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At least 505 records · Page 28Linked to original sources
PubMed2003

Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex.

We investigated whether angiotensin II (ANG II), a peptide that plays a central role in the genesis of hypertension, alters the coupling between synaptic activity and cerebral blood flow (CBF), a critical homeostatic mechanism that assures adequate cerebral perfusion to active brain regions. The somatosensory cortex was activated by stroking the facial whiskers in anesthetized C57BL/6J mice while local CBF was recorded by laser-Doppler flowmetry. Intravenous ANG II infusion (0.25 mug.kg-1.min-1) increased mean arterial pressure (MAP) from 82 +/- 2 to 102 +/- 3 mmHg (P < 0.05) without affecting resting CBF (P > 0.05). ANG II attenuated the CBF increase produced by whisker stimulation by 65% (P < 0.05) but did not affect the response to hypercapnia or to neocortical application of the nitric oxide donor S-nitroso-N-acetyl penicillamine (P > 0.05). The effect of ANG II on functional hyperemia persisted if the elevation in MAP was offset by controlled hemorrhage or prevented by topical application of the peptide to the activated cortex. ANG II did not reduce the amplitude of the P1 wave of the field potentials evoked by whisker stimulation (P > 0.05). Infusion of phenylephrine increased MAP (P > 0.05 from ANG II) but did not alter the functional hyperemic response (P > 0.05). The data suggest that ANG II alters the coupling between CBF and neural activity. The mechanisms of the effect are not related to the elevation in MAP and/or to inhibition of the synaptic activity evoked by whisker stimulation. The imbalance between CBF and neural activity induced by ANG II may alter the homeostasis of the neuronal microenvironment and contribute to brain dysfunction during ANG II-induced hypertension.

Angiotensin II↗
PubMed2003

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease.

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer's disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Abeta) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Abeta production with mitochondrial dysfunction, caspase pathway, and neuronal loss.

Alzheimer Disease↗
PubMed1987

Serotonin pharmacodynamics in hypothalamic tissues from young and old female rats.

The purpose of this study was to determine the effects of aging on serotonin (5-HT) pharmacodynamics in rostral hypothalamic tissue of female rats. Monoamine oxidase (MAO) activity was greater in old (19 months old) than in young (3 months old) animals. This difference resulted from a higher Vmax for hypothalamic MAO from old rats, whereas Km's were comparable in both age groups. These enzymatic changes were accompanied by altered uptake and release of [3H]5-HT. Although [3H]5-HT uptake was not different at equilibrium between groups, the equilibrium state was achieved more slowly by hypothalamic tissue from old rats. Basal and potassium-stimulated efflux of [3H]5-HT was significantly greater in old rats compared with young ones and these differences remained during multiple depolarizations. The findings of this study suggest that synaptic levels of hypothalamic 5-HT increase with age. Since pharmacological simulation of this condition in young rats produces physiologic dysfunction, the spontaneous changes that occur in hypothalamic 5-HT pharmacodynamics during aging have the potential to promote senescence.

Aging↗
PubMed2000

Increased protein levels of serotonin transporter in frontal cortex of patients with Down syndrome.

Serotonin transporters (SERTs) are presynaptic proteins specialized for the clearance of serotonin from the synaptic cleft. A large body of evidence exists on altered platelet serotonin uptake and metabolism in Down syndrome (DS). Besides, dysregulation of SERTs expression have been reported in various complex behavioural traits and disorders including, neurodegenerative disorders. This prompted us to investigate SERT protein levels in adult brain specimens. Western blot analyses were performed in frontal cortex and cerebellum of aged controls and patients with DS and Alzheimer's disease (AD). The result revealed that frontal cortex SERT was significantly increased (P<0.05) in DS, whereas in AD it was comparable to controls. In cerebellum, no significant difference was observed among the study populations. A remarkable difference was noted when SERT was normalized vs. neuron specific enolase (NSE), a neuronal marker. The increase in SERT/NSE was highly significant (P<0.01) in DS frontal cortex compared to controls. Neither AD frontal cortex nor DS and AD cerebellum did show any significant difference. These findings indicate that a region specific alteration in SERT expression may exist in DS with AD-like pathology. As little is known about the status of serotenergic synaptic markers in DS brain, the findings may contribute to an effort made to delineate the underlying causes of serotonergic dysfunction in DS and the quest for therapeutic strategies. The study also suggest caution should be taken in applying data obtained from DS to model AD biochemical defects.

Adult↗
PubMed1989

Neural degeneration and non-neuronal cellular reactions in the hypoglossal nucleus following an intraneural injection of toxic ricin.

The present study describes neuronal degeneration and its accompanying non-neuronal cellular reaction in the hypoglossal nucleus following an intraneural injection of Ricinus communis agglutinin-60 (RCA-60) into the hypoglossal nerve. The first noticeable structural changes were observed in neurons in hamsters killed 3 days after the RCA injection. Drastic alterations occurred in the period extending from the 5th to the 15th postoperative day. Two forms of neuronal degeneration were observed: light and dark types. In the light type, masses of free ribosomes were observed; other changes included the dilation of Golgi saccules and the presence of abnormal mitochondria. In the dark type of degeneration, the cells became condensed with vacuoles in their cytoplasm. Axon terminals presynaptic to the degenerating cells during this period appeared to be normal. A massive influx of mononuclear leucocytes by diapedesis occurred at the large venules. Some of the infiltrated cells were clearly lymphocytes, while others were monocytes which became indistinguishable from indigenous microglia once they were in the neuropil. Neural macrophages, most probably derived both from microglia and the infiltrated monocytes, were engaged in the phagocytosis of neuronal debris. A remarkable finding in the present study was the wide-spread occurrence of dark axon terminals in the neuropil in longer surviving animals (90 and 120 days). The structural alterations, e.g., clumping and swelling of some of the synaptic vesicles in the enhanced cytoplasmic density, suggest that these were undergoing atrophic changes resulting from the long period of dysfunction following the death of postsynaptic neurons induced by RCA.

Animals↗
PubMed1976

Sexual impotence: studies of the hypothalamic-pituitary-thyroid axis and the effect of oral thyrotropin-releasing factor.

Thyrotropin-releasing factor was given orally to 12 impotent patients in a dose of 43 mg daily for 4 weeks in a double-blind crossover technique and compared with placebo. TRF showed no beneficial effect over placebo. In these patients, thyroid function and the hypothalamic-pituitary-thyroid axis were examined by measuring T3, T4, and TSH before and after the TRF test. There were no pathological findings for patients included in this study.

Adult↗
PubMed2005

Selective serotonin reuptake inhibitor treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction.

Prenatal stress has long-lasting effects on cognitive function and on the hypothalamic-pituitary-adrenal response to stress. We previously reported that the serotonin concentration and synaptic density in the hippocampus were reduced following prenatal stress [Int J Dev Neurosci 16 (1998) 209]. Since serotonin plays a role in the formation and maintenance of synapses, we hypothesized that a neonatal reduction in hippocampal serotonin levels may lead to learning disabilities in prenatally stressed mice. To test this hypothesis, we treated prenatally stressed mice with a selective serotonin reuptake inhibitor in order to normalize their postnatal serotonin turnover levels. What we found was that the oral administration of a selective serotonin reuptake inhibitor to prenatally stressed mice during postnatal weeks 1-3 but not 6-8 normalized their corticosterone response to stress, serotonin turnover in the hippocampus, and density of dendritic spines and synapses in the hippocampal CA3 region. Concomitantly, such treatment partially restored their ability to learn spatial information.

Age Factors↗
PubMed2005

Enhanced susceptibility of S-100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human beta-amyloid.

S-100B is an astrocyte-derived protein that is increased in focal areas of the brain most severely affected by neuropathological changes in Alzheimer's disease (AD). Cell-based and clinical studies have implicated S-100B in progression of a pathologic, glial-mediated pro-inflammatory state in the CNS. However, the relationship between S-100B levels and susceptibility to AD-relevant neuroinflammation and neuronal dysfunction in vivo has not been determined. To test the hypothesis that overexpression of S-100B increases vulnerability to beta-amyloid (Abeta)-induced damage, we used S-100B-overexpressing transgenic (Tg) and S-100B knockout (KO) mice in a mouse model that involves intracerebroventricular infusion of human oligomeric Abeta1-42. This model mimics many features of AD, including robust neuroinflammation, Abeta plaques, synaptic damage and neuronal loss in the hippocampus. S-100B Tg, KO, and wild-type (WT) mice were infused with Abeta for 28 days, sacrificed at 60 days, and hippocampal endpoints analyzed. We found that Tg mice showed increased vulnerability to Abeta-induced neuropathology relative to either WT or KO mice. Specifically, Tg mice exhibited enhanced glial activation and neuroinflammation, increased nitrotyrosine staining (a marker of glial-induced neuronal damage), and more pronounced loss of synaptic markers. Interestingly, Tg mice showed no significant differences in Abeta plaque burden compared with WT or KO mice, suggesting that, as in the human situation, the severity of neuronal dysfunction did not correlate with amyloid deposition. Our data are consistent with a model in which S-100B overexpression in AD enhances glial activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.

Amyloid beta-Peptides↗
PubMed1994

Induction of beta-amyloid-containing polypeptides in hippocampus: evidence for a concomitant loss of synaptic proteins and interactions with an excitotoxin.

Long-term cultures of brain slices were used to test if the lysosomotropic agent chloroquine induces beta-amyloid-related peptides in hippocampus and if such effects are accompanied by other manifestations of brain aging. Chloroquine administration resulted in the appearance of a carboxyl-terminal fragment of the beta-amyloid precursor protein (APP); the 27-kDa antigen was detectable after 24 h, increased rapidly for 6-10 days, and was eliminated upon drug washout. Immunocytochemical analyses showed that beta-amyloid immunoreactivity accumulated in the perikarya of pyramidal neurons, primarily in the form of punctate bodies. These effects were accompanied by a correlated loss (and recovery) of the presynaptic marker synaptophysin and by a delayed reduction of postsynaptic glutamate receptors, while cytoskeletal proteins were unchanged. Acute administration of chloroquine had no evident effects on synaptic responses but prolonged applications caused a decrease in the maximum amplitude of field potentials. Finally, a brief pretreatment with the excitotoxin kainic acid had little effect with regard to APP fragments or synaptophysin, but altered the events following from a subsequent infusion of chloroquine. Buildup of the 27-kDa APP fragment and loss of synaptophysin were more rapid and, more importantly, did not reverse upon washout of chloroquine. These findings indicate that lysosomal dysfunction in hippocampus results in the accumulation of a particular APP fragment and suggest that this event, or a variable correlated with it, is linked to the loss of synaptic proteins. They also raise the possibility that certain aspects of brain aging reflect a synergism between lysosomal disturbances and excitotoxicity.

Amyloid beta-Peptides↗
PubMed1999

Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia.

The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1alpha (SDF-1alpha), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1alpha, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1alpha/beta was detected predominantly in astrocytes and at low levels in MDM. SDF-1beta/beta was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1beta induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD.

AIDS Dementia Complex↗
PubMed2000

The 5-HT(1A) receptor agonist 8-OH-DPAT reduces rats' accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT(1A) receptors.

RATIONALE: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. OBJECTIVE: The present study investigated the role of pre- and postsynaptic 5-HT1A receptors on rats' attentional performance in the five-choice serial reaction time task (5-CSRT). METHODS: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT1A receptor agonist, at various subcutaneous (SC) doses (10-100 microg/kg) on measures of rats' discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. RESULTS: A dose of 100 microg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10-100 microg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT's effect on choice accuracy but did not modify the other effects on rats' performance. An ICV injection of 150 microg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT's effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 microg/0.5 microl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. CONCLUSIONS: The results suggest that stimulation of presynaptic 5-HT1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of post-synaptic 5-HT1A receptors.

5,7-Dihydroxytryptamine↗
PubMed2003

The relationship between membrane pathology and language disorder in schizophrenia.

Receptive language disorder in schizophrenia has been hypothesized to involve a fundamental deficit in the temporal (time-based) dynamics of brain function that includes disruptions to patterns of activation and synchronization. In this paper, candidate mechanisms and pathways that could account for this basic deficit are discussed. Parallels are identified between the patterns of language dysfunction observed for schizophrenia and dyslexia, two separate clinical disorders that may share a common abnormality in cell membrane phospholipids. A heuristic is proposed which details a trajectory involving an interaction of brain fatty acids and second-messenger function that modulates synaptic efficacy, and, in turn, influences language processing in schizophrenia patients. It is additionally hypothesized that a primary deficit of functional excitation originating in the cerebellum, in combination with a compensatory decrease of functional inhibition in the prefrontal cortex, influences receptive language dysfunction in schizophrenia.

Brain↗
PubMed2001

A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice.

Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.

Alleles↗
PubMed2006

Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.

A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms.

Alzheimer Disease↗
PubMed1983

Noradrenalin-inducible cyclic-AMP accumulation in rat cerebral cortex: changes during complete global ischemia.

Neurologic dysfunction after cerebral ischemic insults may be due not only to neuronal death, but also to a possibly reversible failure in synaptic transmission. Because noradrenaline (NA)-inducible cyclic-AMP (cAMP) accumulation in brain may reflect the integrity of synaptic transmission mechanisms and brain viability, we studied its changes in cerebral cortex after various durations of decapitation ischemia. Unanesthetized rats were decapitated and the brains were kept at 37 degrees C for times ranging from 0 to 60 min. Cerebral cortical slices were incubated in vitro and NA (11.2 microM)-induced cAMP accumulation was evaluated over 10 min. At 0 min of ischemia, NA-induced cAMP accumulation was 56 pmol/mg protein/10 min. Between 0 and 20 min of ischemia, a linear eightfold increase, to 435 +/- 49 pmol/mg protein/10 min, occurred in NA-induced cAMP accumulation, with no further increase after longer durations of ischemia. The mechanisms modulating the increase in cortical NA-inducible cAMP accumulation with a maximum response after 20 min of ischemia remain to be defined.

Animals↗
PubMed2000

Methamphetamine dependence: medication development efforts based on the dual deficit model of stimulant addiction.

Converging lines of evidence indicate that withdrawal from prolonged exposure to stimulants and alcohol results in synaptic deficits of both dopamine (DA) and serotonin (5-HT). According to the dual deficit model proposed by the authors, DA dysfunction during cocaine or alcohol withdrawal underlies anhedonia and psychomotor retardation, whereas 5-HT dysfunction gives rise to depressed mood, obsessional thoughts, and lack of impulse control. This model predicts that pharmacotherapies which correct only one of the two neurochemical deficits will not be effective. On the other hand, pharmacotherapies which "correct" both of the proposed DA and 5-HT abnormalities should be effective in treating stimulant and alcohol dependence. This paper reviews two approaches, based on the dual deficit model, taken by our laboratory to develop medications to treat stimulant abuse.

Animals↗
PubMed2007

Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's disease, and addiction.

Alzheimer Disease↗