Visual pathway mediating pineal response to environmental light.

Activity of the melatoninforming enzyme, hydroxyindole-O-methyltransferase, in rat pineal is increased when the animal is exposed to continuous darkness, and it is decreased by exposure to continuous light. Response to environmental light is initiated in the retina and transmitted to the pineal by way of the central nervous system and the cervical sympathetics. The central visual pathway essential for mediation of this response is the inferior accessory optic tract. Visual pathways to thalamus and tectum do not participate in this response.

Light-induced changes in pineal hydroxyindole-O-methyltransferase: abolition by lateral hypothalamic lesions.

The activity of hydroxyindole-O-methyltransferase, the melatoninforming enzyme in the pineal gland, is several times greater in rats kept in continuous darkness than in those kept in continuous light. Lesions transecting the medial forebrain bundle in the lateral hypothalamus suppress these differences in enzyme activity and abolish light-induced changes in pineal weight. These findings indicate that the medial forebrain bundle may participate in the control of this enzymatic response to environmental lighting.

Reduced number of hypocretin neurons in human narcolepsy.

Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy.

Two alpha-herpesvirus strains are transported differentially in the rodent visual system.

Uptake and transneuronal passage of wild-type and attenuated strains of a swine alpha-herpesvirus (pseudorabies [PRV]) were examined in rat visual projections. Both strains of virus infected subpopulations of retinal ganglion cells and passed transneuronally to infect retino-recipient neurons in the forebrain. However, the location of infected forebrain neurons varied with the strain of virus. Intravitreal injection of wild-type virus produced two temporally separated waves of infection that eventually reached all known retino-recipient regions of the central neuraxis. By contrast, the attenuated strain of PRV selectively infected a functionally distinct subset of retinal ganglion cells with restricted central projections. The data indicate that projection-specific groups of ganglion cells are differentially susceptible to the two strains of virus and suggest that this sensitivity may be receptor mediated.

Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study.

BACKGROUND AND PURPOSE: The diagnosis of Parkinson disease (PD) is made typically on the basis of motor abnormalities. PD is now recognized to have both motor and non-motor manifestations, indicating a need for the development of reliable non-motor diagnostic tests for PD. The aim of the present study was to compare the accuracy of various clinical motor and non-motor tests for the diagnosis of PD. METHODS: Forty-five PD patients (Hoehn and Yahr stages 1-3; mean age 59.5 +/- 10.0 years) and 45 healthy controls matched for gender and age completed a clinimetric motor test battery to assess limb bradykinesia, tremor and balance. Non-motor tests consisted of depression, anxiety and smell identification ratings. Area under the receiver operator characteristic curve (AUC) analysis was used. RESULTS: We found that smell identification was the most accurate predictor of the presence of PD within the overall group of patients and matched control subjects (AUC = 0.886) and also in the subgroups of mild severity (Hoehn and Yahr stages 1-1.5; AUC = 0.923), young-onset (AUC = 0.888) and female PD patients (AUC = 0.797). The second best diagnostic test was the grooved pegboard test for the clinically most affected body side. CONCLUSIONS: We conclude that olfactory function is the most accurate diagnostic predictor within a heterogeneous sample of patients with PD.

Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia.

AIM: To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson's disease (PD) and parkinsonian dementia (PDem). METHODS: Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [11C]methyl-4-piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD). RESULTS: Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = -0.5, p = 0.007. This correlation remained significant after controlling for Mini-Mental State Examination scores. CONCLUSION: Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.

Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia.

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer's disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson's disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (-20.9%) and PD (-12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = -0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

Organization of the primate circadian system.

The circadian timing system has three principal elements: the retina, the intergeniculate leaflet (IGL) of the thalamus, and the suprachiasmatic nucleus (SCN). Since the human circadian timing system cannot be studied experimentally, we have used another primate, the macaque monkey, to help provide insight into the organization of the human circadian system. The retinohypothalamic tract (RHT) in the monkey projects to the SCN, the anterior and lateral hypothalamic areas, and the retrochiasmatic area in a pattern very similar to that in the rat. The monkey SCN has a population of vasoactive intestinal polypeptide-containing (VIP+) neurons in a zone that overlaps the RHT termination and the termination of neuropeptide Y-containing (NPY+) axons arising in the IGL. This zone is surrounded by a population of vasopressin-containing (VP+) neurons. The human SCN is similar to that of other mammals with populations of VIP+ and VP+ neurons, but it differs in having a large population of neurotensin-containing (NT+) neurons that extends over the entire nucleus, and a moderate population of NPY+ neurons located centrally in the nucleus in the presumed area of RHT termination. The lateral geniculate nucleus in the monkey and human is quite different from that in rodents, but contains an area in the pregeniculate nucleus that receives bilateral retinal projections in the monkey and is characterized in both the monkey and human by a population of NPY+ neurons and a plexus of enkephalin- and substance P-containing axons. This nucleus appears homologous to the rodent IGL.

Calmodulin inhibitors produce phase shifts of circadian rhythms in vivo and in vitro.

The effect of calmodulin inhibitors on the circadian rhythm of locomotor activity and on the rhythm of suprachiasmatic nuclear (SCN) neuron firing rate recorded in vitro from hypothalamic slices was examined. Trifluoperazine produces changes in a dose-dependent manner in the phase of the activity rhythm, with phase advances throughout most of the subjective day extending into the subjective night. These phase changes in the activity rhythm occur rapidly and without induction of locomotor activity at the time of treatment. Similarly, trifluoperazine and the naphthalenesulfonamide W-7 produce changes in phase delays in the subjective night extending into early subjective day. The effects are greater with respect to amplitude when measured acutely after treatment than in the next cycle, and both the acute and next-day effects are greater than those observed in vivo, indicating that data from in vitro studies need to be interpreted with caution. These observations indicate that calmodulin inhibitors affect rhythms directly in vivo by altering SCN neuron pacemaker function, as this reflects involvement of calcium-calmodulin binding with activation of a calmodulin-dependent kinase, either to alter intracellular cAMP levels or to alter gene expression directly to modulate the phase of the SCN clock.

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.

Comparative anatomy of the mammalian hypothalamic suprachiasmatic nucleus.

A detailed analysis of the cytoarchitecture, retinohypothalamic tract (RHT) projections, and immunohistochemical localization of major cell and fiber types within the hypothalamic suprachiasmatic nuclei (SCN) was conducted in five mammalian species: two species of opossum, the domestic cat, the guinea pig, and the house mouse. Cytoarchitectural and immunohistochemical studies were conducted in three additional species of marsupial mammals and in the domestic pig. The SCN in this diverse transect of mammalian taxonomy bear striking similarities. First, the SCN are similar in location, lying close to the third ventricle (3V) dorsal to the optic chiasm (OC), with a cytoarchitecture characterized by small, tightly packed neurons. Second, in all groups studied, the SCN receive bilateral retinal input. Third, the SCN contain immunohistochemically similar elements. These similarities suggest that the SCN developed characteristic features early in mammalian phylogeny. Some details of SCN organization vary among the species studied. In marsupials, vasopressin-like immunoreactive (VP-LI) and vasoactive intestinal polypeptide-like immunoreactive (VIP-LI) cells codistribute primarily in the dorsomedial aspects of the SCN, while in eutherians, VP-LI and VIP-LI cells are separated into SCN subnuclei. Furthermore, the marsupial RHT projects to the periventricular dorsomedial region, whereas the eutherian RHT projects more ventrally in the SCN into the zone that typically contains VIP-LI perikarya.

Distribution of immunoreactive calcitonin in the rat pituitary gland.

Immunohistochemical (immunoperoxidase) studies were performed on 478 sections from 97 rat pituitary glands with rabbit antisera to unconjugated human synthetic calcitonin beta-endorphin, and/or ACTH-(17--39). Calcitonin-positive cells were present in a majority of the anterior lobes studied, whereas they were present in only a minority of the intermediate lobes. Calcitonin-positive cells were also present in chronically thyroidectomized animals. Beta-Endorphin-positive cells were uniformly present in the intermediate lobes as were the ACTH-positive cells. In the anterior pituitary lobes, beta-endorphin-positive cells were more populous than the ACTH-positive cells, and in general, there was a dissociation of the cellular elements containing beta-endorphin, ACTH, and calcitonin. Although it remains possible that there is calcitonin-like immunoreactivity within a precursor molecule that is differentially processed by pituitary cells, these studies are more consistent with the view that immunoreactive calcitonin is present in pituitary cells which are not as yet precisely and consistently related to any identifiable population of hormone-producing cells.

Demonstration by immunoperoxidase histochemistry of calcitonin in the anterior lobe of the rat pituitary.

We have demonstrated by a specific immunoperoxidase procedure the presence of calcitonin-containing cells in the rat pituitary gland. These cells are widely distributed throughout the anterior lobe and seem to constitute the entire population of cells of the intermediate lobe. No such cells were seen in the posterior lobe. The presence of calcitonin-containing cells in the pituitary provides novel implications about the physiological significance of this hormone.

Cranial motor neurons contain either galanin- or calcitonin gene-related peptidelike immunoreactivity.

The demonstration of coexistence of a peptide or peptides in neurons that produce a small molecule neurotransmitter has become increasingly frequent. The calcitonin gene-related peptide (CGRP) is known to be colocalized in the cholinergic neurons of both cranial and spinal motor nuclei. The present study demonstrates that all somatic motor cranial nerve nuclei contain CGRP- and galaninlike immunoreactivity. The perikaryal content of both peptides is increased by colchicine pretreatment and by transecting axons arising from the perikarya, and both peptides are found in nerve fibers innervating striated musculature. CGRP- and galaninlike immunoreactivity appear to be present in different populations of neurons. In contrast to CGRP, galaninlike immunoreactivity was not detected in spinal motor neurons. These observations suggest that galanin and CGRP participate in the process of synaptic transmission at the neuromuscular junction of cranial motor neurons.

Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex.

The intergeniculate leaflet (IGL) in the rat is a distinctive subdivision of the lateral geniculate complex that participates in the regulation of circadian function through its projections to the circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. The present investigation was undertaken to provide a precise definition of the IGL and a characterization of its neuronal organization including neuronal morphology, chemical phenotype, connections, and synaptic organization. The IGL extends the entire rostrocaudal length of the geniculate complex and contains a distinct population of small to medium neurons. In Golgi preparations, the neurons are multipolar with dendrites largely confined to the IGL. The neurons can be subdivided into three groups on the basis of neurotransmitter content and projections: (1) neurons that contain GABA and neuropeptide Y and project to the SCN; (2) neurons that contain GABA and enkephalin and project to the contralateral IGL; and (3) a small group of neurons that projects to the SCN but not characterized as yet by neurotransmitter content. The IGL receives dense, bilateral input from retinal ganglion cells and dense substance P input of unknown origin. A number of neurons in the anterior hypothalamic area and, particularly, the retrochiasmatic area project to the IGL, and there are sparse projections from brainstem monoamine and cholinergic neurons. The synaptic organization of the IGL is complex with afferents terminating in glomerular complexes that include axoaxonic synaptic interactions. Virtually all IGL afferents synapse upon dendrites and spines, with the densest synaptic input occurring on the distal portions of the dendritic arbor. The organization of the IGL and its connections as revealed in this analysis is in accord with its role in the integration of visual input with other information to provide feedback regulation of the SCN pacemaker.

Glutamic acid decarboxylase-like immunoreactivity in brainstem auditory nuclei of the rat.

The distribution of GABA-producing neurons in the brainstem auditory nuclei of the rat was investigated immunohistochemically by using an antibody to glutamic acid decarboxylase (GAD). In the cochlear nuclei, GAD immunoreactive neurons are present only in the superficial granular and molecular layers, whereas terminals are found in all subdivisions of the nuclei and are particularly dense surrounding large spherical cells and one type of stellate cell. In the superior olivary complex, GAD immunoreactive neurons are located in the lateral olivary nucleus and throughout the periolivary region. Immunoreactive terminals are distributed along dendrites of principal cells of the medial and lateral olivary nuclei and are clustered around somata of globular neurons of the nucleus of the trapezoid body. An extremely dense band of immunoreactive somata and terminals is present along the ventral edge of the olivary complex. The ventral, intermediate, and dorsal nuclei of the lateral lemniscus contain small fusiform GAD-immunoreactive neurons and a moderately dense plexus of immunoreactive terminals. The inferior colliculus contains a large population of GAD-immunoreactive perikarya and an extremely dense accumulation of immunoreactive terminals in the central, dorsomedial, and external nuclei. These observations indicate that GABA systems are involved in function at all levels of the brainstem auditory pathway.

Synaptic reorganization in the motor trigeminal nucleus of the rat following neonatal 6-hydroxydopamine treatment.

The synaptic organization of the motor trigeminal nucleus in adult rats treated neonatally with 6-hydroxydopamine (6-OHDA) was investigated quantitatively and compared with control nuclei. No statistically significant change was detected in the distribution of axon terminals in the neuropil, and the total number of axosomatic contacts per unit length of membrane was identical in the control and 6-OHDA-treated groups. However, 6-OHDA treatment causes a significant redistribution of the four morphologically distinct bouton populations forming axosomatic contacts with trigeminal motoneurons. Terminals containing lucent axoplasm and spherical synaptic vesicles have been identified as norepinephrine neuron terminals (Card et al.: J. Comp. Neurol. 250:469-484, '86). These and terminals with lucent axoplasm and pleomorphic vesicles are increased in number whereas terminals with dense axoplasm and either spherical or pleomorphic synaptic vesicles are decreased in number in the 6-OHDA-treated brains compared to controls. These results confirm that the norepinephrine hyperinnervation observed in histofluorescence preparations following neonatal 6-OHDA treatment reflects an increase in absolute numbers of norepinephrine terminals. The finding that the total number of axosomatic contacts per unit length of membrane remains constant while the proportions of individual afferent classes vary may indicate that the trigeminal motoneuron plays a major role in determining the overall density but not necessarily the individual specificity of its axosomatic innervation. The motor trigeminal nucleus is a useful model system in which to investigate both the response of norepinephrine fibers to neonatal 6-OHDA treatment and the respective roles of a target neuron and its afferents in the regulation of appropriate quantitative innervation patterns in the central nervous system.

Retinohypothalamic projection and suprachiasmatic nucleus of the house sparrow, Passer domesticus.

The distribution of retinohypothalamic projections and the organization of the suprachiasmatic region of the hypothalamus was investigated in the house sparrow (Passer domesticus). Retinohypothalamic projections (RHT) were studied by two anterograde tracing methods, and hypothalamic organization was investigated immunohistochemically with antisera against a number of substances known to be present in the mammalian suprachiasmatic nucleus (SCN): bombesin (BBS), glutamic acid decarboxylase (GAD), 5-hydroxytryptamine (5HT), neuropeptide Y (NPY), neurotensin (NT), somatostatin (SS), substance P (SP), vasoactive intestinal polypeptide (VIP), and arginine vasopressin (AVP). Observations from these experiments were analysed within the framework of a cytoarchitectural study using Nissl-stained material. From this study, we have identified an area in the anterior hypothalamus which we believe is an avian homologue of the mammalian SCN. This area contains a nucleus located in close apposition to the optic chiasm between the dorsal supraoptic decussation (DSD) and the ventral lateral geniculate body (GLv) for much of its rostrocaudal extent. The central portion of this nucleus contains neurons that exhibit GAD- and BBS-like immunoreactivity and is the terminal field for the RHT. For this reason, we term this nucleus the visual SCN. It also contains axon plexuses exhibiting 5HT-like, SP-like, and NPY-like immunoreactivity and is bordered ventrally by AVP-like, SP-like, and NT-like immunoreactive cells and medially by VIP-like and SS-like immunoreactive cells. Although it is not established that these cell groups together compose a single suprachiasmatic nucleus, the organization in the avian brain of a nuclear complex with a retinorecipient area surrounded by nonvisual components would be very similar to that of the mammalian SCN.

Origin and organization of brainstem catecholamine innervation in the rat.

The catecholamine (CA) innervation of the rat brainstem was studied by biochemical analysis of discrete nuclei or areas and by glyoxylic acid-formaldehyde freeze dry fluorescence histochemistry. CA assays demonstrate that the highest norepinephrine (NE) content in brainstem is present in the trigeminal motor nucleus, nucleus tractus solitarius, dorsal motor nucleus of the vagus and nucleus raphe dorsalis. Bilateral locus coeruleus (LC) lesions do not significantly alter NE content in these nuclei but do decrease NE content in the superior and inferior colliculi, medial geniculate body, interpeduncular nucleus, pontine nuclei and the main sensory trigeminal nucleus (60-75%). Dopamine (DA) and epinephrine (E) are found in significant concentration in only a few of the nuclei examined. Fluorescence histochemical analysis indicates that two groups of NE axons innervate rat brainstem. LC neuron axons with a distinctive morphology principally innervate sensory and association nuclei of the brainstem. These disappear completely after bilateral LC lesions. The second group of axons originates from lateral and dorsal tegmental NE cell groups. Primary motor and visceral nuclei are densely innervated by fine and thick axons from these groups. Lesions of LC do not alter the NE innervation in any of the nuclei which contain axons of the second group. These results indicate that the brainstem NE innervation is divided into two major systems. The locus coeruleus complex innervates mainly primary sensory and association nuclei whereas the lateral tegmental NE neurons innervate primary motor and visceral nuclei. Although some overlap is present, the LC and lateral tegmental NE systems predominantly innervate separate and functionally distinct areas of the brainstem. DA and E neurons provide a very minor component of the brainstem CA innervation.

Hippocampal innervation by serotonin neurons of the midbrain raphe in the rat.

The organization of the brainstem serotonin neuron projection to the hippocampal formation was analyzed in the rat. This projection arises in the raphe nuclei of the midbrain. Following destruction of the midbrain raphe nuclei, chiefly nucleus centralis superior, there is a 72% decrease in hippocampal serotonin content. Injection of tritiated amino acid into the midbrain raphe nuclei results in transport of tritiated protein to the hippocampal formation and this transport is blocked in animals pretreated by intraventricular administration of 5,6-dihydroxytryptamine (5,6-DHT). Autoradiographic analysis indicates that the transport reaches the hippocampal formation primarily via two major pathways, the cingulum and the fornix. Cingulum fibers terminate predominantly in the dorsal hippocampus whereas the fornix distributes throughout the entire hippocampal formation. Some fibers reach the ventral hippocampus from the entorhinal area. Within the hippocampus there is dense labeling in a restricted lamina of the CA1 stratum lacunosum-moleculare with moderate labeling in stratum radiatum. Stratum oriens is sparsely labeled in CA1 and moderately so in CA2 and CA3. Stratum radiatum and stratum lacunosum-moleculare are moderately densely labeled in CA2 and Ca3. The area dentata is sparsely to moderately labeled in the molecular layer and heavily labeled in a thin lamina of the hilar zone immediately beneath the granule cell layer. The remaining hilar zone is moderately labeled. All of the discrete labeling of the hippocampus and area dentata described above is absent in animals pretreated with 5,6-DHT. These observations indicate that serotonin neurons of the midbrain raphe provide a highly organized innervation of the hippocampal formation in the rat.