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PubMed1997

Neuronal activation in the forebrain following electrical stimulation of the cuneiform nucleus in the rat: hypothalamic expression of c-fos and NGFI-A messenger RNA.

Forebrain neuronal connections associated with the cardiovascular response to unilateral, low-intensity, electrical stimulation of the mesencephalic cuneiform nucleus were examined in the halothane-anesthetized and paralysed rat by in situ hybridization histochemistry using specific 35S-labelled oligonucleotides for detection of c-fos and nerve growth factor inducible-A gene (NGFI-A) messenger RNAs. Stimulation of the cuneiform nucleus led to increases in mean arterial pressure and heart rate, whereas no cardiovascular response was observed in animals stimulated in the inferior colliculus or in sham-operated animals [see concurrent mid- and hindbrain study [Lam W. et al. (1996) Neuroscience 71, 193-211]. Cuneiform nucleus stimulation was associated with increased c-fos and NGFI-A messenger RNA levels bilaterally in the ventromedial, dorsomedial and lateroanterior hypothalamic nuclei, lateral and anterior hypothalamic areas, and ipsilaterally in the medial amygdaloid nucleus, at levels significantly greater than those in inferior colliculus-stimulated, sham-operated and naive, unoperated animals. C-fos, but not NGFI-A, messenger RNA expression was increased bilaterally in the piriform cortex and subparafascicular thalamic nucleus. These results are consistent with the existence of direct and indirect projections between the cuneiform nucleus and the aforementioned activated areas, the functions of which may include the control of reproduction and metabolism, as well as cardiovascular regulation. The ipsilateral nature of responses in certain brain areas may be explained by the absence of decussating pathways and/or the presence of multisynaptic connections which attenuate bilateral signal transmission. The existence of structures that are known to receive afferent projections from the cuneiform nucleus, but that were not activated, may be explained by synaptic depolarization not reaching the threshold for immediate early gene expression or by a net inhibitory effect on innervated neurons. Characterization of these activated forebrain regions using other compatible labelling techniques should further elucidate the mechanisms by which these central nervous system structures are integrated in the response to stimulation of the cuneiform nucleus.

Animals↗
PubMed1997

Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system.

We have generated and characterized a multi-functional polyclonal anti-brain-derived neurotrophic factor antibody. Western blot analysis, dorsal root ganglion neurite outgrowth and dorsal root ganglion neuron survival assays showed that this antibody specifically recognized brain-derived neurotrophic factor and not the other neurotrophins. Furthermore, it was capable of blocking the functional effects of brain-derived neurotrophic factor. Using this antibody, we examined the expression of brain-derived neurotrophic factor in adult rat brains by immunohistochemistry. We found distinct brain-derived neurotrophic factor immunoreactivity in several structures of the brain. These included the neocortex, piriform cortex, amygdaloid complex, hippocampal formation, claustrum, some thalamic and hypothalamic nuclei, the substantia nigra and some brainstem structures. In contrast to brain-derived neurotrophic factor messenger RNA expression, brain-derived neurotrophic factor immunoreactivity was also found in the lateral septum, bed nucleus of the stria teminalis, medial preoptic nucleus, olivery pretectal nucleus, lateral paragigantocellular nucleus and the dorsal horn of the spinal cord. In normal adult rat brains, there was little or no staining in the CA1 region or the granule cell layer of the dentate gyrus of the hippocampus. However, kainate treatments greatly increased brain-derived neurotrophic factor immunoreactivity in the pyramidal cells of the CA1 region, as well as in the dentate gyrus, CA2 and CA3 hippocampal regions. We present evidence for both the subcellular localization and anterograde transport of endogenous brain-derived neurotrophic factor in the central nervous system. The detection of brain-derived neurotrophic factor protein in several discrete regions of the adult brain, and brain-derived neurotrophic factor's dramatic up-regulation following kainate treatment, strongly supports a role of brain-derived neurotrophic factor in the maintenance of adult neurons and synapses. Since several populations of neurons lost during neurodegenerative diseases synthesize brain-derived neurotrophic factor protein, modulation of brain-derived neurotrophic factor levels may be clinically beneficial. The antibody described in this paper will be helpful in determining more precisely the functional activities of brain-derived neurotrophic factor in the adult.

Animals↗
PubMed1996

Localization of preprogalanin messenger RNA in rat brain: identification of transcripts in a subpopulation of cerebellar Purkinje cells.

Galanin, a 29 amino acid peptide, is widely distributed throughout both the peripheral and central nervous systems and is thought to be involved in multiple physiological functions including smooth muscle relaxation, stimulation of feeding, blood pressure regulation, control of hormone secretion and modulation of nociception. Galanin has been shown to co-exist with several neurotransmitters throughout the neuroaxis and in some cases to modify their presynaptic and postsynaptic actions. In the present study, the anatomical distribution of preprogalanin messenger RNA in rat brain was examined by in situ hybridization histochemistry using specific 35S-labelled oligonucleotide probes. Neurons expressing preprogalanin messenger RNA were found throughout the brain and were particularly abundant in the hypothalamus. High densities of preprogalanin messenger RNA-positive neurons were found in the anteroventral preoptic, supraoptic, paraventricular and dorsomedial nuclei of the hypothalamus, in the locus coeruleus and in the nucleus of the solitary tract. Moderate densities of preprogalanin messenger RNA-positive cells were apparent in the periventricular and arcuate nuclei of the hypothalamus, in the dorsal raphe and dorsal cochlear nuclei. Low densities of preprogalanin messenger RNA-expressing neurons were observed in the piriform cortex, medial septum and the retrochiasmatic area. These findings are consistent with results of previous in situ localization studies of preprogalanin messenger RNA and also with studies reporting the distribution of galanin-like immunoreactivity in rat brain. A novel finding, however, was the detection of preprogalanin messenger RNA in Purkinje cells in the caudal cerebellar vermis (lobules 6 to 10) and the flocculus and paraflocculus of the lateral hemispheres of the cerebellum. Galanin is presumably co-localized in these cells with GABA, which is normally present in Purkinje cells and possibly with tyrosine hydroxylase, which has recently been detected in a similar subpopulation of cerebellar Purkinje cells in both rat and mouse. Thus, the present study reveals a previously unreported site of galanin gene expression in the cerebellum which represents a novel, putative site of action for galanin to add to its already varied physiological roles.

Animals↗
PubMed1997

Endothelin receptors in kainic acid-induced neural lesions of rat brain.

Seven days after an intracerebroventricular injection of 0.8 microgram kainic acid, a time of neural tissue-repair after damage, we applied our receptor autoradiographic method to examine changes in the endothelin receptors in kainic acid-induced neural lesions of the rat brain. There were belt-shaped areas with the de novo expressed [125I]endothelin-1 binding sites in the damaged hippocampus CA1, CA3, and CA4 subfields. We also noted a homogeneous zone with a low binding-density, the area sandwiched by the belt-shaped areas. In a "remote" area corresponding anatomically to the deep soma layer of the piriform cortex plus lateral parts of amygdaloid complex we noted a well-defined area with "punched hole-figure" of low density [125I]endothelin-1 binding sites. The lesion was surrounded by areas rich in binding sites. The de novo expressed [125I]endothelin-1 binding sites were characterized endothelin B receptor. Microglia were present in the area with "punched hole-figure" and in the hippocampus pyramidal cell layer with neuronal death. In contrast to microglia, astrocytes were rich with hypertrophia in kainic acid-induced neural lesions anatomically corresponding to areas with the de novo endothelin B receptor. Taken together with the present observations of microscopic evidence of cellular distribution, we suggest that the de novo expressed endothelin B receptor was carried by astrocytes aggregating in neural lesions. In light of our findings, the possibility that astrocytes can be activated by the endothelin B receptor in response to neural tissue repair after damage to neurons would have to be considered.

Animals↗
PubMed1997

Effect of global system for mobile communication microwave exposure on the genomic response of the rat brain.

The acute effect of global system for mobile communication (GSM) microwave exposure on the genomic response of the central nervous system was studied in rats by measuring changes in the messenger RNAs of hsp70, the transcription factor genes c-fos and c-jun and the glial structural gene GFAP using in situ hybridization histochemistry. Protein products of transcription factors, stress proteins and marker proteins of astroglial and microglial activation were assessed by immunocytochemistry. Cell proliferation was evaluated by bromodeoxyuridine incorporation. A special GSM radiofrequency test set, connected to a commercial cellular phone operating in the discontinuous transmission mode, was used to simulate GSM exposure. The study was conducted at time averaged and brain averaged specific absorption rates of 0.3 W/kg (GSM exposure), 1.5 W/kg (GSM exposure) and 7.5 W/kg (continuous wave exposure), respectively. Immediately after exposure, in situ hybridization revealed slight induction of hsp70 messenger RNA in the cerebellum and hippocampus after 7.5 W/kg exposure, but not at lower intensities. A slightly increased expression of c-fos messenger RNA was observed in the cerebellum, neocortex and piriform cortex of all groups subjected to immobilization, but no differences were found amongst different exposure conditions. C-jun and GFAP messenger RNAs did not increase in any of the experimental groups. 24 h after exposure, immunocytochemical analysis of FOS and JUN proteins (c-FOS, FOS B, c-JUN JUN B, JUN D), of HSP70 or of KROX-20 and -24 did not reveal any alterations. Seven days after exposure, neither increased cell proliferation nor altered expression of astroglial and microglial marker proteins were observed. In conclusion, acute high intensity microwave exposure of immobilized rats may induce some minor stress response but does not result in lasting adaptive or reactive changes of the brain.

Animals↗
PubMed1998

Forebrain expression of c-fos due to active maternal behaviour in lactating rats.

To reveal brain sites simultaneously active during the expression of maternal behaviour in lactating rats, we used immunocytochemical visualization of the nuclear protein product Fos of the immediate-early gene c-fos as a marker of neuronal activity. After a 48 h separation from their litter, day 7 postpartum dams received a 1 h period of physical interaction with pups either capable or incapable of suckling, inaccessible pups in a wire-mesh box, an empty box, or no stimulation. Physical interaction with pups elicited high levels of pronurturant maternal behaviour (retrieval, licking, mouthing), and suckling elicited nursing behaviour as well. Exposure to the box, with or without pups, elicited high levels of investigatory sniffing, self-grooming, and general activity. Distal stimulation from pups did not differentially activate Fos in any of 20 sites, including olfactory-processing structures such as the piriform cortex and medial amygdala. Physical interaction with pups, with or without suckling, elicited higher levels of Fos-immunoreactive nuclei than that of other conditions in numerous sites, including many previously implicated in maternal behaviour (medial preoptic nucleus, nucleus accumbens, lateral septum, lateral habenula, and the bed nucleus of the stria terminalis). Similar group patterns of Fos expression also occurred in sites not previously implicated in maternal behaviour (somatosensory cortex and paraventricular thalamic nucleus). Interaction with nonsuckling pups elicited the highest levels of Fos in the cortical amygdala, whereas suckling did not activate higher Fos than nonsuckling interaction in any site included in this report, including hypothalamic nuclei involved in lactation (paraventricular, supraoptic, and arcuate). There was little or no Fos in cingulate cortex, olfactory tubercle, medial septum, medial habenula, or ventromedial hypothalamus. These data suggest that trigeminal stimuli received by lactating rats during the performance of pronurturant maternal behaviour promote cellular activity resulting in neuronal expression of c-fos in many forebrain sites including the medial preoptic nucleus, several sites connected with it that are part of the mesotelencephalic dopamine system, and in the somatosensory cortex. In contrast, in these forebrain sites suckling does not elicit greater levels of Fos than that seen in nonsuckled rats and distal stimuli from pups are ineffective in increasing Fos levels compared with non-stimulated controls.

Animals↗
PubMed1998

The anti-apoptosis bcl-2 proto-oncogene is preferentially expressed in limbic structures of the primate brain.

By virtue of its capacity to prevent apoptosis the protooncogene bcl-2 is believed to play a crucial role in CNS development. Studies in rodents have shown that the anti-apoptosis Bcl-2 protein is widely expressed during CNS development, but undergoes a marked down-regulation during maturation and is present only at low concentrations in adult CNS. In contrast, current data suggest that Bcl-2 protein in adult monkey brain results from microglial expression. In the present immunohistochemical study, however, numerous subsets of Bcl-2-immunoreactive neurons were encountered in the amygdala, hippocampus, hypothalamus, limbic cortices and striatum of squirrel monkeys. Of particular interest was the presence in the basal portion of the amygdala and adjoining piriform cortex of numerous intensely immunoreactive cells with long and thick immunopositive processes that ran into the ventral amygdalofugal pathway. At striatal level Bcl-2-positive neurons were strictly confined to calbindin-poor striosomes, which are specifically innervated by limbic cortices. This study has provided the first evidence for the occurrence of Bcl-2 in mature monkey brain. It has further shown that this protein is preferentially expressed in limbic structures in primate forebrain. The sustained expression of this anti-apoptosis protein may protect limbic system neurons from various injuries or neurodegeneration. It may also be involved in the functional and structural changes that occur throughout adulthood in some regions of the primate limbic system.

Animals↗
PubMed1998

Regional alterations in neuronal activity in dystonic hamster brain determined by quantitative cytochrome oxidase histochemistry.

The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.

Animals↗
PubMed1998

Distribution of Fos- and Jun-related proteins and activator protein-1 composite factors in mouse brain induced by neuroleptics.

The mechanisms by which the direct actions of neuroleptics are translated into therapeutic effects are unknown. We immunocytochemically investigated the expression of Fos- and Jun-related proteins and examined activator protein-1 DNA-binding activity in ddY mouse brain 120 min after the administration of haloperidol (1 mg/kg), (-)-sulpiride (20 mg/kg) and a selective dopamine D1 receptor antagonist, SCH23390 (1 mg/kg). The densities of Fos-, FosB-, Fra-1-, Jun- and JunD-immunoreactive nuclei induced by haloperidol and sulpiride in the hippocampus, piriform cortex and accumbens nucleus were higher than those in the control groups. The same regions showed higher densities of FosB-, Fra-1- and JunD-immunoreactive nuclei induced by SCH23390 compared with the control groups. We investigated further the activator protein-1 composite factors using super gel shift assays. These results suggested that induced Fos, FosB, Fra-1, Jun and JunD proteins constitute the activator protein-1 complex after the administration of haloperidol and sulpiride. In contrast, FosB, Fra-1 and JunD appear to constitute the activator protein-1 complex after the administration of SCH23390. Therefore, the diversity of activator protein-1 composite factors suggests that various kinds of gene are induced to act by some neuroleptics.

Animals↗
PubMed1999

Spatiotemporal expression gradients of the carbohydrate antigen (CD15) (Lewis X) during development of the human basal ganglia.

The developmental expression pattern of the carbohydrate epitope CD15 (Lewis X, Le X) (alpha1-->3-fucosyl-N-acetyl-lactosamine) has been immunocytochemically evaluated in paraffin sections within the human basal ganglia from 10 weeks gestation to three years after birth. At 11 weeks of gestation, CD15 (Le X) positive radial glial cells were located in the anterior and dorsal parts of the lateral ganglionic eminence. Their processes ran from the subventricular zone radially in a highly ordered fashion to the dorsolateral margin of the caudate nucleus and further to the lateral rim of the putamen. At 12 weeks of gestation, strands of CD15 (Le X) material continued to the pial surface, forming a continuous CD15 (Le X) positive borderline separating the accumbens nucleus and olfactory tubercle from the piriform cortex. At 13 weeks of gestation the dorsal putamen was completely CD15 (Le X) immunoreactive along its perimeter and CD15 (Le X) patches, consisting of fine granular material, appeared at the dorsolateral margin of the putamen at this age; while the first CD15 (Le X) patches in the caudate nucleus were observed four weeks later. The matrix compartment of the caudate and dorsal putamen became gradually stained by granular CD15 (Le X) positive material into which CD15 (Le X) immunoreactive somata were embedded. The striking contrast in staining between patch and matrix compartments disappeared shortly after birth. The ventral striatum did not become immunoreactive until the last few weeks before birth. After the formation of CD15 (Le X) positive patches in the striatum (from 12 weeks of gestation), delicate CD15 (Le X) fibres, often accumulated in bundles and related to the striatal patches, became apparent coursing towards the external pallidal lamina and the globus pallidus. Immunoreactivity in the globus pallidus itself was transient, emerging from 16 weeks of gestation, reaching a peak at 21 weeks of gestation and disappearing by birth. Both processes, i.e. the occurrence of CD15 (Le X) striatopallidal fibres and the emerging immunoreactivity in their pallidal target, may be interrelated, so that ingrowing CD15 (Le X) positive axons from the striatum provoke CD15 (Le X) expression in the external and internal pallidum. The variable patterns and intensities of CD15 (Le X) expression are possibly related to periods of maturation of the striatum and the establishment of functional interactions within the basal ganglia. Differential staining of patch and matrix in the developing neostriatum suggests that a distinct phase of cellular adhesion or dishesion mediated by the CD15 (Le X) epitope occurs during establishment of the patch and matrix regions.

Aging↗
PubMed1999

Carboxypeptidase D is a potential candidate to carry out redundant processing functions of carboxypeptidase E based on comparative distribution studies in the rat central nervous system.

Post-translational processing is essential for the biological activation of many proteins and peptides. After precursor cleavage at specific single residues or pairs of basic residues by the proprotein convertases, the C-terminal basic residues are removed. Carboxypeptidase E was thought to be the only enzyme responsible. Recent studies with carboxypeptidase E-deficient mice, Cpe(fat)/Cpe(fat), indicated the existence of carboxypeptidase E-like carboxypeptidases, such as carboxypeptidase D. In order to define potential redundant functions in vivo, we compared the distributions of both carboxypeptidases in the rat central nervous system and selected endocrine tissues. Carboxypeptidase D messenger RNA was abundantly expressed in glial cells in the gray and white matter, while neurons in several brain regions, such as the piriform cortex, basolateral amygdala and hippocampus, also expressed high levels of carboxypeptidase D messenger RNA. Co-localization of carboxypeptidases E and D messenger RNAs was observed in many brain regions, the spinal cord and endocrine tissues. Immunohistochemistry showed the intracellular distribution of carboxypeptidase D with a perinuclear pattern. The extensive distribution of carboxypeptidase D in both glial and neuronal cells indicates the important role of carboxypeptidase D in peptide processing, possibly working together with furin, a ubiquitously expressed proprotein convertase. The co-localization of carboxypeptidases D and E suggests that carboxypeptidase D may, at least partially, compensate for carboxypeptidase E processing functions in Cpe(fat)/Cpe(fat) mice.

Adrenal Glands↗
PubMed1999

Differential expression of bcl-w and bcl-x messenger RNA in the developing and adult rat nervous system.

The bcl-2 family of proteins comprises both anti-apoptotic and pro-apoptotic members, which play a pivotal role in regulating cell death. Bcl-w is a recently identified member of this family, which was shown to inhibit apoptosis in haemopoietic cell lines. However, the function and expression patterns of bcl-w in the nervous system have so far not been described. We have cloned complementary DNA corresponding to rat bcl-w and analysed the expression of bcl-w messenger RNA during rat brain development, using RNA blotting and in situ hybridization techniques. We also compared the expression patterns of bcl-w with those of bcl-xL. During brain development, the levels of bcl-w messenger RNA were found to increase, with highest expression located to specific regions of the mature brain, such as hippocampus, cerebellum, piriform cortex and locus coeruleus. Bcl-w messenger RNA was expressed by neurons, as shown with double labeling with neuronal markers. In contrast to bcl-w, bcl-xL messenger RNA expression levels were highest during early development, particularly in cortex, hippocampus, thalamus, spinal cord and dorsal root ganglia. During postnatal development the expression of bcl-xL messenger RNA decreased and were only detected at low levels in the adult nervous system. As shown earlier for bcl-2, the expression of bcl-w and bcl-x messenger RNA in cultured cerebellar granule cells was not altered by the deprivation of neurotrophic factors. The present results suggest that bcl-w may play an important role in the mature nervous system.

Aging↗
PubMed1999

Endothelin converting enzyme-1-, endothelin-1-, and endothelin-3-like immunoreactivity in the rat brain.

Neurons likely to use endothelin as a neurotransmitter/neurohormone were mapped in the rat brain using polyclonal antibodies directed against endothelin-converting enzyme-1, endothelin-1, and endothelin-3. Anti-endothelin-converting enzyme-1 antibodies produced the most robust staining, permitting the best visualization of the distribution and morphology of neurons. Labeled neurons were found in the dorsal thalamic nuclei and reticular thalamic nuclei, medial preoptic area, pontine nucleus, and locus coeruleus. Localization of endothelin-converting enzyme-like immunoreactivity in the locus coeruleus and in the reticular nucleus of the thalamus suggests that endothelin is co-localized with norepinephrine and GABA, respectively. Additionally, endothelin-converting enzyme-like immunoreactivity was found in the globus pallidus, septal nuclei, and in both the vertical and horizontal limbs of the nucleus of the diagonal band of Broca, and the ventrolateral area of the caudate-putamen. Strong endothelin-converting enzyme-like immunoreactivity was found in a continuous band of pyramidal neurons throughout the neocortex primarily in layer V, extending into the cingulate gyrus and piriform cortex. Motor nuclei, including oculomotor, facial, and trigeminal nuclei, were also endothelin-converting enzyme-immunoreactive. In the cerebellum, Purkinje cells were stained. Non-neuronal cells such as oligodendroglia, microglia, and astrocytes generally were not endothelin-converting enzyme-immunoreactive, although astrocytes were rarely stained. Endothelin-converting enzyme-, endothelin-1-, and endothelin-3-like immunoreactivities were generally found co-existing in given nuclei. The diversity of neurons immunostained for endothelin suggests multiple roles of endothelin in the CNS.

Animals↗
PubMed2000

Differential messenger RNA distribution of lactate dehydrogenase LDH-1 and LDH-5 isoforms in the rat brain.

The role of lactate in brain energy metabolism has recently received renewed attention. Although blood-borne monocarboxylates such as lactate poorly cross the blood-brain barrier in the adult brain, lactate produced within the brain parenchyma may be a suitable substrate for brain cells. Lactate dehydrogenase is crucial for both the production and utilization of lactate. In this article, we report the regional distribution of the messenger RNAs for lactate dehydrogenase isoforms 1 and 5 in the adult rat brain using in situ hybridization histochemistry with specific [alpha-(35)S]dATP 3' end-labeled oligoprobes. The autoradiographs revealed that the lactate dehydrogenase-1 messenger RNA is highly expressed in a variety of brain structures, including the main olfactory bulb, the piriform cortex, several thalamic and hypothalamic nuclei, the pontine nuclei, the ventral cochlear nucleus, the trigeminal nerve and the solitary tractus nucleus. In addition, the granular and Purkinje cell layers of the cerebellum showed a strong labeling. The neocortex (e.g., cingular, retrosplenial and frontoparietal cortices) often exhibits a marked laminar pattern of distribution of lactate dehydrogenase-1 messenger RNA (layers II/III, IV and VI being most strongly labeled). In contrast, expression of the lactate dehydrogenase-5 messenger RNA generally seemed more diffusely distributed across the different brain regions. Expression was particularly strong in the hippocampal formation (especially in Ammon's horn and dentate gyrus) and in the cerebral cortex, where no laminar pattern of distribution was observed. Overall, these data are consistent with the emerging idea that lactate is an important energy substrate produced and consumed by brain cells.

Animals↗
PubMed1999

Afferent connections of the interstitial nucleus of the posterior limb of the anterior commissure and adjacent amygdalostriatal transition area in the rat.

The interstitial nucleus of the posterior limb of the anterior commissure is, like the striatum, very rich in tyrosine hydroxylase and acetylcholinesterase, but on the basis of most other neurochemical criteria displays features that are typical of the extended amygdala (Alheid, de Olmos and Beltramino, 1995). Its afferent connections were examined in the rat with retrograde (cholera toxin B subunit) and anterograde (Phaseolus vulgaris leucoagglutinin) tracers and compared to those of the neighboring amygdalostriatal transition area and central amygdaloid nucleus. Deposits of cholera toxin B subunit in the interstitial nucleus of the posterior limb of the anterior commissure result in retrograde labeling that is similar to that seen after cholera toxin B subunit injections in the central amygdaloid nucleus. Retrogradely labeled cells are found in insular, infralimbic, prelimbic, piriform, amygdalopiriform transition, entorhinal and perirhinal cortices, as well as in temporal field CA1 of Ammon horn and ventral subiculum, amygdala (nucleus of the lateral olfactory tract, anterior amygdaloid area, anterior cortical, posterolateral cortical, anterior and posterior basomedial, intercalated cells, basolateral and lateral nuclei), and extended amygdala, primarily in its central division. The latter includes the lateral bed nucleus of the stria terminalis, dorsal portions of the sublenticular region, the lateral pocket of the supracapsular bed nucleus of the stria terminalis and the central amygdaloid nucleus. Retrogradely labeled cells are also seen in midline thalamic nuclei, lateral hypothalamus, ventral tegmental area, retrorubral field, dorsal raphe nucleus, pedunculopontine and dorsolateral tegmental nuclei, locus coeruleus and parabrachial area. The central extended amygdala, lateral hypothalamus and parabrachial area display a substantial retrograde labeling only when the injection involves districts of the interstitial nucleus of the posterior limb of the anterior commissure apposed to the pallidum, i.e. its medial part. Our anterograde results confirm that projections from the lateral bed nucleus of the stria terminalis and central amygdaloid nucleus to the interstitial nucleus of the posterior limb of the anterior commissure target its medial part. They also indicate that structures which provide major afferents to the central extended amygdala (the lateral and posterior basolateral amygdaloid nuclei and the amygdalopiriform transition area) innervate chiefly the medial part of the interstitial nucleus of the posterior limb of the anterior commissure and, to a much lesser degree, its lateral part. The piriform cortex, which has well-acknowledged projections to the ventral striatum, innervates only the rostral sector of the interstitial nucleus of the posterior limb of the anterior commissure. Taken together, these data indicate that the medial part of the interstitial nucleus of the posterior limb of the anterior commissure is closely related to the central extended amygdala. Rostral and lateral parts of the interstitial nucleus of the posterior limb of the anterior commissure, on the other hand, appear as transitional territories between the central extended amygdala and ventral striatum. The afferent connections of the zone traditionally termed amygdalostriatal transition area are in general similar to those of the caudate-putamen, which does not receive projections from the central extended amygdala. After cholera toxin B subunit injections in the caudoventral globus pallidus, a dense retrograde labeling is observed in the amygdalostriatal transition area and overlying striatum, but not in the interstitial nucleus of the posterior limb of the anterior commissure. Our results suggest that the interstitial nucleus of the posterior limb of the anterior commissure and the amygdalostriatal transition area are engaged in distinct forebrain circuits; the former is a dopamine-rich territory intimately related to the central ext

Afferent Pathways↗
PubMed1998

Central connections of the ovine olfactory bulb formation identified using wheat germ agglutinin-conjugated horseradish peroxidase.

Pheromonal stimuli elicit rapid behavioral and reproductive endocrine changes in the ewe. The neural pathways responsible for these effects in sheep are unknown, in part, because the olfactory bulb projections have not been examined in this species. Using the anterograde and retrograde neuronal tracer, wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), we describe the afferent and efferent olfactory bulb connections of the Suffolk ewe. Injections of WGA-HRP limited to the main olfactory bulb resulted in retrograde labeling of cells in numerous telencephalic, diencephalic, and metencephalic regions. Terminal labeling was limited to layer la of ipsilateral cortical structures extending rostrally from the anterior olfactory nucleus (AON), piriform cortex, anterior-, and posterolateral-cortical amygdaloid nuclei to lateral entorhinal cortex caudally. Injections involving the accessory olfactory bulb and AON produced additional labeling of cells within the bed nucleus of the stria terminalis (BNST), medial nucleus of the amygdala, and a few cells in the posteromedial cortical nucleus of the amygdala. Terminal labeling included a small dorsomedial quadrant of BNST and also extended to the far lateral portions of the supraoptic nucleus. A clearly defined accessory olfactory tract and nucleus was not evident, perhaps due to limitations in the sensitivity of the method. With this possible exception, the afferent and efferent olfactory connections in the sheep appear similar to those reported for other species.

Amygdala↗
PubMed2001

Progressive neuronal loss in the ventral posterior lateral and medial nuclei of thalamus in Niemann-Pick disease type C mouse brain.

Niemann-Pick disease type C (NP-C) disease is a progressive and fatal neurological disorder characterized by accumulation of cholesterol and glycosphingolipids in peripheral tissues and that of glycosphingolipids in the brain. A C57BL/KsJ-npc1(spm) mutant strain is a genetically authentic model of NP-C. This study investigated neuronal cell loss and lipid accumulation in the npc1(spm) mouse brain. Nissl-staining revealed abundant swollen neurons in the neocortex, piriform cortex, hippocampus and basal ganglia at 3-4 wk of age. In addition to loss of the Purkinje cells, we found a conspicuous cell loss in the ventral posterial lateral (VPL) and medial (VPM) nuclei of thalamus, which became apparent after 4-5 wk. Biochemical analyses revealed no increase of cholesterol in the lipid extracts whereas a substantial accumulation of cholesterol was detectable in most of the large neurons by filipin staining in the brain of homozygous mice. In contrast to the diffuse staining pattern in normal brains, the neuropils of the neurons in the brain of homozygous mice were stained in a punctate pattern. The ubiquitous accumulation excludes a direct role of cholesterol in the progressive neuronal loss in the Purkinje cell layer and in the VPL and VPM of the thalamus.

Aging↗
PubMed1997

Expression of amyloid precursor protein mRNA isoforms in rat brain is differentially regulated during postnatal maturation and by cholinergic activity.

Pathological processing of the amyloid precursor protein (APP) is assumed to be responsible for the amyloid deposits in Alzheimer-diseased brain tissue, but the physiological function of this protein in the brain is still unclear. The aim of this study is to reveal whether the expression of different splicing variants of APP transcripts in distinct brain regions is driven by postnatal maturation and/or regulated by cortical cholinergic transmission, applying quantitative in situ hybridization histochemistry using 35S-labeled oligonucleotides as specific probes to differentiate between APP isoforms. In cortical brain regions, the expression of both APP695 and APP751 is high at birth and exhibits nearly adult levels. The developmental expression pattern of cortical APP695 displays a peak value around postnatal day 10, while the age-related expression of APP751 demonstrates peak values on postnatal days 10 and 25, with the highest steady state levels of APP751 mRNA on day 25. During early development, the cortical laminar distribution of the APP695, but not APP751, mRNA transiently changes from a more homogeneous distribution at birth to a pronounced laminar pattern with higher mRNA levels in cortical layer III/IV detectable at the age of 4 days and persisting until postnatal day 10. The distinct age-related changes in cortical APP695 and APP751 mRNA levels reflect the functional alterations during early brain maturation and suggest that APP695 might play a role in establishing the mature connectional pattern between neurons, whereas APP751 could play a role in controlling cellular growth and synaptogenesis. Lesion of basal forebrain cholinergic system by the selective cholinergic immunotoxin 192IgG-saporin resulted in decreased levels of APP695 but not APP751 and APP770 transcripts by about 15-20% in some cortical (cingulate, frontal, parietal, piriform cortex), hippocampal regions (CA1, dentate gyrus), and basal forebrain nuclei (medial septum, vertical limb of diagonal band), detectable not earlier than 30 days after lesion and persisting until 90 days postlesion, suggesting that the nearly complete loss of cortical cholinergic input does not have any significant impact on the expression of APP mRNA isoforms in cholinoceptive cortical target regions.

Acetylcholinesterase↗