Lesions Of Nucleus Basalis Magnocellularis Research Articles

The Combined Effect of Donepezil and Lovastatin on the Electrical Activity of Hippocampal Pyramidal Neurons in a rat model of Alzheimer’s disease

Background: Donepezil, a noncompetitive acetylcholinesterase inhibitor, is prescribed to treat mild to moderate Alzheimer's disease but it only has moderate performance. Therefore, combination therapies are more effective. There is much evidence suggesting that statins have neuroprotective effects on neurological disorders including Alzheimer's disease. The present study aimed to investigate the combined effects of Donepezil and Lovastatin on the activity of the pyramidal neurons of the CA1 hippocampus.
 Methods: In the present experiment study, adult male rats were divided into 3 groups: Nucleus Basalis Magnocellularis (NBM) lesion (which received electrically- induced lesion (0.5 mA, 3s) in NBM) group, NBM lesion + injection Donepezil 5mg/kg-Lovastatin 10mg/kg, NBM lesion+ injection Donepezil 15mg/kg-Lovastatin 30mg/kg. Spontaneous activity of pyramidal neurons in CA1 region to injection of Donepezil-Lovastatin was investigated in a rat model of Alzheimer's disease.
 Results: The results of this study showed that electrical lesion of NBM leads to a decrease in the activity frequency of pyramidal neurons in the CA1 region. Administration of Donepezil 5mg/kg-Lovastatin 10mg/kg increased the frequency of pyramidal neurons in rat model of Alzheimer's disease.
 Conclusion: The results of this study suggest that co-administration of Donepezil-Lovastatin (low doses) increases the activity of the CA1 pyramidal neurons in a rat model of Alzheimer’s disease.

Effects of Memantine on the Spontaneous Firing Frequency of Hippocampal CA1 Pyramidal Neurons in Intact and Alzheimer Rat Model: An Electrophysiological Study.

Memantine (MEM) is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically used for the treatment of Alzheimer disease (AD) in mild to severe conditions. The present study was conducted to investigate the effects of memantine on the spontaneous firing frequency of CA1 pyramidal neurons in rats caused by an electrical lesion of Nucleus Basalis Magnocellularis (NBM). Then, this model of AD rats was compared with the intact adult male rats. In this study, adult male rats were divided into two groups. Group I (lesion of NBM, n=53) includes the following subgroups: lesion+saline, sham+saline, lesion+MEM 5 mg/kg, lesion+MEM 10 mg/kg, and lesion+MEM 20mg/kg. Group II (intact, n=48) includes the following subgroups: intact+saline, intact+MEM 3mg/kg, intact+MEM 5mg/kg, and intact+MEM 10mg/kg. Extracellular single-unit recording (15 min baseline+105 min after MEM or saline) was performed under urethane-anesthetized rats. The results showed that the mean frequency of CA1 pyramidal neurons after saline in the lesion+saline (P<0.001) group significantly decreases compared with the intact+saline and sham+saline groups. In addition, after saline and memantine, the mean frequency of CA1 pyramidal neurons in the lesion+MEM 10 mg/kg (P<0.01) and lesion+MEM 20 mg/kg (P<0.001) groups significantly increased compared with the lesion+saline group. Also, the mean frequencies of CA1 pyramidal neurons in the intact+MEM 10 mg/kg (P<0.001) group significantly decreased compared with the intact+saline group. Results showed that memantine increases the electrical activity of CA1 pyramidal neurons in a rat model of AD. Furthermore, in the intact adult male rats, the low-dose memantine, contrary to high dose, does not decrease the electrical activity of CA1 pyramidal neurons.

Modulation of prefrontal cortex function by basal forebrain cholinergic and GABAergic neurons at the behavioral and molecular level.

The present research aimed to study the effects of selective immunolesions of cholinergic or gamma-aminobutyric acid (GABA)ergic neurons in the nucleus basalis magnocellularis (NBM) on memory function as well as cholinergic activity and the level of expression of glutamatergic [NR2B subunit of N-methyl-D-aspartate(NMDA)] receptors in the medial prefrontal cortex (mPFC) and hippocampus of behaviorally characterized rats. In behavioral experiments, working memory was assessed by a spatial alternation testing procedure in a plus-maze, and acquisition and retention of spatial memory was evaluated in a Morris water maze. The rats were divided into three groups: the NBM cholinergic, GABAergic immunolesioned groups and the normal control group. Cholin acetyltransferase or parvalbumin staining of the NBM and acetylcholinesterase staining of the mPFC and hippocampal sections were performed to visualize the effects of immunotoxins. The electrophoresis and immunoblotting were run to evaluate the effect of NBM lesions on the amount of the NR2B subunit of NMDA receptors. The results indicate that the immunolesion of cholinergic NBM neurons impair spatial working memory, as well as long-term spatial memory which is accompanied by significant changes in glutamatergic (the NR2B subunit of NMDA receptor) and cholinergic markers in the mPFC, whereas immunolesion of GABAergic NBM neurons does not affect long-term spatial memory, it does though cause the impairment of working memory with a reduction of the NMDA NR2B receptor signaling in the mPFC. The present results demonstrate that the cholinergic and GABAergic NBM cell groups play diverse and complementary roles and are integrated in distinct NBM-mPFC networks that may play different roles in mPFC memory function.

Effect of Nucleus Basalis Magnocellularis Lesions on Memory and Hippocampal Brain-Derived Neurotrophic Factor, IL-1β, Glucose, and Corticosterone Levels in Adult Rats

Background: The nucleus basalis magnocellularis (NBM) sends projections to the hippocampus that are implicated in learning and memory formation. Despite ample evidence proposing that cognitive function impairment related to neurodegeneration, it may result from alteration of biochemical substances. We aimed to investigate the effects of NBM lesions on the hippocampal interleukin-1beta (IL-1β), brain-derived neurotrophic factor (BDNF), and corticosterone levels, as inflammation markers, and hallmarks of neurodegeneration, stress, and metabolic status. Methods: Thirty-six male Wistar rats were randomly put in control, sham, and NBM-lesioned groups. After inducing the lesion using an intra-NBM injection of 10 μg ibotenic acid (5 μg/μL, each side) in rats, memory was estimated using the passive avoidance test. Moreover, serum and hippocampal IL-1β levels, as well as the hippocampal corticosterone, BDNF, and glucose levels were measured after 42 days. Results: Findings indicated a significant impairment of retention at different intervals in the NBM-lesioned group. BDNF decreased whereas corticosterone, glucose, and IL-1β levels increased in the hippocampus. Also, the levels of serum IL-1β, hippocampal BDNF, corticosterone, and glucose had significant correlations with hippocampal IL-1β levels. Conclusion: The synchronous alterations of some hippocampal factors, including BDNF, corticosterone, IL-1β, and glucose, caused by NBM lesion suggest that their interaction might play a significant role in neurodegeneration and relevant learning and memory impairments.

Improvement of Spatial Learning and Memory Impairments by Fetal Neural Tissue Transplantation in Experimental Rat Model of Alzheimer’s Disease

ABSTRACT Objective: It is known that the acetylcholinergic afferents of the neocortex from subcortical areas participate in learning and memory. Autopsy studies in cases of Alzheimer’s disease have shown that most of the neurons of nucleus basalis magnocellularis are atrophic or decreased in number. In this study, we searched for whether or not it was possible to improve the impaired learning and memory functions with fetal neural tissue transplantation in an experimental model of Alzheimer ‘s disease. Material & Methods: A total of thirty seven young adult male Wistar albino rats were served as experimental subjects.The nucleus basalis magnocellularis on the right side was destroyed by the injection of kainic acid stereotactically so as to make a model of Alzheimer’s disease. The grafts were obtained from 14-16 day old fetuses of the same genus.After the tissue with cholinergic neurons dissected from ventral forebrain and tissue with non-cholinergic neurons dissected from telencephalic vesicle, cell suspensions were prepared and injected stereotactically to the ipsilateral frontal cortex. Spatial learnig and memory functions were tested by Morris’ water maze tasks. Results: Spatial learning and memory functions in rats were impaired by unilateral lesions of nucleus basalis magnocellularis. The impairment observed during the early period partially improved by the time. It was observed that this amelioration was accelerated with both cholinergic and non-cholinergic fetal neural tissue implantation Conclusion: In our study, improvement of spatial learning and memory impairment with both cholinergic and non-cholinergicfetal neural tissue implantation can be explained by reestablishment of impaired connections via proliferation of limited number of surviving cholinergic neurons creating new synapses, as a result of upregulation of endogenous neural stem cells and activation of trophic mechanisms by implantation, rather than creation of functional synapses between the graft andthe recipient tissue.

Effect of co-administration of donepezil and folic acid on spatial memory impairment in adult male rat model of Alzheimer's disease

Background: Alzheimer's disease is a neurodegenerative disorder that is diagnosed with a lack of memory and perception. Objective: The aim of this study was to evaluate the effect of donepezil and folic acid on reference and working memory disorders caused by electrical lesion of nucleus basalis magnocellularis (NBM). Methods: In this experimental study, 49 adult male Wistar rats were divided into 7 groups: control and, nucleus basalis magnocellularis (NBM) lesion group. which received electrically-induced lesion (0.5 mA, 3 s) in NBM, sham group (the electrode was impaled in to the nucleus basalis magnocellularis with no lesion), donepezil group (lesion + donepezil 0.1 mg/kg), folic acid group (lesion + folic acid 5 mg), interaction group (lesion + donepezil-folic acid) and vehicle group (lesion + saline). Acquisition and retention tests were done by using an eight-radial arm maze task. Findings: Results showed that there was a significant difference between control and lesion groups (P<0.05). Combination treatment with donepezil and folic acid improved the parameters of spatial memory errors in the acquisition and retention tasks comparing to the control group (P˂0.05). Conclusion: The degradation of the nucleus basalis magnocellularis caused to increase reference and working memory errors. Also the co-administration of donepezil and folic acid leaded to a reduction in these errors and improved spatial memory of the rat.

Effects of Donepezil Hydrochloride on Neuronal Response of Pyramidal Neurons of the CA1 Hippocampus in Rat Model of Alzheimer's Disease.

Introduction:Donepezil (DON), an Acetylcholinesterase Inhibitor (AChEI), is widely used in the treatment of Alzheimer’s Disease (AD). The current study aimed at evaluating the effect of donepezil hydrochloride on pyramidal neuron response in CA1 region of a rat model of AD.Methods:In the current experimental study, adult male Wistar rats were randomly divided into four groups: Nucleus Basalis Magnocellularis (NBM) lesion (the lesions were induced by an electrical method of 0.5 m A, for 3 s in NBM) and three donepezil groups (lesions plus 5, 10, and 15 mg/kg donepezil intraperitoneal injection). Neuronal spontaneous activity to injection of the donepezil and saline were recorded in CA1 region of hippocampal.Results:The obtained results showed that IntraPeritoneal (IP) injection of donepezil (10 and 15 mg/kg) increased neuronal spontaneous activity in the rat model of AD.Conclusion:The current study results suggested that acute IP injection of donepezil increased neuronal response in CA1 region of hippocampal in a rat model of AD.

The effects of NBM- lesion on synaptic plasticity in rats

The nucleus basalis magnocellularis (NBM) is a major source of cholinergic projections to the neocortex that is vulnerable to degeneration in Alzheimer's disease. Despite numerous anatomical, pharmacological, behavioral, and physiological investigations of NBM, there is no in vivo study of its effects on short- or long-term synaptic plasticity. Hence, this study was devoted to the assessment of the effects of bilateral lesion of the NBM on synaptic plasticity in the dentate gyrus of the hippocampus using electrophysiological techniques. For this purpose, twenty-five male Wistar rats were randomly allocated into the three Control, Sham, and NBM-lesioned groups. Lesion was made via bilateral injections of 5µg/µl ibotenic acid. After twenty-one days, the input–output functions, paired-pulse facilitation/inhibition, and long-term potentiation (LTP) were evaluated in the dentate gyrus while the perforant pathway was stimulated. NBM lesion was found to attenuate the basal synaptic responsiveness, paired-pulse responses, and LTP in the rats’ dentate gyrus, indicating that lesions of this cholinergic nucleus affects both short- and long-term neural plasticity in the dentate gyrus although NBM does not send direct cholinergic projections to the hippocampus.

Event-related oscillations (ERO) during an active discrimination task: Effects of lesions of the nucleus basalis magnocellularis

The cholinergic system in the brain is involved in attentional processes that are engaged for the identification and selection of relevant information in the environment and the formation of new stimulus associations. In the present study we determined the effects of cholinergic lesions of nucleus basalis magnocellularis (NBM) on amplitude and phase characteristics of event related oscillations (EROs) generated in an auditory active discrimination task in rats. Rats were trained to press a lever to begin a series of 1kHz tones and to release the lever upon hearing a 2kHz tone. A time-frequency based representation was used to determine ERO energy and phase synchronization (phase lock index, PLI) across trials, recorded within frontal cortical structures. Lesions in NBM produced by an infusion of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) resulted in (1) a reduction of the number of correct behavioral responses in the active discrimination task, (2) an increase in ERO energy in the delta frequency bands, (3) an increase in theta, alpha and beta ERO energy in the N1, P3a and P3b regions of interest (ROI), and (4) an increase in PLI in the theta frequency band in the N1 ROIs. These studies suggest that the NBM cholinergic system is involved in maintaining the synchronization/phase resetting of oscillations in different frequencies in response to the presentation of the target stimuli in an active discrimination task.

Cholinergic modulation of event-related oscillations (ERO)

The cholinergic system in the brain modulates patterns of activity involved in general arousal, attention processing, memory and consciousness. In the present study we determined the effects of selective cholinergic lesions of the medial septum area (MS) or nucleus basalis magnocellularis (NBM) on amplitude and phase characteristics of event related oscillations (EROs). A time–frequency based representation was used to determine ERO energy, phase synchronization across trials, recorded within a structure (phase lock index, PLI), and phase synchronization across trials, recorded between brain structures (phase difference lock index, PDLI), in the frontal cortex (Fctx), dorsal hippocampus (DHPC) and central amygdala (Amyg). Lesions in MS produced: (1) decreases in ERO energy in delta, theta, alpha, beta and gamma frequencies in Amyg, (2) reductions in gamma ERO energy and PLI in Fctx, (3) decreases in PDLI between the Fctx–Amyg in the theta, alpha, beta and gamma frequencies, and (4) decreases in PDLI between the DHPC–Amyg and Fctx–DHPC in the theta frequency bands. Lesions in NBM resulted in: (1) increased ERO energy in delta and theta frequency bands in Fctx, (2) reduced gamma ERO energy in Fctx and Amyg, (3) reductions in PLI in the theta, beta and gamma frequency ranges in Fctx, (4) reductions in gamma PLI in DHPC and (5) reduced beta PLI in Amyg. These studies suggest that the MS cholinergic system can alter phase synchronization between brain areas whereas the NBM cholinergic system modifies phase synchronization/phase resetting within a brain area.

The effect of treadmill running on memory before and after the NBM-lesion in rats

Some studies have shown the effects of exercise training in retarding onset and progression of memory deficit in neurodegenerative disorders such as Alzheimer's disease. In this research, we investigated the effect of treadmill running on memory function; before, after, and continually (before and after) the nucleus basalis magnocellularis lesions. 66 male rats were randomly divided into six groups, including control, sham operation, the NBM-lesion, exercise before the NBM-lesion, exercise after the NBM-lesion, and exercise before and after the NBM-lesion. Lesion was induced by 5μg/μl bilateral injection of Ibotenic acid. Memory function was assessed by using the passive avoidance learning test. Our results showed that treadmill running delays cognitive decline in the NBM-lesion rats, prevented memory deficit, and has advantageous effects on short-term, intermediate and long-term memory. Exercising on a regular basis may impede memory loss significantly, which may be attributed to specific molecular pathways in the brain.

Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer's disease.

The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. In the first experiments aged animals (30 months) were tested in Morris water maze (MWM) and divided into two groups: impaired memory and unimpaired memory. Impaired groups were divided into two groups and cannulated bilaterally at the CA1 of the hippocampus for delivery of mesenchymal stem cells (500 × 103/μL) and PBS (phosphate buffer saline). In the second experiment, Ibotenic acid (Ibo) was injected bilaterally into the nucleus basalis magnocellularis (NBM) of young rats (3 months) and animals were tested in MWM. Then, animals with memory impairment received the following treatments: MSCs (500 × 103/μL) and PBS. Two months after the treatments, cognitive recovery was assessed by MWM in relearning paradigm in both experiments. Results showed that MSCs treatment significantly increased learning ability and memory in both age- and Ibo-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and NBM lesions.

Impaired Visual Search in Rats Reveals Cholinergic Contributions to Feature Binding in Visuospatial Attention

The visual search task established the feature integration theory of attention in humans and measures visuospatial attentional contributions to feature binding. We recently demonstrated that the neuromodulator acetylcholine (ACh), from the nucleus basalis magnocellularis (NBM), supports the attentional processes required for feature binding using a rat digging-based task. Additional research has demonstrated cholinergic contributions from the NBM to visuospatial attention in rats. Here, we combined these lines of evidence and employed visual search in rats to examine whether cortical cholinergic input supports visuospatial attention specifically for feature binding. We trained 18 male Long-Evans rats to perform visual search using touch screen-equipped operant chambers. Sessions comprised Feature Search (no feature binding required) and Conjunctive Search (feature binding required) trials using multiple stimulus set sizes. Following acquisition of visual search, 8 rats received bilateral NBM lesions using 192 IgG-saporin to selectively reduce cholinergic afferentation of the neocortex, which we hypothesized would selectively disrupt the visuospatial attentional processes needed for efficient conjunctive visual search. As expected, relative to sham-lesioned rats, ACh-NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive Search, but not Feature Search trials, thus demonstrating that cholinergic contributions to visuospatial attention are important for feature binding in rats.

Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

Amyloid-β (Aβ) is toxic to neurons and such toxicity is – at least in part – mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. The present study reveals that inhibition of calpain is also neuroprotective in an in vivo model of Aβ oligomer-induced neurodegeneration in rats. Aβ-induced lesions of the nucleus basalis induced a significant decrease in the number of cholinergic neurons and their projecting fibers, as determined by analysis of choline-acetyltransferase in the nucleus basalis magnocellularis and cortical mantle of the lesioned animals. Treatment with the calpain inhibitor A-705253 significantly attenuated cholinergic neurodegeneration in a dose-dependent manner. Calpain inhibition also significantly diminished the accompanying neuroinflammatory response, as determined by immunohistochemical analysis of microglia activation. Administration of β-amyloid markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dose-dependently prevented this behavioral deficit. In order to determine whether pre-treatment with the calpain inhibitor is necessary to exhibit its full protective effect on neurons we induced Aβ toxicity in primary neuronal cultures and administered A-705253 at various time points before and after Aβ oligomer application. Although the protective effect was higher when A-705253 was applied before induction of Aβ toxicity, calpain inhibition was still beneficial when applied up to 1 h post-treatment. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of Aβ oligomer-induced neuronal decline and associated cognitive deterioration.

Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses

Cholinergic innervation of hippocampus and cortex is required for some forms of learning and memory. Several reports have shown that activation of muscarinic m1 receptors induces a long-term depression (mLTD) at glutamate synapses in hippocampus and in several areas of cortex, including perirhinal and visual cortices. This plasticity likely contributes to cognitive function dependent upon the cholinergic system. In rodent models, degeneration of hippocampal cholinergic innervation following lesion of the medial septum stimulates sprouting of adrenergic sympathetic axons, originating from the superior cervical ganglia (SCG), into denervated hippocampal subfields. We previously reported that this adrenergic sympathetic sprouting occurs simultaneously with a reappearance of cholinergic fibers in hippocampus and rescue of mLTD at CA3-CA1 synapses. Because cholinergic neurons throughout basal forebrain degenerate in aging and Alzheimer's disease, it is critical to determine if this compensatory sprouting occurs in other regions impacted by cholinergic cell loss. To this end, we investigated whether lesion of the nucleus basalis magnocellularis (NbM) to cholinergically denervate cortex stimulates adrenergic sympathetic sprouting and the accompanying increase in cholinergic innervation. Further, we assessed whether the presence of sprouting positively correlates with the ability of glutamate synapses in acute visual cortex slices to express mLTD and low frequency stimulation induced LTD (LFS LTD), another cholinergic dependent form of plasticity in visual cortex. We found that both mLTD and LFS LTD are absent in animals when NbM lesion is combined with bilateral removal of the SCG to prevent possible compensatory sprouting. In contrast, when the SCG remain intact to permit sprouting in animals with NbM lesion, cholinergic fiber density is increased concurrently with adrenergic sympathetic sprouting, and mLTD and LFS LTD are preserved. Our findings suggest that autonomic compensation for central cholinergic degeneration is not specific to hippocampus, but is a general repair mechanism occurring in other brain regions important for normal cognitive function.

Lovastatin improves neurological outcome after nucleus basalis magnocellularis lesion in rats

Increasing evidence indicates that statins, specific inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, exerts neuroprotective actions rather than simply lowering cholesterol. However, the underlying mechanism has not been elucidated clearly. Here, the effect of lovastatin on the neurological outcomes of nucleus basalis magnocellularis (NBM)-lesioned rats and the pathophysiological mechanisms were investigated. Sprague–Dawley rats were divided into three groups: (i) a sham group; (ii) a model group: bilateral NBM of rats were injured by infusion of ibotenic acid; and (iii) a lovastatin-treated group: lovastatin was administrated orally for 4 weeks before treated by ibotenic acid. We show that lovastatin significantly improves the neurological outcomes as well as the choline acetyltransferase (ChAT) activity and muscarinic/NMDA receptor binding activity impaired by NBM lesion, and that lovastatin prevents neuron loss and induces Akt whereas inhibits p38 phosphorylation. Overall, the neuro-restorative and -protective effect of lovastatin may be attributed to the regulation of Akt- and p38-mediated signaling pathway together with improvement of muscarinic/NMDA receptor functions. Statins may be useful in the treatment of neurological disorders.

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium-dependent cysteine protease, has been identified as part of such an NMDA receptor-induced excitotoxic signaling pathway. The present study addressed the question of whether inhibition of calpain can prevent neuronal cell death and associated behavioral deficits in a disease-relevant animal model, which is based on excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. Excitotoxic lesions of the nucleus basalis with NMDA induced a markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethlyaminomethylphenyl) ethen-1-yl]benzamide (A-705253), dose-dependently prevented the behavioral deficit. Subsequent analysis of choline acetyltransferase in the cortical mantle of the lesioned animals revealed that application of A-705253 dose-dependently and significantly attenuated cholinergic neurodegeneration. Calpain inhibition also significantly diminished the accompanying gliosis, as determined by immunohistochemical analysis of microglia activation. Finally, inhibition of calpain by A-705253 and the peptidic calpain inhibitor N-acetyl-Leu-Leu-Nle-CHO did not impair long-term potentiation in hippocampal slices, indicating that calpain inhibition interrupts NMDA excitotoxicity pathways without interfering with NMDA receptor-mediated signaling involved in cognition. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of excitotoxicity-induced neuronal decline without interfering with the physiological neuronal functions associated with learning and memory processes. Thus, calpain inhibition may be a promising and novel approach for the treatment of various neurodegenerative disorders.

Aging, Aluminium and Basal Forebrain Lesions Modify Substrate Kinetics of Erythrocyte Membrane Na,K-ATPase in the Rat

Several studies suggested that the activity of erythrocyte Na,K-ATPase declines with aging. Here, it is postulated that alterations in the substrate kinetics of the erythrocyte membrane Na,K-ATPase could be more aggravated in conditions of brain cholinergic dysfunction seen in Alzheimer's disease than in normal aging. To test this hypothesis, we compared the Na,K-ATPase activity (Vmax/Km parameters) in aged rats with those in young rats with brain cholinergic dysfunction induced by electrolytic-, kainic acid-lesioned nucleus basalis magnocellularis (NBM) or by intracerebroventricular AlCl_{3} administration. In the above mentioned groups, Vmax values were significantly lower in comparison to the control animals. Furthermore, Km values were significantly higher in animals with electrolytic-induced NBM lesions, AlCl_{3} treated rats and aged animals. However, Km was significantly lower in kainic acid-induced NBM lesions compared to the control group. The Na,K-ATPase catalytic efficiency, estimated by the ratio Vm/Km, decreased as followed: young animals > aged animals > kainic acid lesion > electrolityc lesion > AlCl_{3}. Our data suggest that neurodegenerative processes similar to those seen in Alzheimer's disease affect the sodium/potassium pump functionality which might be detected in peripheral blood erythrocyte membranes.

Choline pivaloyl ester enhances brain expression of both nerve growth factor and high-affinity receptor TrkA, and reverses memory and cognitive deficits, in rats with excitotoxic lesion of nucleus basalis magnocellularis

The aim of present work was the evaluation of the effects on brain levels of nerve growth factor (NGF) and of its high-affinity tyrosine kinase A receptor (TrkA), induced in rats unilaterally lesioned at nucleus basalis magnocellularis (NBM), by treatment with choline pivaloyl ester (CPE). CPE was daily administered (60 μmol/Kg ip) during 3 weeks to rats selectively lesioned by AMPA infusion into right NBM; the intact left NBM serving as control. NGF levels were determined in cerebral cortex and hippocampus by Elisa assay. TrkA receptor expression was evaluated in right NBM by Western blotting analysis. CPE treatment significantly increased NGF levels in both hippocampus and neocortex in right NBM, compared with intact left counter-part and controls. Western blotting showed an evident enhancement in TrkA receptor expression in lesioned right NBM in comparison with intact left counter-part and controls. CPE treatment was also able to restore, in bilaterally NBM-lesioned rats, the disrupted cortical EEG and HVS activities as well as to reverse deficits in learning and memory in spatial navigation and probe trials, and cognitive capacities in object recognition task.

Selective cholinergic lesions in the rat nucleus basalis magnocellularis with limited damage in the medial septum specifically alter attention performance in the five-choice serial reaction time task

Selective immunotoxic cholinergic lesions in the nucleus basalis magnocellularis (NBM) impair visuospatial attention performance in a 5-choice serial reaction time task (5-CSRT task). The features of the reported deficits, however, do not perfectly match among studies, in which some lesions may have been too weak while others largely encroached onto the septal region. Using the 5-CSRT task, we therefore re-assessed the effects of NBM lesions that produced minimal septal damage. Long-Evans adult male rats were trained to stable 5-CSRT task performance (stimulus duration: 0.5 s) and subsequently subjected to intra-NBM injections of 192 IgG-saporin (200 ng/side). The lesions induced more than 90% loss of choline acetyltransferase–positive neurons in the NBM vs. only 28% in the medial septum. The decrease of the optical density of acetylcholinesterase reaction products was significant in the cortex (−91%), not in the hippocampus. In the 5-CSRT task, the lesions resulted in increased omissions (from 10% to 30%) and decreased correct responses (from 80% to 60%), with negligible or no effects on all other usually collected variables. This deficit disappeared with lengthened stimulus duration (i.e. 0.5–1 and then 5 s). Furthermore, overall performance levels decreased when the stimulus duration was shortened (i.e. 0.5–0.2 s) or its intensity attenuated, and rats with cholinergic lesions remained consistently impaired vs. controls. These results show that disruption of sustained visual attention functions by damage to the NBM cholinergic neurons can be evidenced despite weak or no effects on variables accounting for motivational, locomotion- or impulsivity-related biases. Discrepancies with previously reported results are discussed in terms of differences in lesion extent/specificity and training levels.