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Traumatic brain injury (TBI) is one of the most common causes of neurological disability in young and middle-aged people. Cognitive impairment is the most persistent and universal brain injury syndrome in cases of TBI and, moreover, the best indicator of TBI severity to predict its outcome. Cognitive impairment can persist persistently even after mild TBI, which accounts for 70–90 % of the total number of trauma patients. This may be due to the fact that in cases of mild TBI, the most fragile functions of integrative structures of the frontal and temporal lobes are slowly and not always completely recovered and the dominant clinical manifestation become complex neuropsychological disorders. Individuals with repeated mild TBI are characterized by development of chronic post-traumatic encephalopathy, that is a kind of neurodegenerative disease manifested by slowly increasing cognitive impairment, parkinsonism and a number of other neurological syndromes. Early detection and adequate correction of the cognitive impairments may improve the outcome of injury of diverging severity. Due to the fact that the pathogenesis of TBI is based on disorder of cholinergic system, the patients have predominance of regulatory disorders in the neuropsychological profile, as well as a combination of cognitive and affective disorders. Administration of acetylcholine precursors leads to rapid increase of free choline levels in plasma that penetrates the blood-brain barrier well and enhances cholinergic activity by increasing acetylcholine synthesis and release. The article considers the possibilities of using acetylcholine precursors in connection with their potential to block the progressive impairment of cognitive functions induced by trauma as well as to reduce severity of behavioral and affective disorders.

Anorexia is a behavioral change caused by functional brain disorders in patients with Alzheimer's disease (AD). Amyloid-β (1–42) oligomers (o-Aβ) are possible causative agents of AD that impair signaling via synaptic dysfunction. In this study, we used Aplysia kurodai to study functional disorders of the brain through o-Aβ. Administration of o-Aβ to the buccal ganglia (feeding brain for oral movements) by surgical treatment significantly reduced food intake for at least five days. Furthermore, we explored the effects of o-Aβ on the synaptic function in the feeding neural circuit, focusing on a specific inhibitory synaptic response in jaw-closing motor neurons produced by cholinergic buccal multi-action neurons because we recently found that this cholinergic response decreases with aging, which is consistent with the cholinergic hypothesis for aging. Administration of o-Aβ to the buccal ganglia significantly reduced the synaptic response within minutes, whereas administration of amyloid-β (1–42) monomers did not. These results suggest that o-Aβ may impair the cholinergic synapses, even in Aplysia , which is consistent with the cholinergic hypothesis for AD. • Amyloid-β oligomers (o-Aβ) were administrated to Aplysia buccal ganglia by surgery. • Administration reduced the food intake similar to anorexia in Alzheimer's disease. • Effect of o-Aβ on the feeding neural circuits within the ganglia was also explored. • Administration reduced a specific inhibitory cholinergic synaptic response. • The present results are consistent with the cholinergic hypothesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is one of the leading causes of dementia today. This neurodegenerative disorder results in the progressive decline of cognitive ability and memory. The biochemical processes that characterize this disease include the formation of β-amyloid plaques, the development of neurofibrillary tangles, and the loss of cholinergic neurons in the cerebral cortex. In fact, most of the drugs available to deal with this disease are directed at the affectations suffered by diseased individuals in the cholinergic synapse of the Central Nervous System. It is for this reason that the development of drugs directed to therapeutic targets that allow increasing the availability of acetylcholine in the cholinergic synapse is a field of research of great interest. However, success in the clinical use of these compounds is limited by the side effects they produce and by the multifactorial nature of this disease. The present review aims to provide an overview of the cholinergic dysfunction observed in Alzheimer's disease patients that supports the cholinergic hypothesis in its pathophysiology. In addition, cholinesterase activity inhibitors of clinical and innovative use are discussed as an alternative symptomatic therapy for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase/Butyrylcholinesterase inhibitors are considered an effective method for treating Alzheimer's disease (AD). In this current work, we have computationally analyzed 11 new small molecule drugs used in various neurological diseases and Donepezil, a known inhibitor of acetylcholinesterase, as a positive control. We investigated these drugs for possible fundamental interactions with acetylcholinesterase and butyrylcholinesterase as both are critical in the pathophysiology of Alzheimer's disease. We have selected FDA approved compounds for repurposing as possible inhibitors of these enzymes and novel therapeutic option for Alzheimer's disease. We selected the top two molecules for each protein for their binding energies, interactions, and Donepezil, the most commonly used drug for AD treatment. Molecular simulation and dynamics studies of the top 2 drugs in each case and free energy analysis helped us reach further conclusions about the best possible drugs for repurposing. Brexipirazole and Deutetrabenazine produce encouraging results as butyrylcholinesterase and acetylcholinesterase inhibitors, respectively. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of senile dementia and one of the greatest medical, social, and economic challenges. According to a dominant theory, amyloid-β (Aβ) peptide is a key AD pathogenic factor. Aβ-soluble species interfere with synaptic functions, aggregate gradually, form plaques, and trigger neurodegeneration. The AD-associated pathology affects numerous systems, though the substantial loss of cholinergic neurons and α7 nicotinic receptors (α7AChR) is critical for the gradual cognitive decline. Aβ binds to α7AChR under various experimental settings; nevertheless, the functional significance of this interaction is ambiguous. Whereas the capability of low Aβ concentrations to activate α7AChR is functionally beneficial, extensive brain exposure to high Aβ concentrations diminishes α7AChR activity, contributes to the cholinergic deficits that characterize AD. Aβ and snake α-neurotoxins competitively bind to α7AChR. Accordingly, we designed a chemically modified α-cobratoxin (mToxin) to inhibit the interaction between Aβ and α7AChR. Subsequently, we examined mToxin in a set of original in silico, in vitro, ex vivo experiments, and in a murine AD model. We report that mToxin reversibly inhibits α7AChR, though it attenuates Aβ-induced synaptic transmission abnormalities, and upregulates pathways supporting long-term potentiation and reducing apoptosis. Remarkably, mToxin demonstrates no toxicity in brain slices and mice. Moreover, its chronic intracerebroventricular administration improves memory in AD-model animals. Our results point to unique mToxin neuroprotective properties, which might be tailored for the treatment of AD. Our methodology bridges the gaps in understanding Aβ-α7AChR interaction and represents a promising direction for further investigations and clinical development. [ABSTRACT FROM AUTHOR]

Alzheimer's disease [AD] is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and functional impairment. Despite extensive research, the exact etiology remains elusive. This review explores the multifaceted pathophysiology of AD, focusing on key hypotheses such as the cholinergic hypothesis, hyperphosphorylated Tau Protein and Amyloid β hypothesis, oxidative stress hypothesis, and the metal ion hypothesis. Understanding these mechanisms is crucial for developing effective therapeutic strategies. Current treatment options for AD have limitations, prompting the exploration of alternative approaches, including herbal interventions. Cholinesterase inhibitors, targeting the cholinergic hypothesis, have shown modest efficacy in managing symptoms. Blocking Amyloid β [Aβ] and targeting hyperphosphorylated tau protein are under investigation, with limited success in clinical trials. Oxidative stress, implicated in AD pathology, has led to the investigation of antioxidants. Natural products, such as Punica granatum Linn, Radix Scutellariae, and Curcuma longa have demonstrated antioxidant properties, along with anti-inflammatory effects, offering potential neuroprotective benefits. Several herbal extracts, including Ginkgo biloba, Bacopa monnieri, and Withania somnifera, have shown promise in preclinical studies. Compounds like Huperzine A, Melatonin, and Bryostatin exhibit neuroprotective effects through various mechanisms, including cholinergic modulation and anti-inflammatory properties. However, the use of herbal drugs for AD management faces limitations, including standardization issues, variable bioavailability, and potential interactions with conventional medications. Additionally, the efficacy and safety of many herbal products remain to be established through rigorous clinical trials. This review also highlights promising natural products currently in clinical trials, such as Resveratrol and Homotaurine, and their potential impact on AD progression. DHA, an omega-3 fatty acid, has shown cognitive benefits, while Nicotine is being explored for its neuroprotective effects. In conclusion, a comprehensive understanding of the complex pathophysiology of AD and the exploration of herbal interventions offer a holistic approach to managing this devastating disease. Future research should address the limitations associated with herbal drugs and further evaluate the efficacy of promising natural products in clinical settings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: This study aimed at evaluating the cholinergic hypothesis in Alzheimer's disease (AD) patients utilizing the pupillometry method, cognitive tests and Hamilton Depression Rating Scale (HAM-D), as well as to examine whether a correlation between cognitive tests and pupillometry exists. Methods: Forty-two patients with mean age 69.2 ± 7.0 years and documented AD volunteered to participate in this study, while 33 healthy matched subjects served as controls. All subjects underwent a pupillometric measurement and performed the Wechsler Memory Scale (WMS) and Mini Mental State Examination (MMSE). Also, HAM-D was used to assess the severity of depressive symptoms. The pupillometric parameters studied were (1) latency for the onset of constriction (T1), (2) maximum constriction velocity (VCmax), and (3) maximum constriction acceleration (ACmax). Results: In AD patients MMSE and WMS score were correlated with ACmax ( r = −0.409, p < 0.05 and r = −0.513, p < 0.05, respectively) and VCmax ( r = −0.664, p < 0.05 and r = −0.771, p < 0.05), respectively. Moreover, T1 was found to be significantly increased by 23 % ( p < 0.05) in AD patients compared to healthy subjects. Conversely, the mean scores of VCmax and ACmax were significantly decreased in AD patients by 46 % ( p < 0.05) and by 47 % ( p < 0.05), respectively, as compared to healthy subjects. There was no significant difference between the two groups for HAM-D. Additionally, AD patients showed decreased score in WMS by 40 % ( p < 0.05) and in MMSE by 28.5 % ( p < 0.05) compared to healthy subjects. Of the indices that were studied VCmax and ACmax are governed mainly by the action of the Parasympathetic Nervous System. Conclusions: The results of this study demonstrated that there is a correlation between cognitive tests and pupillometry in AD patients. Thus, pupillometry could be considered as a sensitive technique for the investigation of cholinergic deficits, which indirectly lead to memory and cognitive disorders in AD patients. [ABSTRACT FROM AUTHOR]

The overarching goal of this event-related potential (ERP) study was to examine the effects of scopolamine on the dynamics of brain network activation using a novel ERP network analysis method known as Brain Network Activation (BNA). BNA was used for extracting group-common stimulus-activated network patterns elicited to matching probe stimuli in the context of a delayed matching-to-sample task following placebo and scopolamine treatments administered to healthy participants. The BNA extracted networks revealed the existence of two pathophysiological mechanisms following scopolamine, disconnection, and compensation. Specifically, weaker frontal theta and parietal alpha coupling was accompanied with enhanced fronto-centro-parietal theta activation relative to placebo. In addition, using the characteristic BNA network of each treatment as well as corresponding literature-guided selective subnetworks as combined biomarkers managed to differentiate between individual responses to each of the treatments. Behavioral effects associated with scopolamine included delayed response time and impaired response accuracy. These results indicate that the BNA method is sensitive to the effects of scopolamine on working memory and that it may potentially enable diagnosis and treatment assessment of dysfunctions associated with cholinergic deficiency. [ABSTRACT FROM AUTHOR]

Abstract: The perceptual differentiation of odors can be measured behaviorally using generalization gradients. The steepness of these gradients defines a form of olfactory acuity for odor quality that depends on neural circuitry within the olfactory bulb and is regulated by cholinergic activity therein as well as by associative learning. Using this system as a reduced model for age-related cognitive decline, we show that aged mice, while maintaining almost the same baseline behavioral performance as younger mice, are insensitive to the effects of acutely elevated acetylcholine, which sharpens generalization gradients in young adult mice. Moreover, older mice exhibit evidence of chronically elevated acetylcholine levels in the olfactory bulb, suggesting that their insensitivity to further elevated levels of acetylcholine may arise because the maximum capacity of the system to respond to acetylcholine has already been reached. We propose a model in which an underlying, age-related, progressive deficit is mitigated by a compensatory cholinergic feedback loop that acts to retard the behavioral effects of what would otherwise be a substantial age-related decline in olfactory plasticity. We also treated mice with 10-day regimens of olfactory environmental enrichment and/or repeated systemic injections of the acetylcholinesterase inhibitor physostigmine. Each treatment alone sharpened odor quality acuity, but administering both treatments together had no greater effect than either alone. Age was not a significant main effect in this study, suggesting that some capacity for acetylcholine-dependent plasticity is still present in aged mice despite their sharply reduced ability to respond to acute increases in acetylcholine levels. These results suggest a dynamical framework for understanding age-related decline in neural circuit processing in which the direct effects of aging can be mitigated, at least temporarily, by systemic compensatory responses. In particular, a decline in cholinergic efficacy can precede any breakdown in cholinergic production, which may help explain the limited effectiveness of cholinergic replacement therapies in combating cognitive decline. [Copyright &y& Elsevier]

Abstract: Behavioral and psychological symptoms of dementia (BPSD) include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite impairment. These symptoms have adverse consequences for patients and caregivers, such as greater impairment in activities of daily living, worsening quality of life and earlier institutionalization. While the etiology of BPSD has not been clearly delineated, studies assessing the benefits of acetylcholinesterase inhibitors on BPSD suggest that some of the neuropsychiatric symptoms of dementia such as agitation, apathy and psychosis may represent a specific central cholinergic deficiency syndrome. Biochemical and neuroimaging studies of BPSD in Alzheimer''s patients support these pharmacological data. This review discusses the literature describing the association between cholinergic deficiency and manifestations of BPSD. [Copyright &y& Elsevier]

Abstract: Numerous studies have demonstrated cognitive improvements resulting from the application of nicotine, especially in those tasks aimed at measuring attention. While the neuro-pharmacological relationship between nicotine and acetylcholine-driven attentional processes has been examined, studies tend to focus on the duration of time in which a subject can attend to a specific stimulus or series of stimuli rather than on the subjects’ adaptive attentional capabilities. The present study addresses the possibility that the cholinergic agonist nicotine could improve performance on a task testing the ability to shift attention between sensory modalities under both normal and pharmacologically impaired conditions. In a pilot set of experiments, we tested the effects of nicotine in a cross-modal experimental task designed to tax both the auditory and visual systems of male Sprague–Dawley rats. Nicotine (0.2mg/kg) significantly improved performance on both auditory and visual trials, under repetitive trial conditions, and significantly decreased overall response latency. For the primary study, we tested the effects of decreasing cholinergic neurotransmission by systemic administration of the muscarinic antagonist atropine. Atropine (12.5mg/kg) significantly impaired performance in auditory shift trials and perseverative trials, while significantly increasing the overall response latency. We then tested the effect of nicotine within the impaired model. Systemic administration of nicotine significantly improved performance in auditory and visual shift trials, while showing moderate improvements in response latency and perseverative trial conditions. These results indicate the potential therapeutic use of nicotine as a cognitive enhancer, as well as provide evidence for cholinergic system compensations. [Copyright &y& Elsevier]

Testosterone and ten of its metabolites were examined as inhibitors of butyrylcholinesterase. A significant enzyme inhibition activity (IC50 = 1.55 μM) was observed for androst-4-en-3,7-dione. The kinetic parameters of butyrylcholinesterase inhibition were determined and molecular docking was carried out in order to develop a better understanding of the inhibitor-enzyme interactions. The results showed that the inhibition was non-competitive, stabilized mainly by hydrogen bonds and hydrophobic interactions between the inhibitor and butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical–neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review. A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer’s disease (AD) but for many other disorders involving cognitive deficits. Collectively, our research provided first evidence of the following: aged primates can be used as ‘models’ for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed. Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-β (Aβ) peptide, degeneration of the cholinergic neurons and the development of neurofibrillary tangles. The build-up of Aβ is considered to be a central feature in the pathogenesis of AD. However, other critical molecular and neurochemical alterations too occur, such as a cholinergic dysfunction. As concerns the pathomechanism of the disease, both the amyloid cascade hypothesis and the cholinergic hypothesis of AD are widely accepted. This review surveys recent in vitro and in vivo experimental evidence relating to these two hypotheses. Bidirectional pathways linking them as regards the cholinergic neurotoxicity of Aβ and the regulatory mechanisms of cholinergic receptor activation or enzyme inhibition in the processing of the amyloid precursor protein are also discussed. Further work is warranted to elucidate the exact effects in the interactions between the cholinergic and amyloid hypotheses of the candidate drugs used in AD therapy. [Copyright &y& Elsevier]

The 'cholinergic hypothesis', based on the correlation of the reduction of cholinergic activity in Alzheimer's disease (AD) with cognition and memory, is currently the most widely-held view for AD. Drug treatments for AD focus mainly on inhibition of acetylcholinesterase (AChE), and to some extent butyrylcholinesterase (BChE). In addition to changes in AChE in AD, there is a rise in the level of the sister enzyme BChE. However, the role of the two cholinesterases is poorly understood in vivo. We characterized several proteins immunohistochemically in brain sections from AChE nullizygote (AChE-/-) and wild type AChE+/+ mice. Previous studies had shown that AChE-/- mouse tissues are devoid of AChE activity and that the overall cholinesterase activity is significantly decreased in the knockout group [16]. Despite the differences of cholinesterase activity, we found no significant structural alterations between the experimental groups. Immunohistochemical examination revealed no neuronal, dendritic, astrocytic, synaptic, microglial, and endothelial differences between AChE-/- and AChE+/+ mice. Similarly, the histochemical examination showed no morphologic alterations between AChE-/- and AChE+/+ mice. Our studies show that neither the absence of AChE nor the presence exclusively of BChE is associated with neuroglial and vascular pathology. [ABSTRACT FROM AUTHOR]

The article presents a discussion on the dimensions of the concept of Alzheimer's disease (AD) as a natural disease discerned by sophisticated medical scientific progress. It uses the views of Max Weber in questioning the empirical status of Alzheimer's disease (AD) and its prodromal derivative, mild cognitive impairment (MCI).

Presents a study which discussed the symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Definition of Alzheimer's disease; Effect of the treatment in the wild-type animals; Results of the study.

Summary. The cholinergic hypothesis of Alzheimer's disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-I), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimer's disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-I's. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable Pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function. The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders. [ABSTRACT FROM AUTHOR]

The cholinergic hypothesis states that cholinergic neurons of the basal forebrain nucleus basalis magnocellularis (nbm) that project to cortical and amy-gdalar targets play an important role in memory. Biochemical studies have shown that these target areas are differentially sensitive to different excitotoxins (e.g., ibotenate vs. quisqualate). This observation might explain the finding from many behavioural studies of memory that different excito-toxins affect memory differentially even though they produce about the same level of depletion of cholinergic markers in the cortex and similar cortical electrophysiological effects. Thus, the magnitude of mnemonic impairment might be related to the extent of damage to cholinergic projections to the amygdala more than to the extent of damage to corticopetal cholinergic projections. This explanation might similarly apply to the observation that the immunotoxin 192 IgG-saporin produces mild effects on memory when injected into the nbm. This is because it damages cholinergic neurons projecting to the cortex but not those projecting to the amygdala. Studies comparing the effects on memory of ibotenic acid vs. quisqualic acid lesions of the nbm are reviewed as are studies of the mnemonic effects of 192 IgG-saporin. Results support the cholinergic hypothesis and suggest that amygdalopetal cholinergic neurons of the nbm play an important role in the control of memory. [ABSTRACT FROM AUTHOR]