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Sexual dimorphism of newborn mouse epithalamus after fractionated X-irradiation at late stage of organogenesis.

Fractionated X-irradiation with 3 x 0.95, 3 x 1.05, 3 x 1.15, or 3 x 1.35 Gy on gestational days 11-13 in the mouse results in two discrete, clearly distinguishable forms of an epithalamic malformation observable on gestational day 18. Type A is characterized by a rhombic shape of the dorsal diencephalic sulcus which first narrows at the occipital edge. The habenular diameters in the plane of the habenular commissure are in the range between 81 and 88% of the control measurements. The anterior colliculi are quite well developed. The type B lesion is characterized by a rather narrow epithalamus with a sandglass-shaped dorsal diencephalic sulcus and habenular diameters that are only about 56 to 64% of the control values. With the exception of the group with the lowest radiation dose (3 x 0.95 Gy), the type B lesion predominates. The B:A ratios are 1.5 and 1.6 in the highest dosage groups, and show the most drastic increase to a ratio of 4.0 after application of 3 x 1.05 Gy. Type B lesions occur in female fetuses at a higher frequency than in males and thus shows a clear-cut correlation with the frequency and severity of neocortical lesions in the same individuals. This is again most marked in the 3 x 1.05 Gy dosage group, where the type B lesion occurs five times more frequently in females than in males. This sexual dimorphism in the reaction pattern of the epithalamus after X-irradiation in utero, can best be explained by postulating a causal link with the forebrain lesions which were recently shown to exhibit similar sexual dimorphism. We therefore postulate a retrograde transsynaptic degeneration of the thalamo-cortical fibres that develop pre-term, which is significantly expressed only after a low X-irradiation dose, but is partly abolished in the higher dosage groups. This leads to hypoplastic alterations of the epithalami, a secondary phenomenon to the neocortical lesions in the animals most affected. The resulting dysfunction of the epithalamus in the immediate neonatal period is then responsible for the preferential death of the animals with B-type lesions and also explains why female mortality is significantly higher than male mortality which occurs only in the 3 x 1.05 Gy dosage group.

Abnormalities, Radiation-Induced↗

Epithalamus calcifications in schizophrenia.

We evaluated the prevalence and the size of epithalamus calcifications (EC) and choroid plexus calcifications (CPC) on computed tomography (CT) scans in a group of 64 schizophrenic patients and in a group of 31 healthy controls. The associations between cerebral calcifications, demographic variables, and other brain morphological characteristics (particularly cerebral ventricular size and cortical atrophy) in both, patients and controls, were also considered. A significant increase in size of the epithalamic-region calcifications in schizophrenic patients was found, whereas there was no evidence of increase in both, dimension and prevalence, of choroid plexus calcification. Such dimensional increase was unrelated to the duration of illness and therefore did not seem to be iatrogenic or secondary to the disease. A correlation was found between epithalamus calcifications and cortical atrophy and third-ventricle enlargement, suggesting that calcifications of this cerebral region may be associated with lesions of third-periventricular areas and of circuitries hypothesized to be involved in the pathophysiology of schizophrenia.

Adolescent↗

Asymmetry in the epithalamus of vertebrates.

The epithalamus is a major subdivision of the diencephalon constituted by the habenular nuclei and pineal complex. Structural asymmetries in this region are widespread amongst vertebrates and involve differences in size. neuronal organisation, neurochemistry and connectivity. In species that possess a photoreceptive parapineal organ, this structure projects asymmetrically to the left habenula, and in teleosts it is also situated on the left side of the brain. Asymmetries in size between the left and right sides of the habenula are often associated with asymmetries in neuronal organisation, although these two types of asymmetry follow different evolutionary courses. While the former is more conspicuous in fishes (with the exception of teleosts), asymmetries in neuronal organisation are more robust in amphibia and reptiles. Connectivity of the parapineal organ with the left habenula is not always coupled with asymmetries in habenular size and/or neuronal organisation suggesting that, at least in some species, assignment of parapineal and habenular asymmetries may be independent events. The evolutionary origins of epithalamic structures are uncertain but asymmetry in this region is likely to have existed at the origin of the vertebrate, perhaps even the chordate, lineage. In at least some extant vertebrate species, epithalamic asymmetries are established early in development, suggesting a genetic regulation of asymmetry. In some cases, epigenetic factors such as hormones also influence the development of sexually dimorphic habenular asymmetries. Although the genetic and developmental mechanisms by which neuroanatomical asymmetries are established remain obscure, some clues regarding the mechanisms underlying laterality decisions have recently come from studies in zebrafish. The Nodal signalling pathway regulates laterality by biasing an otherwise stochastic laterality decision to the left side of the epithalamus. This genetic mechanism ensures a consistency of epithalamic laterality within the population. Between species, the laterality of asymmetry is variable and a clear evolutionary picture is missing. We propose that epithalamic structural asymmetries per se and not the laterality of these asymmetries are important for the behaviour of individuals within a species. A consistency of the laterality within a population may play a role in social behaviours between individuals of the species.

Amphibians↗

Neurogenesis in the epithalamus, dorsal thalamus and ventral thalamus of the rat: an autoradiographic and cytological study.

Times of final mitotic division for neurons of the epithalamic, dorsal thalamic and subthalamic nuclei of the rat were determined with the aid of thymidine-H3 autoradiography. Intensely labelled neurons were observed in the brains of animals injected with radiochemical from days 13 to 19 of gestation. The pattern of distribution of the labelled neurons indicated that neurogenesis in the regions followed caudorostral, lateromedial and ventrodorsal neurogenetic gradients, all of which were found to operate simultaneously. Since neurogenesis in the epithalamus, subthalamus and caudolateral thalamic regions began on days 13 and 14 of gestation, the ventrodorsal and lateromedial proliferative gradients were clearly discerned only within the ventral and dorsal thalamus exclusive of the epithalamus. These directional neurogenetic gradients were apparent throughout the entire thalamus and within individual thalamic nuclei. No neurogenetic pattern based upon neuronal size was observed, i.e., large neurons were not preferentially formed earlier than smaller ones. Detailed information has also been provided on the cytological character of each thalamic nucleus.

Animals↗

Epithalamus of the nine-banded armadillo, Dasypus novemcinctus.

The epithalamus of embryonic, neonatal and adult nine-banded armadillo (Dasypus novemcinctus) was examined for evidence of pineal-like tissue. The evagination of the diencephalic roof (the anlage of the epiphysis) was not found in any embryonic specimens. In the adult brain, the epithalamus is dominated by the sub-commissural organ (SCO) which is surrounded entirely by the posterior commissure. At the most caudal aspect of the SCO, previous investigators have observed pineal-like tissue. Using pineal-specific staining techniques however, we found no evidence of this tissue. Because the armadillo produces melatonin in a rhythmic manner, exhibits exacting circadian rhythms, and shows altered rhythms when exposed to exogenous melatonin, we believe other organs, perhaps the retina or Harderian gland, must be involved in maintaining the coordinated melatonin titer.

Animals↗

The morphology of the diencephalon in the Prosimii. II. The Lemuroidea and Lorisoidea. Part II. Epithalamus, subthalamus and hypothalamus.

This study (Part II) deals with the comparative structure of the epithalamus, subthalamus and hypothalamus. The same prosimian species used in the study of the thalamus and metathalamus (Part I) are used here. The epithalamus does not show any remarkable change in the phylogeny of the prosimian diencephalon. In the subthalamus, the nucleus subthalamicus enlarges progressively in size, and shows a very close relationship to the zona incerta, the fields of Forel and the pregeniculate body. The zona incerta is observed to consist of two parts the ventral part relating to the nucleus subthalamicus and the dorsal part ot the nucleus reticularis. The fields of Forel is well differentiated into fields H1 and H2. The hypothalamus is described here having four regions--preoptic, suraoptic, infundibular and mamillary. The preoptic and supraoptic regions appear to be indivisible in all prosimian species, for the constituent nuclei of both regions extend rostrally and caudally in the anterior part of the hypothalamus. The nucleus supraopticus is evidently complicated in structure, as it appears not only to have two separate parts, but also an isthmus that connects these parts. This interlinking strand of cells is termed not the nucleus supraopticus diffuses but the nucleus/area commissuralis postopticus. The nucleus paraventricularis is a massive nucleus, and appears to have a non-neurosecretory part and a neurosecretory part. An interesting feature has been observed in certain prisimian species such as Galago demidovii, Lepilemur and Loris gracilis, the nucleus paraventricularis accessorius which may be regarded as an erratic derivative of either nucleus paraventricularis or nucleus supraopticus. The nucleus tuberalis lateralis makes its first definitive appearance in the Prosimii. The nucleus ventromedialis hypothalami appears to be larger and more clearly defined than the nucleus dorsomedialis hypothalami. From the latter nucleus, a cellular condensation has been observed to stretch lateralwards--nucleus dorsolateralis hypothalami. The hypothalamic areas--anterior, dorsal, lateral and posterior--are not very much different among the prosimian species, although the anterior and posterior hypothalamic areas appear to have more attributes of a nucleus than an area. The mamillary region is very well developed in all prosimian species. The medial mamillary nucleus is clearly divided into several parts. The nucleus mamillaris lateralis is poorly developed, but can be identified lying between the lateral part of the medial mamillary nucleus and the nucleus intercalatus. In regard to the latter nucleus, there is some topographical confusion, but the nucleus intercalatus is easily identified as the bed nucleus of the supramamillary commissure.

Animals↗

The diencephalon of the vervet monkey (Cercopithecus aethiops). Part II: epithalamus, subthalamus and hypothalamus.

The nuclear configuration and topography of the epithalamus, subthalamus and hypothalamus of the vervet monkey (Cercopithecus aethiops) are described and compared with those of other primates, particularly the macaque monkey. The epithalamus does not show any striking structural differences, except some architectonic differentiation in the lateral habenular nucleus. The subthalamus is a phylogenetically stable structure throughout the primate scale; it does not show any significant changes, except that it extends less rostrally and that the nuclei entopeduncularis and peripeduncularis are much smaller and less well defined in the vervet monkey than those in the diencephalon of lower primates. The nucleus subthalamicus and the fields of Forel, though small in size, are comparatively well developed; the zona incerta appears to be differentiated cytoarchitectonically into two parts. The hypothalamus is divided morphologically into four regions--the preoptic, supraoptic, infundibular and mamillary regions. Although the hypothalamus of the vervet monkey is topographically identifiable with those of other primates, there are cyto- and myeloarchitectonic differences to be found in certain hypothalamic nuclei and areas. The preoptic region is small and poorly delimited from the parolfactory region antierorly and the supraoptic region posteriorly. The nucleus paraventricularis is large and well differentiated into secretory and non-secretory portions; the nucleus supraopticus does not show cellular separation into dorsolateral and ventromedial parts as clearly as they are in other primates. The nucleus dorsomedialis is not as well defined as the nucleus ventromedialis like it is in other primates. The nucleus tuberalis lateralis is comparably small, and is not split into several cellular groups as it is in higher primates. The posterior hypothalamic area is morphologically the best definable of the hypothalamic areas. The mamillary region is developmentally advanced, and very well differentiated into medial, lateral and intercalated nuclei.

Animals↗

Impaired cognitive performance in rats after complete epithalamus lesions, but not after pinealectomy alone.

In the midbrain, the epithalamus comprises the habenular nuclei and the pineal gland. Based on evidence including imaging studies in schizophrenia patients, several investigators have postulated that dysfunction of this structure is causally involved in symptoms of schizophrenia. 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. Here, the possible involvement of the pineal gland in the same behaviours was assessed, by examining them in two series of experiments. In the first, these behaviours were examined in pinealectomized rats compared to sham-operated controls. 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 was confirmed post mortem by careful visual inspection. 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. marked memory impairment in the Morris water maze without affecting the amount of social interaction or PPI of the startle reflex. Thus, loss of pineal function causes no deficits in these behaviours and does not alter the qualitative pattern of deficits resulting from habenula damage.

Acoustic Stimulation↗

The epithalamus of the developing and adult frog: calretinin expression and habenular asymmetry in Rana esculenta.

Expression of the calcium binding protein (CaBP) calretinin (CR) was studied with immunohistochemistry in the pineal complex and habenular nuclei (HN) of the developing and adult frog Rana esculenta. The frog pineal complex is a medial structure formed by two interconnected components, the frontal organ and the pineal organ or epiphysis; the habenular nuclei are bilateral and are asymmetric due to subdivision of the left dorsal nucleus into medial and lateral components. In the pineal complex, calretinin immunostaining of cells and fibers was consistently observed in developing and adult frogs. In the habenulae, calretinin immunoreactivity exhibited instead marked variations during development, and was expressed only in cells of the medial subnucleus of the left dorsal habenula. In particular, calretinin was detected at larval stages, peaked during metamorphosis, was markedly downregulated at the end of metamorphosis, and was evident again in adulthood. This sequence of calretinin expression was confirmed by quantitative analysis of immunoreactive cells in the left habenula. In tadpoles, calretinin-positive cells exhibited a dorsoventral gradient of density, while in adulthood, they were distributed throughout the dorsoventral extent of the medial subnucleus. The study demonstrates a peculiar developmental pattern, with transient downregulation, of asymmetric calretinin expression in the frog epithalamus. The findings indicate that calcium and calcium buffering systems may play critical roles in neurogenetic and neuronal migration processes implicated in the formation of the asymmetric habenular portion in amphibians. In addition, the reappearance of calretinin expression in the adult frog supports a distinct functional role of the asymmetric habenular component in amphibians.

Animals↗

Parapineal specific expression of gfi1 in the zebrafish epithalamus.

We describe the isolation of zebrafish growth factor independent 1 (gfi1) and present an analysis of its pattern of expression during early development. As with its murine homologue, gfi1 expression is detected in the ganglion cells of the neural retina and in developing hair cells of the ear. In keeping with a role in the development of sensory hair cells, gfi1 is also expressed in neuromasts of the anterior and posterior lateral line system. Finally, gfi1 is expressed in the developing epithalamus in the dorsal diencephalon where its transcription is restricted to the parapineal.

Amino Acid Sequence↗

Directional asymmetry of the zebrafish epithalamus guides dorsoventral innervation of the midbrain target.

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. The results demonstrate that laterality of the dorsal forebrain influences the formation of midbrain connections and their molecular properties.

Animals↗

Dendritic morphology, local circuitry, and intrinsic electrophysiology of neurons in the rat medial and lateral habenular nuclei of the epithalamus.

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.

Action Potentials↗

The rat epithalamus. I. Correlative scanning-transmission electron microscopy of supraependymal nerves.

Transmission and scanning electron microscopy of the rat epithalamus shows a regional variation in the distribution of supraependymal nerves (SN) which correlates well with supraependymal yellow fluorescence reported by Richards et al. (1974). The medial habenular nucleus, the intercommissural and suprahabenular recesses, the habenular commissure and the fibrae periventriculares thalami have the greatest density of SN/100micron of ependymal surface. The floor of the suprahabenular and intercommisural recesses is covered by non-ciliated ependyma. The significance of these findings is discussed with respect to (1) a direct functional relationship of SN with ependyma, and (2) a possible participation of the non-ciliated ependyma of the suprahabenular and intercommissural recesses in secretory activity whereby the CSF serves as a vehicle for neuroendocrine communication.

Animals↗

Localization of hydroxyindole O-methyltransferase-synthesizing cells in bovine epithalamus: immunocytochemistry and in-situ hybridization.

Hydroxyindole O-methyltransferase (HIOMT)-immunoreactive cells and melatonin synthesis were demonstrated in bovine epithalamus (including the pineal gland) with monoclonal antibodies and cRNA probes to HIOMT. The HIOMT-immunoreactive product was present in the cytoplasm of pinealocytes. All identifiable pinealocytes were clearly labeled in the pineal gland. The expression of the HIOMT gene was first identified in pinealocyte cytoplasm by in-situ hybridization (ISH). The distribution of the hybridization-positive cells in the pineal gland was compatible with that revealed by immunocytochemistry using the monoclonal antibody to HIOMT. In addition, HIOMT transcripts were found in the medial habenular nucleus, and the habenular and posterior commissure; they may correspond to S-antigen-immunoreactive cells demonstrated in the same regions of the hamster and the mouse. In these regions, the hybridization-positive cells did not exhibit HIOMT-immunoreactivity; thus, cells devoid of immunoreactivity may synthesize but rapidly transport the newly synthesized proteins. These results indicate (1) that the conversion of N-acetylserotonin into melatonin takes place in the cytoplasm of pinealocytes, (2) that some epithalamic cells in the habenular area may synthesize melatonin, and (3) that melatonin may act as a chemical messenger in centrally directed processes, as shown by using S-antigen immunocytochemistry.

Acetylserotonin O-Methyltransferase↗

Total number of neurons in the habenular nuclei of the rat epithalamus: a stereological study.

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. Six to eight young adult male rats, and a complete set of serial 40-microm glycolmethacrylate sections for each rat, were used to quantify neuronal numbers. After a random start, a systematic subset (e.g. every third) of the serial sections was used to estimate the total volume of each nucleus using Cavalieri's method. The same set of sampled sections was used to estimate the number of neurons in a known subvolume (i.e. the numerical density N(v)) by the optical disector method. Multiplication of the total volume by N(v) yielded the total number of neurons. 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). These total neuronal numbers provide important data for the transfer of information through these nuclei and for species comparisons.

Animals↗

Distribution of substance P neurons in the epithalamus of the rat: an immunohistochemical investigation.

Substance P (SP) immunoreactivity was studied in the epithalamus of intact and superior cervical ganglionectomized female rats by using the peroxidase-antiperoxidase immunocytochemical technique. Cells containing immunoreactive SP were located in the medial habenula, and SP fibers were observed in the lateral habenula, habenular commissure, pineal stalk, and the pineal organ. Bilateral removal of the superior cervical ganglia did not affect the immunocytochemical staining of SP-containing cells and fibers 15-30 days later. It is suggested that habenular neurons containing SP send projections into the pineal organ of the rat.

Animals↗

Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus.

Chronic-intermittent hypoxia (CIH) was postulated to activate thalamic regions that are synaptically related to autonomic-related areas of the cerebral cortex. Animals exposed to CIH for 30 days exhibited c-fos labeling in paraventricular thalamic and lateral habenular nuclei. Our findings strongly suggest activation of a diencephalic network that participates in behavioral responses to chronic stress.

Animals↗