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PubMed2002

Impaired acquisition in the water maze and hippocampal long-term potentiation after chronic prenatal ethanol exposure in the guinea-pig.

In the hippocampus, the CA1 region is selectively vulnerable to the effects of chronic prenatal ethanol exposure. In the guinea-pig, the number of CA1 pyramidal cells is decreased after chronic prenatal ethanol exposure. We tested the hypotheses that chronic prenatal ethanol exposure (through maternal ethanol ingestion) results in impairments in spatial learning and short- and long-term plasticity in the CA1 region of the postnatal guinea-pig hippocampus. Timed, pregnant guinea-pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric sucrose/pair-feeding, or water throughout gestation. Offspring were studied between postnatal days 40 and 80. In the Morris water maze, animals exposed to ethanol prenatally showed slower acquisition of an escape response to a hidden platform over 5 days of training. The amplitude of the field excitatory postsynaptic potential in the CA1 region in response to contralateral CA3 stimulation was decreased in offspring exposed to ethanol prenatally. Two forms of short-term plasticity (paired-pulse and frequency facilitation) were unaffected by chronic prenatal ethanol exposure. Long-term potentiation (LTP) in response to high-frequency CA3 stimulation was induced reliably and maintained over 60 min in isocaloric-sucrose and water control animals. However, LTP failed to be induced in the CA1 area of the hippocampus in prenatal ethanol-exposed offspring. These data show that chronic prenatal ethanol exposure, through maternal ethanol administration, impairs spatial performance and LTP in CA1 neurons. Hippocampal dysfunction could contribute importantly to the cognitive and behavioural deficits resulting from chronic prenatal ethanol exposure.

Alcohol-Induced Disorders, Nervous System↗

PubMed2002

[Neurologic and muscular mechanisms of fatigue].

Fatigue of voluntary muscular effort is a complex phenomenon, influenced by peripheral and central nervous system factors. Peripheral mechanisms of fatigue include impairment in neurotransmission and impulse propagation down the sarcolemna, dysfunction within the sarcoplasmic reticulum involving calcium release and uptake, impairment in the actin-myosin cross-bridge interactions and substrate depletion or accumulation of metabolites. The central fatigue is associated with reduction of motor cortical excitability, failure to drive the motoneurons adequately, changes in neurotransmitter activity, etc. Is fatigue an unexplained disabling symptom or a protective mechanism to prevent muscle fiber degeneration?

Diagnosis, Differential↗

PubMed2005

Effects of the Ca2+ antagonist nimodipine on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats.

Diabetes mellitus can lead to functional and structural deficits in both the peripheral and central nervous system. The pathogenesis of these deficits is multifactorial, probably involving, among others, microvascular dysfunction and alterations in intracellular calcium homeostasis. The present study examined the effects of treatment with the Ca2+ antagonist nimodipine (20 mg/kg, intraperitoneal injection, every 48 h) on functional deficits in the peripheral and central nervous system in streptozotocin-diabetic rats. In a prevention experiment, treatment was initiated immediately after diabetes induction and continued for 10 weeks. In a reversal experiment, treatment was initiated 16 weeks after diabetes induction and continued for 12 weeks. Sciatic nerve motor and sensory conduction velocity, brainstem auditory-evoked potentials, and visual-evoked potentials were measured in control, untreated, and nimodipine-treated diabetic rats. In addition, long-term potentiation, a form of synaptic plasticity used as a model for learning and memory at the cellular level, was examined in hippocampal slices. Nimodipine treatment partially prevented deficits in nerve conduction velocity and hippocampal long-term potentiation in diabetic rats. However, nimodipine intervention treatment was unable to reverse established deficits in nerve conduction velocity, evoked potential latencies, or long-term potentiation. It is concluded that nimodipine can partially prevent early functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats but is unable to reverse late deficits.

Analysis of Variance↗

PubMedDate not supplied

Transplantation of neuroblastic progenitor cells as a sheet preserves and restores retinal function.

Diseases affecting the outer retina are incurable once photoreceptors are lost, and these diseases usually cause retinal pigment epithelium (RPE) dysfunction. However, the inner retina can remain functional for some time, even though retinal remodeling occurs as compensation for photoreceptor loss. If the damaged part can be replaced with neuroblastic progenitor and RPE cells as sheets with a beneficial effect on function, vision loss may be prevented and vision may be restored. This review presents an overview of the research of transplanting sheets of neural retina, with or without its RPE, to the subretinal space. In different animal models of retinal degeneration, retinal transplants can morphologically reconstruct a damaged retina, and restore visual sensitivity. Good morphological integration of transplants with the host retina can occur, whereas other transplants exhibit a glial barrier. Synaptic connections between transplant and host have been indicated by transsynaptic tracing. Retinal transplants can restore and preserve visual responses in a small area of the superior colliculus corresponding to the placement of the transplant in the retina. The beneficial effect of retinal transplantation likely involves two mechanisms: trophic effects, e.g., rescue of host cones; and synaptic connectivity between transplant and host retina.

Animals↗

PubMed1997

Transient changes in flocculonodular lobe protein kinase C expression during vestibular compensation.

Protein kinase C (PKC) is a family of intracellular signal transduction enzymes, comprising isoforms that vary in sensitivity to calcium, arachidonic acid, and diacylglycerol. PKC isoforms alpha, gamma, and delta are expressed by cerebellar Purkinje cells and neurons in the cerebellar nuclei and vestibular nuclei of the Long-Evans rat. In control rats, these PKCs are distributed symmetrically in the flocculonodular-lobe Purkinje cells. Behavioral recovery from vestibular dysfunction produced by unilateral labyrinthectomy (UL) is accompanied by asymmetric expression of PKC isoforms in these regions within 6 hr after UL. These expression changes were localized within parasagittal regions of the flocculus and nodulus. The distribution of PKCalpha, -gamma, and -delta were identical, suggesting that they are coregulated in cerebellar Purkinje cells during this early compensatory period. The pattern of Purkinje cell PKC expression returned to the control, symmetric distribution within 24 hr after UL. It is hypothesized that these regional changes in Purkinje cell PKC expression are an early intracellular signal contributing to vestibular compensation. In particular, regulation of PKC expression may contribute to changes in the efficacy of cerebellar synaptic plasticity during the acute post-UL period.

Animals↗

PubMed2004

The role of catecholamines in memory impairment in chicks following reduced gas exchange in ovo.

We have shown previously that reducing gas exchange to chick embryos by half wrapping eggs with an impermeable membrane from either days 14-18 (W14-18) or days 10-18 (W10-18) of the 21 day incubation results in post-hatch memory deficits. In the W10-18 chicks, short-term memory following training is impaired, whereas in the W14-18 chicks, memory is intact for 30 min but does not consolidate into long-term storage. The reduction in gas exchange caused by half wrapping eggs resulted in alterations in hematocrit, O2 and CO2 tensions suggesting that the embryos are hypoxic and hypercapnic. Our aim was to test the hypothesis that increases in circulating levels of catecholamines in ovo, as a result of hypoxia, lead to a disturbance of the central noradrenergic pathways resulting in cognitive impairment. Noradrenaline is critical for memory consolidation and a disturbance during development could compromise cognitive ability. In the present study, plasma noradrenaline levels were significantly elevated compared with control levels 2 days after hatch in W14-18 chicks. There was also a decrease in tissue noradrenaline concentration in the anterior forebrain in both W14-18 and W10-18 chicks. The differential ability of centrally administered beta2- and beta3-adrenoceptor agonists to overcome the memory deficit post-training, suggests altered responsiveness of central beta2-adrenoceptors to noradrenaline in W14-18 chicks. By comparing the W10-18 and W14-18 chicks with those from eggs wrapped from W10-14 we show that it is the timing of the prenatal hypoxia, rather than its duration, that determines the nature of cognitive dysfunction. We conclude that prenatal hypoxia induced by restriction of gas exchange can disrupt or alter central noradrenergic transmission causing cognitive impairment.

Adrenergic beta-2 Receptor Agonists↗

PubMed2002

Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative.

Monoamine neurons are believed to use neuronal-specific transporters to remove their own transmitters from the extracellular space and thus terminate transmission to postsynaptic neurons. We report here, for the first time, conclusive evidence that a cross clearance of serotonin into dopamine neurons exists. Such alternative uptake by different neurons is adopted under circumstances when their own transporter function is no longer adequate. When the serotonin transporter (5-HTT) is disrupted in 5-HTT knockout mice, serotonin (5-HT) is found in dopamine (DA) neurons of homozygous (-/-) but not of heterozygous (+/-) mutant mice or their normal littermates. DA neurons containing 5-HT are seen in the substantia nigra and ventral tegmental area (VTA), but not in other brain areas of 5-HTT -/- mice. Normal rats treated with a 5-HT uptake blocker paroxetine also showed similar result. To verify the role of the DA transporter in such ectopic uptake, 5-HTT -/- mice were treated with DA uptake blocker GBR-12935, ectopic 5-HT in DA neurons was disappeared. These data indicate that: (a) 5-HT can be taken into DA neurons in rats and mice when the 5-HTT is not functionally adequate to remove extracellular 5-HT; (b) the 5-HT uptake into DA neurons is not affected by the 5-HT uptake blocker paroxetine; and (c) the DA transporter is responsible for the 5-HT uptake into DA neurons. This study thus demonstrates that cross neuronal type uptake exists and serves as a compensatory backup when a specific transporter is dysfunctional. This study also demonstrates that DA neurons can store 5-HT for possible "false neurotransmitter" or other usage.

Animals↗

PubMed2005

Quantitative neuropathologic correlates of changes in ratio of N-acetylaspartate to creatine in macaque brain.

PURPOSE: To elucidate the neuropathologic basis of transient changes in the ratio of N-acetylaspartate (NAA) to creatine (Cr) in the primate brain by using a simian immunodeficiency virus (SIV)-infected macaque model of the neurologic manifestation of acquired immune deficiency syndrome. MATERIALS AND METHODS: This study was approved by the Massachusetts General Hospital Subcommittee on Research and Animal Care and the Institutional Animal Care and Use Committee of Harvard University. Rhesus macaques infected with SIV were evaluated during the 1st month of infection. A total of 11 animals were studied, including four control animals, three animals sacrificed 12 days after infection, three animals sacrificed 14 days after infection, and one animal sacrificed 28 days after infection. All animals underwent in vivo proton ((1)H) magnetic resonance (MR) spectroscopy, and postmortem frontal lobe tissue was investigated by using high-spectral-resolution (1)H MR spectroscopy of brain extracts. In addition, quantitative neuropathologic analyses were performed. Stereologic analysis was performed to determine neuronal counts, and immunohistochemical analysis was performed to analyze three neuronal markers: synaptophysin, microtubule-associated protein 2 (MAP2), and calbindin. Analysis of variance (ANOVA) was used to determine substantial changes in neuropathologic and MR spectroscopic markers. Spearman rank correlations were calculated between plasma viral load and neuropathologic and spectroscopic markers. RESULTS: During acute infection with SIV, the macaque brain exhibited significant changes in NAA/Cr (P < .02, ANOVA) and synaptophysin (P < .013, ANOVA). There was no significant change in the concentration of Cr. No significant changes were found in neuronal counts or other immunohistochemical neuronal markers. With the Spearman rank test, a significant direct correlation was detected between synaptophysin and ex vivo NAA/Cr (r(s) = 0.72, P < .013). No correlation between NAA/Cr and neuronal counts, calbindin, or MAP2 was found. CONCLUSION: NAA/Cr is a sensitive marker of neuronal injury, not necessarily neuronal loss, and best correlates with synaptophysin, a marker of synaptodendritic dysfunction.

Animals↗

PubMed2006

Cochlear implants: cortical plasticity in congenital deprivation.

Congenital auditory deprivation (deafness) leads to a dysfunctional intrinsic cortical microcircuitry. This chapter reviews these deficits with a particular emphasis on layer-specific activity within the primary auditory cortex. Evidence for a delay in activation of supragranular layers and reduction in activity in infragranular layers is discussed. Such deficits indicate the incompetence of the primary auditory cortex to not only properly process thalamic input and generate output within the infragranular layers, but also incorporate top-down modulations from higher order auditory cortex into the processing within primary auditory cortex. Such deficits are the consequence of a misguided postnatal development. Maturation of primary auditory cortex in deaf animals shows evidence of a developmental delay and further alterations in gross synaptic currents, spread of activation, and morphology of local field potentials recorded at the cortical surface. Additionally, degenerative changes can be observed. When hearing is initiated early in life (e.g., by chronic cochlear-implant stimulation), many of these deficits are counterbalanced. However, plasticity of the auditory cortex decreases with increasing age, so that a sensitive period for plastic adaptation can be demonstrated within the second to sixth months of life in the deaf cat. Potential molecular mechanisms of the existence of sensitive period are discussed. Data from animal research may be compared to electroencephalographic data obtained from cochlear-implanted congenitally deaf children. After cochlear implantation in humans, three phases of plastic adaptation can be observed: a fast one, taking place within the first few weeks after implantation, showing no sensitive period; a slower one, taking place within the first months after implantation (a sensitive period up to 4 years of age); and possibly a third, and the longest one, related to increasing activation of higher order cortical areas.

Animals↗

PubMed2004

Autochronometric abnormalities in patients with cerebral pathology in various locations.

Dysfunction of the limbic structures of the temporal lobe of the brain (predominantly the hippocampus), chiasma, hypothalamus, and epiphysis is accompanied by impairment of internal estimation of time periods. In patients with lesions of the temporal lobes and base of the skull, changes in measures of autochronometry were uniform, were the most marked, and were not directly associated with locomotor parameters or with changes in the general functional state of the CNS. In patients with spinal cord or vertebral lesions, including tumors, and in those with extensive lesions of the frontoparietal areas of the neocortex, there were no profound defects in endogenous time estimation, regardless of impairments of the functional state of the synaptic and motor system. These data identify the cerebral oscillatory formations--the hippocampus, the hypothalamic area, and the epiphysis--as structures directly involved in the physiological mechanisms controlling autochronometry.

Adult↗

PubMed2002

Generation of symptomatic palatal tremor is not correlated with inferior olivary hypertrophy.

Although the generation of symptomatic palatal tremor (SPT) is thought to derive from the abnormal activity of hypertrophic inferior olivary neurones, the actual mechanism of SPT has not yet been elucidated. We therefore investigated the relationship between SPT and the pathological process of inferior olivary hypertrophy (IOH). We examined 16 autopsied subjects with cerebrovascular lesions of the dentate-olivary tracts. We analysed the size of the olives, the number of olivary neurones, synaptic, axonal and astrocytic changes in the olives and the clinical course in the subjects. SPT was observed in eight patients, in seven of whom it appeared 1-2 months after interruption of the afferents then progressed to reach a peak approximately 1-2 years from the onset. SPT persisted for the rest of the subjects' lives without decreasing in severity. Neuronal hypertrophic change began 20-30 days after the onset of the causative lesions and reached maximum size, accompanied by prominent astrocytosis and synaptic and axonal remodelling, 6-7 months later. The number of olivary neurones decreased to <10% of that in controls in patients who survived >6 years. Despite the persistence of SPT, both the myelin and the axons of efferent fibres from olivary neurones were severely degenerated in patients who survived several years. Therefore, the appearance of SPT may depend on the hyperactivity of olivary neurones released from inhibitory inputs until the peak of both IOH and SPT. However, the persistence of peak intensity and distribution of established SPT is probably due to both the disturbance of natural rhythmicity in the body and the lack of feedback from the abnormal movement resulting from the dysfunction of the olive.

Aged↗

PubMed1998

Fetal alcohol syndrome: a Japanese perspective.

To estimate and prevent the effects of prenatal alcohol on the central nervous system (CNS), brain dysfunction in fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE) was compared by both epidemiological and experimental studies. The FAS infants exhibited a more severe degree of CNS involvement than the FAE infants. The CNS involvement features were developmental delay and intellectual impairment in both FAS and FAE. The increased risk of low birth weight and CNS involvement were much more significant in women who were heavy drinkers or alcoholics and smoked. The beneficial effect of supplementary zinc on the fetal cerebrum of FAS or FAE rats was limited, never reaching the unexposed control level. One of the most vulnerable structures in the rat fetus exposed to ethanol in utero was the synaptic formation in the hippocampus. The consistent dysmorphogenesis of synapses during early brain development may be associated with the functional impairment of the CNS in FAS and FAE.

Animals↗

PubMed2006

[Colour vision and acquired colour vision disturbances. Part I: basic aspects].

Colour vision is the most sensitive sensory ability of the human eye, making it possible to distinguish several million nuances of colour. The physiology of colour vision has meanwhile been researched in depth, including the genetic and biochemical principles. This knowledge has facilitated a better understanding of the results of clinical tests on colour vision. These clinical tests provide useful information on the aetiology of very different clinical pictures in ophthalmology and as such are important for the diagnosis of these diseases. Acquired colour vision deficiencies in patients with systemic vascular disease are early signs of dysfunctional microcirculation and play a role in the early diagnostic work-up. Part I of this review summarizes the basic principles of colour vision and its disturbances. Congenital and acquired colour vision disturbances are distinguished. The second part then describes the most commonly employed examination procedures to assess colour vision.

Color Perception↗

PubMed1997

Selective disruption of neurotransmission by acetylcholinesterase antibodies in sympathetic ganglia examined with intracellular microelectrodes.

Antibodies to acetylcholinesterase (AChE) induce adrenergic dysfunction in rats by selective, complement-mediated destruction of preganglionic sympathetic nerve terminals. To analyze this phenomenon at the neuronal level, monoclonal antibodies to AChE (1.6 mg) were injected via the tail vein, and superior cervical ganglia (SCG) or inferior mesenteric ganglia (IMG) were studied in vitro. In control SCG, all impaled neurons generated action potentials during direct injection of depolarizing current or indirect stimulation through the preganglionic nerve. Current injection remained effective in ganglia from treated rats, but preganglionic stimulation was greatly impaired: at 12 h and 3 d, less than 10% of the neurons responded, even to a maximal stimulus (150 V); at 9 d, only 25% responded. By contrast, in IMG, synaptic transmission was much less affected by antibody exposure: 60% or more of examined neurons responded to preganglionic stimulation. Differences in antibody access did not explain differing sensitivities of SCG and IMG since immunohistochemistry showed rapid accumulation of IgG deposits in both ganglia. These results are believed to reflect widespread but subtotal preganglionic sympathectomy by AChE antibodies. Current information indicates that paravertebral ganglia are all antibody-sensitive, but some prevertebral ganglia are resistant, suggesting immunochemical differences between them.

Acetylcholinesterase↗

PubMed2000

Effect of muscle pain and intrathecal AP-5 on electromyographic patterns during treadmill walking in the rat.

1. A physio-neuropharmacological model to assess in the rat the contribution of muscular nociceptive input to motor dysfunction and pharmacological aspects of spinal sensorimotor interaction, during treadmill walking, is presented. 2. Rats were trained to walk on a treadmill prior to chronic electromyographic electrode implantation and intrathecal catheterization. 3. Changes in electromyographic activities were recorded from the median gastrocnemius and tibialis anterior muscles of the right hindlimb, during rhythmic locomotor movements. 4. Intramuscular hypertonic saline 6% was injected into the right triceps surae muscles to produce an experimental muscle pain during treadmill walking. 5. Pain produced a decrease in both median gastrocnemius and tibialis anterior electromyographic activities during rhythmic locomotion. Mean gastrocnemius burst duration decreased while tibialis anterior burst duration increased. 6. AP-5, an NMDA receptor antagonist known to block the synaptic excitatory drive to central pattern generators, was injected intrathecally at the level of the lumbar spinal cord to validate this neuropharmacological model. 7. Intrathecal AP-5 induced a decrease of both median gastrocnemius and tibialis anterior muscle activities during treadmill walking. This pharmacological intervention aggravated behavioural and motor effects of muscle pain.

2-Amino-5-phosphonovalerate↗

PubMed2005

[New results in the experimental psychopathology of visual dysfunctions in schizophrenia].

New theories of schizophrenia put a special emphasis on cognitive deficits, including executive functions, attention, verbal memory, and psychomotor speed. Dysfunctions of low level visual processing are less known. In this paper, the author summarizes recent results from two new tasks and integrates them with the relevant literature of schizophrenia. First, the relationship between the precortical magno (M) and parvocellular (P) pathways was investigated with a new contrast categorization task assessing low level perception, memory, and abstraction. Patients with schizophrenia showed a generalized dysfunction, which suggests contrast-independent memory and abstraction problems. In contrast, siblings were selectively impaired on the task variant that included the 10-15% contrast range, the transition zone between M and P pathway contrast sensitivity. In a second paradigm, the author investigated intrinsic lateral connectivity in the primary visual cortex, the main target of M and P pathways. Using Gabor patches, a reduced facilitation effect of collinear flankers was demonstrated in schizophrenia, which suggests impaired lateral connections in the primary visual cortex. These results are closely related to backward masking and smooth pursuit eye movement abnormalities. As a neurobiological basis of these phenomena, N-methyl-D-aspartate (NMDA) glutamate receptors and integrated synaptic networks may be of special relevance.

Adult↗

PubMed2003

[Clinical Results of PNE Tests in 70 Patients with Different Bladder Dysfunctions].

PURPOSE: Prior to implantation of a sacral neuromodulator we carried out PNE tests (peripheral nerve evaluation test) with bilateral test stimulation to establish which patients might profit from this kind of therapy. In contrast to the original unilateral technique used by Tanagho and Schmidt, we performed bilateral PNE test stimulation. Moreover, we analysed the diagnostic characteristics of those patients who had positive PNE test results and could thus receive a chronic sacral neuromodulator. MATERIALS AND METHODS: We performed bilateral PNE test stimulation in 70 patients (mean age: 53.6 yrs; 41 with retention symptoms and 29 with a hyperactive detrusor) over a minimum of 3 days. Retrospectively, we analysed the distribution of diagnostic characteristics (retention vs. overactive bladder and neurogenic vs. idiopathic) in the implant recipients. RESULTS: All patients received bilateral PNE test stimulation, during which the stimulation amplitudes were adjusted individually for each side. 8 patients were treated with the original PNE-electrode (model 0 041 830 - 002, Medtronic Inc., USA) without success. Of the remaining 62 patients, who were treated with an improved electrode, the PNE test was successful in 32 cases (51.6 %). Twenty-seven of these patients suffered from a neurogenic bladder dysfunction, and, in 5 cases, the causes were idiopathic. CONCLUSIONS: Bilateral PNE-test stimulation and the use of advanced PNE electrodes (model 3057, Medtronic Inc., USA) led to a positive PNE result in 51.6 % of the tested patients. Of these, the group with neurogenic bladder dysfunctions showed the highest response rate. Compared with the success rates in the multicenter study, we were able to increase the overall PNE response rate significantly. For this reason, we prefer a bilateral PNE-test with side-specific stimulation.

Adult↗

PubMed1997

Discussion of Bogerts' temporolimbic system theory of paranoid schizophrenia.

Olney and Farber present their work with N-methyl-D-aspartate (NMDA) antagonists, which are psychotogens, and propose that the structural changes described by Bogerts could be accounted for by a two-stage process. The first stage of the process would occur early in life and would culminate in the selective loss of NMDA-receptor bearing gamma-aminobutyric acid (GABA)ergic neurons and thus render the brain into a NMDA receptor hypofunctional (NRH) state. Such a loss would set the foundation for the second stage in which the neural circuits that have been altered by the loss of these GABAergic interneurons would become activated in late adolescence but would be dysfunctional. Dysfunction of this circuit would lead to the psychopathology of schizophrenia and potentially, if severe enough, to neuronal degeneration. Thus, the changes described by Bogerts could originate partially in early life and partially in adulthood. Based on their animal model, the authors suggest studies that should be carried out in humans.

Adolescent↗