Lateral Hb Research Articles

Transcriptomic analysis of the human habenula in schizophrenia.

Transcriptomic analysis of the human habenula and identification of molecular changes associated with schizophrenia risk and illness state.

Association between increased inflammatory cytokine expression in the lateral habenular nucleus and depressive-like behavior induced by unpredictable chronic stress in rats

Depression induced by unpredictable chronic stress (UCS) has been widely studied using animal models. However, its underlying pathological mechanisms remain unclear. Increased inflammatory cytokines (ICs) in the central nervous system (CNS) are closely related to depressive disorder. UCS was used as an animal model in this study to investigate how UCS-induced changes in cytokine signaling lead to depression. We found that UCS could increase ICs in the CNS, especially in the habenular nucleus (Hb). UCS resulted in decreased expression of Menin in Hb and increased the activation of the NF-κB signaling pathway. Local administration of tumor necrosis factor-α in the lateral Hb (LHb) could induce depressive-like behavior in rats. The anti-inflammatory drug aspirin and the NF-κB inhibitor pyrrolidine dithiocarbamate could alleviate depressive-like behavior. This phenomenon was not observed for local administration in the dorsal raphe nucleus and paraventricular nucleus. These results indicate that LHb is the main central target for ICs to regulate depressive-like behaviors. We also found that LHb lesions could improve the inflammatory response in the hippocampus, reduce the activation of the NF-κB signaling pathway and the expression of ICs, and increase the expression of brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B, collectively improving the neuroinflammation caused by UCS. Moreover, LHb lesions improve not only hippocampal neurogenesis damage caused by UCS by activating the PI3K/mTOR signaling pathway but also hippocampal function by reducing the expression of apoptosis-related proteins, including phosphorylated p53, Bax, Bcl2, and cleaved-caspase3. In conclusion, our study sheds light on the pathogenesis of ICs-induced depression. Anti-inflammation in the CNS could be a new strategy in the treatment of depression.

Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation.

The habenula (Hb) is a bilateral, evolutionarily conserved epithalamic structure connecting forebrain and midbrain structures that has gained attention for its roles in depression, addiction, rewards processing, and motivation. Of its 2 major subdivisions, the medial Hb (MHb) and lateral Hb (LHb), MHb circuitry and function are poorly understood relative to those of the LHb. Prkar2a codes for cAMP-dependent protein kinase (PKA) regulatory subunit IIα (RIIα), a component of the PKA holoenzyme at the center of one of the major cell-signaling pathways conserved across systems and species. Type 2 regulatory subunits (RIIα, RIIβ) determine the subcellular localization of PKA, and unlike other PKA subunits, Prkar2a has minimal brain expression except in the MHb. We previously showed that RIIα-knockout (RIIα-KO) mice resist diet-induced obesity. In the present study, we report that RIIα-KO mice have decreased consumption of palatable, “rewarding” foods and increased motivation for voluntary exercise. Prkar2a deficiency led to decreased habenular PKA enzymatic activity and impaired dendritic localization of PKA catalytic subunits in MHb neurons. Reexpression of Prkar2a in the Hb rescued this phenotype, confirming differential roles for Prkar2a in regulating the drives for palatable foods and voluntary exercise. Our findings show that in the MHb decreased PKA signaling and dendritic PKA activity decrease motivation for palatable foods, while enhancing the motivation for exercise, a desirable combination of behaviors.

Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model.

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

Habenular connectivity may predict treatment response in depressed psychiatric inpatients

IntroductionThe habenula (Hb) is a small midbrain structure that signals negative events and may play a major role in the etiology of psychiatric disorders including depression. The lateral Hb has three major efferent connections: serotonergic raphe nuclei, noradrenergic locus coeruleus, and dopaminergic ventral tegmental area/substantia nigra compacta. We wanted to test whether Hb connectivity may be important to predict treatment outcomes in depression patients. MethodsWe studied whether habenular connectivity at admission into a psychiatric clinic can predict treatment response. We used an inpatient sample (N = 175) to assess habenular connectivity (diffusion tensor imaging and resting state functional connectivity (RSFC) between the Hb and its targets) close to admission. In addition, we obtained the Patient Health Questionnaire-depression module (PHQ-9) close to admission and at discharge. Inpatients in the study entered the clinic with at least moderately severe depression (score 15 and up). Inpatients considered treatment resistant had scores of 9 or more at discharge. ResultsCompared to responders, treatment non-responders had lower fractional anisotropy in the right Hb afferent fibers and lower RSFC between right Hb and median raphe, but higher RSFC between left Hb and locus coeruleus. A logistic regression model was significantly different from chance, and explained 27.7% of the variance in treatment resistance (sensitivity = 75%; specificity = 71.9%). DiscussionThe anatomical and functional connectivity of the Hb may be a predictor of treatment success in psychiatric populations. Limitations include the Hb small size and the limited time (5 min) of resting state data obtained.

An Evolutionary Hypothesis of Binary Opposition in Functional Incompatibility about Habenular Asymmetry in Vertebrates.

Many vertebrates have asymmetrical circuits in the nervous system. There are two types of circuit asymmetry. Asymmetrical circuits in sensory and/or motor systems are usually related to lateralized behaviors. It has been hypothesized that spatial asymmetry in the environment and/or social interactions has led to the evolution of asymmetrical circuits by natural selection. There are also asymmetrical circuits that are not related to lateralized behaviors. These circuits lie outside of the sensory and motor systems. A typical example is found in the habenula (Hb), which has long been known to be asymmetrical in many vertebrates, but has no remarkable relationship to lateralized behaviors. Instead, the Hb is a hub wherein information conveyed to the unilateral Hb is relayed to diverging bilateral nuclei, which is unlikely to lead to lateralized behavior. Until now, there has been no hypothesis regarding the evolution of Hb asymmetry. Here, we propose a new hypothesis that binary opposition in functional incompatibility applies selection pressure on the habenular circuit and leads to asymmetry. Segregation of the incompatible functions on either side of the habenula is likely to enhance information processing ability via creating shorter circuits and reducing the cost of circuit duplication, resulting in benefits for survival. In zebrafish and mice, different evolutionary strategies are thought to be involved in Hb asymmetry. In zebrafish, which use a strategy of structurally fixed asymmetry, the asymmetrical dorsal Hb leads to constant behavioral choices in binary opposition. In contrast, in mice, which use a strategy of functionally flexible lateralization, the symmetrical lateral Hb is functionally lateralized. This makes it possible to process complicated information and to come to variable behavioral choices, depending on the specific situation. These strategies are thought to be selected for and preserved by evolution under selection pressures of rigidity and flexibility of sociability in zebrafish and mice, respectively, as they are beneficial for survival. This hypothesis is highly valuable because it explains how the Hb evolved differently in terms of asymmetry and lateralization among different species. In addition, one can propose possible experiments for the verification of this hypothesis in future research.

Habenula: Recently recognized functions and potential clinical relevance.

The habenula (Hb) (from the Latin, little rein) is a phylogenetically old structure located in the dorsomedial portion of the thalamus and is an important link between the forebrain and brainstem monoaminergic nuclei. The Hb includes 2 subdivisions—lateral and medial—which differ in their neurochemical characteristics and connectivity. The lateral Hb receives inputs from the cerebral cortex, lateral hypothalamus, and globus pallidus (GP) and exerts an inhibitory modulation both on dopaminergic neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and on serotonergic neurons of the median and dorsal raphe nuclei. This inhibitory effect is primarily mediated by γ-aminobutyric acid (GABA)ergic neurons located in the rostromedial tegmental nucleus (RMTg). The medial Hb receives its main inputs from the medial septum and projects to the interpeduncular nucleus (IPN), which in turn controls the activity of monoaminergic brainstem nuclei. Via all these connections, the Hb has a major role in emotional regulation of behavior. For example, the lateral Hb processes negative emotional state information (including disappointment, punishment, and pain) and inhibits the SNc/VTA neurons involved in learning and motivation. Both the lateral Hb and the medial Hb may also participate in sleep regulation, pain modulation, and the mechanism of drug addiction. Neuroimaging studies allow identification of the Hb and its main connections in humans, and showed its activation in response to negative emotions or pain. The increasing interest in the physiology of the Hb and its involvement in neurologic and psychiatric disease is reflected by a large number of recent reviews.1–9

Comparison of Two Scoring Systems for Evaluation of Treatment Outcome in Patients with Complete Bilateral Cleft Lip and Palate

To compare two scoring systems: the Huddart/Bodenham system (HB system) and the Bauru-BCLP yardstick (BCLP yardstick), which classify treatment outcome in terms of dental arch relationships in patients with complete bilateral cleft lip and palate (CBCLP). The predictive value of these scoring systems for treatment outcome was also evaluated. Retrospective longitudinal study. Dental arch relationships of 43 CBCLP patients were evaluated at 6, 9, and 12 years. Setting : Treatment outcome in BCLP patients using two scoring systems. For each age group, the HB scores were correlated with the BCLP yardstick scores using Spearman's correlation coefficient. The predictive value of the two scoring systems was evaluated by backward regression analysis. Intraobserver Kappa values for the BCLP yardstick scoring for the two observers were .506 and .627, respectively, and the interobserver reliability ranged from .427 and .581. The intraobserver reliability for the HB system ranged from .92 to .97 and the interobserver reliability from .88 to .96. The BCLP yardstick scores of 6 and 9 years together were predictors for the outcome at 12 years (explained variance 41.3%). Adding the incisor and lateral HB scores in the regression model increased the explained variance to 67%. The BCLP yardstick and the HB system are reliable scoring systems for evaluation of dental arch relationships of CBCLP patients. The HB system categorizes treatment outcome into similar categories as the BCLP yardstick. In case a more sensitive measure of treatment outcome is needed, selectively both scoring systems should be used.

Circadian firing-rate rhythms and light responses of rat habenular nucleus neurons in vivo and in vitro

The suprachiasmatic nuclei of the anterior hypothalamus serve as the principal pacemaker of the mammalian circadian system. 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. We recorded extracellularly from single neurons in the LHb and medial Hb (MHb), both in vivo and using an in vitro slice preparation, to assess their responses to retinal illumination and the rhythmicity of their firing rates. Of cells recorded in the LHb, 42% were tonically activated or suppressed by retinal illumination, while significantly fewer cells recorded in the MHb responded to retinal illumination (19%). Of photically responsive cells, 68% in the LHb were activated and the remainder suppressed, while only 25% of those recorded in the MHb were activated. Cells in both the LHb and MHb showed higher baseline firing rates during the day than during the night in vivo, while photic responses were of significantly larger amplitude among LHb cells during the projected night than during the projected day. LHb cells recorded in vitro maintained their rhythmicity for two circadian cycles, but MHb cells did not show a rhythm in vitro. 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.

Tooth pulp stimulation induces c-fos expression in the lateral habenular nucleus of the cat.

Detection of Fos protein expression by the peroxidase-antiperoxidase method was used to determine the area in the habenular (Hb) complex responding to electrical stimulation of the tooth pulp in the cat anaesthetized with pentobarbital. In the anaesthetic-injected group, the Fos-positive neurones were found bilaterally in the lateral Hb nucleus (HbL). Tooth pulp stimulation (intensity: 3 times the threshold for jaw-opening reflex) increased the number of positive neurones within the HbL by up to 300%, but did not induce any expression in the medical Hb nucleus. The increase in HbL was inhibited by morphine (2 mg kg-1, i.p.). These findings and the results of previous research suggest that HbL neurones are involved in defensive mechanisms by means of antinociception following noxious stimulation.

Demonstration of habenular neurons which receive afferent fibers from the nucleus accumbens and send their axons to the midbrain periaqueductal gray

After injecting Phaseolus vulgaris leucoagglutinin (PHA-L) and wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP), respectively, into the medial part of the nucleus accumbens (NA) and the midbrain periaqueductal gray including the dorsal raphe nucleus (PAG/DR) on one side of single rat brains, we observed that axon terminals labeled anterogradely with PHA-L made possible synaptic contact with neurons in the habenula (Hb) which were retrogradely labeled with WGA-HRP. These Hb neurons were distributed in the medial part of the lateral Hb. The results indicate that the medial part of the lateral Hb relays neuronal information from the medial part of the NA to the PAG/DR.

Origin and distribution of noradrenergic innervation in the habenula: A neurochemical study

The distribution of norepinephrine (NE) was chemically mapped in discrete regions of the rat habenula (Hb). In addition, the contribution of both peripheral sympathetic and central noradrenergic sources to habenula NE was quantified following selective deafferentations. It was found that NE is distributed hetereogeneously in discrete Hb regions. Furthermore, it was demonstrated that after superior cervical ganglionectomy a small (26%) but significant (P<0.05) decrease in NE occurred only in the medial Hb (MHb), while NE in the lateral Hb (LHb) remained unaltered. In contrast, deafferentation of central noradrenergic innervation, such as lesions in the ascending dorsal noradrenergic bundle (DNB), caused a marked decrease in NE in both MHb (53%) and LHb (50%). Lesioning the dorsal longitudinal fasciculus resulted in NE loss in both MHb and LHb by 31%. These data corroborate the histofluorescent demonstration of the noradrenergic innervation of the Hb.

Afferent connections of the interpeduncular nucleus and the topographic organization of the habenulo-interpeduncular pathway: an HRP study in the rat.

The HRP tracing method was employed to investigate the organization and afferent connections of the interpeduncular nucleus (IPN) in the rat. To study the topographical features of the different projections, a method was devised for obtaining HRP placements of limited size in different areas of the IPN. The main afferent connection of the IPN is a topographically organized projection from the medial habenula (Hb). This projection follows a reversed caudorostral pattern, terminating throughout all but the caudalmost part of the IPN. The dorsal part of the IPN receives a sparse innervation arising mainly from a narrow lateral and ventrolateral area of the medial Hb. The ventral two thirds of the IPN receives a much heavier projection, as follows: A large ventrolateral area of the medial Hb projects to the lateral part of the IPN in a completely bilateral way. An additional projection, which is predominantly ipsilateral, arises from the rostral half of the dorsolateral part of the medial Hb and terminates in the caudal IPN. The medial part of the medial Hb projects preferentially to central areas of the IPN. The projection from the lateral Hb is quantitatively much smaller but appears to be distributed to the entire length of the IPN, following a nonreversed caudorostral arrangement, with the ipsilateral projection predominating. The projections from the medial and lateral Hb to the IPN were confirmed by tracing anterogradely transported HRP as well. No reciprocal connection from the IPN to the Hb could be demonstrated. A sparse projection to the IPN with a strong ipsilateral predominance arises from the horizontal limbs of the nucleus of the diagonal band of Broca. This was the only projection observed from the septal region. Sparse projections from the premammillary and supramammillary nuclei were also demonstrated. Confirmatory data and some details of organization were also obtained for projections to the IPN from other areas, including the medial and dorsal raphe nuclei, the dorsal tegmental nucleus of Gudden, and the adjacent dorsolateral tegmental nucleus. Very small projections from the ventral tegmental nucleus and the locus coeruleus were also found.