Nucleus Basalis Of Meynert Lesion Research Articles

The role of the nucleus basalis of Meynert in neuromodulation therapy: a systematic review from the perspective of neural network oscillations.

As a crucial component of the cerebral cholinergic system and the Papez circuit in the basal forebrain, dysfunction of the nucleus basalis of Meynert (NBM) is associated with various neurodegenerative disorders. However, no drugs, including existing cholinesterase inhibitors, have been shown to reverse this dysfunction. Due to advancements in neuromodulation technology, researchers are exploring the use of deep brain stimulation (DBS) therapy targeting the NBM (NBM-DBS) to treat mental and neurological disorders as well as the related mechanisms. Herein, we provided an update on the research progress on cognition-related neural network oscillations and complex anatomical and projective relationships between the NBM and other cognitive structures and circuits. Furthermore, we reviewed previous animal studies of NBM lesions, NBM-DBS models, and clinical case studies to summarize the important functions of the NBM in neuromodulation. In addition to elucidating the mechanism of the NBM neural network, future research should focus on to other types of neurons in the NBM, despite the fact that cholinergic neurons are still the key target for cell type-specific activation by DBS.

Lesions of the nucleus basalis magnocellularis (Meynert) induce enhanced somatosensory responses and tactile hypersensitivity in rats

We used the immunotoxin 192 immunoglobulin G-saporin to produce a selective cholinergic lesion in the nucleus basalis of Meynert (NBM) of rats and investigated whether the NBM lesion led to tactile hypersensitivity in the forepaw. The paw mechanical threshold test showed that the lesioned rats had a decreased threshold compared to the control. Surprisingly, there was a significant positive correlation between mechanical threshold and survival rate of NBM cholinergic neurons. Furthermore, using local field potential (LFP) recordings and voltage-sensitive dye (VSD) imaging, we found that the forepaw-evoked response in the primary somatosensory cortex (S1) was significantly enhanced in both amplitude and spatial extent in the NBM-lesioned rats. The neurophysiological measures of S1 response, such as LFP amplitude and maximal activated cortical area depicted by VSD, were also correlated with withdrawal behavior. Additional pharmacological experiments demonstrated that forepaw-evoked responses were increased in naive rats by blocking S1 cholinergic receptors with mecamylamine and scopolamine, while the response decreased in NBM-lesioned rats with the cholinergic agonist carbachol. In addition, NBM burst stimulation, which facilitates acetylcholine release in the S1, suppressed subsequent sensory responses to forepaw stimulation. Taken together, these results suggest that neuronal loss in the NBM diminishes acetylcholine actions in the S1, thereby enhancing the cortical representation of sensory stimuli, which may in turn lead to behavioral hypersensitivity.

Evaluation of the pre-treatment effect of Centella asiatica medicinal plants on long-term potentiation (LTP) in rat model of Alzheimer's disease

The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer’s disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats’ brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.

Effects of Delphinidin on Pathophysiological Signs of Nucleus Basalis of Meynert Lesioned Rats as Animal Model of Alzheimer Disease.

Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by cognitive deficits, oxidative stress, inflammation, amyloid plaques deposition, and acetylcholinesterase (AChE) hyper-activation. Growing evidence suggests natural compounds with antioxidant and anti-inflammatory features improve pathophysiological signs of AD. The present study was designed to investigate the effects of Delphinidin (25, 50mg/kg) as an anthocyanidin on spatial memory impairment and AD hallmarks such as hippocampal AChE activity, amyloid plaques deposition, oxidative stress and expression of amyloid precursor protein (APP), AChE, and amyloid beta (Aβ) proteins in nucleus basalis of Meynert (NBM) lesioned rats as the most prevalent animal model of AD. Interestingly, Delphinidin-treated animals showed a significant decrease in escape latency and distance moved. Furthermore, in probe test, NBM lesioned rats treated with both doses of Delphinidin spent more time in the target quadrant zone in Morris water maze task. It could also interact with catalytic site of AChE enzyme and inhibits acetylcholine hydrolysis in in vitro and in vivo conditions. In addition, Delphinidin could scavenge additional produced reactive oxygen molecules dose dependently. Our immunoblotting analysis confirmed high dose of Delphinidin reduced AChE, APP and Aβ contents in AD model. Staining of hippocampus tissue revealed that Delphinidin treatment decreased amyloid plaques formation in NBM lesion rats. It seems that Delphinidin is a plate-like molecule intercalated between β-plated sheets related to Aβ molecules and inhibited amyloid fibril formation. Altogether, Delphinidin and Delphinidin-rich fruits could be suggested as a therapeutic adjuvant in AD and other related cognitive disorders.

Nucleus basalis of Meynert modulates signal processing in rat layer 5 somatosensory cortex but leads to memory impairment and tactile discrimination deficits following lesion

In rodents, exploring through continuous whisking is a process resulted from sensorimotor networking among different layers of somatosensory cortex (SC) such as layer 5 (L5) or barrel field, and regions like the nucleus basalis of Meynert (NBM). NBM is densely packed with cholinergic fibers and its dysfunction leads to diminished acetylcholine release within SC, tactile deficits and Alzheimer’s disease (AD)-like memory impairment. Using extracellular single-unit recording, we investigated mechanisms underlying changes in response characteristics of L5b neurons to single or paired deflection of selected principle and adjacent whiskers (PW and AW), following NBM electrical stimulation in normal rats or ibotenic acid-induced NBM lesion leading to potential tactile deficiency and memory loss during passive avoidance learning (PAL) in AD-like neuropathology. Our results indicated that NBM electrical stimulation decreased ON and OFF response magnitude in nearly half of the units upon vibrissal deflection. The larger the response was evoked to whisker deflection before NBM stimulation, the smaller it gets after stimulation. Neuronal spontaneous activity was not changed with NBM stimulation or lesion. Leading to more sublinear response summation and decreased condition-test ratio, NBM lesion decreased ON response magnitude and facilitation, increased AW surround inhibition in paired whisker deflection, increased excitatory and decreased inhibitory receptive fields, weakened information processing during whisking, and resulted in AD-like declined PAL performance. These findings provide further understandings to develop translational approaches in precision therapeutics to target highly specific regions such as NBM or SC, and pathways like cholinergic system involved in tactile and memory deficits in AD.

Regulation of cortical blood flow responses by the nucleus basalis of Meynert during nociceptive processing

Cerebral blood flow (CBF) is essential for neuronal metabolic functions. CBF is partly regulated by cholinergic projections from the nucleus basalis of Meynert (NBM) during cortical processing of sensory information. During pain-related processing, however, this mechanism may be altered by large fluctuations in systemic mean arterial pressure (MAP). The objective of this study was to investigate the contribution of NBM to CBF responses evoked by nociceptive electrical stimuli and how it may be affected by systemic MAP. CBF was recorded in isoflurane-anesthetized rats (n = 8) using laser speckle contrast imaging, in two conditions (intact vs left NBM lesion). Electrical stimulation was applied to the sciatic nerve. Sciatic stimulation produced intensity dependent increases in MAP (p < 0.001) that were almost identical between conditions (intact vs left NBM lesion; p = 0.96). In both conditions, sciatic stimulation produced intensity dependent CBF increases (p < 0.001). After NBM lesion, CBF responses were decreased in the left somatosensory cortex ipsilateral to NBM lesion (p = 0.02) but not in the right somatosensory cortex (p = 0.46). These results indicate that NBM contributes to CBF responses to nociceptive stimulation in the ipsilateral, but not contralateral somatosensory cortex and that CBF response attenuation by NBM lesion is not compensated passively by systemic MAP changes. This highlights the importance of NBM's integrity for pain-related hemodynamic responses in the somatosensory cortex.

Improving effects of Echium amoenum aqueous extract on rat model of Alzheimer'sdisease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder greatly accompanied by oxidative stress and acetylcholine reduction in synaptic cleft that leads to dementia. Previously approved there is correlation between nucleus basalis of Meynert (NBM) degeneration and loss of memory, learning ability and thought. The aim of this study was to investigate improving effects of Echium amoenum aqueous extract on memory deficient, pathophysiological and oxidative damages imposed by NBM lesion in rats as documented AD model. Results showed NBM destruction causes hash oxidative stress that possibly leads to neurodegeneration in hippocampus tissue. Orally administration of plant extract significantly reduced oxidative stress by reactive molecules scavenging that resulted to decrease lipid peroxidation also. Plant extract treatment inhibited acetylcholine esterase enzyme (more than 5 folds) in hippocampus tissue related to NBM lesioned rats. Histological studies approved NBM lesion causes harsh neurodegeneration in hippocampus tissue possibly by acetylcholine reduction that was compensated by plant extract protective effects. Interestingly improving effects of plant in molecular level causes improved spatial learning ability in Morris water maze test. By considering pathophysiological and molecular similarities between AD and NBM lesion model, E. amoenum could be used as a therapeutic adjuvant in patients suffering from Alzheimer or similar cognitive disorders.

Translating TNFR signalling into neuroprotective strategies: Proof of concept in acute in vivo models of neurodegeneration using humanized TNFR mice

TNF is involved in several degenerative brain diseases including stroke, Multiple Sclerosis, Parkinson's disease and Alzheimer's disease (AD). It became apparent in recent years that TNFR1 and TNFR2 signalling diverges with respect to its involvement in neurodegeneration and neuroprotection, respectively (Fontaine et al., 2002; Marchetti et al., 2004; Dolga et al., 2008; 2009; Fischer et al., 2011; Naudé et al., 2012; Maier et al., 2013). Under chronic stimulation TNFR2 mediated signalling counteracts TNFR1 mediated pro‐apoptotic pathways by the activation of a PI3K, PKB/Akt dependent NF‐kB signalling pathway. This allows neuronal survival despite exposure to lethal concentrations of neurotoxins such as glutamate (NMDA) or oligomeric forms of Amyloid beta. Both agents are known to be involved in neuronal cell loss in the course of Alzheimer's disease.Consequently in recent years new compounds have been developed that – instead of targeting TNF itself – selectively target TNFR1 or TNFR2 as potential therapeutics in human neurodegenerative diseases. Here we show the results of blocking either human TNFR1 or activating human TNFR2 in a mouse model with humanized TNFRs. For generating humanized TNFR mice we used gene targeting to replace the extracellular domains of the mouse TNFR genes by their human counterpart.Loss of cholinergic innervation is one of the earliest hallmarks in AD, which leads to severe cognitive impairment. Cholinergic neurons project their fibres from the Nucleus Basalis of Meynert (NBM) into the hippocampus and prefrontal cortex. Therefore loss of neurons in the NBM will reduce fibre density in the hippocampus and prefrontal cortex and lead to memory and learning deficits. We have established the NBM lesion model in humanized TNFR mice to investigate in vivo the potential therapeutic role of either TNFR1 antagonists or TNFR2 agonists. By using optical density measurements of stained cholinergic fibres and microglial activation in brain sections we were able to quantify the amount of neuronal cell loss eight days upon delivery of a toxic dose of NMDA into the Nucleus basalis via stereotactic injection. Controlateral NBM damage was used as internal standard. Behavioural testing was performed to assess cognitive function. Our results suggest that both, blocking TNFR1 or activating TNFR2, results in neuroprotection in this acute lesioning model, which serves as a paradigm for neuronal loss in chronic neurodegenerative diseases such as AD.Support or Funding InformationParts of this work was funded by EU FP6 NeuroproMiSe, ZonMW Deltaplan Dementie Memorabel Program, Internationale Stichting Alzheimer Onderzoek, Netherlands, Carl‐Zeiss‐Stiftung, Hertie Stiftung, BMBF, Germany.

Effect of Rheum Ribes Hydro-Alcoholic Extract on Memory Impairments in Rat Model of Alzheimer's Disease.

Some animal models have been used to study Alzheimer's disease (AD). AD is an irreversible progressive neurodegenerative disease and the most common cause of dementia. Animal studies have shown that there is a relation between decrease in cholinergic functions in the nucleus basalis of Meynert (NBM) and loss of learning capability and memory. The aim of this study was to investigate the effect of Rheum ribes extract (RR) on memory deficit in one of the rat models of AD. Plant (1500gr) was collected from Saman (kahkesh) region of Chaharmahal Va Bakhtiari province in Iran. RR hydro-alcoholic extracts were prepared using maceration method. Rat model of Alzheimer was induced by Nucleus Basalis of Meynert lesions (NBML). Animals (n = 32) received extracts for 20 days and then passive avoidance and Morris water maze tasks were performed for memory evaluation. FRAP and HPLC methods were used for measurement of the antioxidant and Malondialdehyde (MDA) levels in blood. In water maze experiment, probe trial results showed that NBML group spent significantly less time in target quadrant, in which the platform was located on the preceding day. In addition, the time spent in target quadrant was significantly increased in NBML + RR groups (250 and 500 mg/kg) compared to the NBML group. In passive avoidance task, mean initial latency time and step-though latency were significantly decreased in NBML group. RR extracts significantly prolonged step-through latency in NBML + RR groups. Results of this study suggest that Rheum ribes extracts can improve memory deficits induced by bilateral NBM lesions in rats.

Effects of Zizyphus jujube Extract on Memory and Learning Impairment Induced by Bilateral Electric Lesions of the Nucleus Basalis of Meynert in Rat

Alzheimer's disease (AD) is a common neurodegenerative condition that affects the elderly population. Its primary symptom is memory loss. The memory dysfunction in AD has been associated with cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert (NBM). Zizyphus jujube (ZJ) activates choline acetyltransferase and may have beneficial effects in AD patients. This study investigates the effect of ZJ extract in intact rats and in rat model of AD. 49 male Wistar rats were divided into seven equal groups (1-control, without surgery, received water), 2-AD (bilateral NBM lesion, received water), 3 and 4-AD+ZJ (NBM bilateral lesion, received ZJ extract 500 and 1,000mg/kg b.w. per day for 15days), 5-sham (surgery: electrode introduced into NBM without lesion, received water), 6 and 7-without surgery and lesion, received ZJ extract-the same as groups 3 and 4). The learning and memory performance were assessed using passive avoidance paradigm, and the memory cognition for spatial learning and memory was evaluated by Morris water maze. In shuttle box test ZJ extract (500 and 1,000mg) significantly increased step-through latency in AD+ZJ groups compared with AD group. In Morris water maze test (in probe day), both AD+ZJ groups receiving extract (500 and 1,000mg) demonstrated significant preference for the quadrant in which the platform was located on the preceding day as compared with AD group. Our results suggested that ZJ has repairing effects on memory and behavioral disorders produced by NBM lesion in rats and may have beneficial effects in treatment of AD patients.

THE EFFECT OF IBOTONIC ACID LESION OF THE NUCLEUS BASALIS OF MEYNERT (NBM) ON THE RESPONSE OF CORTICAL NEURONS IN THE RAT BARREL CORTEX

In the present study, the effect of NBM lesion on the temporal characteristics of response integration evoked by multiple whisker stimulations in the barrel cortex of rats was studied. Nucleus basalis of Meynert (NBM) projects to widespread areas of the cortex and provides the major cholinergic input (80%) to the cerebral cortex. In this study we examined the effects of NBM lesion on the responses properties of rat barrel cortical cells male Wistar rats weighing 250-350 g were used. The animals were randomly distributed into two groups: One group received bilateral NBM lesions (5 ?g ibotonic/5ul phosphate-buffered saline solution); rats in the other group were sham-operated. Extracellular single-unit recording and controlled whisker stimuli were used to compare response properties of cells in barrel cortex between the two groups. Two neighboring principal and adjacent whiskers in the same row were deflected alone with varying inter-stimulus intervals. Result showed that response magnitude was significantly lower in NBM-lesioned rats as compared to the sham group (P

P.4.11 The effect of rivastigmine on learning and memory processes after bilateral nucleus basalis of Meynert lesions in rats

Cognitive impairment has the greatest impact on illness outcome in schizophrenia. The most significant challenge in schizophrenia therapeutics, thus, is to develop an efficacious treatment for cognitive impairments. Acetylcholinesterase inhibitors, such as Physostigmine and Rivastigmine, are considered effective treatments for cognitive decline in Alzheimer's Disease, where the loss of cholinergic neurons is thought to be responsible for various cognitive deficits. The current study investigated the cognitive effects of Rivastigmine given as an add-on therapy to antipsychotic-treated schizophrenia patients in a placebo-controlled double-blind design. The study initially involved 40 patients, of which 21 patients (11 assigned to Rivastigmine and 10 assigned to placebo) agreed to continued participation, remained on the study drug, and underwent assessment of executive functioning, verbal skills, verbal and spatial working memory, attention and psychomotor speed on three occasions: (i) at baseline, and then (ii) after 12 weeks and (iii) 24 weeks of treatment with placebo or Rivastigmine. The results failed to reveal significant improvement on any cognitive measure with Rivastigmine treatment, compared with the placebo treatment. Some cognitive variables showed significant practice effects in both the placebo and Rivastigmine groups. No effects were noted in symptoms or side effects ratings. The beneficial cognitive effects of Rivastigmine seen in an open-label preliminary study are not substantiated by this study. Future studies should investigate the effects of other procholinergic drugs, such as Galantamine, which also act on the nicotine receptors and may produce stronger cognitive effects in schizophrenia.

Effect of Selective Cholinergic Denervation on the Serotonergic System: Implications for Learning and Memory

The cholinergic system has been widely implicated in cognitive processes and cholinergic loss is a classical hallmark in Alzheimer disease. Increasing evidence supports a role of the serotonergic system in cognition, possibly through a modulation of cholinergic activity. We compared selective cholinergic denervation by administration of the immunotoxin 192 IgG-saporin in the nucleus basalis of Meynert (NBM) with intracerebroventricular (ICV) lesions of the basal forebrain in male rats 7 days after lesioning. NBM lesions induced significant changes in cholinergic markers in the frontal cortex, whereas ICV lesions produced significant decreases in cholinergic markers both in the frontal cortex and hippocampus. Only ICV lesions lead to memory impairments in passive avoidance and Morris water maze tasks. Both models lead to reductions of serotonin levels in the frontal cortex. Similar changes in 5-hydroxytriptophan levels were observed, suggesting a downregulation of the rate-limiting enzyme for the synthesis of serotonin along with the cholinergic deficit. Neither 5-HT1A nor 5-HT1B receptors seem to mediate this process. These data imply that the serotonergic system in the frontal cortex can compensate for diminished cholinergic function and support the investigation of the serotonergic system as a therapeutic target to treat Alzheimer disease.

WEBER'S LAW ORTHOGONAL TO THE PSYCHOMETRIC FUNCTION

Psychometric function plots the percentage of the correct responses among an entire pool of responses (cumulative probability) in a psychophysical task versus the amount of change in an independent variable. These changes in the independent variable are made with reference to a constant initial value. If this initial value is altered, the psychometric function will change according to Weber’s law. In other words, in a task such as the detection of the luminance increment, the psychometric function is stretched to the right for greater initial stimulus intensities and is compressed to left for smaller initial intensities. All of this behavior can be plotted in a 3-D coordinate system. The amount of change in the stimulus intensity, the initial reference intensity, and the above-described probability would be plotted on the X, Y, and Z axes respectively. The formula would be: [Z=1/(1+exp((KY-X)/aKY))]. The intersection of the plot of this formula with any plane parallel to the XY plane would be a line plotting the Weber’s law, and that with any plane parallel to the XZ plane, would be a line plotting the psychometric function. That is why these two functions are called orthogonal in this article. K in the above formula is the same as appears in Weber’s law for just noticeable difference (JND). The coefficient “a” has an arbitrary value that should be at most equal to 0.34 to set the probability of change detection at 5 percents or less when veridically there is absolutely no change in the stimulus intensity. Further implications have been discussed.

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

PS-46-4 The effects of nucleus basalis of meynert lesions on the P-3 like potentials in rabbits

PS-46-4 The effects of nucleus basalis of meynert lesions on the P-3 like potentials in rabbits

Alterations in cerebral cortical galanin concentrations following neurotransmitter-specific subcortical lesions in the rat

Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.

Neuropeptide Y and somatostatin in the neocortex of young and aging rats: Response to nucleus basalis lesions

Lesions of the nucleus basalis of Meynert (NBM) have been used to mimic, in part, cholinergic deficits occurring in age-related neurodegenerative disorders, i.e., Alzheimer's disease. In our study, the effect of a persistent cholinergic denervation of the frontoparietal cortex on neuropeptide Y (NPY) and somatostatin (SOM) was examined in young adult (3 months old) and aging (> 18 months old) rats, 1, 3 and 6 months after bilateral stereotaxic NBM lesions with quisqualic acid. In aging, non-lesioned rats a significant decrease in radioimmunologically and immunohistochemically detectable NPY and SOM was found with no further changes after lesions. Morphological markers for these peptidergic populations (cell size and number, NADPH-diaphorase histochemistry, electron microscopy) demonstrated no signs of alterations in both age groups after lesion. Densitometric analysis of peptide fibre networks displayed a heterogeneous response with a significant rarefication in young rats 1 month after the lesion, followed by restoration and a tendency towards increase 6 months post lesioning in individual animals. These findings were confirmed by radioimmunological measurements. Examination of synaptic and cytoskeletal markers, i.e., synaptophysin, GAP-43, MAP-2, Tau-1 and amyloid precursor protein, did not reveal any signs for neuronal reorganization or sprouting. These data are discussed in the context of plasticity and pathology in age-related neurodegenerative disorders with cholinergic impairment.

Recovery of choline acetyltransferase activity without sprouting of the residual acetylcholine innervation in adult rat cerebral cortex after lesion of the nucleus basalis

In view of the divergent literature concerning the long-term effects of ibotenic acid lesions of the nucleus basalis of Meynert (NBM) on the choline acetyltransferase (ChAT) activity in adult rat cerebral cortex, we have critically reassessed the issue of an eventual recovery of this enzymatic activity by sprouting of the residual acetylcholine (ACh) innervation. At short (1 week) and long survival time (3 months) after unilateral ibotenic acid lesion, ChAT activity was biochemically measured in the ipsi and contralateral fronto-parietal cortex of several rats in which the extent of ACh neuronal loss in NBM was also estimated by counts of ChAT-immunostained cell bodies on the lesioned vs. non-lesioned side. In other lesioned rats, particular attention was paid to the distribution of the residual cortical ACh (ChAT-immunostained) innervation, and that of immunostained vasoactive intestinal polypeptide (VIP) axon terminals known to belong in part to intrinsic cortical ACh neurons which co-localize this peptide. One week after NBM lesion, profound decreases of ipsilateral cortical ChAT activity were tightly correlated with the extent of ACh cell body loss in the nucleus. A significant recovery of cortical ChAT activity could be documented after 3 months, despite persistence of NBM cell body losses as severe as after 1 week. At both survival times, the number of ChAT-immunostained axons was markedly reduced throughtout the ipsilateral fronto-parietal cortex, demonstrating that most ACh fibers of extrinsic origin had been permanently removed. This result also indicated that the long-term recovery of ChAT activity had occurred without sprouting of the residual ACh innervation. The laminar distribution and number of VIP-immunostained terminals remained the same on the lesioned and intact side and comparable to normal, ruling out an extensive sprouting of intrinsic ACh/VIP or VIP alone fibers. The return to a near normal cortical ChAT activity in severely ACh-denervated cortex suggested that the intrinsic ACh innervation was primarily responsible for this recovery.