Epidermal growth factor immunoreactive material in the central nervous system: location and development.

Epidermal growth factor (EGF) is a potent mitogen with hormonal activity in the gastrointestinal tract. Material cross-reacting with EGF was detected in the central nervous system of the developing and adult albino rat by the indirect immunofluorescence technique. High concentrations of EGF-cross-reacting material were identified in forebrain and midbrain structures of pallidal areas of the brain. These include the globus pallidus, ventral pallidum, entopeduncular nucleus, substantia nigra pars reticulata, and the islands of Calleja . Thus, EGF may represent another gut-brain peptide with potential neurotransmitter-neuromodulator functions in pallidal structures of the extrapyramidal motor systems of the brain.

Ependymal stem cells divide asymmetrically and transfer progeny into the subventricular zone when activated by injury.

Evidence is presented to show that cells of the ependymal layer surrounding the ventricles of the mammalian (rat) forebrain act as neural stem cells (NSCs), and that these cells can be activated to divide by a combination of injury and growth factor stimulation. Several markers of asymmetric cell division (ACD), a characteristic of true stem cells, are expressed asymmetrically in the ependymal layer but not in the underlying subventricular zone (SVZ), and when the brain is treated with a combination of local 6-hydroxydopamine (6-OHDA) with systemic delivery of transforming growth factor-alpha (TGFalpha), ependymal cells divide asymmetrically and transfer progeny into the SVZ. The SVZ cells then divide as transit amplifying cells (TACs) and their progeny enter a differentiation pathway. The stem cells in the ependymal layer may have been missed in many previous studies because they are usually quiescent and divide only in response to strong stimuli.

Expression of neuropeptide Y precursor-immunoreactivity in the hypothalamic dopaminergic tubero-infundibular system during lactation in rodents.

Evidence from physiological studies in rats shows that neuropeptide Y (NPY) has marked neuroendocrine effects on anterior pituitary function, and especially on LHRH and LH secretions. However, previous immunohistochemical studies in rats have revealed only scarce NPY-axons of medullary origin in the external zone of the hypothalamic median eminence, the common termination site of neuroendocrine adenohypophysiotropic systems. In view of this apparent contradiction, we used light microscopic immunohistochemistry to reassess the distribution of NPY in the hypothalamus of rodents of both sexes under physiological (estrous cycle in rats, pregnancy in rats, and lactation in both rats and mice) and experimental (gonadectomy in rats and adrenalectomy in both rats and mice) conditions with alterations of reproductive functions. We reasoned that such manipulations could induce changes in immunoreactivity in the NPY system involved in neuroendocrine regulation and would thus make it apparent to us. We show here that immunoreactivity for NPY and its carboxyterminal precursor-associated peptide are dramatically increased in the external median eminence of lactating female animals when compared to the other animal groups. This NYP-precursor-immunoreactivity is present, throughout lactation, in the tyrosine hydroxylase-immunoreactive (and therefore possibly dopaminergic) tubero-infundibular system. This immunoreactivity disappears rapidly from the median eminence after pup-removal. These observations suggest a role for NPY-precursor-derived peptides in the control of the suckling-induced PRL secretion and also demonstrate the chemical plasticity of the median eminence during a normal physiological event. Since in nonlactating animals and especially in normal cycling females NPY-precursor-immunoreactivity was detected in the system of medullary origin only, we conclude that, by exclusion, this system might be the one responsible for modulating gonadotropic secretion at the median eminence and/or pituitary levels.

Prefrontal cortex dysfunction in Borna disease virus (BDV)--infected rats.

Viruses have been proposed to play a role in the pathogenesis of schizophrenia; however, the mechanisms by which infection could cause the affective, cognitive, and movement disorders of schizophrenia are not understood. The neurotropic RNA virus, Borna disease (BD) virus, linked to schizophrenia by serologic studies, causes movement and behavior disorders in a wide variety of mammalian and bird hosts. BD rats have hyperactivity and stereotyped behaviors similar to those that follow neurotoxic or electrolytic lesions in frontal cortex or its catecholamine afferents in rats. BD rats have high levels of viral nucleic acid in the prefrontal cortex (PFC), abnormal mesocortical dopamine activity (elevated levels of DOPAC in PFC), yet no alteration in specific binding of D1 or D2 receptor radioligands in PFC. Since frontal lobe dysfunction is frequently reported in schizophrenia, the BD rat model may provide insights into pathogenesis and management of this debilitating psychiatric disease.

Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex.

OBJECTIVE: Sleep deprivation has been shown to have an antidepressant benefit in a subgroup of depressed patients. Functional imaging studies by the authors and others have suggested that patients with elevated metabolic rates in the anterior cingulate gyrus at baseline are more likely to respond to either sleep deprivation or antidepressant medications than patients with normal metabolic rates. The authors extend their earlier work in a larger group of patients and explore additional brain areas with statistical probability mapping. METHOD: Thirty-six patients with unipolar depression and 26 normal volunteers were studied with positron emission tomography before and after sleep deprivation. Response to sleep deprivation was defined as a 40% or larger decrease in total scores on the Hamilton Depression Rating Scale. RESULTS: One-third of the depressed patients had a significant response to sleep deprivation. Responders had higher relative metabolic rates in the medial prefrontal cortex, ventral anterior cingulate, and posterior subcallosal gyrus at baseline than depressed patients who did not respond to sleep deprivation and normal volunteers. Lower Hamilton depression scores correlated significantly with lower metabolic rates in the left medial prefrontal cortex. After sleep deprivation, significant decreases in metabolic rates occurred in the medial prefrontal cortex and frontal pole in the patients who responded positively to sleep deprivation. CONCLUSIONS: High pretreatment metabolic rates and decreases in metabolic rates after treatment in the medial prefrontal cortex may characterize a subgroup of depressed patients who improve following sleep deprivation and, perhaps, other antidepressant treatments.

Distribution of dynorphin and enkephalin peptides in the rat brain.

The neuroanatomical distribution of dynorphin B-like immunoreactivity (DYN-B) was studied in the adult male and female albino rat. The distribution of DYN B in colchicine- and noncolchicine-treated animals was also compared to that of another opioid peptide derived from the prodynorphin precursor dynorphin A (1-8) (DYN 1-8), and an opioid peptide derived from the proenkephalin precursor met-enkephalin-arg-gly-leu (MERGL). DYN B cell bodies were present in nonpyramidal cells of neo- and allocortices, medium-sized cells of the caudate-putamen, nucleus accumbens, lateral part of the central nucleus of the amygdala, bed nucleus of the stria terminalis, preoptic area, and in sectors of nearly every hypothalamic nucleus and area, medial pretectal area, and nucleus of the optic tract, periaqueductal gray, raphe nuclei, cuneiform nucleus, sagulum, retrorubral nucleus, peripeduncular nucleus, lateral terminal nucleus, pedunculopontine nucleus, mesencephalic trigeminal nucleus, parabigeminal nucleus, dorsal nucleus of the lateral lemniscus, lateral superior olivary nucleus, superior paraolivary nucleus, medial superior olivary nucleus, ventral nucleus of the trapezoid body, lateral dorsal tegmental nucleus, accessory trigeminal nucleus, solitary nucleus, nucleus ambiguus, paratrigeminal nucleus, area postrema, lateral reticular nucleus, and ventrolateral region of the reticular formation. Fiber systems are present that conform to many of the known output systems of these nuclei, including major descending pathways (e.g., striatonigral, striatopallidal, reticulospinal, hypothalamospinal pathways), short projection systems (e.g., mossy fibers in hippocampus, hypothalamo-hypophyseal pathways), and local circuit pathways (e.g., in cortex, hypothalamus). The distribution of MERGL was, with a few notable exceptions, in the same nuclei as DYN B. From these neuroanatomical data, it appears that the dynorphin and enkephalin peptides are strategically located in brain regions that regulate extrapyramidal motor function, cardiovascular and water balance systems, eating, sensory processing, and pain perception.

The ascending projections of the superior colliculus in the rhesus monkey (Macaca mulatta).

We studied and compared the ipsilateral efferents of the superficial and deep layers of the superior colliculus of the rhesus monkey. Using a stereotaxic method, microelectrodes were inserted through the contralateral hemisphere in order to make electrolytic lesions of the superior colliculus. Large lesions involved all layers of the superior colliculus, while smaller lesions involved either the superficial or the deep layers of the superior colliculus. Following various survival times, the brains were prepared with the Fink-Heimer technique ('67). Following lesions of the superficial layers of the superior colliculus, definite degenerated axonal endings were found in the dorsal and ventral lateral geniculate nuclei, inferior pulvinar, centrointermediate nucleus, magnocellular dorsomedial nucleus, anterior pretectal nucleus and pretectal region. Sparse degenerated axonal endings were found in the limitans nucleus, lateral posterior nucleus and some intralaminar nuclei following lesions of the superficial layers in the rostral portion of the superior colliculus. Following lesions of the deep layers of the superior colliculus, degenerated axonal endings were found in the central gray, magnocellular medial geniculate nucleus, suprageniculate nucleus, limitans nucleus, lateral posterior nucleus, medial and oral pulvinar, nucleus of the accessory optic tract, zona incerta, subdivisions of the ventral lateral and ventral posterior lateral nuclei, ventral posterior inferior nucleus, denosocellular and multiform dorsomedial nuclei, all intralaminar nuclei, inferior colliculus, parabigeminal nucleus, olivary nucleus, reunions nucleus, Forel's Field H and an undefined midbrain nucleus. In general the projections were topographically organized in that the caudal portion of the superior colliculus projected to the rostral portions of thalamic nuclei and the rostral portion of the superior colliculus projected to the caudal portions of thalamic nuclei. All the degeneration patterns seen after lesions of the superficial and deep layers were accounted for by large lesions which involved all layers of the superior colliculus. It is concluded that the superficial and deep layers of the rehesus monkey superior colliculus have different ascending projections. The finding, are related to the organization of visual and multimodal thalamocortical systems in primates and other mammals.

The island of Calleja complex of rat basal forebrain. I. Light and electron microscopic observations.

An analysis of the cells and their processes within the island of Calleja complexes (ICC) was made in light and electron microscopic preparations to determine synaptic relationships within this part of the basal forebrain. The light microscopic preparations showed that the ICC contained two cell types, granule cells and large cells. In electron microscopic preparations, the somata of granule cells were grouped together and were directly apposed to other somata of granule cells. Specialized junctions (4-6 nm wide) that occurred at sites of somal apposition suggested ephaptic coupling of granule cells. The granule cell somata had nuclei that contained clumps of heterochromatin adjacent to smooth nuclear envelopes. The perikaryal cytoplasm of these cells consisted of a relatively thin rim containing few organelles. Spinous dendrites of small diameter were occasionally found in continuity with these cells. Axon terminals rarely formed synapses with the somata of granule cells, but were more frequently found to synapse on their dendrites and dendritic spines. These features for granule cells are similar to those for medium-sized spiny neurons in the neostriatum. The somata of the large cells were found either within the core or along the dorsal margin of the ICC. The large cells had infolded nuclei and an abundant perikaryal cytoplasm that contained many organelles. Large diameter dendrites that tapered down to smaller diameters emanated in many directions from these somata. Axon terminals covered nearly the entire surface of these somata and dendrites where they commonly formed symmetric synaptic junctions. These characteristics of large cells indicate a resemblance to the large cells in the globus pallidus and ventral pallidum. Therefore, the ICC have ultrastructural features found in both the neostriatum and globus pallidus.

Catecholamine innervation of the basal forebrain. III. Olfactory bulb, anterior olfactory nuclei, olfactory tubercle and piriform cortex.

The catecholamine innervation of the olfactory bulb, anterior olfactory nuclei, olfactory tubercle and piriform cortex was studied in the rat using biochemical analysis and fluorescence histochemistry. Biochemical studies demonstrate a moderate norepinephrine (NE) content in all olfactory structures, a high dopamine (DA) content in the olfactory tubercle and a low DA content in the olfactory bulb, anterior olfactory nucleus and piriform cortex. Following locus coeruleus lesions NE content decreases 71% in the olfactory bulb, 82% in the anterior olfactory nucleus, 62% in olfactory tubercle and 77% in piriform cortex...

Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum.

In this study the location of dopamine (DA) neuron perikarya in the rostral mesencephalon of the rat was determined using the glyoxylic acid fluorescence histochemical technique. Subsequently the topography of the projection of these mesencephalic neurons on the basal forebrain and striatum was analyzed using the anterograde transport-autoradiographic tracing method and the retrograde transport-horseradish peroxidase (HRP) technique. The results of these anatomical studies were correlated with the biochemical and histochemical studies presented in previous reports (Moore, '78; Fallon and Moore, '78; Fallon et al., '78) to provide the following conclusions. The topography of the DA neuron projection of the basal forebrain and neostriatum is organized in three planes, dorsal-ventral, medial-lateral and anterior-posterior. DA cells are found almost exclusively in the substantia nigra (SN) and ventral tegmental area (VTA). Ventral cells of the SN and VTA project to the dorsal structures of the basal forebrain such as the septum, nucleus accumbens and neostriatum. The latter includes some DA cells located ventrally in the pars reticulata of the SN. Dorsal cells project to ventral structures. The medial-lateral topography is organized such that the medial sectors of the SN-VTA area project to the medial parts of nuclei in the basal forebrain and neostriatum whereas lateral sectors of the SN-VTA area project to the lateral parts of nuclei in the basal forebrain and neostriatum. An anterior-posterior topography also is evident such that anterior parts of the SN-VTA project anteriorly whereas the posterior SN-VTA projects more posteriorly in these areas. These observations are consistent with the view that the DA neurons of the SN-VTA complex form a single nuclear group with a highly topographically organized projection innervating not only deep nuclei of the telencephalon but allocortical structures as well.

Forebrain projections from cholecystokininlike-immunoreactive neurons in the rat midbrain.

The purpose of the present study was to analyze the distribution of cholecystokininlike-immunoreactive (CCK-I) neurons within the rat ventral mesencephalon which project to several forebrain areas. The peroxidase-antiperoxidase immunocytochemical technique was used to examine the anatomical localization of CCK-I within the ventral midbrain and in the following forebrain regions: caudate-putamen, nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, septum, amygdala, and prefrontal, anterior cingulate, and piriform cortices. CCK-I perikarya were distributed throughout the substantia nigra, ventral tegmental area, and several midline raphe nuclei to a greater extent than previously reported, particularly in the substantia nigra pars compacta. Terminallike immunoreactivity for CCK was observed in all of the above forebrain sites. In addition, infrequent CCK-I cell bodies were localized in the caudate-putamen, nucleus accumbens, olfactory tubercle, septum, and bed nucleus of the stria terminalis. To analyze forebrain projections of the ventral midbrain CCK-I neurons, indirect immunofluorescence was combined with fluorescence retrograde tracing. CCK-I neurons of the substantia nigra and/or ventral tegmental area were found to project, to varying extents, to all of the above CCK-I forebrain terminal fields. The nucleus accumbens, olfactory tubercle, and septal and prefrontal cortical projections arose primarily from CCK-I perikarya in the ventral tegmental area whereas the projections to the caudate-putamen and anterior cingulate cortex arose predominantly from immunoreactive neurons in the substantia nigra pars compacta. The amygdala received innervation mainly from CCK-I cell bodies located in the substantia nigra pars lateralis. CCK-I afferents to the bed nucleus of the stria terminalis and piriform cortex originated from perikarya distributed approximately equally across the ventral tegmental area and substantia nigra pars compacta. The general topography of CCK-I forebrain innervation observed in this study is similar to that previously reported for the ascending dopaminergic projections from ventral mesencephalic neurons. CCK-I neurons of the midline raphe nuclei were found to provide relatively minor afferents to the caudate-putamen, bed nucleus of the stria terminalis, septum, and prefrontal cortex and more substantial projections to the amygdala. The results of this study demonstrate that CCK-I neurons of the ventral midbrain supply a much broader innervation of forebrain regions than previously appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)

The islands of Calleja complex of rat basal forebrain. III. Histochemical evidence for a striatopallidal system.

The characteristics of the islands of Calleja complex (ICC) in the basal forebrain of the rat were studied with immunohistochemistry, histofluorescence, acetylcholinesterase staining, India ink vascular perfusions, electron microscopy, and steroid autoradiography. The ICC contains clusters of granule cells and associated medium-sized and large cells in the surrounding neuropil of the olfactory tubercle and septum-nucleus accumbens interface. The ICCs were found to contain monoamine fibers (dopamine and norepinephrine), neuroactive peptide fibers (leu-enkephalin, met-enkephalin, substance P, cholecystokinin, luteinizing hormone-releasing hormone), acetylcholinesterase-containing somata and dendrites, and medium-sized and large cells that concentrate [3H] estradiol. The specific overlap and combination of putative neurotransmitters in separate compartments of the ICC suggest that these structures contain striatum- and pallidumlike components. Striatumlike regions are defined as the zone in the rim regions of the ICC and are innervated predominantly by dopamine and cholecystokinin inputs. Pallidumlike regions are defined as the synaptic zone near the medium-sized and large cells of the cap and core regions of the ICC and they are innervated predominantly by enkephalin, substance P, and gamma aminobutyric acid inputs. The morphology, connections, and neurotransmitter relationships of the ICC, therefore, resemble classical striatopallidal systems. The additional presence of substances involved in the reproductive neuroendocrine systems (luteinizing hormone-releasing hormone, estradiol-binding cells, especially in the medial ICC, suggest that some ICC are involved in an endocrine corticostriatopallidal system. These endocrine systems resemble other neocortically and allocortically originating corticostriatopallidal systems in terms of their cell types, connections, and neurotransmitter systems. A functional role for the ICC in extrapyramidal motor systems is proposed.

Catecholamine innervation of the basal forebrain. II. Amygdala, suprarhinal cortex and entorhinal cortex.

The catecholamine (CA) innervation of the posterior basal forebrain, the amygdala, suprarhinal cortex and entorhinal cortex, was studied in the rat using biochemical assay and fluorescence histochemistry. The assay studies demonstrate a moderate norepinephrine (NE) content in the amygdala and entorhinal cortex with a lower value for the suprarhinal cortex. Following destruction of the locus coeruleus, the decrease in NE content of these basal forebrain structures indicates that their principal NE innervation is from locus coeruleus. An additional small NE input arises from the medullary NE neuron groups. Ablation of dopamine (DA) cell groups (substantia nigra-ventral tegmental area, SN-VTA) indicates that the DA input to the amygdala arises from the lateral VTA and medial half of the SN. Fluorescence histochemical studies using the glyoxylic acid-Vibratome technique demonstrate the presence of four distinct types of CA neuron terminal plexus in the posterior basal forebrain. These include two different DA fiber types arising in SN-VTA, small NE fibers with small varicosities arising in locus coeruleus and NE fibers with larger varicosities arising in other brainstem NE cell groups. The large NE fibers appear to enter the amygdala via the ansa peduncularis-ventral amygdaloid bundle to innervate the central and basolateral nucleus and the anterior amygdaloid area. The locus coeruleus NE fibers appear to enter the posterior basal forebrain via both the stria terminalis and ansa peduncularis-ventral amygdaloid bundle system to form a moderately dense innervation of the central and basolateral nuclei of the amygdala and a less dense innervation of the other areas. The DA neuron axons are concentrated in the central and basal nuclei and intercalated cell groups. Other areas receive a more diffuse DA input, with the exception of the moderately dense innervation of the suprarhinal cortex and DA "islands" in the ventral-anterrior entorhinal cortex, The DA input to the posterior basal forebrain is complex and heterogeneous and the axonal morphology differs greatly among the terminal fields within the amygdala and adjacent cortical areas.

Ventral mesencephalic neurons containing both cholecystokinin- and tyrosine hydroxylase-like immunoreactivities project to forebrain regions.

The coexistence of cholecystokinin- and tyrosine hydroxylase-like immunoreactivities within neurons of the rat ventral mesencephalon was analyzed by using an indirect immunofluorescence technique for the simultaneous demonstration of two antigens in the same tissue section. A high degree of colocalization was observed in the substantia nigra pars compacta, in which 80-90% of all labeled neurons at rostral and up to 70% at intermediate levels contained both cholecystokinin and tyrosine hydroxylase. At caudal levels, the incidence of colocalization declined to approximately 30-50%. All of the immunoreactive perikarya in the substantia nigra pars lateralis were labeled with both substances. Other areas of the ventral midbrain that exhibited a moderate proportion of neurons immunoreactive for both cholecystokinin and tyrosine hydroxylase included the ventral tegmental area, interfascicular nucleus, and rostral and caudal linear nuclei. In addition, coexistence was occasionally observed within neurons of the central and ventral periaqueductal gray matter, supramammillary region, peripeduncular region, retrorubral field, and extremely rarely, within the substantia nigra pars reticulata. Cell bodies containing tyrosine hydroxylase-like immunoreactivity (indicative of dopamine) usually outnumbered those containing the peptide except in the supramammillary region and in the ventral periaqueductal gray matter, where the cholecystokinin perikarya were present in higher numbers. The double-labeling colocalization technique was combined with fluorescence retrograde tracing to determine some of the forebrain projections of these neurons. Ventral midbrain neurons containing both cholecystokinin and tyrosine hydroxylase were found to project to the caudate-putamen, nucleus-accumbens, prefrontal cortex, and amygdala. These projections originated from neurons located predominantly in the substantia nigra pars compacta and the ventral tegmental area. Thus, cholecystokinin occurs within the well-known dopaminergic nigrostriatal pathway in the rat. Overall, these results demonstrate that a significant proportion of the dopamine neurons giving rise to the ascending mesotelencephalic projections also contain the peptide cholecystokinin.

GABAergic and non-GABAergic projections of accessory optic nuclei, including the visual tegmental relay zone, to the nucleus of the optic tract and dorsal terminal accessory optic nucleus in rat.

This study examines the non-gamma-amino butyric acid (GABA)ergic (group I neurons) and GABAergic neurons (group II neurons) of the accessory optic system projecting to the nucleus of the optic tract (NOT)/dorsal terminal nucleus (DTN) of the accessory optic system in rat. These nuclei include the dorsal (MTNd) and ventral (MTNv) divisions of the medial terminal nucleus, the lateral terminal nucleus, the interstitial nucleus of the superior fasciculus, the posterior fibers, and the visual tegmental relay zone. GABAergic neurons of these nuclei that do not target the NOT/DTN (group III neurons) have also been observed. The fluorescent retrograde tracer fluoro-gold was injected into the pretectum, targeting the NOT/DTN and the tissue prepared immunocytochemically to reveal neurons containing the neurotransmitter GABA. Three groups of neurons (groups I, II, and III neurons) were examined in terms of their distribution, density, and percentage present. Group I neurons are single-labeled with fluoro-gold and represent non-GABAergic neurons projecting to the NOT/DTN. These neurons are of the highest density in the lateral terminal nucleus (204 neurons/mm2). Their densities are also substantial in the MTNv (120 neurons/mm2), interstitial nucleus of the superior fasciculus, posterior fibers (96 neurons/mm2), and visual tegmental relay zone (93 neurons/mm2). Group II neurons are double-labeled with fluoro-gold and GABA. They form a system of GABAergic neurons projecting to the NOT/DTN, which are exceedingly dense in the MTNd (78 neurons/mm2) but are also dense in both the visual tegmental relay zone (49 neurons/mm2) and MTNv (33 neurons/mm2). Group III neurons are GABAergic neurons that do not target the NOT/DTN but must project to other brain nuclei and/or be interneurons. These are of extremely high concentration in the visual tegmental relay zone (316 neurons/mm2) and are also of substantial densities in the MTNd (77 neurons/mm2), lateral terminal nucleus (72 neurons/mm2), and MTNv (44 neurons/mm2). The MTNd has the highest percentage of GABAergic neurons projecting to the NOT/DTN (72%). GABAergic neurons also form significant percentages of the projections to the NOT/DTN from the visual tegmental relay zone (34%) and MTNv (21%). The percentage of the total GABAergic neurons that project to the NOT/DTN is the highest in the MTNd (50%) and MTNv (42%). The described GABAergic afferents to the NOT/DTN may function to process information concerned with the compensation for retinal slip.

The islands of Calleja: organization and connections.

The islands of Calleja (IC) in the rate are composed of seven small groups of granule cells in the polymorph layer of the olfactory tubercle and one large group, the insula magna, which lies along the border between septum, nucleus accumbens and nucleus of the diagonal band. The cytoarchitecture and neuronal morphology of the IC and surrounding cells, studied using Nissl-stained and Golgi-Kopsch material, are described. In addition, the afferent and efferent connections of the IC were analyzed using fluorescence histochemistry, the autoradiographic tracing method, and the anterograde and retrograde horseradish peroxidase methods. Topographically organized projections to the IC from the dopamine-containing cells of the substantia nigra-ventral tegmental area are demonstrated by the glyoxylic acid fluorescence histochemical method and the autoradiographic tracing technique. Anterograde and retrograde horseradish peroxidase studies provide evidence for reciprocal, topographically organized interconnections between the IC and the septum, nucleus accumbens, amygdala and piriform cortex. These observations indicate that the IC constitute a unique population of granule cells, located in the olfactory tubercle, innervated by dopamine neurons of the mesencephalon and interconnected with olfactory and non-olfactory components of the basal forebrain.

Substantia nigra and ventral tegmental area projections to cortex: topography and collateralization.

The substantia nigra and ventral tegmental area of the rat were examined by retrograde transport methods to determine the topography and collateralization patterns of projections to cortex and certain subcortical sites. The topographical relationships between cells and their terminal fields were confirmed and clarified by the horseradish peroxidase retrograde transport technique. The collateralization of axons was analyzed by the use of multiple fluorescent tracers. These experiments indicated that individual ventral tegmental area cells do not collateralize extensively to either subcortical or cortical terminal fields. Substantia nigra cells, however, give rise to more highly collateralized axons and single cells may simultaneously innervate different regions of cortex as well as subcortical sites. Substantia nigra cells can be divided with respect to their cortical collateralization patterns into three groups: (1) those that innervate cingulate cortices, (2) those that project to prefrontal and suprarhinal cortices, and (3) those that innervate entorhinal cortex.

IRIDIUM exposure increases c-fos expression in the mouse brain only at levels which likely result in tissue heating.

With the rapid development of wireless communication technology over the last 20 years, there has been some public concern over possible health effects of long-term, low-level radiofrequency exposure from cellular telephones. As an initial step in compiling a database for risk analysis by government agencies, the effects of 1-h exposure of mice to a 1.6-GHz radiofrequency signal, given as either a continuous wave or pulse modulated at 11 Hz with a duty cycle of 4:1 and a pulse duration of 9.2 ms IRIDIUM), on c-fos gene expression in the brain was investigated. The IRIDIUM signal is the operating frequency for a ground-to-satellite-to-ground cellular communications web which has recently become fully operational, and was named as such due to the original designed employment of the same number of low orbiting satellites as there are electrons orbiting the nucleus of an iridium atom. The expression of c-fos was not significantly elevated in the brains of mice until exposure levels exceeded six times the peak dose and 30 times the whole body average dose as maximal cellular telephone exposure limits in humans. Higher level exposure using either continuous wave (analog) or IRIDIUM signals elevated c-fos to a similar extent, suggesting no obvious pulsed modulation-specific effects. The pattern of c-fos elevation in limbic cortex and subcortex areas at higher exposure levels is most consistent with a stress response due to thermal perception coupled with restraint and/or neuron activity near thermoregulatory regions, and not consistent with any direct interaction of IRIDIUM energy with brain tissue.

D2 dopamine receptor polymorphism and brain regional glucose metabolism.

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia.

A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto-striatal connectivity in schizophrenia.