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F E Bloom

Publications and source records attributed to F E Bloom.

At least 55 records · Page 3Linked to original sources
PubMed1998

The central 5-HT3 receptor in CNS disorders.

Among the characterized 5-HT receptors of the central nervous system, the type 3 receptor subtype (5-HT3R) is the only one known to be a ligand-gated ion channel. Its early pharmacological characterization and mapping by radioligand binding autoradiography suggested that this receptor may, among other actions, regulate dopamine release in the nigro-striatal pathway and reduce alcohol consumption in experimental animals while antagonists of this receptor have been reported to treat anxiety disorders. Following the cloning of this receptor in 1991, direct cellular localization was made possible by in situ hybridization and immunohistochemical analysis. Here we summarize our recent efforts showing that 5-HT3R-expressing neurons are mainly GABA containing cells in the rat neocortex, olfactory cortex, hippocampus, and amygdala which also often contain cholecystokinin (CCK) immunoreactivity. These results provide a means to unify some of the initial pharmacological observations.

Animals↗
PubMed1997

Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of interleukin-6 in the CNS of mice.

Interleukin-6 (IL-6) and IL-6 receptor mRNA and protein have been reported in different brain regions under normal and pathophysiological conditions. Although much is known about the hypothalamic-pituitary-adrenal (HPA) axis stimulation after acute administration, less is known about the chronic effects of IL-6 on the function of the HPA axis. In the present study, we examined the function of the HPA axis in transgenic mice in which constitutive expression of IL-6 under the control of the glial fibrillary acidic protein (GFAP) promoter was targeted to astrocytes in the CNS. GFAP-IL6 mice heterozygous or homozygous for the IL-6 transgene had normal basal plasma corticosterone levels but, after restraint stress, showed abnormally increased levels in a gene dose-dependent manner. The increased plasma corticosterone levels in the IL-6 transgenic mice were associated with increased adrenal corticosterone content and hyperplasia of both adrenal cortex and medulla. Notably, plasma adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content were either not changed or decreased in these mice, whereas plasma arginine vasopressin (AVP) was increased, supporting a role for AVP in response to acute immobilization stress. The reduced ACTH response together with the adrenal hyperplasia in the IL-6 transgenic mice suggests direct activation at the level of the adrenal gland that may be directly activated by AVP or sensitized to ACTH. A similar mechanism may play a role in the blunted ACTH response and elevated corticosterone levels under pathophysiological conditions observed in humans with high brain levels of IL-6.

Adrenal Glands↗
PubMed1997

Lipopolysaccharide-induced IL-12 expression in the central nervous system and cultured astrocytes and microglia.

We examined whether the cytokine IL-12 could be induced locally in the brain or in glial cell cultures following LPS treatment. In the brain, expression of IL-12 p35 mRNA was constitutive and did not alter following i.p. injection of LPS. In contrast, IL-12 p40 mRNA was only detectable in the brain of mice given two staggered injections of LPS. Dual labeling in situ analysis revealed IL-12 p40 RNA-positive cells scattered throughout the brain parenchyma, with a small number of these cells being identified as astrocytes, while the majority of IL-12 p40 RNA-expressing cells appeared to be microglia. In cultured microglia or astrocytes, LPS and to a much lesser degree IL-1beta, but not IFN-gamma or TNF-alpha, induced the expression of IL-12 p40 mRNA. Numerous glial fibrillary acidic protein-immunopositive cells colabeled for IL-12 p40 RNA; indicating that LPS-stimulated astrocytes expressed IL-12 in vitro. Immunoblot analysis of lysates from LPS-treated astrocytes revealed the presence of multiple species of 40, 43, 75, and 120 kDa containing the IL-12 p40 protein. Finally, secretion of the IL-12 p75 heterodimer was detectable by ELISA from astrocytes treated with LPS plus IFN-gamma, but not with LPS alone. The findings indicate that IL-12 gene expression can be activated in the brain, with the resident glial cells being a prodigious source of this cytokine. The localized production of IL-12 may have a significant impact on the development of cell-mediated immune responses within the central nervous system.

Animals↗
PubMed1997

Distribution of tumor necrosis factor receptor messenger RNA in normal and herpes simplex virus infected trigeminal ganglia in the mouse.

PURPOSE: to investigate the distribution of p55 and p75 tumor necrosis factor (TNF) receptor mRNA in normal murine trigeminal ganglia, and in murine trigeminal ganglia acutely infected with McKrae strain herpes simplex virus (HSV). METHODS: in situ hybridization with antisense 35S-labeled riboprobes for mRNA encoding both the p55 and p75 TNF receptor (TNFR) subtypes was used in normal and HSV-infected murine trigeminal ganglia. Sense riboprobes were used as controls. RESULTS: in situ hybridization with both p55 and p75 riboprobes produced a strong autoradiographic signal over many, but not all, trigeminal sensory neurons. Signal for mRNA encoding both TNFR subtypes was also present over the arachnoid layers surrounding trigeminal ganglia. Acute ocular HSV infection was accompanied by an intense leukocytic infiltrate into the ophthalmic portion of the trigeminal ganglia, and, in this setting, increased p55 and p75 mRNA signal was closely related to the location and number of infiltrating white blood cells. The distribution and number of trigeminal sensory neurons expressing mRNA for the two TNFR subtypes did not appear to change following infection. Signal over control sections hybridized with sense p55 and p75 TNFR cRNA probes was comparable to background. CONCLUSIONS: the observed distribution of p55 and p75 TNFR mRNA over trigeminal sensory neurons and over the arachnoid layers surrounding trigeminal ganglia supports suggestions that TNF has a direct effect on neurons, either as a neuromodulator or neurotrophic factor, and that TNF may play a central role in blood-brain barrier regulation. Increased signal for TNFR mRNA in acutely infected trigeminal ganglia appears to reflect infiltration by receptor-bearing white blood cells.

Animals↗
PubMed1997

The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon.

The type 3 serotonin receptor (5-HT3R) is a ligand-gated ion channel whose presence in the CNS has been established by radioligand binding, in situ hybridization, and immunohistochemical analysis. To analyze further the role of the 5-HT3R in the CNS, we used in situ hybridization and immunocytochemistry to determine that 5-HT3R-expressing neurons are mainly GABA-containing cells in the rat telencephalon. We determined that 5-HT3R/GABA-containing neurons do not exhibit somatostatin immunoreactivity but often contain cholecystokinin (CCK) immunoreactivity. 5-HT3R-expressing cells with CCK immunoreactivity were observed in the neocortex, olfactory cortex, hippocampus, and amygdala. The 5-HT3R/CCK interneurons represent between 35 and 66% of the total population of CCK-containing cells in the neocortex. Further characterization of the 5-HT3R/GABAergic neurons was based on their calcium-binding protein immunoreactivity and showed that these neurons lack parvalbumin (PV) and represent a subpopulation of calbindin (CB)-containing interneurons that were preferentially present in the CA1-CA3 subfield of the hippocampus. Although some 5-HT3R/GABAergic neurons with calretinin (CR) were found in the neocortex, olfactory cortex, hippocampus, and amygdala, these neurons were more often present in the agranular insular and piriform cortices. We conclude that the neuronal expression of the 5-HT3R is selective within the GABA neuron population in the rat telencephalon. These 5-HT3R-expressing interneurons might contain CCK, CB, and CR. We suggest that serotonin through the 5-HT3R may regulate GABA and CCK neurotransmission in the telencephalon.

Animals↗
PubMed1997

Simian immunodeficiency virus: a model for neuroAIDS.

In addition to its profound effects on the immune system, HIV also infects the CNS and can cause abnormalities in infected individuals ranging from mild cognitive and motor disorders to frank dementia. We have been actively investigating the molecular and cellular mechanisms underlying the CNS manifestations of lentivirus infection through the comparative evaluation of brain pathophysiology under a number of parallel interrelated strategies. Here we describe our ongoing studies with the SIV/rhesus macaque system. We have applied an interdisciplinary multistep approach, utilizing viral, immunological, pathological, behavioral, and electrophysiological techniques to assess disease and study CNS dysfunction induced by SIV. The profile of the infection and the host response, and the resulting cognitive, motor, and neurophysiological abnormalities in SIV-infected monkeys, recapitulates many aspects of the functional impairments associated with HIV-induced CNS disease in humans. Consequently, the SIV model is ideal for examining the mechanisms underlying these functional abnormalities and for testing potential therapeutic agents.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol.

Alcohol consumption in humans is characterized by a wide range of behavioral effects and pathological consequences that suggest several neuroanatomical targets for this drug. To identify these targets we have mapped alcohol-induced changes in the expression of the c-Fos protein in the rat brain. Administration of a moderate dose of alcohol (1.5 g kg-1) led to a suppression of basal and novel environment-induced c-Fos expression in the hippocampus and simultaneous induction of this protein in regions important for the reinforcing as well as aversive properties of drugs. These include the extended amygdala (including the central nucleus of amygdala, bed nucleus of stria terminals and nucleus accumbens), regions processing sensory information (including the Edinger-Westphal nucleus and the paraventricular nucleus of the thalamus) and in stress-related areas (including the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract and several neocortical areas). Repeated administration of the same dose of alcohol did not decrease alcohol-mediated suppression of c-Fos in the hippocampus, but decreased alcohol-induced expression of c-Fos in other areas. A lower dose of acute alcohol (0.5 g kg-1) reduced basal c-Fos expression in several areas of the neocortex, hippocampus and hypothalamus. However, while this low dose of alcohol was unable to counteract the environmental novelty-induced c-Fos expression in these areas, it increased c-Fos expression in the central nucleus of amygdala (an effect similar to the one observed previously for diazepam). Our data suggest that the effects of low doses of alcohol may be due to selective GABA-like effects of ethanol, whereas higher doses of ethanol involve effects on multiple neurotransmitter systems.

Animals↗
PubMed1997

Coloboma hyperactive mutant mice exhibit regional and transmitter-specific deficits in neurotransmission.

The mouse mutant coloboma (Cm/+), which exhibits profound spontaneous hyperactivity and bears a deletion mutation on chromosome 2, including the gene encoding synaptosomal protein SNAP-25, has been proposed to model aspects of attention-deficit hyperactivity disorder. Increasing evidence suggests a crucial role for SNAP-25 in the release of both classical neurotransmitters and neuropeptides. In the present study, we compared the release of specific neurotransmitters in vitro from synaptosomes and slices of selected brain regions from Cm/+ mice with that of +/+ mice. The release of dopamine (DA) and serotonin (5-HT) from striatum, and of arginine vasopressin and corticotropin-releasing factor from hypothalamus and amygdala is calcium-dependent. Glutamate release from and content in cortical synaptosomes of Cm/+ mice are greatly reduced, which might contribute to the learning deficits in these mutants. In dorsal striatum of Cm/+ mutants, but not ventral striatum, KCl-induced release of DA is completely blocked and that of 5-HT is significantly attenuated, suggesting that striatal DA and 5-HT deficiencies may be involved in hyperactivity. Further, although acetylcholine failed to induce hypothalamic corticotropin-releasing factor release from Cm/+ slices, restraint stress increased plasma corticosterone levels in Cm/+ mice to a significantly higher level than in +/+ mice, suggesting an important role for arginine vasopressin in hypothalamic-pituitary-adrenal axis activation. These results suggest that reduced SNAP-25 expression may contribute to a region-specific and neurotransmitter-specific deficiency in neurotransmitter release.

Acetylcholine↗
PubMed1997

Magnetic source imaging of abnormal low-frequency magnetic activity in presurgical evaluations of epilepsy.

PURPOSE: Regional cortical dysfunction associated with epileptogenic activity was predicted from interictal localized abnormal low frequency neuromagnetic activity (ALFMA) using Magnetic Source Imaging (MSI). ALFMA can be detected in patients who show no interictal spikes. METHODS: A large array biomagnetometer was used in a blinded, rapid screening protocol. The MSI procedure required no alteration in epileptic medications. MSI results were compared with the presumed epileptogenic region as determined by a consensus of standard techniques, which included MR and electroclinical monitoring. RESULTS: One or more sites of localized abnormality were detected by MSI ALFMA in 29 of the 33 epileptic patients. ALFMA mapped with MSI showed a 48.5% specificity with respect to the presumed epileptogenic region. MSI ALFMA was in agreement with the final consensus as often as was ictal noninvasive video EEG monitoring, and was exceeded in specificity overall only by invasive ictal video EEG monitoring, which was required for conventional localization in 21 of the 33 patients tested with MSI. CONCLUSIONS: ALFMA measurements with MSI may augment the array of noninvasive methods used for reaching a consensus for epilepsy surgery.

Adult↗
PubMed1997

Cortical neuronal cytoskeletal changes associated with FIV infection.

HIV-1 infection is often complicated by central nervous system (CNS) dysfunction. Degenerative neuronal changes as well as neuronal loss have been documented in individuals with AIDS. Feline immunodeficiency virus (FIV) infection of cats provides a model for both the immune and the central nervous system manifestations of HIV infection of humans. In this study we have examined neurons in the frontal cortex of feline immunodeficiency virus-infected cats and controls for immunoreactivity with SMI 32, an antibody recognizing a non-phosphorylated epitope on neurofilaments. We noted a significant increase in the number of immunoreactive pyramidal cells in infected animals compared to controls. The changes seen in the neuronal cytoskeleton as a consequence of the inoculation with FIV were similar to those seen in humans undergoing the normal aging process as well as those suffering from neurological diseases, including Alzheimer's and dementia pugilistica. The changes we noted in the feline brain were also similar to that reported in animals with traumatic injuries or with spontaneously occurring or induced motor neuron diseases, suggesting that the increase in reactivity represents a deleterious effect of FIV on the central nervous system.

Animals↗
PubMed1997

Localization of tumor necrosis factor receptor messenger RNA in normal and herpes simplex virus-infected mouse eyes.

PURPOSE: To investigate the distribution of p75 and p55 tumor necrosis factor receptor (TNFR) mRNA in normal mouse eyes and in mouse eyes acutely infected with McKrae strain herpes simplex virus (HSV). METHODS: In situ hybridization with antisense 35S-labeled riboprobes for p55 and p75 TNFR subtypes was used in uninfected and HSV-infected mouse eyes. Controls included the use of sense riboprobes and corneas inoculated with vehicle alone. RESULTS: In uninfected and infected mouse eyes, in situ hybridization produced an autoradiographic signal for mRNA, encoding both p75 and p55 over the corneal endothelium, iris, ciliary body, choroid, and arachnoid layers of the optic nerve sheath. In addition, the signal was observed over scattered cells at the vitreoretinal interface. Signal for p75, but not p55, was observed over cells in the retinal ganglion cell layer. Acute HSV infection was accompanied by an intense leukocytic infiltrate in the conjunctiva, the corneal subepithelium and stroma, the anterior and posterior chambers, the iris root and ciliary body, and the vitreous cavity. In this setting, increased p75 and p55 mRNA signal was correlated closely with the number and location of receptor-bearing white blood cells. Signal over control sections hybridized with sense p75 and p55 TNFR cRNA probes was comparable to background. Signal over control eyes inoculated with sterile vehicle showed slight increased signal in the immediate vicinity of the traumatic keratitis, but otherwise it was comparable to that observed in uninfected animals. CONCLUSIONS: The observed distribution of p75 and p55 TNFR mRNA in normal and acutely infected mouse eyes, and particularly over the heavily vascularized uveal tract and over cells at the vitreoretinal interface, supports a role for TNF as a mediator of intraocular inflammation, perhaps as a key regulator of the blood-ocular barrier.

Acute Disease↗
PubMed1997

Inhibition of astrocyte glutamate uptake by reactive oxygen species: role of antioxidant enzymes.

BACKGROUND: The recent literature suggests that free radicals and reactive oxygen species may account for many pathologies, including those of the nervous system. MATERIALS AND METHODS: The influence of various reactive oxygen species on the rate of glutamate uptake by astrocytes was investigated on monolayers of primary cultures of mouse cortical astrocytes. RESULTS: Hydrogen peroxide and peroxynitrite inhibited glutamate uptake in a concentration-dependent manner. Addition of copper ions and ascorbate increased the potency and the efficacy of the hydrogen peroxide effect, supporting the potential neurotoxicity of the hydroxyl radical. The free radical scavenger dimethylthiourea effectively eliminated the inhibitory potential of a mixture containing hydrogen peroxide, copper sulphate, and ascorbate on the rate of glutamate transport into astrocytes. The inhibitory effect of hydrogen peroxide on glutamate uptake was not altered by the inhibition of glutathione peroxidase, whereas the inhibition of catalase by sodium azide clearly potentiated this effect. Superoxide and nitric oxide had no effect by themselves on the rate of glutamate uptake by astrocytes. The absence of an effect of nitric oxide is not due to an inability of astrocytes to respond to this substance, since the same cultures did respond to nitric oxide with a sustained increase in cytoplasmic free calcium. CONCLUSION: These results confirm that reactive oxygen species have a potential neurotoxicity by means of impairing glutamate transport into astrocytes, and they suggest that preventing the accumulation of hydrogen peroxide in the extracellular space of the brain, especially during conditions that favor hydroxyl radical formation, could be therapeutic.

Animals↗
PubMed1996

Central nervous system expression of HIV-1 Gp120 activates the hypothalamic-pituitary-adrenal axis: evidence for involvement of NMDA receptors and nitric oxide synthase.

The impact of HIV-1 expression in the brain on the development of AIDS is unknown. In the present study, we examined the hypothalamic-pituitary-adrenal (HPA) axis in a transgenic model in which expression of the HIV-1 envelope glycoprotein gp120 induced central nervous system (CNS) damage similar to that seen in HIV-1-infected patients. Compared with nontransgenic littermates, gp120 transgenic mice showed significant increases in plasma corticosterone and adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content. To determine whether this activation of the HPA axis could be mediated by ACTH secretagogues, the effect of recombinant gp120 on the release of these factors from hypothalamic slices was investigated in vitro. Recombinant gp120 induced release of the ACTH secretagogue arginine vasopressin from nontransgenic hypothalamic slices in a calcium-dependent fashion. This effect was inhibited by antagonists of N-methyl-D-aspartate (NMDA) receptors or of nitric oxide synthase (NOS), suggesting a role for NMDA receptor stimulation and NOS activity. Further evidence for a role of free radicals was obtained from bigenic mice coexpressing gp120 and the free radical scavenger human copper/zinc superoxide dismutase which showed normal corticosterone levels. This might relate to superoxide dismutase-mediated scavenging of superoxides generated by NOS. These findings demonstrate that CNS expression of a viral envelope protein can activate the HPA axis and thereby alter peripheral levels of immunomodulatory hormones.

Adrenocorticotropic Hormone↗
PubMed1996

Microglia-passaged simian immunodeficiency virus induces neurophysiological abnormalities in monkeys.

Four rhesus macaques were inoculated intravenously with a cryopreserved stock of microglia obtained from a simian immunodeficiency virus (SIV)-infected rhesus macaque. Before infection, three of the four monkeys were trained and tested daily on a computerized neuropsychological test battery. After SIV infection, behavioral testing continued to monitor deficits associated with disease progression. Five additional age-matched, behaviorally trained monkeys served as controls. Neurophysiological testing for visual and auditory evoked responses was accomplished 37-52 weeks after infection in all monkeys. Subsequently, all four SIV-infected monkeys and one control subject were sacrificed, and samples of brain tissue were taken for pathological analysis. SIV-infected monkeys demonstrated abnormal responses in both auditory and visual evoked responses. In addition, around the time of electrophysiological recording, all three SIV-infected, behaviorally trained monkeys exhibited significant decreases in progressive-ratio performance, reflecting a reduction in reinforcer efficacy. One subject also demonstrated impairments in shifting of attentional set and motor ability at that time. Neuropathological evaluation revealed that all four SIV-infected monkeys exhibited numerous perivascular and parenchymal infiltrating T cells. These findings document that SIV causes electrophysiological, behavioral, and neuropathological sequelae similar to what has been observed in the human neuroAIDS syndrome. Our observations further validate the simian model for the investigation of the pathogenesis of AIDS dementia and for the investigation of drugs with potential therapeutic benefits.

AIDS Dementia Complex↗