Midline Thalamus Research Articles

Expression of a Novel Neuropeptide Y Receptor Subtype Involved in Food Intake: An in Situ Hybridization Study of Y5 mRNA Distribution in Rat Brain

Our group has reported on the cloning of a novel rat neuropeptide Y (NPY) receptor involved in NPY-induced food intake, the Y5 receptor. The distribution in rat brain of the mRNA encoding this receptor has been determined by in situ hybridization histochemistry, using radiolabeled oligonucleotide probes. Control experiments were carried out in cell lines transfected with either rat Y1 or rat Y5 cDNAs. With the exception of the cerebellum, only the antisense probes yielded hybridization signal in rat brain tissue sections. A number of brain regions contained hybridization signals indicative of Y5 mRNA localization. Chief among these were various hypothalamic nuclei, including the medial preoptic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the lateral hypothalamus. Other regions with substantial hybridization signals included the midline thalamus, parts of the amygdala and hippocampus, and some midbrain and brain-stem nuclei. In general a low density of Y5 mRNA was observed in most cortical structures, with the exception of the cingulate and retrosplenial cortices, each of which contained a moderate abundance of Y5 hybridization signal. The distribution of this receptor mRNA is consistent with a role for the Y5 receptor in food intake and also suggests involvement in other processes mediated by NPY.

Autoradiographic localization of 125I[Tyr14]orphanin FQ/nociceptin and 125I[Tyr10]orphanin FQ/nociceptin(1–11) binding sites in rat brain

The endogenous ligand for the orphan opioid receptor, orphanin FQ/nociceptin (OFQ), has recently been characterized. The OFQ peptide sequence contains paired basic amino acids, suggesting the possibility of posttranslational processing to a peptide containing the first 11 amino acids of the OFQ peptide. This peptide has been reported in the brain and it has a unique pharmacology. In the present study, we compared the autoradiographic distribution of 125I[Tyr14]OFQ and 125I[Tyr10]OFQ(1–11) in coronal rat brain sections. Nonspecific binding was defined with unlabeled OFQ or OFQ(1–11), respectively. Both radioligands demonstrated high levels of specific binding (>95% of total binding), with no appreciable binding in white matter areas with either ligand. 125I[Tyr14]OFQ binding was widely distributed throughout the rat brain. In contrast, 125I[Tyr10]OFQ(1–11) binding was more restricted. The highest 125I[Tyr14]OFQ binding levels measured in this study were found in the locus coeruleus, an area which contained very low 125I[Tyr10]OFQ(1–11) binding. Both ligands labeled the cortex, hippocampus and amygdala. In the thalamus, 125I[Tyr14]OFQ binding was prominent in most nuclei, whereas 125I[Tyr10]OFQ(1–11) binding was restricted to the midline thalamus. 125I[Tyr14]OFQ binding was heavy in the suprachiasmatic hypothalamus, and moderate in other hypothalamic nuclei. 125I[Tyr10]OFQ(1–11) binding in the hypothalamus, however, was present mainly in the ventromedial hypothalamic nucleus. Lower binding levels of both ligands were found in the caudate putamen. The distinct autoradiographic patterns of these two ligands are consistent with different binding sites, which might help explain their different functional activities. J. Comp. Neurol. 423:319–329, 2000. © 2000 Wiley-Liss, Inc.

Interruption of supramammillohippocampal afferents prevents the genesis and spread of limbic seizures in the hippocampus via a disinhibition mechanism

In this study we describe the preventive effect of interruption of the supramammillohippocampal afferents on the Fos expression in the forebrain and epileptic discharges in the hippocampal electroencephalogram in rat model of kainic acid-induced limbic seizure. Little was known about the contribution of different degrees of neural activity of hippocampal principal cells to the genesis and spread of limbic seizures in the forebrain structures. Following kainic acid injection to the amygdala with or without concurrent injection of muscimol to the supramammillary nucleus, behavioral changes and electroencephalograms were observed in freely moving rats. The animals were processed for Fos immunocytochemical analysis at several time points. The latest expression of Fos at 2 h was seen in hippocampal CA1–CA3, ventrolateral thalamic nuclei and mediodorsal caudate putamen, while the early Fos expression at 0.5 h was seen in the piriform, entorhinal and other cortices, the thalamic midline nuclei and hypothalamic nuclei. Muscimol injection to the supramammillary nucleus prevented Fos expression in the CA1–CA3 region and reduced that in the forebrain regions with the latest Fos expression, but did not affect Fos expression in other forebrain regions with early Fos expression. This treatment also eliminated epileptic discharges and attenuated all waves in hippocampus. These findings indicate that an acute interruption of the facilitatory hypothalamic afferents by intrasupramammillary injection of muscimol may cause the inactivation of the disinhibition mechanism for hippocampal throughput at the dentate gyrus, resulting in the blockade of the genesis and spread of limbic seizures in the hippocampus.

Interferon-γ-responsive neuronal sites in the normal rat brain: receptor protein distribution and cell activation revealed by Fos induction

Constitutive expression of the interferon-γ receptor protein (IFN-γR), and the distribution of cells in which Fos, a marker of cell activation, is induced by intracerebroventricular administration of IFN-γ, were studied in the rat brain by immunohistochemistry. IFN-γR immunopositivity was found in neuronal elements, which exhibited a selective distribution being concentrated in the piriform and entorhinal cortex, midline thalamus and medial hypothalamic structures, brainstem nociceptive relays (including the periaqueductal gray, the parabrachial nuclei and the caudal part of the spinal trigeminal nuclei), and circumventricular organs such as the median eminence and area postrema. IFN-γ-induced Fos expression mostly corresponded to neuronal sites of receptor distribution. Because of its topographical distribution, it is suggested that activation of the IFN-γR in neurons may play a role to limit spread of infections in the brain and, in concert with other proinflammatory cytokines, to modulate adaptive responses to an antigen challenge mediated by the central nervous system.

Efferent connections of the anterior hypothalamic nucleus: a biocytin study in the cat

The efferent connections of the anterior hypothalamic nucleus (AH) were examined using biocytin as anterograde tracer in the cat. The results provide several new findings in addition to confirming earlier observations. In the hypothalamus, the AH projections terminated mainly in the medial regions which are related to the defensive, reproductive and feeding behaviors, and autonomic functions. Moreover, we found dense patches of the AH terminals in the medial preoptic area and ventromedial hypothalamic nucleus, which suggests the existence of modular connections between sub-regions of each nucleus. In addition, the AH projected to regions which may be related to the emotional and autonomic responses, i.e., such regions in the amygdala, midline thalamus, septum, subthalamus, and midbrain. The data suggest that the AH may play an important role in the autonomic functions and behaviors between animals, and thus may play a key role in the defensive behavior elicited in the medial preoptic area and ventromedial hypothalamic nucleus.

Androgenic–anabolic steroids blunt morphine-induced c- fos expression in the rat striatum: possible role of β-endorphin

Self-administration of large doses of androgenic–anabolic steroids (AAS) in a significant portion of the population suggests that these agents are drugs of abuse. However, acute administration of AAS did not induce striatal immediate-early genes (IEG) expression in male rats, indicating that AAS do not share a common mechanism of action with other drugs of abuse. Surveys have indicated that people who abuse AAS are more likely to self-administer other drugs of abuse than do people who do not take AAS. In the present study, chronic administration of AAS blunted the striatal c- fos response to morphine, indicating that AAS can alter the molecular responses to at least one drug of abuse. Chronic administration of AAS also increased the content of β-endorphin in the midline thalamus, suggesting a possible mechanism by which AAS may modulate the response to morphine through regulation of thalamo-striatal neurons.

Autoradiographic localization of125I[Tyr14]orphanin FQ/nociceptin and125I[Tyr10]orphanin FQ/nociceptin(1-11) binding sites in rat brain

The endogenous ligand for the orphan opioid receptor, orphanin FQ/nociceptin (OFQ), has recently been characterized. The OFQ peptide sequence contains paired basic amino acids, suggesting the possibility of posttranslational processing to a peptide containing the first 11 amino acids of the OFQ peptide. This peptide has been reported in the brain and it has a unique pharmacology. In the present study, we compared the autoradiographic distribution of (125)I[Tyr(14)]OFQ and (125)I[Tyr(10)]OFQ(1-11) in coronal rat brain sections. Nonspecific binding was defined with unlabeled OFQ or OFQ(1-11), respectively. Both radioligands demonstrated high levels of specific binding (>95% of total binding), with no appreciable binding in white matter areas with either ligand. (125)I[Tyr(14)]OFQ binding was widely distributed throughout the rat brain. In contrast, (125)I[Tyr(10)]OFQ(1-11) binding was more restricted. The highest (125)I[Tyr(14)]OFQ binding levels measured in this study were found in the locus coeruleus, an area which contained very low (125)I[Tyr(10)]OFQ(1-11) binding. Both ligands labeled the cortex, hippocampus and amygdala. In the thalamus, (125)I[Tyr(14)]OFQ binding was prominent in most nuclei, whereas (125)I[Tyr(10)]OFQ(1-11) binding was restricted to the midline thalamus. (125)I[Tyr(14)]OFQ binding was heavy in the suprachiasmatic hypothalamus, and moderate in other hypothalamic nuclei. (125)I[Tyr(10)]OFQ(1-11) binding in the hypothalamus, however, was present mainly in the ventromedial hypothalamic nucleus. Lower binding levels of both ligands were found in the caudate putamen. The distinct autoradiographic patterns of these two ligands are consistent with different binding sites, which might help explain their different functional activities.

Sites of action of thyrotropin-releasing hormone on central nervous system neurons revealed by expression of the immediate-early gene c- fos in the rat

Centrally administered thyrotropin-releasing hormone produces a number of physiological and behavioral changes, e.g., a general antidepressant effect, increasing body temperature, and elevated blood pressure. However, the specific brain sites of action responsible for the centrally activating property of thyrotropin-releasing hormone have not been precisely determined. Using chloral hydrate-anesthetized adult Sprague–Dawley rats, we compared the distribution of Fos-like immunoreactivity after intracerebroventricular administration of thyrotropin-releasing hormone with the results after intracerebroventricular injection of vehicle alone. Some rats were paralysed and artificially ventilated to avoid possible Fos expression secondarily induced by autonomic (e.g., respiratory) disturbances. In thyrotropin-releasing hormone administered rats, selective Fos-like immunoreactivity was observed in V/VI layers of the pre- and infralimbic areas of the medial prefrontal cortex, the ventral midline thalamus, and the nucleus of the solitary tract as well as in the adjacent reticular formation. Fos-like immunoreactivity was significantly reduced in most areas of the cerebral cortex (II/III layers), the shell of the nucleus accumbens, the medial amygdaloid nucleus, parts of the hypothalamus, and the periaqueductal gray. These data suggest that various behavioral and autonomic responses induced by centrally administered thyrotropin-releasing hormone might be produced through the complex neural circuitry comprising the above structures, which are presumed to be implicated in limbic and/or autonomic functions.

Thalamic excitation of hippocampal CA1 neurons: a comparison with the effects of CA3 stimulation

CA1 is the major output area for the hippocampus, and current evidence shows that it is excited primarily from ipsilateral and contralateral CA3 pyramidal cells in the rat. Direct connections from the midline thalamic nuclei to the hippocampus have been described anatomically, but the physiological role of these connections has not been reported until the recent observation that these inputs may have a mild excitatory effect (subthreshold for population spikes). In this study, we report a more powerful excitatory effect of thalamic stimulation on the response of the CA1 neurons in the urethane-anesthetized rat. Electrical stimulation to the midline thalamus induced responses similar to responses from stimulation of the contralateral hippocampus (CA3), with well-developed field excitatory postsynaptic potentials and large population spikes. The latency of the CA1 response suggested that the thalamic connection was monosynaptic, and there was a laminar CA1 response profile that depended on the site of stimulation (contralateral CA3 or thalamus). In an initial examination of possible differences in the physiological effects of these two pathways on the CA1 region, we tested both sites for long-term potentiation of CA1, for the effects of repetitive stimulation on CA1 responses (e.g., possible augmenting responses) and for the effect of paired-pulse stimulation. In these three measures, there were clear and statistically significant differences between the effects of CA3 and thalamic stimulation on CA1 responses. This study demonstrates that the well-described thalamic connection to the hippocampus allows for the direct and powerful excitation of the CA1 region. This thalamohippocampal connection bypasses the trisynaptic/commissural pathway that has been thought to be the exclusive excitatory drive to CA1. In addition, preliminary data indicate that the thalamus and CA3 inputs have different physiological effects on CA1 pyramidal cells.

Selective targeting of habenular, thalamic midline and monoaminergic brainstem neurons by neurotropic influenza A virus in mice.

Infections caused by influenza A virus have been proposed to be associated with neuropsychiatric complications, the mechanisms of which remain to be unravelled. We here report that a neurotropic strain of influenza A virus (A/WSN/33) introduced into the olfactory bulbs of C57BL/6 (B6) mice, selectively attacks habenular, paraventricular thalamic, and brainstem monoaminergic neurons. In the habenular and paraventricular thalamic areas, infection was followed by an almost total loss of neurons within 12 days. In the brain stem monoaminergic areas, viral gene products were eliminated from neurons by 12 days in B6 wildtype mice, but remained for at least 35 days in immunodefective TAP1 (Transporter associated with Antigen Presentation 1) mutant mice. In conclusion, we show that influenza A virus infection in the brain selectively targets regions which have been implicated in neuropsychiatric disturbances, and that this virus can remain for a significant period of time in specific regions of the brain in immunodefective mice.

Large-Scale Functional Connectivity in Associative Learning: Interrelations of the Rat Auditory, Visual, and Limbic Systems

Large-scale functional connectivity in associative learning: interrelations of the rat auditory, visual, and limbic systems. J. Neurophysiol. 80: 3148-3162, 1998. Functional relations between specialized parts of the brain may be important determinants of learned behaviors. To study this, we examined the interrelations of the auditory system with several extraauditory structures in two groups of rats having different behavioral histories. Both groups were trained to associate a tone conditional stimulus (CS) with an aversive unconditional stimulus (US). For one group, a light presented with the tone predicted the absence of the US (group TL-). In the other group, the light was a neutral stimulus (group TL0). Fluorodeoxyglucose (FDG) incorporation was measured in the presence of the tone-light compound. Because the tone-light compound was physically identical for both groups, neural differences between groups reflected differences in the learned associative properties of the stimuli. Covariances of FDG uptake in the auditory system and extraauditory structures were examined using partial least squares. Three strong covariance or functional connectivity patterns were identified. The first pattern mainly reflected similarities between groups, with strong interrelations between the subcortical auditory system and the thalamocortical visual system, cerebellum, deep cerebellar nuclei, and midline thalamus. This pattern of interactions may represent part of a common circuit for relaying the associative value of the tone CS to the cerebellum and the midline thalamus. The external nucleus of the inferior colliculus and medial division of the medial geniculate nucleus were associated more strongly with this pattern for group TL-, which was interpreted as representing the change of the associative value of the tone by the light, mediated through extraauditory influences on these two regions. A second pattern involved midbrain auditory regions, superior colliculus, zona incerta, and subiculum and was stronger for group TL0. The relations between midbrain structures may represent the excitatory conditioned response (CR) evoked by the tone in this group. The final pattern was strongest in group TL- and involved interrelations of the thalamocortical auditory system with hippocampus, basolateral amygdala, and hypothalamus. This pattern may represent the learned inhibition of the CR to the tone in the presence of the light. These findings are consistent with behavioral studies suggesting that at least two types of associations are formed during associative learning. One is the sensory relation of the stimuli and another is the relation between the CS and the affective components of the US. These behavioral associations are mapped to the patterns of functional connectivity between auditory and extraauditory regions.

Functional anatomy of limbic epilepsy: a proposal for central synchronization of a diffusely hyperexcitable network.

The limbic/mesial temporal lobe epilepsy syndrome has been defined as a focal epilepsy, with the implication that there is a well defined focus of onset, traditionally centered around the hippocampus. The pathology of the hippocampus in this syndrome has been well described and a number of physiological abnormalities have been defined in this structure in animal models and humans with epilepsy. However, anatomical and physiological abnormalities have also been described in other limbic sites in this form of epilepsy. Previous studies have shown broadly synchronized or multifocal seizure onset within the limbic system of the animal models and human patients. We hypothesized that the epileptogenic circuit for the initiation of seizures was distributed throughout the limbic system with a possible central synchronizing process. In vitro studies showed that multiple limbic sites in epileptic animals (hippocampus, entorhinal cortex, piriform cortex and amygdala) have epileptiform changes with prolonged depolarizations and multiple superimposed action potentials. In vivo studies revealed that thalamic stimulation yields short latency excitatory responses in the entorhinal cortex and hippocampus. In addition, in epileptic animals, thalamic stimulation caused epileptiform responses in the hippocampus. Based on the findings of this study and on previous anatomy and physiology reports, we hypothesize that the process of seizure initiation involves broad circuit interactions involving multiple independent limbic structures, and that the midline thalamus may act as a physiological synchronizer. We offer a new proposal for the functional anatomy of limbic epilepsy that takes widespread hyperexcitability in the limbic system and the potential for thalamic synchronization into consideration.

Regional localization of agmatine in the rat brain: an immunocytochemical study

The distribution of agmatine (decarboxylated arginine) was mapped in the central nervous system (CNS) in the rat. Agmatine-like immunoreactivity was identified by light microscopy, exclusively in the cytoplasm of neuronal perikarya. Immunoreactive neurons were present in the cerebral cortex, predominantly within laminae VI and V and, to a lesser extent, III and mainly in retrosplenial, cingulate, primary somatosensory and auditory cortices, and the subiculum. In the lower brainstem, immunoreactivity was selectively localized to visceral relay nuclei: the nucleus tractus solitarii and pontine parabrachial complex, and periventricular areas including the laterodorsal nucleus, locus coeruleus and dorsal raphe. In the midbrain, immunolabeled cells were concentrated in the ventral tegmental area and periaqueductal gray. In the forebrain, subcortical neurons were labeled predominantly in the preoptic area, amygdala, septum, bed nucleus of the stria terminalis, midline thalamus, and the hypothalamus. Ultrastructural analysis of layer V of the somatosensory cortex demonstrated agmatine-immunoreactivity in neurons, primarily in large dense-core vesicles located in the cytoplasm. Agmatine immunoreactivity was also affiliated with endoplasmic reticulum and the plasmalemma. Cortical neurons and the subiculum were labeled in animals not administered the axonal transport inhibitor, colchicine; thus, may normally contain higher concentrations of the amine than other brain regions. The central distribution of agmatine is consistent with the hypothesis that the amine may be a novel neurotransmitter of neurons involved in behavioral and visceral control.

Effects of lesions of thalamic intralaminar and midline nuclei and internal medullary lamina on spatial memory and object discrimination.

Effects of lesions of thalamic intralaminar and midline nuclei and internal medullary lamina on spatial memory and object discrimination.

Effects of lesions of thalamic intralaminar and midline nuclei and internal medullary lamina on spatial memory and object discrimination.

Male Sprague-Dawley rats received either radiofrequency lesions of the lateral internal medullary lamina (IML) or ibotenic acid lesions of the lateral intralaminar nuclei (ILN) and midline nuclei (MLN) or sham treatment. Neither lesion group was impaired in the retention of 3 object pair discriminations acquired before surgery nor in the acquisition of a new object pair after surgery. Rats with ILN, but not IML, lesions were impaired in acquiring an initial and 5 subsequent hidden platform locations in a water maze task. These results suggest that damage to both ILN and MLN are needed to produce spatial learning deficits and that extensive damage to the IML or ILN has no detectable effects on retrograde or anterograde memory of object discriminations.

Chapter 12 Molecular determinants of NMDA receptor pharmacological diversity

Publisher Summary This chapter describes the molecular basis of the known pharmacologically distinct N-methyl-D-aspartate (NMDA) receptor subtypes. The potent excitotoxic effect of NMDA receptor overactivation has made this receptor a prime suspect in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and AIDS dementia. Two general approaches have been taken to develop agents with a higher therapeutic index—using compounds that act at different regulatory domains on the NMDA receptor or identifying compounds that act at subtypes of NMDA receptors. NMDA receptors display a rich diversity of sites at which pharmacological agents can modify activity. In addition to the glutamate and glycine agonist binding sites, there are sites for channel blockers, polyamines, redox reagents, ifenprodil, protons, steroids, Zn 2+ , Mg 2+ , and histamine. Two families of NMDA receptor subunits have been cloned, together these consist of 12 different subunits. In specific nuclei of the midline thalamus, for example, the paraventricular and intermediodorsal thalamic nuclei and other diencephalic structures, NMDA receptors display a distinct pharmacological profile at both the glutamate recognition site and the channel blocker-binding site.

Preproenkephalin messenger RNA-expressing neurons in the rat parabrachial nucleus: subnuclear organization and projections to the intralaminar thalamus

The pontine parabrachial nucleus, which is a key structure in the central processing of autonomic, nociceptive and gustatory information, is rich in a variety of neuropeptides. In this study we have analysed the distribution of parabrachial neurons that express preproenkephalin messenger RNA, which encodes for the precursor protein for enkephalin opioids. Using an in situ hybridization method, we found that preproenkephalin messenger RNA-expressing neurons were present in large numbers in four major areas of the parabrachial nucleus: the Kölliker–Fuse nucleus, the external lateral subnucleus, the ventral lateral subnucleus, and in and near the internal lateral subnucleus. Many preproenkephalin messenger RNA-expressing neurons were also seen in the central lateral subnucleus, and in the medial and external medial subnuclei. Few labeled neurons were found in the dorsal and superior lateral subnuclei. Injection of the retrograde tracer substance cholera toxin subunit B into the midline and intralaminar thalamus demonstrated that the enkephalinergic neurons in and near the internal lateral subnucleus were thalamic-projecting neurons. Taken together with the results of previous tract-tracing studies, the present findings show that many of the enkephalinergic cell groups in the parabrachial nucleus are located within the terminal zones of the ascending projections that originate from nociresponsive neurons in the medullary dorsal horn and spinal cord, as well as from viscerosensory neurons within the nucleus of the solitary tract. The enkephalinergic neurons in the parabrachial nucleus may thus transmit noci- and visceroceptive-related information to their efferent targets. On the basis of the present and previous observations, we conclude that these targets include the intralaminar and midline thalamus, the ventrolateral medulla and the spinal cord. Through these connections, nociceptive and visceroceptive stimuli may influence several functions, such as arousal, respiration and antinociception.

Discrete thalamic lesions attenuate winter adaptations and increase body weight.

The midline thalamus (e.g., the paraventricular thalamic nuclei and the reuniens nucleus) of Siberian hamsters and other mammals has been reported to contain specific binding sites for melatonin, a hormone that is essential for photoperiodically induced winter adaptations such as reproductive quiescence, loss of body weight, daily torpor, and the winter molt. The first experiment investigated whether the midline thalamus is necessary for these winter adaptations. Adult Siberian hamsters received discrete neurotoxic lesions of the paraventricular thalamic nuclei or the reuniens nucleus while under pentobarbital sodium-induced anesthesia. After recovery, the hamsters were monitored for winter adaptations while they were exposed to short photoperiods (10 h light/day) for 12 wk at 22 degrees C then for 60 days at 7 degrees C. Lesions of the reuniens nucleus, but not of the paraventricular thalamic nuclei, significantly inhibited short photoperiod-induced loss of body weight and tended to increase food consumption and decrease daily torpor. The second experiment showed that lesions of the reuniens nucleus increased body weight gain compared with that in controls during exposure to long photoperiods at 22 degrees C for 16 wk. In summary, these findings show that the reuniens nucleus is an important site for regulation of body weight and suggest that lesions of the reuniens nucleus may attenuate winter metabolic adaptations by causing an increase in body weight.

Glutamate, aspartate and co-localization with calbindin in the medial thalamus. An immunohistochemical study in the rat.

Topographical and quantitative features of medial thalamic neurons in which aspartate (ASP) or glutamate (GLU) might act as neurotransmitters were investigated in the rat. The calcium-binding protein calbindin D-28k (CB) was exploited as a marker of neuronal subsets, thus allowing us to study also the relationships between the CB-containing neurons and those immunoreactive to excitatory amino acids. Double immunocytochemistry of ASP and CB or GLU and CB was performed in 40-microm-thick sections. The three markers were distributed in the thalamic midline, mediodorsal, anterior intralaminar and ventromedial nuclei, with regional variations. ASP-immunoreactive neurons appeared more numerous than the GLU-immunoreactive ones throughout these structures; ASP-CB or GLU-CB double-immunostained neurons were evident. ASP-, GLU- and CB-immunoreactive cells were then quantitatively evaluated in 5-microm-thick consecutive sections. Interindividual variations and different anti-ASP and anti-GLU antibodies did not result in significant differences. ASP and GLU were not co-localized. Single ASP- or GLU-immunoreactive neurons accounted for 60% of the total number of immunostained cells, and single ASP-immunopositive cells represented more than half of these neurons. Among the CB-immunoreactive cells (40% of the total), half were double immunostained; the proportion of double CB-ASP-immunopositive neurons was sevenfold higher than that of the CB-GLU-immunoreactive ones. These results indicate that ASP may act as excitatory neurotransmitter in a relatively high proportion of medial thalamic neurons, in which ASP frequently coexists with CB. Approximately 50% of the CB-immunoreactive cells did not contain either ASP or GLU, suggesting that some medial thalamic neurons may utilize a different neurotransmitter.

Circadian rhythms: basic neurobiology and clinical applications.

Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the retinohypothalamic tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders.