Biomedical subjects

G L Wenk

Publications and source records attributed to G L Wenk.

At least 19 recordsLinked to original sources

PubMed1998

Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease.

Inflammatory processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimer's disease (AD). In the present study, lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria was used to produce chronic, global inflammation within the brain of young rats. Chronic infusion of LPS (0.25 microgram/h) into the 4th ventricle for four weeks produced (1) an increase in the number of glial fibrillary acidic protein-positive activated astrocytes and OX-6-positive reactive microglia distributed throughout the brain, with the greatest increase occurring within the temporal lobe, particularly the hippocampus, (2) an induction in interleukin-1 beta, tumor necrosis factor-alpha and beta-amyloid precursor protein mRNA levels within the basal forebrain region and hippocampus, (3) the degeneration of hippocampal CA3 pyramidal neurons, and (4) a significant impairment in spatial memory as determined by decreased spontaneous alternation behavior on a T-maze.

Alzheimer Disease↗

PubMed1997

The nucleus basalis magnocellularis cholinergic system: one hundred years of progress.

The nucleus basalis magnocellularis (NBM) contains a population of large cholinergic (Ch) neurons that send their axons to the entire cortical mantle, the olfactory bulbs, and the amygdala. This is the centennial anniversary of the first exact description of this nucleus by Von Kölliker, who named it in honor of its discoverer. This review will focus upon recent attempts to understand the role of the NBM Ch neurons in higher cognitive function by the use of selective lesion analyses and electrophysiological recording techniques. Behavioral deficits associated with NBM lesions produced by injections of excitatory amino acid agonists have been demonstrated in a variety of tasks. Performance decrements produced by these lesions were initially interpreted as being the result of impairments in learning and memory abilities. However, the precise role of the Ch NBM neurons in these performance deficits could not be more thoroughly investigated until it became possible to produce selective and discrete lesions by injection of the immunotoxin, IgG-192 saporin. The results of investigations using this immunotoxin supported a role for NBM Ch neurons in the performance of tasks that require selected attentional abilities rather than learning and memory per se. These lesion analysis studies suggested that the corticopetal NBM Ch system may be involved in the control of shifting attention to potentially relevant, and brief, sensory stimuli that predict a biologically relevant event, such as a food reward. Electrophysiological evidence has implicated NBM Ch cells in the control of attentional processes, as well as a role in the control and maintenance of arousal and sleep states. Electrophysiological studies also suggest that NBM Ch neurons might influence cortical EEG activity in two ways, by its direct excitatory inputs and by an indirect inhibitory projection to the thalamic reticular nucleus. Taken together with the results of histological and anatomical studies of the basal forebrain, NBM Ch cells appear to be ideally located within the basal forebrain for evaluating sensory stimuli for their level of significance, via inputs from the midbrain and limbic system, and also to modulate intrinsic cortical responsiveness appropriately in order to attend to brief, highly salient sensory stimuli.

Animals↗

PubMed1997

The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat.

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.

Acetylcholine↗

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↗

PubMed1997

Rett syndrome: neurobiological changes underlying specific symptoms.

Rett syndrome (RS) is a progressive disorder that is predominant in females. It is associated with cortical atrophy, stereotyped hand movements mimicking hand-washing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The cause of RS is unknown; no consistent genetic abnormalities, at either the cellular or mitochondrial levels, have been identified. The diagnosis still depends solely upon clinical evidence. The clinical progression of RS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of appropriate trophic factors. Neuropathological studies have confirmed (1) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Biochemical studies have identified (1) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of beta-endorphin levels in the thalamus and glutamate levels in the CSF; (4) no evidence for mitochondrial dysfunction. These data suggest that there is a primary deficit in cholinergic function that might underlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RS is a neurodevelopmental disorder that has its greatest effects upon a limited number of neural systems during the first few years of postnatal life.

Humans↗

PubMed1997

Analysis of galanin and the galanin antagonist M40 on delayed non-matching-to-position performance in rats lesioned with the cholinergic immunotoxin 192 IgG-saporin.

Galanin is a 29-amino-acid neuropeptide that is overexpressed in Alzheimer's disease (AD) and impairs performance on rodent learning and memory tasks. M40, a peptidergic galanin receptor ligand, blocks galanin-induced impairments on delayed non-matching-to-position (DNMTP). The present experiments used the 192IgG-saporin lesion model of AD to evaluate the actions of galanin and M40 on DNMTP when cholinergic transmission was reduced. Hippocampal choline acetyltransferase levels were correlated with DNMTP choice accuracy in lesioned rats. Intracerebroventricular (icv) galanin reduced choice accuracy in both the lesioned and sham groups. M40 alone, either icv or intrahippocampal, did not affect choice accuracy in either group. These results suggest that excess galanin can produce further deficits in DNMTP performance in a lesion model of AD, but blocking endogenous galanin is not sufficient alone to improve performance in lesioned rats.

Alzheimer Disease↗

PubMed1996

The effects of mitochondrial failure upon cholinergic toxicity in the nucleus basalis.

Increased glutamate or acetylcholine receptor stimulation may interact with mitochondrial failure to increase the vulnerability of cholinergic neurons within the nucleus basalis. Understanding of the mechanisms that underlie this vulnerability may lead to a therapy to prevent the degeneration of these neurons in Alzheimer's disease. In the presence of a mitochondrial energy deficit, excess stimulation of N-methyl-D-aspartate (NMDA) receptors was not required for cytotoxicity. Furthermore, stimulation of cholinergic receptors was cytotoxic to cholinergic neurons but this toxicity was not enhanced by NMDA stimulation. Chronic administration of NMDA antagonists, such as memantine, amantadine or MK-801, attenuated the effects of mitochondrial failure in the presence or absence of excessive cholinergic or NMDA receptor stimulation.

Acetylcholine↗

PubMed1996

Choline acetyltransferase activity and vesamicol binding in Rett syndrome and in rats with nucleus basalis lesions.

The decline in choline acetyltransferase activity has been identified previously within the brains of patients with Rett syndrome and Alzheimer's disease. The level of [3H]vesamicol binding to a terminal vesicular acetylcholine transporter is inversely related to the decline in cortical choline acetyltransferase activity in Alzheimer's disease, which may be due to compensatory processes within surviving cholinergic terminals. In order to investigate whether similar cholinergic compensatory processes are present in the Rett syndrome brain and are altered by normal aging, we investigated the density of cholinergic vesicular transporters in (i) the brains of Rett syndrome patients, and (ii) young and old rats with experimentally-induced cholinergic cell loss. In Rett syndrome, a significant decline in choline acetyltransferase activity within the putamen and thalamus was directly correlated with a decline in [3H]vesamicol binding. In both young and old rats, basal forebrain lesions decreased cortical choline acetyltransferase activity significantly, while [3H]vesamicol binding was unchanged. In contrast to young and old lesioned rats and patients with Alzheimer's disease, cholinergic cells in the brains of patients with Rett syndrome do not compensate for the loss of cholinergic cells by increasing acetylcholine vesicular storage.

Acetylcholine↗

PubMed1996

Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.

The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory).

Animals↗

PubMed1996

Rett syndrome: evidence for normal dopaminergic function.

Rett syndrome (RS) is a neurological disorder associated with cortical atrophy, stereotyped hand movements, dementia, and extrapyramidal dysfunction. In a small number of RS patients, dopaminergic function has been reported to be decreased throughout the neocortex and basal ganglia. The present study investigated for changes in endogenous levels of dopamine, its metabolite homovanillic acid, dopamine reuptake sites and dopamine type-2 receptors in the brains of 12 RS patients (4-30 yrs) and 14 normal female controls (2.5-20 yrs). The levels of each biomarker did not differ significantly between RS and controls in any brain region examined. These data support the hypothesis that dopaminergic neuronal function may be relatively normal in RS.

Adolescent↗

PubMed1995

Neuroprotection and selective vulnerability of neurons within the nucleus basalis magnocellularis.

Neurons within the nucleus basalis may die due to their selective vulnerability to endogenous excitatory amino acid neurotransmitters, nitric oxide and free radicals. The factors influencing the selective vulnerability of neurons within the nucleus basalis depend upon many different factors related to the presence of these agents and the neuron's ability to defend itself against the consequences of exposure. Many different mechanisms have been investigated to provide neuroprotection for neurons within the nucleus basalis and throughout the central nervous system. This review summarizes the results of studies that have investigated our current capability to either attenuate the neurotoxicity of endogenous excitatory amino acids, such as glutamate, or to provide effective neuroprotection during circumstances of neurotoxin exposure.

Animals↗

PubMed1995

MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis.

The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.

Amantadine↗

PubMed1995

Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat.

The nucleus basalis magnocellularis (NBM) contains cholinergic neurons that project to the neocortex and is densely innervated by excitatory amino acid-containing terminals. A dysfunction in the balance of excitatory inputs or an alteration in the sensitivity of NBM cells to glutamate may underlie the selective vulnerability to aging. Some large NBM neurons contain neurokinin B (NKB) mRNA. The present study investigated whether alpha-2-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) differentially destroy NKB-containing, NKB-receptive, or cholinergic NBM cells, and whether this vulnerability is altered by aging. Injections of AMPA or NMDA significantly decreased neocortical ChAT activity, as compared to control levels, across all three age groups, with no interaction between lesion and age group. The results of in situ hybridization histochemistry and NKB receptor studies suggest that NKB-containing neurons in the NBM, and the neurons they innervate, are not vulnerable to NMDA or AMPA in either young or old rats. While NKB mRNA-positive cells were diffusely distributed throughout the basal forebrain, only a small proportion of the large NBM cells contained NKB mRNA. The results suggest that NKB does not extensively colocalize with acetylcholine within the basal forebrain of rats and that NBM NKB neurons do not directly innervate cholinergic cells.

Acetylcholine↗

PubMed1995

Alterations in dopaminergic function in Rett syndrome.

Rett syndrome is a neurological disorder associated with cortical atrophy, stereotyped hand movements, dementia, and extrapyramidal dysfunction. Endogenous levels of dopamine and its metabolites are decreased throughout the neocortex and basal ganglia and the number of dopamine type 2 receptors are decreased in the putamen. The present study investigated changes in dopamine uptake sites and dopamine type-1 receptors in the brains of eleven Rett syndrome patients (4-30 yrs) and ten normal female controls (2.5-20 yrs). The number of dopamine type 1 receptors within the caudate nucleus were unchanged. The density of dopamine reuptake sites were unchanged in the cingulate and midfrontal gyri but decreased within the caudate nucleus and putamen. The results of the present study suggest that: 1) in the basal ganglia of Rett syndrome patients, dopamine receptive neurons are intact whereas the number and activity of dopamine terminals are decreased, and 2) in the midfrontal and cingulate cortex, dopaminergic neuronal activity may be increased in order to compensate for fewer terminals that contain less dopamine.

Adolescent↗

PubMed1994

Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat.

The present study investigated the specific ways by which cytotoxicity due to glutamate receptor stimulation could be attenuated by the administration of agonists and antagonists of the ionotropic and metabotropic glutamate receptors within the nucleus basalis magnocellularis (NBM) of rats as measured by cortical choline acetyltransferase activity. The results of these studies suggest that (1) the cytotoxicity of ibotenate to NBM cholinergic cells is not dependent upon stimulation of metabotropic glutamate receptors, but results from activation of N-methyl-D-aspartate (NMDA) receptors, (2) the cytotoxicity of quisqualate to cholinergic cells within the NBM is not dependent upon stimulation of NMDA or metabotropic receptors, and (3) the cytotoxicity of NMDA was prevented by administration (i.p.) of the un-competitive NMDA antagonist memantine (30 mg/kg), resulting in plasma levels of 2.5 micrograms/ml, a concentration known to block efficiently NMDA receptors in vitro. Finally, performance of a food-motivated, delayed-alternation task on a T-maze was impaired by injections of NMDA into the NBM, but was prevented by co-administration of NMDA with memantine.

Acetylcholine↗

PubMed1994

Glucose attenuates a morphine-induced decrease in hippocampal acetylcholine output: an in vivo microdialysis study in rats.

Systemic injections of morphine impair performance in memory tests. Glucose administration ameliorates memory deficits produced by morphine treatment. The memory impairments induced by morphine may be related to opioid inhibition of acetylcholine release with reversal of this effect by glucose. The present experiment determined whether: (1) systemic morphine treatment decreases acetylcholine output in the hippocampal formation; and (2) systemic glucose administration attenuates the effect of morphine treatment. Employing microdialysis, samples were collected at 12-min intervals and assayed for acetylcholine using HPLC with electrochemical detection. Morphine (10 mg/kg)/saline injections resulted in an immediate decrease in acetylcholine output (20-35%) that was observed up to the third postinjection sample (36 min). Glucose (100 mg/kg) administered concurrently with morphine attenuated the reduction in acetylcholine output in the second and third samples. These findings suggest that glucose may attenuate morphine-induced memory impairments by reversing a decrease in acetylcholine output produced by morphine.

Acetylcholine↗

PubMed1994

Nitric oxide formation does not underlie the memory deficits produced by ibotenate injections into the nucleus basalis of rats.

Basal forebrain (BF) injections of ibotenic (IBO) acid impair memory, whereas quisqualic (QUIS) acid injections do not. The authors investigated whether the cytotoxicity and differential behavioral effects of IBO and QUIS in rats depend on the generation of nitric oxide (NO). Injections of IBO or sodium nitroprusside (NP), but not QUIS, significantly increased BF NO formation, as determined by guanosine 3,5-cyclic monophosphate levels. IBO, alone or coinjected with methylene blue (MB), and QUIS, alone or coinjected with NP, decreased cortical choline acetyltransferase (ChAT) activity and the number of ChAT-positive BF neurons. The BF levels of galanin or neuropeptide Y were unchanged in all lesion groups. QUIS, but not IBO, dose-dependently destroyed NO-producing BF cells. Injections of IBO, with or without MB, impaired choice accuracy in a T-maze alternation task. The results suggest that the generation of NO in the BF does not underlie the spatial working memory deficit produced by IBO.

Animals↗

PubMed1994

Behavioral, biochemical, histological, and electrophysiological effects of 192 IgG-saporin injections into the basal forebrain of rats.

The behavioral, biochemical, histological, and electrophysiological effects of a basal forebrain injection of saporin, a ribosome-inactivating protein, coupled to a monoclonal antibody against the low-affinity NGF receptor (192 IgG) were investigated in adult rats. Within the basal forebrain region, the low-affinity NGF receptor is exclusively expressed by cholinergic neurons in the medial septal area, diagonal band, and nucleus basalis magnocellularis (NBM). The presence of this receptor upon these cells confers a degree of specificity to the 192 IgG-saporin that could not previously be achieved by previous lesioning techniques, such as excitatory amino acids. Rats with unilateral injections of different amounts of 192 IgG-saporin were prepared to determine the optimal conditions in order to produce a lesion restricted to the NBM that would not destroy cholinergic afferents to hippocampus or nearby regions. Electroencephalographic (EEG) recordings were taken from these lesioned rats before and during treatment with scopolamine (1 mg/kg, i.p.). Another group of rats received bilateral NBM injections of 192 IgG-saporin and were behaviorally tested using a rewarded, delayed-alternation task on a T-maze and a passive avoidance task. Finally, histological and biochemical investigations confirmed the effectiveness and specificity of the 192 IgG-saporin. The results showed that the 192 IgG-saporin did not destroy neurotensin, galanin, somatostatin, NADPH-diaphorase, or neuropeptide Y neurons within the NBM. Also, biomarkers of cholinergic function were significantly decreased throughout the neocortex and within the NBM, but not in the olfactory bulbs, hippocampus, or dorsal caudate nucleus. Intraperitoneal injections of scopolamine, but not NBM injections of 192 IgG-saporin, increased total power across all frequency bands; however, slow-wave frequencies showed a greater increase in power as compared to fast-wave frequencies. Acquisition, and performance of the delayed-alternation or passive avoidance tasks were not impaired by the lesions. These data confirm the effectiveness and specificity of this novel lesioning tool and suggest that selective loss of NBM cholinergic cells is not sufficient to impair performance in these behavioral tasks.

Animals↗