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PubMed2003

8-OHDPAT-induced disruption of prepulse inhibition in rats is attenuated by prolonged corticosterone treatment.

The present study investigated the impact of acute and repeated administrations of corticosterone (10 mg/kg, twice daily, for 7 days) on serotonin (5-HT)(1A) receptor function, density and expression. The effect on 5-HT(1A) receptor function was assayed in rats by assessing the corticosterone-induced modulation of disruption of prepulse inhibition (PPI) of acoustic startle response induced by 8-OHDPAT, a 5-HT(1A) receptor agonist. Our experiments revealed that repeated but not acute treatment with corticosterone attenuated the 8-OHDPAT-evoked disruption of PPI without having any effect on PPI or startle amplitude alone. Chronic corticosterone treatment modulated also the neuronal activity of serotonergic pathways in the brain decreasing the level of 5-HIAA in the raphe nuclei and increasing both 5-HT and 5-HIAA levels in the hippocampus. Nevertheless, the effects of 8-OHDPAT on 5-HT metabolism were not changed by corticosterone. However, 5-HT(1A) receptor binding in the ventral hippocampus and entorhinal cortex but not in the raphe nuclei was decreased after chronic corticosterone treatment. It is concluded that chronically elevated corticosterone level is capable of inducing functional desensitization of 5-HT(1A) receptors which is paralleled by decreases in the 5-HT(1A) receptor binding in the ventral hippocampus and entorhinal cortex, the brain structures shown to be engaged in the regulation of PPI. Alterations in 5-HT(1A) receptors may be one of important mechanisms by which glucocorticoids/stress influence various psychiatric conditions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Monoclonal antibody identification of subpopulations of cerebral cortical neurons affected in Alzheimer disease.

Neuronal degeneration is one of the hallmarks of Alzheimer disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, we have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mABs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAB 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1, to the best of our knowledge, do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands on immunoblots of homogenates of normal and AD cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible.

Alzheimer Disease↗
PubMed1996

Beta-amyloidosis in normal aging and transmitter signaling in human temporal lobe.

Interactions between abnormal amyloid precursor protein metabolism and cholinergic dysfunction are increasingly apparent. Both of these major features of Alzheimer's disease occur in restricted loci in normal aging--a potential model for early Alzheimer type pathology. Entorhinal cortex is particularly vulnerable to beta-amyloidosis and compared with other cortical areas is remarkable for the relatively high density of nicotinic (3H-nicotine) but not other cholinergic or glutamate receptor binding. With increasing age, post-maturity, there is a persistent decline in nicotinic receptor binding in entorhinal cortex whereas muscarinic M1 and non-M1, glutamate NMDA and non-NMDA receptors are spared. Normal elderly individuals, distinguished by the absence of beta A4 immunoreactive plaques in this area, are differentiated from those with plaques by higher nicotine binding. Amongst individuals with an established history of smoking tobacco, nicotinic receptor binding and hippocampal choline acetyltransferase were elevated compared with non-smokers and preliminary evidence indicates a reduced density of cortical plaques. These findings are consistent with the hypothesis that down regulation of the nicotinic cholinergic receptor--a ligand gated calcium channel known to control the expression of neurotrophins--plays a role in the evolution of Alzheimer-type pathology.

Adolescent↗
PubMed1988

Control of sensory activation of granule cells in the fascia dentata by extrinsic afferents: septal and entorhinal inputs.

Three groups of rats were trained to perform a differential discrimination task in a 2-tone operant conditioning paradigm. One group received electrolytic lesions of the medial septal nuclei, another received electrolytic or knife cut lesions of the entorhinal cortex. These groups were compared with a normal control group. Recordings of granule cells in the fascia dentata were obtained in all animals during criterion performance of the behavioral task. Both lesions produced disruption of behavioral discrimination in the form of increased error and intertrial responding. Granule cell discharges to the tone stimuli were disrupted by each type of lesion. Septal lesions reduced the differential discharge tendency to CS+ and CS- and changed granule cell firing on all trials to statistically resemble firing on CS- trials in normal animals. Extensive lesions in the entorhinal cortex or knife cuts that severed the perforant path caused near elimination of the tone-evoked discharges to both the CS+ and CS-tones. Septal and entorhinal lesions caused marked changes in the sequential dependence of the granule cell discharge compared with intact animals. Results are discussed in terms of the control of the granule cell discharge by the remaining afferent pathways in each type of lesion condition.

Acoustic Stimulation↗
PubMed1994

AMPA/kainate receptor gene expression in normal and Alzheimer's disease hippocampus.

Alzheimer's disease is a progressive dementia characterized by pronounced degeneration of certain populations of neurons in the hippocampus and cerebral cortex of the brain. One theory is that glutamate receptor-mediated toxicity plays a role in cell loss associated with Alzheimer's disease. We used in situ hybridization to examine GluR1, GluR2, and GluR3 messengerRNAs (encoding alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptor subunits) in sections of autopsy samples of Alzheimer's disease brains and age-, sex-, and post-mortem delay-matched brains from non-demented (control) subjects. GluR1 and GluR2 exhibited a heterogeneous distribution in control brain. GluR1 was expressed in granule cells of the dentate gyrus, in pyramidal cells of the CA1 and CA3 hippocampal subfields and in neurons of the subiculum and entorhinal cortex. GluR2 mRNA was at high density in the dentate gyrus and in CA3, but was at low density in CA1, subiculum, and entorhinal cortex. GluR3 hybridization was at very low levels but selectively localized to the dentate gyrus and CA3. In cerebellum, GluR1 was found in granule and Purkinje cell layers. In sections from Alzheimer's disease brain, a high degree of intersubject variability was observed: some samples showed markedly reduced GluR1 mRNA levels in dentate gyrus, CA1 and CA3 relative to controls; others showed no changes. Microscopic observation of emulsion-dipped sections revealed that the reduction of GluR1 seen in the dentate gyrus and CA3 of some Alzheimer's disease subjects was not due to cell loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1986

Distinct substrates influence the acquisition of self-stimulation of the hippocampus and the prefrontal cortex.

Self-stimulation (SS) of both the medial prefrontal cortex (MPFC) and the dorsolateral hippocampus (HPC) is known to develop slowly, over a period of days. In both cases, the acquisition of bar-pressing can be markedly hastened by delivery of noncontingent electrical stimulation for several days prior to SS training. The similarity of these effects suggests that there might be a common substrate mediating the acquisition process. However, in the present experiment, pre-training noncontingent electrical stimulation of the MPFC had no effect on how rapidly rats acquired the bar-pressing response for HPC stimulation, or vice versa. A further dissociation of the elements governing the acquisition process for these two SS sites was suggested by the observation that pre-training noncontingent stimulation of the entorhinal cortex facilitated the speed of acquisition of SS of the HPC but not of the MPFC. It seems that the HPC and entorhinal cortex can be excluded from the subset of neural structures which are known to influence the acquisition process governing MPFC SS. These and other data suggest that the development of SS of the MPFC and HPC can be regarded, at least in part, as involving a process rooted in distinct substrates.

Animals↗
PubMed1995

Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer's disease brain increases with disease severity.

Bcl-2 protein has been suggested to be one of the proteins preventing apoptosis in a variety of cell types. Recently, apoptosis has been suggested to have an important role in the pathogenesis of Alzheimer's disease (AD). We have utilized Bcl-2 immunohistochemical methods to examine Bcl-2 in the hippocampus and entorhinal cortex of AD patients ranging in clinical and neuropathological severity from mild to severe and compared these results to those obtained from age-matched controls. Immunoreactivity for Bcl-2 was predominantly found within neurons. Bcl-2 immunostaining within AD tissue was increased relative to controls in most neurons of the entorhinal cortex, subiculum, CA1, CA2, CA3, hilus and dentate gyrus. Relative Bcl-2 staining increased in parallel with increasing disease severity. However, neurons exhibiting immunoreactivity for markers of neurofibrillary tangle formation (AT8 and PHF-1) showed reduced Bcl-2 staining, suggesting that Bcl-2 may be down regulated in these degenerating neurons. Bcl-2 immunoreactivity within astrocytes and the vasculature was also increased in AD. These results suggest that Bcl-2 protein may have a role in compensation responses to AD pathology, perhaps affording to the remaining neurons a margin of protection from apoptosis.

Aged↗
PubMed1986

Autoradiographic localization of glucocorticosteroid and progesterone binding sites in the human post-mortem brain.

The presence of glucocorticosteroid and progesterone binding sites in the human brain has been investigated with an in vitro autoradiographic approach using [3H]RU 38486. The present data revealed that the hippocampus, the entorhinal cortex, the subiculum, the fimbria and the amygdala showed a different pattern of [3H]RU 38486 labeling using various unlabeled steroids (RU 38486, RU 28362, cortisol, RU 27987 and dexamethasone). RU 38486 is the best competitor in all these structures. The hippocampus seems to possess mainly glucocorticosteroid binding sites whereas the entorhinal cortex and the subiculum reveal the presence of both glucocorticosteroid and progesterone binding sites. Furthermore, the amygdaloid complex and the fimbria show a high density of glucocorticosteroid binding sites.

Autopsy↗
PubMed2002

Central olfactory connections in the microsmatic marmoset monkey (Callithrix jacchus).

The mammalian primary olfactory system consists of a set of different telencephalic structures, including paleo-, archi-, periarchi- and mesocortical components. We present the first characterisation of the normal and connectional anatomy of the primary olfactory cortex of the common marmoset, a microsmatic simian species increasingly used in primate research. The centrifugal and centripetal bulbar projections were determined by injections of the anterograde and retrograde tracer wheat germ agglutinin-conjugated horseradish peroxidase and fluorescent dyes into the ipsilateral main olfactory bulb. The efferent projections of the marmoset bulb are organised entirely ipsilaterally and are established via a rudimentary medial olfactory tract and the dominant lateral olfactory tract. Target areas are the anterior olfactory nucleus, the entire prepiriform cortex, ventral tenia tecta, periamygdaloid cortex and the rostral part of the entorhinal cortex. The bulbar axons predominantly terminate in the outer part of layer I. The anterior olfactory nucleus receives a weak additional input within layer II and III, which is not found in macrosmatic rodents. Further anterograde labelling was found in the endopiriform nucleus deep under the prepiriform cortex and within an anterolateral strip of the olfactory tubercle. However, control injections into the olfactory tubercle suggest that the marmoset olfactory tubercle receives a bisynaptic olfactory input only. Retrograde labelling after bulb injections revealed that, except for the olfactory tubercle, all primary olfactory cortices contributed to an ipsilateral bulbopetal feedback projection. Like in rodents, the only bulbopetal projection organised bilaterally in the marmoset is maintained by the anterior olfactory nucleus. With few exceptions, the projections of the marmoset olfactory brain are organised similarly to that of the macaque monkey or those of macrosmatic species.

Animals↗
PubMed2001

Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies.

The consistent regional and laminar distribution of cortical Lewy bodies (LB) in brains of patients with dementia with Lewy bodies (DLB) suggests that only a certain subpopulation of neurons develops these alpha-synuclein-immunoreactive cytoplasmic inclusions. This study examined whether four non-overlapping neuronal subpopulations, defined by the expression of non-phosphorylated neurofilaments (SMI-32) and several calcium binding proteins (parvalbumin, calretinin and calbindin D28k), are vulnerable to LB formation. We performed peroxidase immunostaining to examine the distribution and to quantitate each neuronal subpopulation within the superior temporal sulcus (STS) area, and double-label immunohistochemistry to test for colocalization of alpha-synuclein and each neuronal marker in the STS and the entorhinal cortex. There were no significant differences between DLB brains and controls in the proportional quantity or laminar distribution of each neuronal subpopulation. Parvalbumin-immunoreactive neurons represented around 7%, calbindin D28k 8%, calretinin 10%, and SMI-32 about 20% of the total neuronal population in the STS cortex. Neurons expressing parvalbumin and SMI-32 showed a widespread distribution across layers II to VI. Neurons expressing calretinin were present in superficial layers (II to IV), and calbindin D28k-immunoreactive neurons were mostly distributed within granular layers II and IV. None of the LB observed in the STS or the entorhinal cortex were located in neurons expressing calcium binding proteins; 25% of the LB were contained in SMI-32 immunoreactive neurons. In conclusion, cortical neurons expressing calcium binding proteins are spared in DLB, while SMI-32-positive neurons are affected in proportion to their density in the cortex. However, the majority of cortical LB develop in neurons not identified by any of these markers.

Aged↗
PubMedDate not supplied

Neonatal septal implants: development of afferent lamination in the rat dentate gyrus.

The technique of tissue implantation into neonatal rats was used to assess mechanisms underlying the development of afferent lamination in the rat hippocampal formation. Septal nuclei, dissected from the brains of rat embryos (E17-E20), were implanted into the occipital or entorhinal cortex of 2--3 day old neonates that simultaneously received fimbrial transections to remove hippocampal innervation by native septal efferents. As visualized with acetylcholinesterase (AChE) histochemistry, the distribution of enzyme activity in implant-innervated hippocampi is qualitatively identical to the pattern in unoperated animals. Fibers from septal implants placed into the entorhinal cortex, appear to interact with commissural/associational afferents and produce altered laminar zones in the dentate gyrus.

Acetylcholinesterase↗
PubMed2001

Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice.

Intraneuronal filamentous tau inclusions such as neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer's disease (AD) and related sporadic and familial tauopathies. NFTs identical to those found in AD brains have also been detected in the hippocampus and entorhinal cortex of cognitively normal individuals as they age. To recapitulate age-induced NFT formation in a mouse model, we examined 12- to 24-month-old transgenic (Tg) mice overexpressing the smallest human brain tau isoform. These Tg mice develop congophilic tau inclusions in several brain regions including the hippocampus, amygdala, and entorhinal cortex. NFT-like inclusions were first detected in Tg mice at 18 to 20 months of age and they were detected by histochemical dyes that bind specifically to crossed beta-pleated sheet structures (eg, Congo red, Thioflavin S). Moreover, ultrastructurally these lesions contained straight tau filaments comprised of both mouse and human tau proteins but not other cytoskeletal proteins (eg, neurofilaments, microtubules). Isolated tau filaments were also recovered from detergent-insoluble tau fractions and insoluble tau proteins accumulated in brain in an age-dependent manner. Thus, overexpression of the smallest human brain tau isoform resulted in late onset and age-dependent formation of congophilic tau inclusions with properties similar to those in the tangles of human tauopathies, thereby implicating aging in the pathogenesis of fibrous tau inclusions.

Aging↗
PubMed1997

Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B.

The present study investigated whether chronic, low dose therapy with memantine could (1) prevent the loss of basal forebrain cholinergic cells induced by injection of N-methyl-D-aspartate (NMDA) into the nucleus basalis magnocellularis (NBM) of rats, and (2) attenuate impaired performance in the radial maze of rats with entorhinal cortex lesions. In addition, we investigated whether neuroprotection could be provided by neurokinin B (NKB). Following an injection of NMDA (0.015 M) into the NBM, rats were implanted with osmotic minipumps containing memantine (20 or 0.20 mg/kg/day for 2 weeks). Other rats were given unilateral NBM injections of 1.0 microliter of Solution A (0.5 microliter containing 8.26 mM NKB and 0.24 units of bacitracin and 0.5 microliter containing 0.03 M NMDA) or Solution B (0.5 microliter of PBS containing 0.24 U of bacitracin and 0.5 microliter containing 0.03 M NMDA). Two weeks later, the anterior cortex was analyzed for choline acetyltransferase (ChAT), a specific marker for the loss of acetylcholinergic neurons. Both chronic administration of memantine, and acute administration of NKB, prevented the decline in cortical ChAT activity associated with injection of NMDA into the NBM, and attenuated a reference memory deficit in the radial maze produced by entorhinal cortex lesions. Thus, memantine infusion at low doses leading to steady-state serum levels within a therapeutic range provides both neuroprotection and cognitive enhancement-an optimal combination for the treatment of neurodegenerative disorders.

Acetylcholine↗
PubMed2006

Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease.

The concept of amnestic mild cognitive impairment (MCI) describes older people who show a decline predominantly in memory function, but who do not meet criteria for dementia. Because such individuals are at high risk for developing Alzheimer's disease, they are of great interest for understanding the prodromal stages of the disease process. The mechanism underlying memory dysfunction in people with MCI is not fully understood. The present study uses quantitative, high-resolution structural MRI techniques to investigate, in vivo, the anatomical substrate of memory dysfunction associated with MCI. Changes in brain structures were assessed with two imaging techniques: (i) whole-brain, voxel-based morphometry to determine regions of reduced white matter volume and (ii) sensitive volumetric segmentation of the entorhinal cortex and hippocampus, gray matter regions that are critically important for memory function. In participants with amnestic MCI, compared with age-matched controls, results showed a significant decrease in white matter volume in the region of the parahippocampal gyrus that includes the perforant path. There was also significant atrophy in both the entorhinal cortex and the hippocampus. Regression models demonstrated that both hippocampal volume and parahippocampal white matter volume were significant predictors of declarative memory performance. These results suggest that, in addition to hippocampal atrophy, disruption of parahippocampal white matter fibers contributes to memory decline in elderly individuals with MCI by partially disconnecting the hippocampus from incoming sensory information.

Aged↗
PubMed1991

Quantification of magnetic resonance scans for hippocampal and parahippocampal atrophy in Alzheimer's disease.

The brains of patients with Alzheimer's disease (AD) invariably exhibit neuropathology in the hippocampus and entorhinal cortex when examined postmortem. Magnetic resonance imaging (MRI) offers a noninvasive, high-resolution method for quantifying volumetric changes in the AD brain antemortem. Eight patients diagnosed with probable AD and 7 age-matched controls had MRI scans and were tested on a battery of cognitive and olfactory tests. The hippocampus and entorhinal cortex (parahippocampal gyrus) showed significant atrophy, with over 40% reduction in size. Areas of the brain that are not highly involved in the degenerative state of AD, such as the striatum, did not show significant volumetric changes. Hippocampal and parahippocampal gyrus volumes had the highest correlation with scores on the Mini-Mental State Examination (r = 0.89), with lower correlations for a smell identification test (r = 0.65), odor match-to-sample test (r = 0.72), and a visual match-to-sample test (r = 0.26).

Aged↗
PubMed1999

Decrease in the levels of NGF and BDNF in brains of mice fed a tryptophan-deficient diet.

The roles of dietary tryptophan (Trp) were evaluated in regulation of production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT)-3 in the various brain regions in ddY mice. Feeding the mice a Trp-deficient diet for 2 weeks significantly decreased in the hippocampal level of NGF but not those of BDNF and NT-3, as compared with feeding an adequate Trp diet. The mice fed excess Trp did not have different levels of any of these neurotrophins than in the mice fed an adequate Trp diet. The levels of BDNF in the cerebral cortex were also significantly lower in the mice fed on a Trp-deficient diet, while the levels of NGF and NT-3 in the region were not modulated upon feeding of the diet. The dietary Trp level had no significant effect on the levels of NGF, BDNF, or NT-3 in the entorhinal cortex nor septum of the mice. These results demonstrate that the brain levels of NGF and BDNF are dependent on the dietary content of tryptophan.

Alzheimer Disease↗
PubMed1992

Alteration of 5-HT1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography.

Ipsapirone, a high-affinity ligand for the 5-hydroxytryptamine1A (5-HT1A) receptor subtype, has been shown to be a full agonist at presynaptic serotonergic sites and a partial agonist at postsynaptic sites. Several recent studies have examined the effects of chronic treatment with ipsapirone or other structurally related pyrimidinylpiperazine compounds, including buspirone and gepirone, on 5-HT1A binding sites with mixed results. Since the neural mechanism responsible for the anxiolytic and antidepressant properties of these compounds is currently uncertain, further investigation of this issue appeared warranted. [3H]8-hydroxy-2-(di-n-propylamino)-tetralin ([3H]8-OH-DPAT), a ligand specific for the 5-HT1A site, has been used successfully to label these sites using both membrane binding assays and autoradiography. Experiments were performed to determine whether chronic treatment with ipsapirone would differentially affect binding to 5-HT1A receptors at different brain sites. Rats were treated twice daily with ipsapirone (10 mg/kg i.p.) for 1 day or for 1, 2, or 3 weeks. Quantitative analyses were done of autoradiograms of in vitro [3H]8-OH-DPAT binding to selected brain regions. Binding in vehicle-treated rats was highest in the hippocampus, septal nucleus, interpeduncular nucleus, entorhinal cortex, and dorsal raphe nucleus. Following 3 weeks of treatment with ipsapirone, a large decline in binding was measured in the dorsal raphe nucleus. This decline was not seen with ipsapirone treatments for shorter periods. With the 3-week treatment, there were less robust declines in [3H]8-OH-DPAT binding in the entorhinal cortex and interpeduncular nucleus. Binding in the other brain regions analyzed was unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Excitotoxic amino acid receptors in human complex partial epilepsy.

It has long been recognized that mesial temporal sclerosis is the most common pathologic finding in temporal lobes removed for the treatment of medically refractory complex partial epilepsy. The regions of the hippocampus most vulnerable contain the highest densities of excitatory amino acid receptors in the brain. We used receptor autoradiography to determine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors from 5 patients undergoing such surgery and compared the findings with 6 specimens obtained at postmortem. A 2-fold increase in the density of NMDA receptors and an increased density of KA receptors was found in entorhinal cortex in epileptic specimens. Loss of NMDA and KA receptor density was apparent in the sclerotic regions CA3 and CA1, but not in other areas of the hippocampus or dentate gyrus. These findings suggest that damage in the hippocampus may result, at least in part, from the presence of aberrant excitatory circuits in the entorhinal cortex.

Autoradiography↗