kindled animals was increased in the entorhinal cortex, medial Habenula and the compact part of substantia nigra.  

Among its efferent targets are the Habenular nucleus (Hb), especially the lateral Hb (LHb), which plays an important role in conveying input from the limbic forebrain to midbrain structures. The Habenula may play a role in linking circadian and motivational systems and may contribute to photic regulation of these systems, as well as to the rhythmicity of their function..  

Differences in cytochrome oxidase activity in areas like the paraventricular hypothalamus, frontal cortex, Habenula, septum, and hippocampus correlate with differences in susceptibility to display learned helplessness, and differences in activity in the dentate gyrus and perirhinal and posterior parietal cortex correlate with differences in hyperactivity.  

Other brain regions implicated in LH and capable of affecting 5-HT systems, such as the bed nucleus of the stria terminalis (BNST), amygdala, and Habenula, could contribute to DRN 5-HT hyperactivity during uncontrollable stress. Wheel running, regardless of duration, did not affect c-Fos expression anywhere in the amygdala or Habenula.  

The Habenulae are part of an evolutionarily highly conserved limbic-system conduction pathway that connects telencephalic nuclei to the interpeduncular nucleus (IPN) of the midbrain . In zebrafish, unilateral activation of the Nodal signaling pathway in the left brain specifies the laterality of the asymmetry of Habenular size . We show "laterotopy" in the habenulo-interpeduncular projection in zebrafish, i.e., the stereotypic, topographic projection of left-sided Habenular axons to the dorsal region of the IPN and of right-sided Habenular axons to the ventral IPN. This asymmetric projection is accounted for by a prominent left-right (LR) difference in the size ratio of the medial and lateral Habenular sub-nuclei, each of which specifically projects either to ventral or dorsal IPN targets.  

The Habenular complex of the epithalamus in the mammalian brain receives input from the limbic forebrain and pallidum and, in turn, projects to numerous midbrain structures. Traditionally, the Habenular complex is divided into the medial nucleus and two divisions of the lateral nucleus. Based on their distinct input and output pathways, the Habenula is considered to constitute three, partially overlapping channels that regulate information flow from the limbic forebrain and pallidum to the midbrain. As a step to improve our understanding of how information delivered from the limbic forebrain and pallidum is processed in the Habenula, we examined the electrical property and morphology of medial and lateral Habenular cells. For this study, we generated live brain slices from rat Habenula and performed whole cell recording. During recording, we filled Habenular cells with biocytin. Medial Habenular cells generate tonic trains of action potentials, whereas lateral Habenular cells are capable of producing action potentials in burst mode. Lateral Habenular cells produce dendrites that are much longer than those of medial Habenular cells. Two distinct intrinsic circuits exist in the medial Habenular nucleus, whereas in the lateral Habenular nucleus, intrinsic axons travel largely from medial to lateral direction. The connection between the two Habenular nuclei is asymmetrical in that only the medial Habenula sends projection to the lateral Habenula. The differences in the electrical and morphological properties of medial and lateral Habenular cells indicate that the two nuclei process and integrate information in distinct fashions that is delivered from the limbic forebrain and pallidum..  

The sexually dimorphic extrahypothalamic arginine-vasopressin (AVP) projections from the bed nucleus of the stria terminalis to the lateral septum (LS) and lateral Habenula (LHb) are denser in males than females and, in rats, require males' perinatal exposure to gonadal hormones but the absence of such exposure in females.  

A smaller subset of regions affected in adults showed significantly less metabolic activity in the newborn brains, including paraventricular hypothalamus, Habenula, hippocampus, subiculum, lateral septal nucleus, anterior cingulate cortex, infralimbic cortex, and medial orbitofrontal cortex.  

This study was designed to investigate whether there are innate differences in NPY mRNA in cerebral cortical areas, dentate gyrus (DG) of the hippocampus and medial Habenular nucleus (MHb) between P and alcohol-nonpreferring (NP) rats, as these discrete brain regions are rich in NPY mRNA.  

The Habenular nuclear complex is a major influence on brainstem cell groups that influence attention, but its role in attentional performance has not previously been explored. The present study investigated how Habenula lesions affect attentional function as assessed by the 5-choice serial reaction time task (5-CSRTT) in male Lister-Hooded rats. Rats were pretrained in the 5-CSRTT before receiving discrete bilateral lesions of the Habenula or a sham procedure. These opposite time courses strongly imply that different mechanisms mediate these two effects of the Habenula lesion. The results are consistent with the view that elevated premature responding in Habenula-lesioned animals is mediated by increased dopaminergic activity, whereas impaired choice accuracy is not. Implications of these findings for the hypothesis that Habenula dysfunction is involved in cognitive symptoms of schizophrenia are discussed..  

By in vitro receptor autoradiography, high densities of cortistatin-14 and somatostatin-14 specific binding sites were detected in the cortex, hippocampal formation, basolateral amygdala and medial Habenula. In somatostatin receptor subtype-2 knock-out (KO) mice, autoradiographic iodinated somatostatin-14 binding was observed in the hippocampus and Habenula but was removed in the cortex and amygdaloid nuclei, specific iodinated cortistatin-14 binding sites were found in the hippocampus, Habenula and throughout the cortex.  

LY404187 (0.5 mg/kg) produced significant elevations in glucose utilization in 28 of the 52 anatomical regions analyzed, which included rostral neocortical areas and the hippocampus, as well the dorsal raphe nucleus, lateral Habenula, and locus coeruleus.  

This paper reviews Habenula (Hb) and interpeduncularis nucleus (IPN) literature from the perspective that the axial anatomy of Hb-IPN could be shared by numerous brain circuits that subserve diverse functions.  

METH was also more toxic than MDMA to dopamine terminals in the Habenula, and posterior retrosplenial cortex.  

In vivo studies revealed significant reduction of alpha3 mRNA levels in both thalamus and medial Habenula, regions known to express alpha3, following continuous (7 days) intracerebroventricular (i.c.v.) infusion of Isis 106567 in rats. Consistent with functional alpha3 knockdown, epibatidine-induced c-Fos expression in the medial Habenula was attenuated in aON-treated rats.  

These include the dorsal gray of the rostral spinal cord, the dorsal column nuclei, the octavolateral area, the nucleus of the solitary tract, the medial rhombencephalic reticular formation, the lateral tegmentum of the rostral rhombencephalon, the torus semicircularis, the optic tectum, the Habenula, the mammillary area, the dorsal thalamic area, the lateral hypothalamus, and the septum area.  

A significant increase of Fos immunoreactive cells were observed in the solitary tract nucleus, locus ceruleus, lateral parabrachial nucleus, ventrolateral part of central gray, medial amygdaloid nucleus, central amygdaloid nucleus, ventromedial part of thalamus, dorsomedial part of thalamus, hypothalamic paraventricular nucleus, lateral Habenula, and lateral septum nucleus following SEB challenge.  

central amygdala, lateral Habenula, dorsomedial caudate putamen) or sensitized (e.g. medial nucleus accumbens core, central amygdala, lateral Habenula) methamphetamine treatment were identified, thereby providing a comprehensive map of the short and long-term effects of methamphetamine on mouse brain activity per se.  

Nicotine-treated animals had a significantly higher maximal efflux in cerebral cortex and superior colliculus, but not in thalamus or interpeduncular nucleus plus medial Habenula. Binding was significantly increased after 2 weeks nicotine exposure in cortex, superior colliculus and thalamus, but not in interpeduncular nucleus plus medial Habenula.  

The spatial expression of the Php protein was in the neuronal fibers of the medial part of lateral Habenula nucleus, thalamus, hypothalamus, stria terminalis, zona incerta, amygdaloid body and cingulum, olfactory bulb, hippocampus, cerebral cortex and cerebellum.  

The Msx1 mutants display severe hydrocephalus at birth, while the subcommissural organ, the Habenula, and the posterior commissure fail to develop correctly.  

Electric stimulation also increased Fos-B immunoreactivity in the octavolateral and the Habenula-fasciculus retroflexus-interpeduncular systems. These results confirm that the octavolateral system is associated with electroreception and suggest that the Habenula-fasciculus retroflexus-interpeduncular system may be pan of the electroreceptive network..  

Following tracer injections into the lateral valvular nucleus, neurons were labeled in the ipsilateral dorsal part of dorsal telencephalic area, corpus glomerulosum pars anterior, dorsomedial thalamic nucleus, central nucleus of the inferior lobe, mammillary body, semicircular torus, valvular and cerebellar corpus, in the bilateral rostral regions of the central part of dorsal telencephalic area, dorsal region of the medial part of dorsal telencephalic area, Habenula, anterior tuberal nucleus, posterior tuberal nucleus, and spinal cord, and in the contralateral lateral funicular nucleus.  

Efferent projections of the ventral telencephalon terminate in the supracommissural nucleus of area ventralis telencephali, the posterior zone of area dorsalis telencephali, Habenula, periventricular pretectum, paracommissural nucleus, posterior dorsal thalamus, preoptic region, midline posterior tuberculum (especially the area dorsal to the posterior tuberal nucleus), tuberal (midline) hypothalamus and interpeduncular nucleus.  

Neuronal cell bodies containing ChAT are present in the telencephalon (lateral nucleus of ventral telencephalic area), preoptic region (anterior/posterior parvocellular and magnocellular preoptic nuclei), diencephalon (Habenula, dorsal thalamus, posterior tuberculum), mesencephalon (Edinger-Westphal (EW) nucleus, oculomotor nerve nucleus, rostral tegmental nucleus, tectal type XIV neurons), isthmic region (nucleus lateralis valvulae, secondary gustatory-viscerosensory nucleus, nucleus isthmi (NI), perilemniscal nucleus, superior reticular nucleus (SRN)) and rhombencephalon (trochlear, trigeminal, abducens, facial, glossopharyngeal-vagal motor nerve nuclei, rostral and caudal populations of octavolateralis efferent neurons).  

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