Biomedical subjects

H G Bernstein

Publications and source records attributed to H G Bernstein.

At least 19 recordsLinked to original sources

PubMed2006

Expression of corticosteroid-binding protein in the human hypothalamus, co-localization with oxytocin and vasopressin.

Corticosteroid-binding globulin, a specific steroid carrier in serum with high binding affinity for glucocorticoids, is expressed in various tissues. In the present study, we describe the immunocytochemical distribution of this protein in neurons and nerve fibers in the human hypothalamus. CBG immunoreactive perikarya and fibers were observed in the paraventricular, supraoptic, and sexual dimorphic nuclei in the perifornical region, as well as in the lateral hypothalamic and medial preoptic areas, the region of the diagonal band, suprachiasmatic and ventromedial nuclei, bed nucleus of the stria terminalis and some epithelial cells from the choroid plexus and ependymal cells. Stained fibers occurred in the median eminence and infundibulum. Double immunostaining revealed a partial co-localization of corticosteroid-binding globulin with oxytocin and, to a lesser extent, with vasopressin in the paraventricular and the supraoptic nuclei. Double immunofluorescence staining showed coexistence of these substances in axonal varicosities in the median eminence. We conclude that neurons of the human hypothalamus are capable of expressing corticosteroid-binding globulin, in part co-localized with the classical neurohypophyseal hormones. The distribution of CBG immunoreactive neurons, which is widespread but limited to specific nuclei, indicates that CBG has many physiological functions that may include neuroendocrine regulation and stress response.

Aged↗

PubMed2005

Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleus.

Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.

Adult↗

PubMed2002

Circumscribed numerical deficit of dorsal raphe neurons in mood disorders.

BACKGROUND: Neurocircuits comprising limbic, striato-pallidal and thalamo cortical brain areas are assumed to be involved in the pathophysiology of mood disorders. All these brain regions receive serotonergic afferents arising from the rostral raphe, mainly the dorsal raphe. Although serotonergic systems appear to be involved in the pathology of mood disorders, there is uncertainty as to whether structural alterations in raphe nuclei exist alongside a functional dysregulation of the serotonergic system. METHODS: In the brains of 12 patients with mood disorders (major depressive disorder N= 6, bipolar disorder N = 6) and 12 normal subjects we performed a morphometric post-mortem study on neuronal morphology in all subnuclei of the dorsal raphe nucleus using Nissl stained 20 microm axial serial sections of the brainstem. RESULTS: The number of neurones of the ventrolateral subnucleus of the dorsal raphe was reduced by 31 % in patients with mood disorders compared with non-psychiatric control subjects. Ventrally located subnuclei of the rostral dorsal raphe (ventrolateral, ventral, interfascicular) taken together also showed a smaller number of neurones. Neurone numbers of the dorsal and the caudal subnucleus and volumes of all single subnuclei appeared to be unchanged. Analysis of morphological neuronal types revealed a smaller number of triangular neurones in the ventrolateral subnucleus. Numbers of ovoid and round neurones in the ventrolateral subnucleus also showed a trend to reduction. No correlation was found between neurone numbers in any subnucleus of the dorsal raphe and duration of illness. Neurone numbers did not differ in any subnucleus between patients with unipolar and those with bipolar affective disorder. CONCLUSIONS: Results indicate that patients with primary mood disorders have a circumscribed numerical neuronal deficiency in the dorsal raphe. This structural deviation may contribute to impaired serotonergic innervation of brain regions which are involved in the pathology of mood disorders.

Adult↗

PubMed2002

Fewer beta-endorphin expressing arcuate nucleus neurons and reduced beta-endorphinergic innervation of paraventricular neurons in schizophrenics and patients with depression.

In order to elucidate whether the hypothalamic expression of beta-endorphin is altered in patients with mental disorders we studied the cellular localization of the peptide in arcuate nucleus neurons as well as the beta-endorphinergic innervation of paraventricular neurons in nine schizophrenics, six subjects with depression, and nine controls. A polyclonal antiserum against beta-endorphin was employed for the immunohistochemical detection of the peptide in sections of postmortem human brains. Quantitative analysis revealed that the number of beta-endorphin-containing arcuate neurons was statistically reduced in schizophrenics and depressives in comparison to controls. Moreover, the number of endorphinoceptive (i.e. beta-endorphin-innervated) paraventricular nerve cells was also lower in psychiatric patients than in control cases. Our results showing an altered endorphinergic system in human hypothalami of schizophrenics and depressives might contribute to a renewal of interest in this peptide as a possible factor of importance in psychiatric disorders.

Adult↗

PubMed2001

The neuronal calcium sensor protein VILIP-1 is associated with amyloid plaques and extracellular tangles in Alzheimer's disease and promotes cell death and tau phosphorylation in vitro: a link between calcium sensors and Alzheimer's disease?

To investigate whether the observed association of intracellular neuronal calcium sensor (NCS) proteins with amyloid plaques and neurofibrillar tangles in Alzheimer brains is linked to a possible neuroprotective or neurotoxic activity of the protein, we performed cytotoxicity tests in PC12 cells transfected with the calcium sensor protein VILIP-1 (visinin-like protein) and the calcium buffer protein calbindin-D28K. Whereas VILIP-1 expression enhanced the neurotoxic effect of ionomycin already at low ionophore concentrations, calbindin-D28K protected against ionomycin-induced cytotoxicity only at high ionomycin and therefore calcium concentrations. However, in double-transfected cells calbindin-D28K rescued VILIP-1-mediated cytotoxicity at low ionomycin concentrations. Since VILIP-1 was found to be associated with fibrillar tangles in Alzheimer brains, we tested whether VILIP-1 has an influence on tau hyperphosphorylation. VILIP-1 expression enhanced hyperphosphorylation of tau protein compared to nontransfected or calbindin-D28K-transfected cells. These results raise the possibility that the observed reduction in VILIP-1-expressing cells may indicate a selective vulnerability of these neurons and that the calcium sensor protein is involved in the pathophysiology of Alzheimer's disease. The calcium sensor protein may influence tau phosphorylation and have a role in calcium-mediated neurotoxicity opposed to the previously discovered protective effect of calcium buffer proteins.

Alzheimer Disease↗

PubMed2001

Increased number of nitric oxide synthase immunoreactive Purkinje cells and dentate nucleus neurons in schizophrenia.

There is growing interest in the cerebellum as a site of neuropathological changes in schizophrenia. Reports showing that schizophrenics have higher nitric oxide synthase (NOS) activity and MAPKinase levels in the vermis, point to possible aberrations in the cerebellar signal transduction of schizophrenics. It has been speculated that Ca(2+)-dependent extracellular to intracellular signal transduction may be disrupted in the cerebellum of schizophrenics. We decided to test this hypothesis by studying the nitrergic system and markers of the Ca(2+)-triggered signal cascade in the cerebellum of schizophrenics, depressives and controls. The cellular distribution of two calcium sensor proteins (VILIP-1 and VILIP-3) and of neuronal NOS immunoreactivity was studied morphometrically in the flocculonodulus, the inferior vermis and the dentate nucleus of 9 schizophrenics, 7 depressive patients and 9 matched controls. In comparison to controls and depressed patients there were fewer Nissl-stained neurons in the dentate nucleus of schizophrenics. The number of NOS-expressing Purkinje neurons was however strongly increased. In the flocculonodulus and the vermis no differences between the groups were found with regard to the density of Nissl-stained Purkinje cells. The number of NOS-expressing Purkinje neurons was increased in schizophrenics, however. No differences between schizophrenics, depressives and controls were found in the number of VILIP-1 immunoreactive dentate nucleus neurons and VILIP-3 immunoreactive vermal and flocculonodular Purkinje cells. Our data provide further histochemical evidence in favor of structural abnormalities in discrete cerebellar regions of schizophrenics. They confirm and extend earlier reports of increased cerebellar NOS immunoreactivity in schizophrenia and point to possible neurodevelopmental disturbances. Our failure to show an altered expression of two calcium sensor proteins possibly points to a less important role of calcium signaling in cerebellar pathology of the disease.

Adult↗

PubMed2001

Lack of neuronal NOS has consequences for the expression of POMC and POMC-derived peptides in the mouse pituitary.

The relevance of NO in neuroendocrine signalling has been investigated by analysis of cellular expression of pro-opiomelanocortin (POMC) and the POMC-derived peptides beta-endorphin, alpha-melanocyte stimulating hormone and adrenocorticotropin. Expression patterns were studied in the pituitary gland of 150-day old wild-type and neuronal-NOS (nNOS) knock-out mice by using immunohistochemistry, in situ hybridization and Northern blot analysis. Remaining NO-generating capacities in the knock-out mice were demonstrated by immunohistochemical localization of inducible, endothelial and neuronal NOS isoforms. Quantitative analysis revealed that cellular expression of POMC mRNA was drastically reduced in the pituitary of knock-out mice in comparison to controls. In situ hybridization studies demonstrated that this reduction was most pronounced in the intermediate lobe, while the anterior lobe was much less affected. Immunostaining for the proteolytic fragments of POMC was significantly reduced in the intermediate lobe cells of knock-out mice. A moderate reduction of immunostaining for these peptides was also observed in adenopituitary cells of nNOS knock-out mice. Our data demonstrate that the lack of nNOS substantially affects cellular levels of pituitary opioid peptides, which may have consequences for the response of these animals to stress and pain.

Adrenocorticotropic Hormone↗

PubMed2000

Low and infrequent expression of nitric oxide synthase/NADPH-diaphorase in neurons of the human supraoptic nucleus: a histochemical study.

The gas nitric oxide is a messenger in brain signaling. In the hypothalamo-hypophyseal system nitric oxide is involved in the control of the expression and/or release of peptide hormones (corticotropin-releasing hormone, gonadotropin-releasing hormone, vasopressin and oxytocin). Nitric oxide synthase (NOS), the enzyme generating nitric oxide, is abundantly present in the magnocellular nuclei of the rat hypothalamus. Its localization in the human hypothalamus is less well studied. Hence, we investigated the anatomical distribution of neuronal nitric oxide synthase in the human supraoptic nucleus by use of immunohistochemical and enzyme histochemical techniques. The immunohistochemical localization of NOS was studied in 31 matched human hypothalami (13 control cases, eight depressed patients and ten schizophrenics). NADPH-diaphorase studies were carried out on seven additional hypothalami (three normal brains, four schizophrenics). Apparent inter-individual differences exist with regard to the occurrence of the enzyme in supraoptic neurons. In a majority of cases no immunostaining or histochemical reaction for the enzyme was observed. In seven cases (three controls, two schizophrenics, two depressives) a population of nitrergic nerve cells was seen in the dorsomedial part of the nucleus. This group of cells also stained for NADPH-diaphorase. Also, there were a few NOS-immunopositive neurons scattered throughout the nucleus. Additionally, thin NADPH-diaphorase positive fibers were observed to cross the nucleus. Our data show that, unlike the rat, the human supraoptic nucleus contains only a small number of nitrergic neurons. No correlation was found between the expression of the enzyme in supraoptic neurons and the psychiatric status of the patients.

Aged↗

PubMed1999

Cellular changes in rat brain areas associated with neonatal hippocampal damage.

The neonatal destruction of the ventral hippocampus was introduced as a model to recreate features of schizophrenia in the rat. While behavioral consequences of this intervention have been studied in detail, less is known about the cellular processes underlying the deviant behavior. We studied in rats (neonatally or adult lesioned, controls) brain areas receiving or not receiving hippocampal projections. The number of neurons and the expression of the cell markers L-ornithine decarboxylase, nitric oxide synthase/NADPH diaphorase, calretinin and GFAP were estimated. Reduced numbers of neurons and increased immunostaining for ornithine decarboxylase and nitric oxide synthase in the prefrontal, perirhinal and entorhinal cortex of neonatally but not adult lesioned rats or controls demonstrate persistent cellular changes after ventral hippocampus damage.

Aging↗

PubMed1999

Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques.

The anatomical distribution of insulin-degrading enzyme (IDE) was studied in normal and Alzheimer's disease (AD) human brains. By use of a monospecific, polyclonal antiserum against the enzyme we identified IDE antigen in multiple cortical and subcortical neurons. Glia did not show IDE immunoreactivity. In AD brains immunostaining appeared stronger than in controls and appeared not only in neurons but also in senile plaques. In a probable case of Lewy body variant of AD Lewy bodies in neurons of the Nuc. basalis of Meynert were immunopositive for IDE. Our anatomical data suggest that the enzyme is associated with typical neuropathologic hallmarks of AD and its expression appears up-regulated in some brain areas.

Adult↗

PubMed1999

Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis.

RATIONALE: Neonatal ibotenic acid lesion of the ventral hippocampus was proposed as a relevant animal model of schizophrenia reflecting positive as well as negative symptoms of this disease. Before and after reaching maturity, specific alterations in the animals' social behaviour were found. OBJECTIVE: In this study, social behaviour of ventral hippocampal lesioned rats was analysed. For comparison, rats lesioned either in the ventral hippocampus or the dorsal hippocampus at the age of 8 weeks were tested. METHODS: Rats on day 7 of age were lesioned with ibotenic acid in the ventral hippocampus and social behaviour was tested at the age of 13 weeks. For comparison, adult 8-week-old rats were lesioned either in the ventral or the dorsal hippocampus. Their social behaviour was tested at the age of 18 weeks. RESULTS: It was found that neonatal lesion resulted in significantly decreased time spent in social interaction and an enhanced level of aggressive behaviour. This shift is not due to anxiety because we could not find differences between control rats and lesioned rats in the elevated plus-maze. Lesion in the ventral and dorsal hippocampus, respectively, in 8-week-old rats did not affect social behaviour. CONCLUSIONS: The results of our study indicate that ibotenic acid-induced hippocampal damage per se is not related to the shift in social behaviour. We favour the hypothesis that these changes are due to lesion-induced impairments in neurodevelopmental processes at an early stage of ontogenesis.

Aggression↗

PubMed1999

Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients.

Noradrenergic neurons of the locus coeruleus (LC) have been implicated in the neurobiology of depression and suicidal behavior. The current postmortem study determined numbers of noradrenergic neurons by immunostaining the synthesizing enzyme tyrosine hydroxylase in the LC of 12 non-elderly depressed patients with a mood disorder as compared to 12 age- and sex-matched normal controls. Six patients were suicide victims, the other six patients died of natural causes. Non-suicidal patients had fewer neurons immunoreactive for tyrosine hydroxylase (TH-ir) than suicide victims or controls. No difference appeared between the number of TH-ir neurons in suicide patients and controls. Numbers of pigmented LC neurons were equal in patients and controls. The differences of TH-immunoreactivity could neither be attributed to drug influences nor to polarity of depressive disorder (i.e., unipolar/bipolar). Numbers of TH-ir neurons correlated positively with mean doses of tri- or tetracyclic antidepressants. Results of this study suggest a presynaptic noradrenergic deficit of the LC in depressed non-suicidal patients. Indirect evidence is provided that suicide is not related to decreased noradrenergic function and that traditional antidepressants may enhance noradrenergic activity of the LC in depressed patients.

Adult↗

PubMed1999

Unipolar-bipolar dichotomy of mood disorders is supported by noradrenergic brainstem system morphology.

BACKGROUND: The biological basis of unipolar-bipolar dichotomy of mood disorders was investigated in this postmortem study by morphological comparison of the locus coeruleus (LC) as the main source of noradrenergic transmission in the brain. METHODS: Numbers and the rostro-caudal as well as ventro-dorsal distribution of neuromelanin-containing neurones in the LC were determined in brainstem of 12 patients with bipolar disorder (n = 6) or major depression (n = 6), and 12 normal comparison subjects. RESULTS: Bipolar patients had significantly more neurones on both sides of the LC as a whole than patients with major depression. Topographical analysis revealed that this difference was restricted to the rostral two thirds and the dorsal part of the LC, in which bipolar patients showed at least a trend to higher neurone numbers as compared to unipolar patients or to controls. LIMITATIONS: Small case numbers. CONCLUSIONS: Results suggest differences of innervation arising from the LC of bipolar patients as compared to patients with major depression. These first data of brainstem transmitter system morphology in unipolar and bipolar disorder are in line with neuroanatomical studies of other brain regions indicating a biological basis of the unipolar-bipolar dichotomy of mood disorders.

Adult↗

PubMed1999

The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems.

Natural polyamines, spermidine and spermine, and their precursor putrescine, are of considerable importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effects in the nervous system, including control of nucleic acid and protein synthesis, modulation of ionic channels and calcium-dependent transmitter release. The polyamine system is also known to be involved in various brain pathologic events (seizures, stroke, Alzheimer's disease and others). While cerebral polyamine concentrations and the activities of polyamine-metabolizing enzymes have been studied in great detail, much less is known about the cells that are responsible for cerebral polyamine synthesis and interconversion. With the present review the attempt is made to show how exact knowledge about the regional distribution and cellular localization of polyamines and the polyamine-synthesizing enzymatic machinery (and especially of L-ornithine decarboxylase) may help to better understand the functional interplay between polyamines and other endogenous agents (transmitters, receptors, growth factors neuroactive drugs etc.). Polyamines have been localized both in neurones and glial cells. However, the main cellular locus of the ODC is the neuron--both in the immature and adult central nervous system. Each period of normal brain development and ageing seems to have its own, characteristic temporo-spatial pattern of neuronal ODC expression. During strong functional activation (kindling, epileptic seizures, neural transplantation) astrocytes and other non-neuronal cells do also express ODC and other polyamine-metabolizing enzymes. Astroglial expression of ODC is accompanied by an increase in glial fibrillary acidic protein in these cells. This shift in the cellular mechanisms of polyamine metabolism is currently far from being understood. In human brain diseases (Alzheimer's disease, schizophrenia) certain neurones show an increased expression of ODC, the first and rate-limiting enzyme of polyamine metabolism. Since polyamines are structurally related to psychoactive drugs (neuroleptics, antidepressants) the polyamine system might be of importance as a putative target for drug intervention in psychiatry.

Animals↗

PubMed1999

Disruption of latent inhibition in rats with postnatal hippocampal lesions.

Disruption of latent inhibition has been proposed as a possible model of cognitive abnormalities that underlie positive symptoms of a schizophrenia. We tested neonatal hippocampal lesioned rats in a latent inhibition paradigm. Lesions of the ventral hippocampus were induced by bilateral injections of ibotenic acid in 7 days old rats. The behavior of lesioned rats was tested postpubertally. We found a hyperresponsiveness to dopaminergic stimulation by apomorphine in locomotion tests. Latent inhibition was tested using the acquisition of a conditioned reaction in a two-way shuttle box. Sham operated control animals showed after preexposure of the to-be-conditioned stimulus (combined tone and light stimulus) a low acquisition. Ibotenic acid lesioned animals learned the conditioned reaction with and without preexposure in the same way, indicating disturbed latent inhibition. These results demonstrate disturbances in early postnatal hippocampal lesioned rats comparable with those seen in schizophrenic patients, thus further validating this procedure as a useful animal model of some aspects of schizophrenia.

Anesthesia↗

PubMed1999

Regional and cellular distribution of neural visinin-like protein immunoreactivities (VILIP-1 and VILIP-3) in human brain.

Neural visinin-like proteins (VILIPs) are members of the neuronal subfamily of intracellular EF-hand calcium sensor proteins termed the NCS family, which are thought to play important roles in cellular signal transduction. While numerous studies suggest a wide but uneven distribution of these proteins in rat and chicken brain, their location in, and possible significance for, the human brain, remains to be established. We used specific polyclonal antisera to map the human brain for VILIP-1 and VILIP-3 immunoreactivities. VILIP-1 was detected in cortical pyramidal cells and interneurons, septal, subthalamic and hippocampal neurons (subfields CA1 and CA4 pyramidal cells and especially hilar interneurons) as well as in cerebellar Golgi, basket, granule, stellate and dentate nucleus neurons. Purkinje cells were free of immunoreaction. VILIP-3 was more restricted in its distribution. It was identified in cerebellar Purkinje cells and a subpopulation of granule neurons. Further, neurons belonging to different nuclei of the brain stem and multiple subcortical nerve cells stained for visinin-like protein 3. A weak immunoreaction appeared in cortical and hippocampal neurons. Intracellularly the immunoreactivity appeared in the perikarya, dendrites and some axons. Sometimes, immunostaining was found in the neuropil. Glia did not express visinin-like proteins. Our findings support, from a neuroanatomical viewpoint, the idea that these calcium sensor proteins may be of relevance for neuronal signalling in the human CNS.

Animals↗

PubMed1999

Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study.

Volumes of basal ganglia in postmortem brains of 8 patients with mood disorders and 8 control subjects without neuropsychiatric disorder were determined. Morphometry of serial whole-brain sections under the control of postmortem artifacts revealed reduced volumes of the left nucleus accumbens (-32%, P = 0.01), the right and left external pallidum (-20%, P = 0.04), and the right putamen (-15%, P = 0.04) in the patient group compared with the control group. These results suggest that, in particular, the limbic loop of the basal ganglia involving the nucleus accumbens and the pallidum is affected in mood disorders.

Adult↗

PubMed1998

Morphometric studies of the entorhinal cortex in neuropsychiatric patients and controls: clusters of heterotopically displaced lamina II neurons are not indicative of schizophrenia.

Subtle cytoarchitectural abnormalities of the rostral entorhinal cortex have been reported to be characteristic for schizophrenics. A main finding was the heterotopic displacement of clusters of lamina II neurons (which appeared morphologically immature) into layer III. Recent findings suggesting a considerable cytoarchitectural heterogeneity of the normal entorhinal cortex renewed interest in this problem and prompted the question of the extent to which 'aberrantly' located cell clusters are really disease-related. Being blind to the clinical diagnosis, we analyzed quantitatively the amount of entorhinal heterotopias in schizophrenics (n = 31), controls (n = 45) and depressive patients (n = 7). It was revealed that heterotopic cell clusters occurred in schizophrenics and controls with roughly the same frequency (amount of clusters per section). In depressive, there were significantly more heterotopias than in controls (right hemisphere). Our data show that heterotopias are common to the rostral part of the human entorhinal cortex and are not a suitable neuroanatomical marker of schizophrenia.

Adult↗