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R Y Moore

Publications and source records attributed to R Y Moore.

At least 19 recordsLinked to original sources
PubMed1999

Neuroinvasiveness of pseudorabies virus injected intracerebrally is dependent on viral concentration and terminal field density.

Pseudorabies virus (PRV), a neurotropic swine alpha herpesvirus, has been used extensively for transneuronal analysis ofmultisynaptic circuitry after peripheral injection. In the present analysis, we examined the influence of viral concentration and neuronal architecture on the invasiveness, replication, and transynaptic passage of an attenuated strain of PRV (PRV-Bartha) injected into rat striatum. Different concentrations of PRV-Bartha were injected into the striatum at a constant rate of infusion (10 nl/minute), and animals were killed 50 hours later. Viral concentration was manipulated by either altering the volume of the inoculum (100, 50, 20 nl) or by diluting the inoculum within a constant volume of 100 nl. Immunohistochemical localization of infected neurons revealed dramatic differences in the progression of infection that were dependent directly on the concentration of injected virus. In every case, the pattern of infection was consistent with preferential uptake of virions by axon terminals and retrograde transynaptic passage of virus from the injection site. The known topographically organized corticostriatal projections permitted a precise definition of the zone of viral uptake. This analysis demonstrated that the "effective zone of viral uptake" (i.e., the zone within which viral uptake led to productive replication of virus) varied in relation to the concentration of injected virus, with the highest concentration of PRV invading terminals within a 500 microm radius of the canula. Concentration-dependent changes in the progression of retrograde transynaptic infection also were observed. The highest concentration of virus produced the most extensive infection. The distribution of infected neurons in these cases included those with known afferent projections to striatum as well as those that became infected by retrograde transynaptic infection. Lesser concentrations of PRV-Bartha produced an increasingly restricted infection of the same circuitry within the same postinoculation interval. It is noteworthy that neurons known to elaborate dense striatal terminal fields were less sensitive to reduction in viral concentration than those giving rise to terminal fields of lesser density. Collectively, the data indicate that the onset of viral replication after intracerebral injection of PRV is directly dependent on virus concentration and terminal field density at the site of virus injection.

Animals↗
PubMed1999

Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei.

The Clock gene is an essential regulator of circadian rhythms. It encodes a member of the basic helix-loop-helix/PER-ARNT-SIM family of transcription factors known to play a central role in the control of diverse cellular events. Previously we described the functional identification and molecular isolation of the Clock gene in the mouse, its interaction with the BMAL1 protein, and the role of this complex as a transcriptional activator in the circadian pacemaker. Here, we report the cloning, exon organization, chromosomal location, and mRNA expression of the human CLOCK gene. The coding sequence of human CLOCK extends for 2538 bp and is 89% identical to its mouse ortholog; its deduced amino acid sequence is 846 residues long and is 96% identical to mouse CLOCK. Radiation hybrid mapping localized human CLOCK to the long arm of human chromosome 4 (4q12). Direct sequencing of a genomic CLOCK clone indicated that the coding sequence of human CLOCK extends over 20 exons and that its intron/exon organization is identical to that of the mouse ortholog. Northern blot analysis indicated widespread expression of two major transcripts of 8 and 10 kb, and in situ hybridization of human brain tissue revealed elevated expression of CLOCK mRNA in the suprachiasmatic nuclei, the locus of circadian control in mammals, and in the cerebellum. Comparison of cDNA clones revealed two single nucleotide polymorphisms in noncoding sequence flanking the CLOCK open reading frame. The central role of Clock in the organization of circadian rhythms suggests that it will be a useful candidate gene for genetic analyses of disorders associated with dysfunction of the circadian system.

Alleles↗
PubMed1999

Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport.

The suprachiasmatic nucleus (SCN) of the hypothalamus, the principal circadian pacemaker, is a paired structure with two subdivisions, a ventral core receiving photic input and a dorsal shell receiving non-photic input. Rhythmicity is thought to be generated by individual SCN neurons which are coupled to achieve synchrony [D.K. Welsh, D.E. Logothetis, M. Meister, S.M. Reppert, Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing patterns, Neuron, 14 (1995) 697-706]. Normally, the core and shell, and the nuclei on each side, act in unison to transmit rhythmicity to effector systems. It is not known how coupling between neurons in the two subdivisions, and between the two SCNs, takes place. In the present study, we analyze the intrinsic, commissural, and efferent projections of the SCN using the swine herpesvirus (pseudorabies virus, PRV) as a tool for transynaptic analysis of circuits and small iontophoretic injections of the conventional tracer horseradish peroxidase (HRP) conjugated to fluorescein. We find that the core and shell each project through commissural efferents to homologous contralateral areas. The core projects densely to shell but we find little reciprocal innervation. The two subdivisions project to different hypothalamic areas, with the core projecting to the lateral subparaventricular zone and shell to the dorsomedial hypothalamic nucleus and medial subparaventricular zone. These data are the first demonstration that connections within the SCN, and from the SCN to effector regions, are topographically organized and lend insight into the flow of information through and out of the pacemaker.

Animals↗
PubMed1998

Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging.

Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.

Aged↗
PubMed1998

A method for the assessment of the functional neuroanatomy of human sleep using FDG PET.

Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assessment of brain function in humans (related to cognitive operations) during sleep has been limited, until recently, to surface electrophysiologic recordings that limit analysis of regional function, particularly in deep structures. The current report describes one method of assessing human forebrain activation during sleep using the [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) method and positron emission tomography (PET) measures of regional cerebral glucose utilization. In comparison with other functional brain imaging techniques (e.g., assessment of blood flow or functional magnetic resonance imaging), this method offers the advantage of a more naturalistic study of sleep since subjects do not have to sleep in a scanning device. This leads to a higher rate of successful completion of studies. The primary disadvantage of this method is the decreased temporal resolution necessitating assessments of global sleep states (e.g., REM or NREM) as opposed to assessing events within a sleep state (e.g., sleep spindles or rapid eye movements).

Electroencephalography↗
PubMed1997

Organization of neural inputs to the suprachiasmatic nucleus in the rat.

The circadian timing of the suprachiasmatic nucleus (SCN) is modulated by its neural inputs. In the present study, we examine the organization of the neural inputs to the rat SCN using both retrograde and anterograde tracing methods. After Fluoro-Gold injections into the SCN, retrogradely labeled neurons are present in a number of brain areas, including the infralimbic cortex, the lateral septum, the medial preoptic area, the subfornical organ, the paraventricular thalamus, the subparaventricular zone, the ventromedial hypothalamic nucleus, the posterior hypothalamic area, the intergeniculate leaflet, the olivary pretectal nucleus, the ventral subiculum, and the median raphe nuclei. In the anterograde tracing experiments, we observe three patterns of afferent termination within the SCN that correspond to the photic/raphe, limbic/hypothalamic, and thalamic inputs. The median raphe projection to the SCN terminates densely within the ventral subdivision and sparsely within the dorsal subdivision. Similarly, areas that receive photic input, such as the retina, the intergeniculate leaflet, and the pretectal area, densely innervate the ventral SCN but provide only minor innervation of the dorsal SCN. A complementary pattern of axonal labeling, with labeled fibers concentrated in the dorsal SCN, is observed after anterograde tracer injections into the hypothalamus and into limbic areas, such as the ventral subiculum and infralimbic cortex. A third, less common pattern of labeling, exemplified by the paraventricular thalamic afferents, consists of diffuse axonal labeling throughout the SCN. Our results show that the SCN afferent connections are topographically organized. These hodological differences may reflect a functional heterogeneity within the SCN.

Afferent Pathways↗
PubMed1997

Identification of retinal ganglion cells projecting to the lateral hypothalamic area of the rat.

The objective of the present study was to identify the retinal ganglion cells projecting to the lateral hypothalamic area of the rat. The retinohypothalamic tract has been divided into a medial and a lateral component on anatomical and developmental grounds. The medial component projects to the suprachiasmatic nucleus and adjacent structures such as the anterior hypothalamic and retrochiasmatic areas. The lateral component terminates in the lateral hypothalamic are dorsal to the supraoptic nucleus. Injections of the retrograde tracer FluoroGold were made into the retinorecipient region of the lateral hypothalamic area and retinal whole mounts were immunohistochemically processed for retrogradely labeled retinal ganglion cells. With FluoroGold injections confined to the lateral hypothalamic area, retrogradely labeled retinal ganglion cells are located almost exclusively in the superior temporal quadrant of the retina. Their size and morphology indicates that they are a homogeneous subset of type III cells, but a definitive classification would require a more complete fill of dendritic arbors than is available in our retrograde material. In contrast, injections involving fibers of passage in the optic tract, or centered in the medial terminal nucleus of the accessory optic system, label cells distributed across the entire retinal surface. Unlike the retinal ganglion cells projecting to the suprachiasmatic nucleus [Moore et al., J. Comp. Neurol., 352 (1995) 351-366], the cells labeled after restricted lateral hypothalamic injections are not distributed evenly across the retinal surface. The difference in location of the retinal ganglion cells projecting to the lateral hypothalamic area supports the view that this retinohypothalamic projection is anatomically and functionally distinct from the projection to the suprachiasmatic nucleus and adjacent medial hypothalamus.

Animals↗
PubMed1997

Forebrain activation in REM sleep: an FDG PET study.

Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the 18F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal-ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.

Adult↗
PubMed1997

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.

Animals↗
PubMed1996

Putative excitatory amino acid projections to the suprachiasmatic nucleus in the rat.

Retrograde axonal transport of the select neuronal tracer [3H]D-aspartate was used to demonstrate possible sources of excitatory input to the suprachiasmatic nucleus (SCN) in the albino rat. Following injection of [3H]D-aspartate into the SCN, neurons were retrogradely labeled in the infralimbic cortex, the lateral septal nucleus, the paraventricular thalamic nucleus, the medial preoptic area, the ventromedial, dorsomedial and posterior hypothalamic nuclei, the zona incerta, the intergeniculate leaflet and the ventral subiculum. Retinal ganglion cells, which project to the SCN and use glutamate as a neurotransmitter, were not labeled in our [3H]D-aspartate experiments, demonstrating a limitation of this method (i.e., false negatives). Our results show that the [3H]D-aspartate neuronal tracer labels a subset of areas known to project to the SCN, indicating these areas as likely sources of excitatory input to the SCN.

Animals↗
PubMed1996

The sexually dimorphic nucleus of the hypothalamus contains GABA neurons in rat and man.

The sexually dimorphic nucleus of the preoptic area (SDN-POA) is the most striking structure displaying a morphological sex difference in the rat brain. A potentially homologous nucleus has been identified in the human hypothalamus. The objective of the present study was to pursue the putative homology of the rat and human SDN-POA by determining whether they express the same transmitter phenotype. We employed in situ hybridization histochemistry for GAD mRNA to show whether the neurons of the SDN-POA produce GABA. In both the rat and human, high levels of GAD65 and GAD67 mRNA are present in most, if not all, SDN-POA neurons. No sex difference is evident in the level of expression in either the rat or human. The data indicate that neurons of the SDN-POA in both the rat and human are GABA-producing and argue for the homology of these nuclei in the rat and human hypothalamus.

Animals↗
PubMed1996

Neural control of the pineal gland.

The rhythm in melatonin production by the mammalian pineal gland is generated by the circadian timing system. The components of that system which mediate the function are: (1) visual projections through the retinohypothalamic tract to the circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus; (2) the SCN which generates a circadian signal transmitted by SCN projections to the parvocellular autonomic component of the paraventricular nucleus; (3) paraventricular nucleus projections to the upper thoracic intermediolateral cell column; (4) preganglionic sympathetic fibers to the superior cervical ganglion; (5) postganglionic sympathetic fibers from the superior cervical ganglion to the pineal.

Animals↗
PubMed1996

New insights into the mammalian circadian clock.

The focus of this review is recent studies of the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The anatomy of the SCN and its major afferents from the retina, raphe, and intergeniculate leaflet (IGL) of the thalamus are considered, with a special emphasis on the effects of afferent interaction on the circadian timekeeping system. What is known of the endogenous clock mechanism is reviewed in comparison with known molecular circadian mechanisms in other species. Efferents of the SCN are also discussed with a view toward understanding how circadian information is transmitted to the rest of the central nervous system. Where possible, anatomical, electrophysiological, neuropharmacological, molecular, and behavioral data are integrated in an attempt to illuminate the mechanisms of circadian timekeeping.

Animals↗
PubMed1996

Glutamic acid decarboxylase message isoforms in human suprachiasmatic nucleus.

The rat suprachiasmatic nucleus (SCN) is comprised of neurons that contain gamma-amino butyric acid (GABA) colocalized with one or more peptides. In the present study, the authors employed in situ hybridization histochemistry to determine whether the human SCN also contains GABA neurons using synthetic oligonucleotide probes complementary to sequences of two isoforms of the GABA-forming enzyme, glutamic acid decarboxylase (GAD), GAD65, and GAD67. Most, if not all, SCN neurons appear to express both GAD65 mRNA and GAD67 mRNA with the content of GAD67 greater than GAD65. Both isoforms also are expressed in some neurons of the anterior hypothalamic area, in small neurons of the paraventricular nucleus but not in the supraoptic nucleus. These data indicate that neurons in the human SCN, like those in rodents, use GABA as a neurotransmitter.

Animals↗
PubMed1995

GABAA-receptor subunit composition in the circadian timing system.

In the present study, the distribution of GABAA-receptor alpha 1-, alpha 2-, alpha 3-, alpha 5-, beta 2.3- and gamma 2-subunits were localized immunohistochemically with subunit specific antibodies in the rat circadian timing system (CTS). The areas examined include the principal circadian pacemaker, the suprachiasmatic nucleus (SCN), and areas that receive important SCN input including the intergeniculate leaflet (IGL), subparaventricular zone (SPVZ), paraventricular hypothalamic nucleus (PVH), the retrochiasmatic area (RCh) and the paraventricular nucleus of the thalamus (PVT). The SCN has an unusual pattern with immunoreactivity for the alpha 2-, alpha 3-, alpha 5-, and gamma 2-subunits but not for the commonly expressed alpha 1- and beta 2.3-subunits. In all of the areas receiving SCN efferent input (SPVZ, PVH, RCh, PVT and IGL), staining is present either for all six subunits or for the three common subunits, alpha 1-, beta 2.3-, and gamma 2. There is some evidence for a differential distribution of subunits at the cellular level. The alpha 2-, and beta 2.3-subunits are predominantly expressed in neuropil, the alpha 3-, alpha 5- and gamma 2-subunits are predominantly expressed over perikarya and the alpha 1-subunit is expressed over both neuropil and perikarya in the areas in which subunit immunoreactivity is found. The demonstration of this regional and cellular expression of GABAA-receptor subunits should contribute to our understanding of GABAergic neurotransmission in the CTS.

Animals↗