Article

Cholinergic modulation of the hippocampus during encoding and retrieval

December 2003
Neurobiology of Learning and Memory 80(3):332-42

December 2003
80(3):332-42

DOI:10.1016/S1074-7427(03)00063-7

Source
PubMed

Authors:

Jason Rogers

Noldus Information Technology

Raymond P Kesner

University of Utah

The present experiments were aimed at determining whether acetylcholine (ACh) plays a role in encoding and retrieval of spatial information using a modified Hebb-Williams maze. In addition, the present experiments tested two computational models of hippocampal function during encoding and retrieval using a maze sensitive to hippocampal disruption. Thirty male, Long-Evans rats served as subjects. Chronic cannulae were implanted bilaterally into the CA3 (n=26) and CA1 (n=5) subregions of the hippocampus. Rats were tested using a modified Hebb-Williams maze. In the first experiment, rats were injected with either saline or scopolamine hydrobromide 10 min before testing for each day. The number of errors made per day per group was used as the measure of learning. Encoding was assessed by the average number of errors made on the first five trials of Day 1 compared to the last five trials of Day 1, whereas the average number of errors made on the first five trials of Day 2 compared to the last five trials of Day I was used to assess retrieval. No deficit was found for the saline group. The scopolamine group showed a deficit in encoding, but not retrieval. In the second experiment, rats were injected with either saline or physostigmine 10 min before testing each day. In contrast to the scopolamine groups, the physostigmine group showed a deficit in retrieval, but not encoding. To test whether the retrieval deficit was due to a disruption in storage or gaining access to the information two groups of rats received either saline on Day 1 and physostigmine on Day 2 or physostigmine on Day 1 and saline on Day 2. In addition, one group received physostigmine immediately after testing on Day 1. Data indicate that physostigmine causes a disruption of retrieval by means of a disruption in consolidation process. In conclusion, the cholinergic antagonist, scopolamine, disrupts encoding in both CA3 and CA1 subregions of the hippocampus. Furthermore, the cholinesterase inhibitor, physostigmine, boosts ACh action during a time when cholinergic levels need to decline for proper consolidation.

Deleterious and protective effects of epothilone-D alone and in the context of amyloid β- and tau-induced alterations

Article

Full-text available

Oct 2023

Amyloid-β (Aβ) and hyperphosphorylated tau (P-tau) are Alzheimer’s disease (AD) biomarkers that interact in a complex manner to induce most of the cognitive and brain alterations observed in this disease. Since the neuronal cytoskeleton is a common downstream pathological target of tau and Aβ, which mostly lead to augmented microtubule instability, the administration of microtubule stabilizing agents (MSAs) can protect against their pathological actions. However, the effectiveness of MSAs is still uncertain due to their state-dependent negative effects; thus, evaluating their specific actions in different pathological or physiological conditions is required. We evaluated whether epothilone-D (Epo-D), a clinically used MSA, rescues from the functional and behavioral alterations produced by intracerebroventricular injection of Aβ, the presence of P-tau, or their combination in rTg4510 mice. We also explored the side effects of Epo-D. To do so, we evaluated hippocampal-dependent spatial memory with the Hebb–Williams maze, hippocampal CA1 integrity and the intrinsic and synaptic properties of CA1 pyramidal neurons with the patch-clamp technique. Aβ and P-tau mildly impaired memory retrieval, but produced contrasting effects on intrinsic excitability. When Aβ and P-tau were combined, the alterations in excitability and spatial reversal learning (i.e., cognitive flexibility) were exacerbated. Interestingly, Epo-D prevented most of the impairments induced Aβ and P-tau alone and combined. However, Epo-D also exhibited some side effects depending on the prevailing pathological or physiological condition, which should be considered in future preclinical and translational studies. Although we did not perform extensive histopathological evaluations or measured microtubule stability, our findings show that MSAs can rescue the consequences of AD-like conditions but otherwise be harmful if administered at a prodromal stage of the disease.

Abnormal innate and learned behavior induced by neuron–microglia miscommunication is related to CA3 reconfiguration

Article

May 2022

Neuron-microglia communication through the Cx3cr1-Cx3cl1 axis is essential for the development and refinement of neural circuits, which determine their function into adulthood. In the present work we set out to extend the behavioral characterization of Cx3cr1-/- mice evaluating innate behaviors and spatial navigation, both dependent on hippocampal function. Our results show that Cx3cr1-deficient mice, which show some changes in microglial and synaptic terminals morphology and density, exhibit alterations in activities of daily living and in the rapid encoding of novel spatial information that, nonetheless, improves with training. A neural substrate for these cognitive deficiencies was found in the form of synaptic dysfunction in the CA3 region of the hippocampus, with a marked impact on the mossy fiber (MF) pathway. A network analysis of the CA3 microcircuit reveals the effect of these synaptic alterations on the functional connectivity among CA3 neurons with diminished strength and topological reorganization in Cx3cr1-deficient mice. Neonatal population activity of the CA3 region in Cx3cr1-deficient mice shows a marked reorganization around the giant depolarizing potentials, the first form of network-driven activity of the hippocampus, suggesting that alterations found in adult subjects arise early on in postnatal development, a critical period of microglia-dependent neural circuit refinement. Our results show that interruption of the Cx3cr1-Cx3cl1/neuron-microglia axis leads to changes in CA3 configuration that affect innate and learned behaviors.

Effects of nicotine on implicit and explicit memory

Article

Full-text available

Jan 2018
Acta Psychol Sin

Scopolamine does not Impact Declarative and Motor Memory Consolidation Across a Night of Sleep or a Day of Wakefulness

Article

Aug 2018

Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons

Article

Full-text available

Feb 2018

Significance Memory formation is a complex process that involves information transfer to the hippocampus for temporary storage (i.e., encoding) and the reciprocal circuit that relays the temporary information back to the neocortex for long-term storage (i.e., consolidation). Acetylcholine has been shown to play a critical role in memory function by differentially modulating encoding and consolidation, but the underlying mechanism is yet unclear. We found that acetylcholine suppresses the hippocampus–entorhinal cortex pathway, which is the gateway to the consolidation pathway. We show that this inhibition is mediated by oriens lacunosum moleculare interneurons and that the ablation of these interneurons impairs proper memory encoding. We provide evidence that demonstrates how acetylcholine tones down the memory consolidation pathway for efficient memory encoding.

Cholinergic modulation of the hippocampal region and memory function

Article

Aug 2017

Acetylcholine ( AC h) plays an important role in memory function and has been implicated in aging‐related dementia, in which the impairment of hippocampus‐dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus‐dependent learning, and the circuits involved. In addition, we will discuss the complexity of AC h actions in memory function to better understand the physiological role of AC h in memory. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms . image

Muscarinic and N‐methyl‐D‐aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone

Article

Aug 2022

We hypothesize that hippocampal local field potentials in acetylcholine (ACh)‐deficient mutant mice, compared to wild‐type (WT) mice, will show lower sensitivity to muscarinic cholinergic antagonist scopolamine (5 mg/kg i.p.) but higher sensitivity to NMDA receptor antagonist 3‐(2‐carboxypiperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP, 10 mg/kg i.p.). Recordings were made during walk and awake‐immobility (IMM) in WT mice, and in mice with forebrain knockout (KO) of the vesicular acetylcholine transporter (VAChT) gene, or heterozygous knockdown of VAChT gene (KD). Scopolamine or CPP did not significantly alter walk theta frequency, which was higher in KD than WT/KO mice. Scopolamine decreased theta power peak rise during walk in WT/KD mice but not in KO mice, while CPP suppressed theta peak rise more in WT/KO mice than KD mice. During IMM, scopolamine decreased gamma1 (γ1, 30–58 Hz) power more in KD/WT mice than KO mice, while delta (1–4 Hz) power and delta‐gamma cross‐frequency coherence (CFC) were increased in all mouse groups during IMM or walk. During walk, scopolamine increased delta and beta (13–30 Hz) power and decreased gamma2 (γ2, 62–100 Hz) power and theta‐γ2 CFC more in WT/KD than KO mice. Theta‐γ2, but not theta‐γ1, CFC increased with theta‐peak‐frequency in WT/KD mice, and was suppressed by scopolamine at high theta (8–10 Hz) frequency; theta‐γ2 CFC in KO mice was not significantly altered by scopolamine. CPP decreased beta and gamma power more in KD/KO mice compared to WT mice, while delta power and delta‐gamma CFC were increased in all mouse groups. ACh deficiency exacerbates the attenuation of beta and gamma power by CPP. We conclude that both muscarinic and NMDA transmission contribute toward hippocampal theta, beta, and gamma power, and a decrease in gamma power or theta‐gamma CFC may be associated with loss of arousal and cognitive functions.

A synaptic signal for novelty processing in the hippocampus

Article

Full-text available

Jul 2022

Episodic memory formation and recall are complementary processes that rely on opposing neuronal computations in the hippocampus. How this conflict is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarisation upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the synaptic response to novelty may bias granule cell population activity, which can drive downstream attractor networks to a new state, favouring the switch from recall to new memory formation when faced with novelty. Such a novelty-driven switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

Circuits for State-Dependent Modulation of Locomotion

Article

Full-text available

Nov 2021
FRONT HUM NEUROSCI

Brain-wide neural circuits enable bi- and quadrupeds to express adaptive locomotor behaviors in a context- and state-dependent manner, e.g., in response to threats or rewards. These behaviors include dynamic transitions between initiation, maintenance and termination of locomotion. Advances within the last decade have revealed an intricate coordination of these individual locomotion phases by complex interaction of multiple brain circuits. This review provides an overview of the neural basis of state-dependent modulation of locomotion initiation, maintenance and termination, with a focus on insights from circuit-centered studies in rodents. The reviewed evidence indicates that a brain-wide network involving excitatory circuit elements connecting cortex, midbrain and medullary areas appears to be the common substrate for the initiation of locomotion across different higher-order states. Specific network elements within motor cortex and the mesencephalic locomotor region drive the initial postural adjustment and the initiation of locomotion. Microcircuits of the basal ganglia, by implementing action-selection computations, trigger goal-directed locomotion. The initiation of locomotion is regulated by neuromodulatory circuits residing in the basal forebrain, the hypothalamus, and medullary regions such as locus coeruleus. The maintenance of locomotion requires the interaction of an even larger neuronal network involving motor, sensory and associative cortical elements, as well as defined circuits within the superior colliculus, the cerebellum, the periaqueductal gray, the mesencephalic locomotor region and the medullary reticular formation. Finally, locomotor arrest as an important component of defensive emotional states, such as acute anxiety, is mediated via a network of survival circuits involving hypothalamus, amygdala, periaqueductal gray and medullary premotor centers. By moving beyond the organizational principle of functional brain regions, this review promotes a circuit-centered perspective of locomotor regulation by higher-order states, and emphasizes the importance of individual network elements such as cell types and projection pathways. The realization that dysfunction within smaller, identifiable circuit elements can affect the larger network function supports more mechanistic and targeted therapeutic intervention in the treatment of motor network disorders.

Activation of cholinergic system partially rescues olfactory dysfunction-induced learning and memory deficit in mice

Article

Apr 2021
BEHAV BRAIN RES

Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer’s disease. A recent study reported that intranasal zinc sulfate (ZnSO4)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO4-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO4-induced learning and memory deficits. We found that intranasal ZnSO4-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO4, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO4 decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO4-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.

Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications

Article

Apr 2023
EUR J NEUROSCI

Deficits in hippocampus-dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety, and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via activation of hypothalamic-pituitary adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation, and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signaling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress-related disorders. We argue that such efforts should consider recent conceptualizations on the dynamic nature of cholinergic signaling in modulating distinct subcomponents of memory, and its interactions with cellular substrates that regulate the adaptive stress response.

Effect of sulfonamide derivatives of phenylglycine on scopolamine‐induced amnesia in rats

Article

Full-text available

Feb 2023

Alzheimer's disease is a neurodegenerative disease responsible for dementia and other neuropsychiatric symptoms. In the present study, compounds 30 and 33, developed earlier in our laboratory as selective butyrylcholinesterase inhibitors, were tested against scopolamine‐induced amnesia to evaluate their pharmacodynamic effect. The efficacy of the compounds was determined by behavioral experiments using the Y‐maze and the Barnes maze and neurochemical testing. Both compounds reduced the effect of scopolamine treatment in the behavioral tasks at a dose of 20 mg/kg. The results of the neurochemical experiment indicated a reduction in cholinesterase activity in the prefrontal cortex and the hippocampus. The levels of antioxidant enzymes superoxide dismutase and catalase were restored compared to the scopolamine‐treated groups. The docking study on rat butyrylcholinesterase (BChE) indicated tight binding, with free energies of −9.66 and −10.23 kcal/mol for compounds 30 and 33, respectively. The two aromatic amide derivatives of 2‐phenyl‐2‐(phenylsulfonamido) acetic acid produced stable complexes with rat BChE in the molecular dynamics investigation. In scopolamine‐induced amnestic rats, the sulfonamide‐based compounds, butyrylcholinesterase (BChE) inhibitors, led to improved alteration and novel arm entries in the Y maze, and improved latency time and reduced errors in the Barnes maze task. Neurochemical analysis showed inhibition of cholinesterase activity in the rat brain. The in silico analysis showed stable BChE inhibition with the use of the test compounds.

Temporal dynamics of cholinergic activity in the septo-hippocampal system

Article

Full-text available

Aug 2022

Cholinergic projection neurons in the medial septum and diagonal band of Broca are the major source of cholinergic modulation of hippocampal circuit functions that support neural coding of location and running speed. Changes in cholinergic modulation are known to correlate with changes in brain states, cognitive functions, and behavior. However, whether cholinergic modulation can change fast enough to serve as a potential speed signal in hippocampal and parahippocampal cortices and whether the temporal dynamics in such a signal depend on the presence of visual cues remain unknown. In this study, we use a fiber-photometric approach to quantify the temporal dynamics of cholinergic activity in freely moving mice as a function of the animal’s movement speed and visual cues. We show that the population activity of cholinergic neurons in the medial septum and diagonal band of Broca changes fast enough to be aligned well with changes in the animal’s running speed and is strongly and linearly correlated to the logarithm of the animal’s running speed. Intriguingly, the cholinergic modulation remains strongly and linearly correlated to the speed of the animal’s neck movements during periods of stationary activity. Furthermore, we show that cholinergic modulation is unaltered during darkness. Lastly, we identify rearing, a stereotypic behavior where the mouse stands on its hindlimbs to scan the environment from an elevated perspective, is associated with higher cholinergic activity than expected from neck movements on the horizontal plane alone. Taken together, these data show that temporal dynamics in the cholinergic modulation of hippocampal circuits are fast enough to provide a potential running speed signal in real-time. Moreover, the data show that cholinergic modulation is primarily a function of the logarithm of the animal’s movement speed, both during locomotion and during stationary activity, with no significant interaction with visual inputs. These data advance our understanding of temporal dynamics in cholinergic modulation of hippocampal circuits and their functions in the context of neural coding of location and running speed.

Cholinergic Regulation of Hippocampal Theta Rhythm

Article

Full-text available

Mar 2022

Cholinergic regulation of hippocampal theta rhythm has been proposed as one of the central mechanisms underlying hippocampal functions including spatial memory encoding. However, cholinergic transmission has been traditionally associated with atropine-sensitive type II hippocampal theta oscillations that occur during alert immobility or in urethane-anesthetized animals. The role of cholinergic regulation of type I theta oscillations in behaving animals is much less clear. Recent studies strongly suggest that both cholinergic muscarinic and nicotinic receptors do actively regulate type I hippocampal theta oscillations and thus provide the cholinergic mechanism for theta-associated hippocampal learning. Septal cholinergic activation can regulate hippocampal circuit and theta expression either through direct septohippocampal cholinergic projections, or through septal glutamatergic and GABAergic neurons, that can precisely entrain hippocampal theta rhythmicity.

Presynaptic Inhibitory Effects of Acetylcholine in the Hippocampus: A 40-Year Evolution of a Serendipitous Finding

Article

Full-text available

Apr 2021

Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980's we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons to dendrites of CA1 pyramidal cells. We characterized this effect at cellular and pharmacological levels, published the findings in the first volume of the Journal of Neuroscience and proceeded to pursue other scientific directions. We were surprised and thrilled to see that nearly 40 years later, the paper is still being cited and downloaded because the data became an integral piece of the foundation of the science of cholinergic regulation of hippocampal function in learning and memory. This Progressions article is a story of how single laboratory findings evolve through time to be confirmed, challenged and reinterpreted by other laboratories to eventually become part of the basis of fundamental concepts related to important brain functions.

Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model

Preprint

Full-text available

Mar 2021

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca ²⁺ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of acetylcholine on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca ²⁺ -activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles. Highlights - Using biophysical computational models of CA3 pyramidal neurons we estimated the quantitative effects of acetylcholine on nonlinear synaptic integration. - Nonlinear NMDA spikes can be triggered by fewer synapses in distal dendrites due to increased local input resistance. - Acetylcholine broadly reduces the number of synapses needed to trigger NMDA spikes, but the magnitude of the effect varies across dendrite branches within a single neuron. - No single potassium channel type is the dominant mediator of the excitability effects of acetylcholine.

Effects of Mulberry on The Central Nervous System: A Literature Review

Article

Full-text available

May 2020

Background Mulberry, including several species belonging to genus Morus, has been widely used as a traditional medicine for a long time. Extracts and active components of mulberry have many positive neurological and biological effects and can become potential candidates in the search for new drugs for neurological disorders. Objectives We aimed to systematically review the medical literature for evidence of mulberry effects on the central nervous system. Methods We conducted a systematic search in nine databases. We included all in vivo studies investigating the effect of mulberry on the central nervous system with no restrictions. Results We finally included 47 articles for quality synthesis. Our findings showed that mulberry and its components possessed an antioxidant effect, showed a reduction in the cerebral infarct volume after stroke. They also improved the cognitive function, learning process, and reduced memory impairment in many animal models. M. alba and its extracts ameliorated Parkinson's disease-like behaviors, limited the complications of diabetes mellitus on the central nervous system, possessed anti-convulsant, anti-depressive, and anxiolytic effects. Conclusion Mulberry species proved beneficial to many neurological functions in animal models. The active ingredients of each species, especially M. alba, should be deeper studied for screening potentially candidates for future treatments

Muscarinic Activity in Hippocampus and Entorhinal Cortex is Crucial for Spatial and Fear Memory Retrieval

Article

Feb 2019

Background: Hippocampus and entorhinal cortex are key players of learning and memory. Despite their established role in memory processes, the contribution of muscarinic receptor activity in these brain regions during memory retrieval remains elusive. This study was aimed to assess the role of hippocampal CA1 and medial entorhinal cortex muscarinic receptors in memory retrieval. Method: Mice were implanted with bilateral cannulas in the hippocampus CA1 and medial entorhinal cortex. After recovery they were trained for Morris water maze test, novel object recognition test and contextual fear conditioning. Scopolamine was infused 10 min prior to retrieval test. Results: Pre-test scopolamine infusion in hippocampal CA1 and medial entorhinal cortex significantly reduced overall exploration of objects (p<0.001). Similarly, pre-retrieval inactivation dorsal hippocampal CA1 and medial entorhinal cortex muscarinic activity caused significant impairment of spatial and fear memories retrieval (p<0.05). Conclusion: These findings showed vital role of muscarinic activity in retrieving hippocampal and entorhinal cortex dependent memories and suggest a possible target for treating retrograde amnesia.

La mémoire hippocampo-dépendante : altérations dans un modèle de vieillissement accéléré et régulation par le système nociceptinergique chez la souris

Thesis

Dec 2017

Khaoula Rekik

La mémoire est définie comme une activité biologique et psychique qui permet d'emmagasiner, de conserver et restituer des informations. La formation de la mémoire à long terme a lieu en plusieurs étapes : acquisition, consolidation. Une fois consolidée, la mémoire peut être réactivée puis reconsolidée. C'est un processus dynamique qui au cours de la vie d'un individu peut subir des altérations physiologiques (vieillissement) ou pathologiques (maladies neurodégénératives, syndrome de stress post traumatique (PTSD)). Dans un premier temps nous avons caractérisé du point de vue comportemental les souris Werner (WRN), un modèle de vieillissement accéléré. Nos résultats ont montré que les souris WRN de différents âges (3, 5 et 8 mois) ne présentaient aucun problème moteur ni d'anxiété, deux paramètres altérés chez des souris âgées de 21 mois. Ces souris ne montrent pas non plus de déficit de mémoire non hippocampo-dépendante mais par contre présentent des déficits de mémoire hippocampo-dépendante. En termes d'intégrité fonctionnelle de l'hippocampe, les souris Werner sont capables de stocker l'information après un apprentissage mais à partir de 8 mois, elles présentent un déficit de flexibilité comportementale dans les tests de mémoire spatiale et contextuelle, un défaut caractéristique des animaux agés. Nos résultats montrent qu'au niveau comportemental, les souris WRN sont un bon modèle pour étudier le vieillissement car elles présentent dès 8 mois des déficits comparables à des souris normales âgées sans effets confondants liés à des troubles de la locomotion ou de l'anxiété. Dans un second temps nous avons évalué l'effet d'un système neuropeptidergique, le système nociceptine (peptide N/OFQ, récepteur NOP), sur la mémoire à long terme. Nous avons tout d'abord montré que différents agonistes du récepteur NOP inhibaient spécifiquement la reconsolidation de la mémoire aversive de type contextuelle dans le test du conditionnement de peur. Cet effet inhibiteur a également été observé dans un test hippocampo-dépendant non aversif, le test de localisation d'objet. Puisque l'activation des récepteurs NOP produit un effet amnésiant on peut émettre l'hypothèse que leur inhibition par des antagonistes pourrait favoriser l'apprentissage et la mémoire. Nos premiers résultats montrent en effet que l'injection d'un antagoniste NOP améliore les performances dans le test de localisation d'objet chez des souris Tg2576, modèles d'une forme familiale de la maladie d'Alzheimer. L'ensemble de ces résultats valident l'intérêt du système nociceptinergique en tant que cible thérapeutique pour atténuer les formes pathologiques de mémoire aversive comme dans le cas du PTSD ou au contraire améliorer les performances mnésiques chez les patients Alzheimer.

Cholinergic Mechanisms of Target Oddball Stimuli Detection: The Late “P300-Like” Event-Related Potential in Rats

Article

Full-text available

Oct 2018
Neural Plast

Event-related potentials (ERPs) and oscillations (EROs) provide powerful tools for studying the brain’s synaptic function underlying information processing. The P300 component of ERPs indexing attention and working memory shows abnormal amplitude and latency in neurological and psychiatric diseases that are sensitive to pharmacological agents. In the active auditory oddball discriminant paradigm, behavior and auditory-evoked potentials (AEPs) were simultaneously recorded in awake rats to investigate whether P300-like potentials generated in rats responding to rare target oddball tones are sensitive to subcutaneous modulation of the cholinergic tone by donepezil (1 mg/kg) and scopolamine (0.64 mg/kg). After operant training, rats consistently discriminate rare target auditory stimuli from frequent irrelevant nontarget auditory stimuli by a higher level of correct lever presses (i.e., accuracy) in target trials associated with a food reward. Donepezil attenuated the disruptive effect of scopolamine on the level of accuracy and premature responses in target trials. Larger P300-like peaks with early and late components were revealed in correct rare target stimuli trials as compared to frequent tones. Donepezil enhanced the peak amplitude of the P300-like component to target stimuli and evoked slow theta and gamma oscillations, whereas scopolamine altered the amplitude of the P300-like component and EROs to target stimuli. Pretreatment with donepezil attenuated effects of scopolamine on the peak amplitude of the P300-like component and on EROs. This study provides evidence that AEP P300-like responses can be elicited by rats engaged in attentive and memory processing of target stimuli and outline the relevance of the cholinergic system in stimulus discrimination processing. The findings highlight the sensitivity of this translational index for investigating brain circuits and/or novel pharmacological agents, which modulate cholinergic transmission associated with increased allocation of attentional resources.

The analysis of hippocampus neuronal density (CA1 and CA3) after Ocimum sanctum ethanolic extract treatment on the young adulthood and middle age rat model

Article

Full-text available

Feb 2018

Aim: This study aimed to assess the changes in neuronal density in CA1 and CA3 regions in the hippocampus of young adulthood and middle age rat model after feeding by Ocimum sanctum ethanolic extract. Materials and Methods: In this research, 30 male Wistar rats consist of young to middle-aged rats were divided into three groups (3, 6, and 9 months old) and treated with a different dosage of O. sanctum ethanolic extract (0, 50, and 100 mg/kg b.w.) for 45 days. Furthermore, cresyl violet staining was performed to analyze hippocampus formation mainly in CA1 and CA3 area. The concentrations of acetylcholine (Ach) in brain tissues were analyzed by enzyme-linked immunosorbent assay. Results: In our in vivo models using rat model, we found that the administration of O. sanctum ethanolic extract with a dosage of 100 mg/kg b.w. for 45 days induced the density of pyramidal cells significantly in CA1 and CA3 of the hippocampus. These results were supported by an increase of Ach concentrations on the brain tissue. Conclusion: The administration of O. sanctum ethanolic extract may promote the density of the pyramidal cells in the CA1 and CA3 mediated by the up-regulated concentration of Ach.

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors

Article

Full-text available

Dec 2017

This article provides a review of the effects of activation of muscarinic and nicotinic receptors on the physiological properties of circuits in the hippocampal formation. Previous articles have described detailed computational hypotheses about the role of cholinergic neuromodulation in enhancing the dynamics for encoding in cortical structures and the role of reduced cholinergic modulation in allowing consolidation of previously encoded information. This article will focus on addressing the broad scope of different modulatory effects observed within hippocampal circuits, highlighting the heterogeneity of cholinergic modulation in terms of the physiological effects of activation of muscarinic and nicotinic receptors and the heterogeneity of effects on different subclasses of neurons.

The Protective Effect of Lavender Essential Oil and Its Main Component Linalool against the Cognitive Deficits Induced by D-Galactose and Aluminum Trichloride in Mice

Article

Full-text available

Apr 2017
EVID-BASED COMPL ALT

Lavender essential oil (LO) is a traditional medicine used for the treatment of Alzheimer’s disease (AD). It was extracted from Lavandula angustifolia Mill. This study was designed to investigate the effects of lavender essential oil (LO) and its active component, linalool (LI), against cognitive impairment induced by D-galactose (D-gal) and AlCl 3 in mice and to explore the related mechanisms. Our results revealed that LO (100 mg/kg) or LI (100 mg/kg) significantly protected the cognitive impairments as assessed by the Morris water maze test and step-though test. The mechanisms study demonstrated that LO and LI significantly protected the decreased activity of superoxide dismutase (SOD), glutathione peroxidase (GPX), and protected the increased activity of acetylcholinesterase (AChE) and content of malondialdehyde (MDA). Besides, they protected the suppressed nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression significantly. Moreover, the decreased expression of synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), p-CaMKII, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were increased with drug treatment. In conclusion, LO and its active component LI have protected the oxidative stress, activity of cholinergic function and expression of proteins of Nrf2/HO-1 pathway, and synaptic plasticity. It suggest that LO, especially LI, could be a potential agent for improving cognitive impairment in AD.

A Brief Review of Neurotoxicity Induced by Melamine

Article

Full-text available

Aug 2017
NEUROTOX RES

In September 2008, in China, tens of thousands of children were hospitalized, several even died, as a result of infant-formula milk adulterated with a synthetic chemical compound, melamine, and in the next few months, this crisis became the focus of attention worldwide. Although there are a number of articles about nephrotoxicity of melamine, the evidence of melamine toxicity on other organs is still scanty. Specially, several recent studies indicated that melamine can perturb the central nervous system (CNS) function and induce cognitive deficits, breaking the previous view that melamine toxicity is limited to the urinary system. This review focuses on some developmental consequences of melamine exposures through various routes in vitro and in vivo, from ethology to molecular and cellular assessments. The evidences demonstrate that the neurotoxic effects of melamine were varied from different route exposure. Finally, the relevant literature on the mechanisms of these aspects has been discussed, and some suggestions towards further researches have been presented.

Toxin-Induced Experimental Models of Learning and Memory Impairment

Article

Full-text available

Sep 2016
INT J MOL SCI

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.

The molecular biology of dendritic spine plasticity in memory processing

Chapter

Full-text available

Jan 2015

The functional organization of neural circuits that underlies learning and memory is defined by very specific synaptic contacts. Under normal conditions, the synaptic contacts between neurons can be modified by experience in order to establish other brain responses. In most cases such modifications tend to promote re-adaptation, although they can also lead to aberrant behaviour. Whatever the case, a wide range of changes can occur in nerve tissue at different levels of organization, tending to maintain an adequate balance between the individual's activity and their environmental demands. The adaptation of nerve cells to novel or adverse conditions, whether effective or not, is known as neuroplasticity. Experimental studies of plasticity in the nervous system have shown that the ability to acquire new information from the environment (learning) and to evoke stored information (memory) is closely related to structural changes in neuronal cytoarchitecture, specifically in the synaptic contacts mediated by dendritic spines. Dynamic modifications to the molecular components of both pre- and post-synaptic synaptic elements involved in plasticity underlie and define these cytoarchitectonic changes.

The cellular and molecular mechanisms driving the estrogenic modulation of synaptic activity in mnemonic information processing

Chapter

Full-text available

Jan 2015

Estrogen receptors (ER) can be activated by their natural ligand estradiol (E2), although several cytoplasmic and nuclear ERs have been identified that may be activated in a different manner, such as ER-a66 and ER-ß. The cloning of human ER-a66 led to the identification of variants of this receptor, including the ER-a46 splice variant and more recently, the novel ERa-36 variant. On the other hand, five splice variants of ER-ß have also been identified named Erb1, Erb2, Erb1d3, Erb2d3 and Erb1d4, possibly with distinct biological activities. Both ER-a and ER-ß receptors are expressed extensively in the brain, and even in the spinal cord. Furthermore, ER-a/ER-ß receptor expression overlaps in several brain regions, although often to a different extent, and the functional role of such an overlapping distribution is still unclear. While ER-a plays a key role in the regulation of reproductive behavior and neuroendocrine activity, ER-ß is more strongly involved in non-reproductive psychoneural processes of a cognitive nature, such as learning and memory. In fact, ER-ß expression predominates over ERa in several cognition-related brain regions, such as the hippocampus and prefrontal cortex. Nevertheless, both ER-a and ER- ß are thought to modulate the excitatory synaptic activity underlying the transmission of cognitive information at dendritic spines, both in the hippocampus and prefrontal cortex. In this sense they favor and protect the integrity of learning- and mnemonic-associated information to yield adequate behavioral patterns, although the precise role of the αand β ERs in these events has yet to be elucidated. In addition, ER activation could have a distinct cognitive significance depending on the origin of E2 synthesis (i.e., gonadal or locally in the brain).

Consolidation, retrieval, and extinction: Dissimilar molecular requirements

Chapter

Full-text available

Jan 2015

Memory is an essential process that allows animals to adapt to their environment. This process has several stages in which learned information is acquired, stored, retrieved, and it is susceptible to extinction. In this chapter, we will mention the principal concepts used in the field of memory, and we will talk about the neurobiological features common to the different stages of memory, and about characteristics that differentiate them. In spite of the attributes that have been proposed to characterize each of the memory stages, it seems that the relative importance of particular mechanisms correlates with the strength of learning. A growing body of evidence shows that typical treatments that impede memory consolidation of learning mediated by low or moderate degrees of training, become innocuous when learning results from high degrees of training. These dissimilar training-dependent effects illustrate how far we still are from understanding the rules that govern consolidation, retrieval, and extinction of learned behaviors.

Synaptic fundamentals of memory performance

Book

Full-text available

Jan 2015

Ignacio González-Burgos

Memory could be conceptualized as the capability to encode, store and retrieve information to guide behavior. Memory may be stored in different manners depending on synaptic characteristics for information processing, which may modulate synchronization of firing of neuronal assemblies. This book focuses on some of the mechanisms that modulate the synaptic activity underlying both the organization and expression of memory. Thus, memory is viewed from the point of view of its synaptic determinants. This book is the integrated compilation of a large body of experimental evidence related to some cellular and subcellular events underlying plastic changes of neural circuits forming the memory traces related to some memory systems. Moreover, this view of memory is considered from both a normal viewpoint and from that of some atypical situations.

Mulberry Fruit Mitigates Alcohol Neurotoxicity and Memory Impairment Induced by Chronic Alcohol Intake

Article

Full-text available

Jan 2012

Problem statement: To date, the therapeutic strategy efficacy against memory impairment induced by alcohol intoxication is still limited. The novel therapeutic strategy which is easy to approach, less toxic and less cost is required. Based on the role of oxidative stress in memory impairment induced by alcohol, the neuroprotective effect of substance possessing antioxidant has gained much attention. Therefore, we aimed to determine the effect of Morus alba fruits, substance possessing antioxidant, on spatial memory and brain damage in hippocampus. Approach: Male Wistar rats were induced alcoholism by increasing the alcohol concentration in drinking water gradually increased to 30% within 15-week period. Then, the alcoholic rats were orally given mulberry fruits powder at doses of 2, 10 and 50 mg kg -1 BW at a period of 14 days. The memory was assessed using Morris water maze after single administration and every 7 days until the end of the experimental period and at the end of experiment, hippocampus was isolated and determined the neuron density. In addition, the evaluation of Acetylcholinesterase (AChE) activity and Malondialdehyde (MDA) level were also performed. Results: Our results showed that all doses of mulberry fruits enhanced spatial memory and neurons density in hippocampus. The suppression of both AChE activity and MDA level were also observed. These results suggested that the neuroprotection of mulberry fruits might occur partly via the decreased oxidative stress damage while the cognitive enhancing effect might occur partly via the increased hippocampal neuron density and the suppression of AChE activity. Conclusion: Mulberry fruits can protect against brain damage and memory impairment induced by alcoholism. Therefore, mulberry fruits may be served as natural resource for developing food supplement against alcoholism. However, further researches about possible active ingredient and pharmacokinetic are required before moving forward to clinical trial study.

Mulberry Fruit Mitigates Alcohol Neurotoxicity and Memory Impairment Induced by Chronic Alcohol Intake

Article

Apr 2012
Am J Appl Sci

Mohammed

Problem statement: To date, the therapeutic strategy efficacy against memory impairment induced by alcohol intoxication is still limited. T he novel therapeutic strategy which is easy to approach, less toxic and less cost is required. Ba sed on the role of oxidative stress in memory impairment induced by alcohol, the neuroprotective effect of substance possessing antioxidant has gained much attention. Therefore, we aimed to deter mine the effect of Morus alba fruits, substance possessing antioxidant, on spatial memory and brain damage in hippocampus. Approach: Male Wistar rats were induced alcoholism by increasing the alco hol concentration in drinking water gradually increased to 30% within 15-week period. Then, the alcoholic rats were orally given mulberry fruits powder at doses of 2, 10 and 50 mg kg -1 BW at a period of 14 days. The memory was assessed using Morris water maze after single administration and e very 7 days until the end of the experimental period and at the end of experiment, hippocampus was isolated and determined the neuron density. In addition, the evaluation of Acetylcholinesterase (A ChE) activity and Malondialdehyde (MDA) level were also performed. Results: Our results showed that all doses of mulberry frui ts enhanced spatial memory and neurons density in hippocampus. The suppression of both AChE activity and MDA level were also observed. These results suggested that th e neuroprotection of mulberry fruits might occur partly via the decreased oxidative stress damage wh ile the cognitive enhancing effect might occur partly via the increased hippocampal neuron density and the suppression of AChE activity. Conclusion: Mulberry fruits can protect against brain damage a nd memory impairment induced by alcoholism. Therefore, mulberry fruits may be serve d as natural resource for developing food supplement against alcoholism. However, further res earches about possible active ingredient and pharmacokinetic are required before moving forward to clinical trial study.

Evaluating the efficacy of chronic galantamine on sustained attention and cholinergic neurotransmission in a pre-clinical model of traumatic brain injury

Article

Jun 2024

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent

Article

Jul 2023
BRAIN BEHAV IMMUN

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three-months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or LPS (30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task, irrespective of stress history. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

Muscarinic Cholinergic Receptor Antagonism Impairs Spatial Memory Retrieval and Minimizes Retrieval-Induced Alterations in Matrix Metalloproteinase-9

Article

Apr 2023
BEHAV BRAIN RES

Cholinergic dysfunction in the hippocampus causes memory impairment, and degradation of the forebrain cholinergic system has been implicated in several neurological disorders. One such disorder, Alzheimer's Disease (AD) is associated with the abnormal expression of various proteins including matrix metalloproteinase-9 (MMP-9), an enzyme known to regulate hippocampus-dependent memory. Memory involves several stages including acquisition, consolidation, and retrieval, but the neurobiological correlates of retrieval have been studied much less than other stages of memory. We sought to investigate the potential relationship between cholinergic signaling and hippocampal MMP-9 expression and the involvement of each in spatial memory retrieval. We trained rats in the water maze until the task was well-learned, then, seven days later, we allowed some to retrieve the memory after an intracerebroventricular injection of scopolamine or vehicle. Western blot analysis of hippocampal tissue shows elevated levels of a truncated form of MMP-9 associated with spatial memory retrieval. Additionally, our results indicate that centrally administered scopolamine both impairs spatial memory retrieval and prevents retrieval-induced elevations in MMP-9. These findings provide evidence for a potential link between cholinergic dysregulation and abnormal MMP-9 levels seen in the brains of AD patients. An important, yet unresolved question is whether MMP-9 serves to support memory retrieval itself or if it is involved in maintaining the ongoing stability of a retrieved memory.

Acetylcholine-sensitive control of long-term synaptic potentiation in hippocampal CA3 neurons

Article

Apr 2023
HIPPOCAMPUS

Randa Kassab

A Hebbian form of long-term potentiation (LTP) is believed to be the basis of memory storage at CA3 recurrent synapses. Abnormalities in CA3 intrinsic connectivity have been related to memory deficits in a variety of neurological disorders. Despite the promise of computational modeling for illuminating the pathogenic implication of connectivity changes, common Hebbian-based models with preset structural topologies fall short in this regard. Here, I introduce a structure-independent approach to modeling CA3 network focusing on how LTP shapes CA3 functional connectivity. Network simulations demonstrate that only a small fraction of the active synapses should be potentiated onto engram-bearing cells for reaching CA3 optimal performance, and that this fraction should be actively regulated at the single-cell level to maintain precise control over excitatory inputs to and from overlapping engram cells. In light of these findings, I develop a theory suggesting that synaptic potentiation is regulated through extrinsic and intrinsic cellular mechanisms involving the cholinergic modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The theory posits that the progressive increase of acetylcholine release during learning is commensurate with the rate of AMPA receptor trafficking during LTP development and that this dynamics is intended to conceal AMPA receptor potentiation and thereby to propel LTP progression until a target level of potentiation is attained at a restricted number of the active synapses. Functionally, this form of regulation allows encoding and retrieval dynamics to be dictated at the single-cell level and thereby acts at the cell-population level as a secondary mechanism complementing dentate gyrus-mediated pattern separation or compensating for possible deficiencies. Conversely, when this regulation fails, the strength of AMPA receptors and their variability across synapses change over time and lead to pathological states.

Honey and Alzheimer’s Disease—Current Understanding and Future Prospects

Article

Full-text available

Feb 2023

Alzheimer’s disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD.

Acetylcholine

Chapter

Sep 2022

Acetylcholine (Ach) is an excitatory neurotransmitter formed from choline and acetic acid through the process of esterification. It is the primary neurotransmitter in the parasympathetic autonomic nervous system, a chemical transmitter at the neuromuscular junction, and a neuromodulator in the brain. This chapter outlines the history, neurochemical profile, receptor functioning, metabolism, pharmacological importance, and the clinical application of Ach.KeywordsAcetylcholineCholinergic transmissionParasympathomimeticNeurotransmitter

Sleep driving improvement of declarative memory

Chapter

Aug 2022

Recent research is indication of an increasing number of studies that have shown a strong relationship between sleep and memory. Here we summarize a series of our own studies in humans supporting a beneficial influence of Slow-Wave Sleep (SWS) on declarative memory formation and try to identify some mechanisms that might underlie this influence. Specifically, these experiments show that declarative memory benefits mainly from sleep periods dominated by SWS, whereas there is no consistent benefit of this memory from periods rich in Rapid Eye Movement (REM) sleep. A main mechanism of declarative memory formation is believed to be the reactivation of newly acquired memory representations in hippocampal networks that stimulates a transfer and integration of these representations into neocortical neuronal networks. Consistent with this model, spindle activity and slow oscillation-related Electroencephalogram (EEG) coherence increase during early sleep after intense declarative learning in humans, signs that together point toward a neocortical reprocessing of the learned material. In addition, sleep seems to provide an optimal milieu for declarative memory reprocessing and consolidation by reducing cholinergic activation and the cortisol feedback to the hippocampus during SWS.

Deep brain stimulation of the nucleus basalis of Meynert in an experimental rat model of dementia: Stimulation parameters and mechanisms

Article

Full-text available

Jun 2022
NEUROBIOL DIS

Background/objective Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has gained interest as a potential therapy for treatment-resistant dementia. However, optimal stimulation parameters and mechanisms of action are yet to be elucidated. Methods First, we assessed NBM DBS at different stimulation parameters in a scopolamine-induced rat model of dementia. Rats were tested in the object location task with the following conditions: (i) low and high frequency (20 Hz or 120 Hz), (ii) monophasic or biphasic pulse shape (iii) continuous or intermittent DBS (20s on, 40s off) and 100 μA amplitude. Thereafter, rats were stimulated with the most effective parameter followed by 5-bromo-2′-deoxyuridine (BrdU) administration and perfused 4 weeks later. We then evaluated the effects of NBM DBS on hippocampal neurogenesis, synaptic plasticity and on cholinergic fibres in the perirhinal and cingulate cortex using immunohistochemistry. We also performed in-vivo microdialysis to assess circuit-wide effects of NBM DBS on hippocampal acetylcholine levels during on and off stimulation. Results Biphasic, low frequency and intermittent NBM DBS reversed the memory impairing effects of scopolamine when compared to sham rats. We found that acute stimulation promoted proliferation in the dentate gyrus, increased synaptic plasticity in the CA1 and CA3 subregion of the hippocampus and increased length of cholinergic fibres in the cingulate gyrus. There was no difference regarding hippocampal acetylcholine levels between the groups. Conclusion These findings suggest that the potential mechanism of action of the induced memory enhancement through NBM DBS might be due to selective neuroplastic and neurochemical changes.

Acetylcholine bidirectionally regulates learning and memory

Article

Full-text available

Jun 2022

Acetylcholine (ACh) is one of the most important neurotransmitters in the central cholinergic system; it specifically binds to muscarinic and nicotinic receptors and is degraded by acetylcholinesterase (AChE). ACh plays a crucial role in learning and memory. It is generally believed that, in the central nervous system, ACh promotes the conduction of brain nerves and accelerates information transmission. Besides, increasing central ACh levels can enhance memory ability and comprehensively improve brain function. Thus, AChE inhibitors (AChEI), which inhibit the degradation of ACh by AChE, have been used to treat Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). However, recent studies have shown that excessive ACh in the central nervous system impairs learning and memory. Here we review the roles of ACh in learning and memory; we focus on the adverse effects of excessive ACh, the possible mechanisms, and the bidirectional role of ACh in the pathology and cure of AD and PDD. We conclude that the timing and dose of ACh administration should be carefully prescreened when using it to alleviate learning and memory in dementia patients.

Electrical Brain Stimulation for the Treatment of Neurological Disorder

Book

Full-text available

Apr 2022

In this book, Electrical Brain Stimulation for the Treatment of Neurological Disorders, the authors present their embodiment for a closed loop, feedback controlled, non-invasive application of electrical stimulation of the brain to enhance individual/group performance or to treat neurological disorders. Using a combination of modeling and experimental work, the authors have developed a unique approach to the field in combination with new technology from the perspectives of electro-magnetic and electrical engineering, computation of image processing, machine learning and neural networking, and in conjunction with the medicine of neurology and understanding of neuron behavior. They claim that non-invasive brain stimulation (NIBS) will provide new treatment methods with much greater simplicity, lower cost, improved safety, and in some cases, possibly greater effectiveness than well-established pharmacological methods or more recent invasive electrical deep brain stimulation (DBS) techniques. The authors explain their techniques and the results of their experimental studies and assert that the application of tailored and individualized control of their approach can be combined with other therapy methods to treat neurological disorders while minimizing or even eliminating the use of pharmaceuticals.

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model

Article

Nov 2021
NEUROSCIENCE

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca²⁺ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca²⁺-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.

Association of short- and long-latency afferent inhibition with human behavior

Article

Apr 2021
CLIN NEUROPHYSIOL

Transcranial magnetic stimulation (TMS) paired with nerve stimulation evokes short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI), which are non-invasive assessments of the excitability of the sensorimotor system. SAI and LAI are abnormally reduced in various special populations in comparison to healthy controls. However, the relationship between afferent inhibition and human behavior remains unclear. The purpose of this review is to survey the current literature and synthesize observations and patterns that affect the interpretation of SAI and LAI in the context of human behavior. We discuss human behaviour across the motor and cognitive domains, and in special and control populations. Further, we discuss future considerations for research in this field and the potential for clinical applications. By understanding how human behavior is mediated by changes in SAI and LAI, this can allow us to better understand the neurophysiological underpinnings of human motor control.

A synaptic novelty signal in the dentate gyrus supports switching hippocampal attractor networks from generalization to discrimination

Preprint

Full-text available

Feb 2021

Episodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice navigating in familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarization of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favoring the switch from generalization to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

Sleep Promoting Improvement of Declarative Memory

Chapter

Aug 2019

Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories

Article

Feb 2020
NAT REV NEUROSCI

The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions, indicating that the rest of the hippocampus (CA1–CA3) can operate autonomously under certain conditions. An extensive body of theoretical work has proposed how the architectural elements and various cell types of the DG may underlie its function in cognition. Recent studies recorded and manipulated the activity of different neuron types in the DG during memory tasks and have provided exciting new insights into the mechanisms of DG computational processes, particularly for the encoding, retrieval and discrimination of similar memories. Here, we review these DG-dependent mnemonic functions in light of the new findings and explore mechanistic links between the cellular and network properties of, and the computations performed by, the DG.

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

Article

Full-text available

Nov 2016
LEARN MEMORY

Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M3 and cooperative activity of RSC M1 and M3, and (3) memory retrieval is more impaired by inactivation of multiple M1-M4 mAChR in DH or RSC than inactivation of individual receptor subtypes. Contrary to the view that acetylcholine supports learning but is detrimental to memory retrieval, we found that coactivation of multiple mAChR is required for retrieval of both recently and remotely acquired context memories. Manipulations with higher receptor specificity were generally less potent than manipulations targeting multiple receptor subtypes, suggesting that mAChR act in synergy to regulate memory processes. These findings provide unique insight into the development of therapies for amnestic symptoms, suggesting that broadly acting, rather than receptor-specific, mAchR agonists and positive allosteric modulators may be the most effective therapeutic approach.

Acetylcholinergic Nicotinic Receptors as Pharmacological Targets for Cognitive Enhancement: Emerging Evidence from Psychosis Populations

Chapter

Nov 2016

Cognitive deficits have been recognised since the first conceptualisation of psychosis; indeed it was initially labelled ‘dementia praecox’, or presenile dementia, in recognition of the primacy of these problems. However, these were largely ignored – in part due to a lack of effective interventions – in the sixty or so years since the discovery of dopaminergic antagonist antipsychotic medications. In recent times there has been a renewed growth of interest in putative cognitive enhancers in this condition, with much work looking at agents that modulate the acetylcholinergic (ACh) system that is intimately linked with cognition and memory. Unlike memory sparing medications in dementia, which prevent the enzymatic degradation of synaptic ACh, in psychosis the emphasis has been on direct agonists. To date, several compounds have been tested in humans, and interesting early results support a pro-cognitive effect in some, but not all. A challenge, however, is understanding why only some appear to derive benefit, and whether any such factors can be used for predictive prescribing, so that more efficacious future agents can be developed.

Paradoxical Sleep as a Tool for Understanding Hippocampal Mechanisms of Contextual Memory

Article

Full-text available

Sep 2008
ZH VYSSH NERV DEYAT+

Isabella G Silkis

Existing data on hippocampal involvement in contextual memory and the fact that contextual memory is deranged during REM sleep dreams allowed Lis to assume that one of the reasons for this derangement could be a change in the efficacy of synaptic transmission in the hippocampus because of a rise (as compared to wakefulness) of acetylcholine, cortisol, and dopamine concentrations and lack of serotonin and norepinephrine. The earlier performed analysis showed that, during REM sleep, the LTD Could be induced at all steps of the polysynaptic pathway through the hippocampal formation, whereas the LTP Could be induced in the entorhinal inputs to hippocampal areas CA1 and CA3 and in associative connections within the CA3 field. We Suggested that the effective signal transmission in each units of the polysynaptic pathway through the hippocampus is necessary for correct functioning of episodic memory and generation of neuronal representation of the context. During retrieval in the state of wakefulness, the representation of episodic context stored in the hippocampus could be activated together with the neuronal representations of episodic details stored in those neocortical areas wherein they were processed. it follows from the proposed mechanism that any neuromodulator or neuropeptide which promotes UP in the polysynaptic hippocampal pathway can improve episodic memory. Since the consequences of the proposed mechanism agree with the known experimental data, this phenomenon can be used for the development of drugs improving episodic memory.

Memory and attention impairment after traumatic brain injury

Article

Jan 2013

Background: Deficits in memory and attention have been reported following traumatic brain injury (TBI) and there is evidence that the cholinergic system is frequently involved in these cognitive consequences. Objective: To study the effect of moderate to severe TBI on the cognitive functions facilitated by the cholinergic system. Methods: The data of 25 patients with history of TBI on admission was reviewed including: Glasgow coma scale (GCS), Marshall Score, and the number of days of admission in ICU. During the follow up visit after 6 months of the trauma, all patients underwent neurological examination including mini mental state examination (MMSE) and Glasgow outcome scale (GOS). Neuropsychological assessment was done by using Cambridge Neuropsychological Test Automated Battery (CANTAB). Results: The median GCS on admission was eight. The surviving population at 6 months consisted of two (8%) patients with GOS of 3, 10 (40%) with GOS of 4 and 13(52%) with GOS of 5. There was a significant difference between the groups on the MMSE score, although both groups were within the normal range. Performance on the CANTAB showed that spatial span, spatial working memory and set shifting did not differ between the two groups. On the other hand, there was a significant difference on rapid visual information processing, pattern and spatial recognition, reaction time and paired associate learning. Conclusion: These cognitive results are consistent with cholinergic dysfunction. The cholinergic enhancers may be considered helpful in the treatment of cognitive deficits after TBI.

Persistent Short Term Memory Deficits in Hebb–Williams Maze Performance Are Shown by Rats With Unilateral Entorhinal Cortex Lesions

Article

Full-text available

Feb 1997

The spatial abilities of adult, male Sprague-Dawley rats in the Hebb–Williams maze were examined at 6 months after unilateral electrolytic entorhinal cortex lesions. Compared with sham-operated rats, their performance was impaired in both initial entry and repeat entry errors over 12 consecutive problems, using immediate starting replacement for the 6 trials per problem. The configurations of the 12 maze problems are independent, and deficits were seen over the entire course of the testing. This study indicates that Hebb–Williams maze performance deficits after unilateral entorhinal cortex lesion are persistent and can be seen up to 6 months after injury.

Neural models of memory

Article

Full-text available

May 1999
CURR OPIN NEUROBIOL

Neural models assist in characterizing the processes carried out by cortical and hippocampal memory circuits. Recent models of memory have addressed issues including recognition and recall dynamics, sequences of activity as the unit of storage, and consolidation of intermediate-term episodic memory into long-term memory.

Effects of posttraining injection of cholinergic agonists and antagonists into the amygdala on retention of passive avoidance training in rats

Article

Full-text available

Oct 1978
J Comp Physiol Psychol

Rats were given a single footshock while licking a water tube and tested 24 hr later for retention of the footshock experience. A single bilateral injection of a subseizure dose of physostigmine into the amygdala applied immediately, but not 18 hr, after the footshock imparied retention. This effect appeared to be somewhat localized, as physostigmine injected into the hippocampus or lateral ventricles did not disrupt retention. Conversely, a subseizure dose of atropine sulfate into the amygdala, given immediately or 18 hr after the footshock did not impair retention. Atropine injected concurrently with physostigmine into the same amygdaloid loci counteracted a potential physostigmine-induced retention deficit. Injection of carbachol into the amygdala also impaired retention; however, carbachol precipitated seizures and possibly exerted proactive consequences on performance. The time-dependent nature of the deficit following physostigmine is consistent with the view that injection of cholinergic agonists into the amygdala disrupts memory for the footshock experience.

Oral Tetrahydroaminoacridine in Long-Term Treatment of Senile Dementia, Alzheimer Type

Article

Full-text available

Dec 1986

We treated 17 patients who had moderate to severe Alzheimer's disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimer's Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer's disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

An age comparison of the rates of acquisition and forgetting of hippocampal synapses

Article

Full-text available

Dec 1985

Age differences in the rates of acquisition and forgetting of a spatial memory problem were compared with corresponding differences in the rates of increase and decay of long-term synaptic enhancement (LTE) of hippocampal synapses, induced by high-frequency stimulation of perforant path fibers. Old animals approached their final asymptotic performance levels more slowly than did the young animals and exhibited faster rates of forgetting of the problem. Similarly, LTE reached its maximum more slowly in the old animals and decayed more quickly. Although the absolute rates of behavioral acquisition and forgetting were different from the corresponding rates of increase and decay of LTE, the relative differences between age groups were rather similar. This was particularly true for the comparison of forgetting with LTE decay. The relation of these data to the hypothesis that LTE underlies spatial learning and memory is discussed.

Bartus RT, Dean III RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunctions. Science 217: 408-417

Article

Full-text available

Aug 1982

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

Dynamics of Learning and Recall at Excitatory Recurrent Synapses and Cholinergic Modulation in Rat Hippocampal Region CA3

Article

Full-text available

Aug 1995

Hippocampal region CA3 contains strong recurrent excitation mediated by synapses of the longitudinal association fibers. These recurrent excitatory connections may play a dominant role in determining the information processing characteristics of this region. However, they result in feedback dynamics that may cause both runaway excitatory activity and runaway synaptic modification. Previous models of recurrent excitation have prevented unbounded activity using biologically unrealistic techniques. Here, the activation of feedback inhibition is shown to prevent unbounded activity, allowing stable activity states during recall and learning. In the model, cholinergic suppression of synaptic transmission at excitatory feedback synapses is shown to determine the extent to which activity depends upon new features of the afferent input versus components of previously stored representations. Experimental work in brain slice preparations of region CA3 demonstrates the cholinergic suppression of synaptic transmission in stratum radiatum, which contains synapses of the longitudinal association fibers.

Acety1choline and memory

Article

Full-text available

Jul 1993
TRENDS NEUROSCI

Acetylcholine may set the dynamics of cortical networks to those appropriate for learning of new information, while decreased cholinergic modulation may set the appropriate dynamics for recall. In slice preparations of the olfactory cortex, acetylcholine selectively suppresses intrinsic but not afferent fiber synaptic transmission, while decreasing the adaptation of pyramidal cells. In biologically realistic models of this region, the selective suppression of synaptic transmission prevents recall of previously learned memories from interfering with the learning of new memories, while the decrease in adaptation enhances the response to afferent input and the modification of synapses. This theoretical framework may serve to guide future studies linking neuromodulators to cortical memory function.

Laminar selectivity of the cholinergic suppression of synaptic transmission in rat hippocampal region CA1: Computational modeling and brain slice physiology

Article

Full-text available

Jul 1994

ACh may set the dynamics of cortical function to those appropriate for learning new information. In models of the putative associative memory function of piriform cortex, selective suppression of intrinsic but not afferent fiber synaptic transmission by ACh prevents recall of previous input from interfering with the learning of new input (Hasselmo, 1993). Selective cholinergic suppression may play a similar role in the hippocampal formation, where Schaffer collateral synapses in stratum radiatum (s. rad) may store associations between activity in region CA3 and the entorhinal cortex input to region CA1 terminating in stratum lacunosum-moleculare (s. I-m). A computational model of region CA1 predicts that for effective associative memory function of the Schaffer collaterals, cholinergic suppression of synaptic transmission should be stronger in s. rad than in s. I-m. In the hippocampal slice preparation, we tested the effect of the cholinergic agonist carbachol (0.01-500 μM) on synaptic transmission in s. rad and s. I- m. Stimulating and recording electrodes were simultaneously placed in both layers, allowing analysis of the effect of carbachol on synaptic potentials in both layers during the same perfusion in each slice. Carbachol produced a significantly stronger suppression of stimulus-evoked EPSPs in s. rad than in s. I-m at all concentrations greater than 1 μM. At 100 μM, EPSP initial slopes were suppressed by 89.1 ± 3.0% in s. rad, but only by 40.1 ± 4.1% in s. I-m. The muscarinic antagonist atropine (1 μM) blocked cholinergic suppression in both layers. These data support the hypothesis that synaptic modification of the Schaffer collaterals may store associations between activity in region CA3 and the afferent input to region CA1 from the entorhinal cortex. In simulations, feedback regulation of cholinergic modulation based on activity in region CA1 sets the appropriate dynamics of learning for novel associations, and recall for familiar associations.

Pharmacological evaluation of novel Alzheimer's disease therapeutics: Acetylcholinesterase inhibitors related to galanthamine

Article

Full-text available

Jun 1996

Acetylcholinesterase (AChE) inhibitors from several chemical classes have been tested for the symptomatic treatment of Alzheimer's disease; however, the therapeutic success of these compounds has been limited. Recently, another AChE inhibitor, galanthamine hydrobromide (GAL), has shown increased clinical efficacy and safety. Using biochemical, behavioral and pharmacokinetic analyses, this report compares GAL with two of its analogs, 6-O-acetyl-6-O-demethylgalanthamine hydrochloride (P11012) and 6-O-demethyl-6-O[(adamantan-1-yl)-carbonyl]galanthamine hydrochloride (P11149), for their therapeutic potential. P11012 and P11149 were found to be potent, competitive and selective inhibitors of AChE, demonstrating central cholinergic activity, behavioral efficacy and safety. P11012 and P11149, though pharmacokinetic analyses, were shown to act as pro-drugs, yielding significant levels of 6-O-demethylgalanthamine. In vitro, 6-O-demethylgalanthamine was 10- to 20-fold more potent than GAL as an inhibitor of AChE, and it demonstrated greater selectivity for inhibition of AChE vs. butyrylcholinesterase. Like GAL, both P11012 and P11149 showed central cholinergic activity biochemically, by significantly inhibiting rat brain AChE; physiologically, by causing hypothermia; and behaviorally, by attenuating scopolamine-induced deficits in passive avoidance. In addition, GAL, P11012 and P11149 enhanced step-down passive avoidance, another measure of behavioral efficacy. By comparing efficacious doses with primary overt effects, P11012 and P11149 had better oral therapeutic indices than GAL. Oral pharmacokinetic analyses of GAL, P11012 and P11149 revealed differences. Although P11012 and P11149 exhibited similar area under the curve values, 191149 had slower, lower and more sustained concentration maximum levels. P11012 and GAL rapidly reached their concentration maximums, but GAL, in brain had the highest area under the curve and concentration maximum. Because of its composite profile, including duration of action, oral therapeutic index and pharmacokinetics, P11149 is considered the better therapeutic candidate for the treatment of Alzheimer's disease.

Functionally Dissociating Aspects of Event Memory: the Effects of Combined Perirhinal and Postrhinal Cortex Lesions on Object and Place Memory in the Rat

Article

Full-text available

Feb 1999

Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.

Grady CL, Craik FI. Changes in memory processing with age. Curr Opin Neurobiol 10: 224-231

Article

Full-text available

May 2000
CURR OPIN NEUROBIOL

Over the years, a large body of literature has shown that humans display losses in memory with age, but that not all types of memory are affected equally. Similarly, recent evidence from functional neuroimaging experiments has revealed that, depending on the task, older adults can display greater or lesser activity in task-relevant brain areas compared with younger adults. Recent behavioral and neurophysiological experiments are furthering our understanding of the effects of aging on cognition. It appears that some brain changes seen with age may be compensatory.

The representation of space in the primate hippocampus, and its role in memory

Chapter

Dec 1998

Edmund T Rolls

As we move around in our environment, and interact with it, many of the most important problems we face involve the processing of spatial information. We have to be able to navigate by perceiving and remembering the locations and orientations of the objects around us relative to ourself; we have to sense and act upon these objects; and we need to move through space to position ourselves in favourable locations or to avoid dangerous ones. While this appears so simple that we don't even think about it, the difficulty of solving these problems has been shown in the repeated failure of artificial systems to perform these kinds of tasks efficiently. In contrast, humans and other animals routinely overcome these problems every single day. This book examines some of the neural substrates and mechanisms that support these remarkable abilities. The hippocampus and the parietal cortex have been implicated in various core spatial behaviours, such as the ability to localise an object and navigate to it. Damage to these areas in humans and animals leads to impairment of these spatial functions. This collection of papers, written by internationally recognized experts in the field, reviews the evidence that each area is involved in spatial cognition, examines the mechanisms underlying the generation of spatial behaviours, and considers the relative roles of the parietal and hippocampal areas, including how each interacts with the other. The papers integrate a wide range of theoretical and experimental approaches, and touch on broader issues relating to memory and imagery. As such, this book represents the state of the art of current research into the neural basis of spatial cognition. It should be of interest to anyone - researchers or graduate students - working in the areas of cognitive neuroscience, neuroanatomy, neuropsychology, and cognition generally.

Systematic review of the efficacy of rivastigmine for patients with Alzheimer's disease

Article

Jan 1998

Cholinesterase inhibition appears to be the most promising current option for the symptomatic treatment of the primary cognitive deficits of Alzheimer's disease (AD). We review three prospective, randomized, double- blind, placebo-controlled studies of rivastigmine, an acetylcholinesterase (AChE) subtype-selective, 'pseudo-irreversible' AChE inhibitor, and report results from a pooled analysis of these studies. The overall phase III assessment program enrolled more than 3300 patients at 116 centers in 10 countries. Two studies were based in the USA and one predominantly in Europe, with some US and Canadian centers. The three clinical trials reviewed here included 2126 patients with mild to moderately severe probable AD treated with a flexible dosage range of rivastigmine 6-12 mg/day or 1-4 mg/day, a fixed-dose regimen of 3, 6 or 9 mg/day, or placebo for 26 weeks. In all trials patients showed significant benefit in measures of cognition (Alzheimer's Disease Assessment Scale-cognitive subscale) and clinician's assessment of change (Clinician Interview-Based Impression of Change incorporating caregiver information); in the two pivotal studies patients also showed significant improvement in activities of daily living (as measured prospectively by the domain-specific Progressive Deterioration Scale). The pooled analyses further confirm the efficacy of rivastigmine in the treatment of both the cognitive and functional deficits of mild to moderately severe AD.

Neurotransmitter metabolism in the aging brain

Article

Jan 1976
NEUROBIOL AGING

Functions of Neuronal Networks in the Hippocampus and Neocortex in Memory

Article

Dec 1989

Edmund T Rolls

This chapter discusses the functions of neuronal networks in the hippocampus and neocortex in memory. It also presents the experimental evidence and theoretical approaches to the function of the hippocampus and of backprojections in the neocortex. The theories are at the level of neuronal networks and are based on evidence on the fine architecture of the networks, on the rules of synaptic modifiability incorporated, and on the systems-level connections. It is suggested that this approach will be useful in the future in linking anatomical evidence on structure to physiological evidence on modifiability. The approach will also be useful in understanding the global properties of the networks and, thus, understanding the role of the networks in brain function and behavior.

Nicotinic Autoreceptors Mediating Enhancement of Acetylcholine Release Become Operative in Conditions of “Impaired” Cholinergic Presynaptic Function

Article

Nov 1996
J NEUROCHEM

The existence in the mammalian CNS of release-inhibiting muscarinic autoreceptors is well established. In contrast, few reports have focused on nicotinic autoreceptors mediating enhancement of acetylcholine (ACh) release. Moreover, it is unclear under what conditions the function of one type of autoreceptor prevails over that of the other. Rat cerebrocortex slices, prelabeled with [3H]choline, were stimulated electrically at 3 or 0.1 Hz. The release of [3H]ACh evoked at both frequencies was inhibited by oxotremorine, a muscarinic receptor agonist, and stimulated by atropine, a muscarinic antagonist. Nicotine, ineffective at 3 Hz, enhanced [3H]ACh release at 0.1 Hz; mecamylamine, a nicotinic antagonist, had no effect at 3 Hz but inhibited [3H]ACh release at 0.1 Hz. The cholinesterase inhibitor neostigmine decreased [3H]ACh release at 3 Hz but not at 0.1 Hz; in the presence of atropine, neostigmine potentiated [3H]ACh release, an effect blocked by mecamylamine. In synaptosomes depolarized with 15 mM KCI, ACh inhibited [3H]ACh release; this inhibition was reversed to an enhancement when the external [Ca2+] was lowered. The same occurred when, at 1.2 mM Ca2+, external [K+] was decreased. Oxotremorine still inhibited [3H]ACh release at 0.1 mM Ca2+. When muscarinic receptors were inactivated with atropine, the K+ (15 mM)-evoked release of [3H]ACh (at 0.1 mM Ca2+) was potently enhanced by ACh acting at nicotinic receptors (EC50⋍ 0.6 µM). In conclusion, synaptic ACh concentration does not seem to determine whether muscarinic or nicotinic autoreceptors are activated. Although muscarinic autoreceptors prevail under normal conditions, nicotinic autoreceptors appear to become responsive to endogenous ACh and to exogenous nicotinic agents under conditions mimicking impairment of ACh release. Our data may explain in part the reported efficacy of cholinesterase inhibitors (and nicotinic agonists) in Alzheimer's disease.

Galanthamine, an acetylcholinesterase inhibitor: A time course of the effects on performance and neurochemical parameters in mice

Article

Oct 1989
PHARMACOL BIOCHEM BE

The time course of the effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on a spatial navigation task and on AChE and acetylcholine (ACh) levels were investigated in mice. Mice received either saline or ibotenic acid injections into the nucleus basalis magnocellularis (nBM). The control and nBM group were then trained to perform a modified Morris swim task and the time to find the hidden platform was recorded. The nBM group took significantly longer to find the platform than the control group in the reversal phase of testing. Galanthamine attenuated the performance deficit in the nBM-lesioned group in a time-dependent manner, with peak performance at four hours after injection of 5.0 mg/kg galanthamine IP. This dose impaired performance of the task in control mice, with the most severe deficits observed at two hours after injections when motor activity was severely reduced. Galanthamine (5.0 mg/kg IP) significantly decreased cortical AChE activity and significantly increased cortical ACh content in control mice in a time-dependent manner. The time courses of the neurochemical effects, however, did not correlate precisely with the behavioral time course. Galanthamine concentrations up to 1 × 10−5 M did not affect choline acetyltransferase (ChAT) activity, [3H]hemicholinium-3 (HCh-3) binding to the choline carrier, [3H]quinuclidinylbenzilate (QNB) binding to muscarinic receptors, or [3H]acetylcholine binding to nicotinic receptors in cortical homogenates. AChE activity was inhibited by galanthamine in cortical homogenates with an IC50 of 4.1 × 10−7 M. Galanthamine's ability to reverse cognitive deficits induced by nBM lesions, its relatively long half-life and its specificity of effects suggest that this drug may be effective in treating the central cholinergic deficits in Alzheimer's disease and related disorders.

The pharmacology of galantamine and its analogues

Article

Feb 1995
PHARMACOL THERAPEUT

Alan L Harvey

Galanthamine is an alkaloid found in the bulbs of snowdrops and several Amaryllidaceae plants. At submicromolar concentrations, it inhibits acetylcholinesterase activity, but it is much less potent against butyrylcholinesterase activity. Galanthamine has been used in anaesthetics to reverse neuromuscular paralysis by tubocurarine-like muscle relaxants, but it is a tertiary amine that gets into the brain to cause central effects. Galanthamine is being studied as a possible therapeutic agent in Alzheimer's disease because of its central cholinergic effects. Positive effects have been demonstrated in several learning and memory tests in animals.

A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice

Article

Sep 1988
PHARMACOL BIOCHEM BE

The effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on spatial memory were investigated in mice. Mice received ibotenic acid or sham lesions to the nucleus basalis magnocellularis (nBM). Groups of nBM-lesioned and control mice were then trained on a modified Morris swim maze task. Each mouse was first placed on a platform and then into quadrants of the swim tank in a random order. Time required to find the hidden platform was measured. In different phases of testing, the animal had to find a platform that either remained in the same quadrant (reference memory component) or was moved daily (working memory component). The nBM-lesioned mice took significantly longer to find the platform as compared to controls on the working, but not on the reference, memory component of the task. Galanthamine (5.0 mg/kg, IP), given 3.5 hours before testing, improved performance on the working memory task in nBM-lesioned mice by 70% and strikingly impaired performance in controls. Galanthamine's ability to reverse cognitive deficits induced by nBM lesions and its comparatively long half-life suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease patients.

Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze spatial navigation in aged rats

Article

Jan 1998
EUR J PHARMACOL

We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on the defect of water maze spatial navigation in rats induced by aging. Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.) enhanced acquisition of the water maze task. A combination of subthreshold doses of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water maze acquisition, but a combination of lower subthreshold doses (tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective. Consolidation in water maze test was not improved by tetrahydroaminoacridine (3 mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of spatial navigation in aged rats.

Maze performance in rats with hippocampal perforant paths lesions: Some aspects of functional recovery

Article

Nov 1975
PHYSIOL BEHAV

Trond Myhrer

The performance of two experimental groups--one with lesions of the perforant paths projecting to the dorsal hippocampus (the D group) and one with lesions of the perforant paths to both the dorsal and ventral hippocampus (the DV group)--was compared with the performance of a lesioned control group and an intact control group during two test sessions in the Hebb-Williams maze. Both experimental groups displayed impaired maze learning in Session I. The DV group showed some recovery of function in Session II, and the D group was indistinguishable from controls. The results are discussed in terms of reduced sensory information to the hippocampal formation resulting from perforant paths lesions. It is suggested that the hippocampus is involved in relating new stimuli to previous experience.

Blokland A, Honig W, Raaijmakers WGM. Effects of intra-hippocampal scopolamine injections in a repeated spatial acquisition task in the rat. Psychopharmacology 109: 373-376

Article

Feb 1992

The involvement of hippocampal cholinergic synapses in spatial discrimination learning was evaluated by locally administering scopolamine into the hippocampus. Sixteen 16-month-old male Lewis rats received bilaterally implanted cannulae aimed at the dorsal part of the hippocampus. The rats were trained on a repeated acquisition test in the Morris water-escape task. In this procedure the invisible platform is randomly moved from day to day to one of four possible locations. Thus, the rat has to learn to localize the platform from day to day. On each day the rats received four pairs of trials. Scopolamine injections (35 micrograms in 1 microliter per hippocampus) were given to one group (n = 8) on days 5 and 7. On days 6 and 8 all rats received saline injections. Place learning was retarded in the scopolamine-treated rats during the first swims of pairs of trials. During second swims the scopolamine-treated rats showed a general performance deficit, indicating that first and second swims were differentially affected. The data support the hypothesis that cholinergic neurotransmission in the dorsal hippocampus is involved in spatial learning processes.

Dellu F, Mayo W, Cherkaoui J, Le Moal M, Simon H. A two-trial memory task with automated recording: study in young and aged rats. Brain Res 588: 132-139

Article

Sep 1992
BRAIN RES

A two-trial recognition task, based on place or object exploration in a Y-maze, was developed to study memory in adult and aged rats. This paradigm avoids the use of electric shocks or deprivation that may have non-specific influences on the responses, and the task does not require learning of a rule. A number of behavioral parameters in several animals could be recorded automatically. These behavioral parameters were found to be differently influenced both by the type of recognition (place vs. object) and by the inter-trial interval (recognition retention time). Impaired recognition was also detected in 18-months-old rats. This recognition task which combines simplicity, sensitivity and high specificity may thus be a useful adjunct to our current battery of memory tasks.

Muscarinic receptor subtypes and sexual behavior in female rats

Article

Feb 1991
PHARMACOL BIOCHEM BE

Cholinergic muscarinic systems are involved in the regulation of female sexual behavior in rats and hamsters. This series of experiments was designed to determine whether sexual behavior in female rats is controlled preferentially by one of the traditional muscarinic receptor subtypes. Intraventricular infusion of the muscarinic antagonist scopolamine (10 micrograms bilaterally) which binds with high affinity to both M1 and M2 subtypes inhibited sexual behavior, as indicated by the incidence of lordosis, in ovariectomized rats treated with estrogen and progesterone. In contrast, the M1-selective antagonist pirenzepine failed to reduce the incidence of lordosis following intraventricular infusion (10 to 80 micrograms bilaterally). Biochemical analyses revealed that intraventricular infusion of scopolamine (10 micrograms bilaterally) inhibited both M1 and M2 binding in brain tissues while intraventricular infusion of pirenzepine (10 micrograms bilaterally) completely inhibited M1 binding without affecting M2 binding. Intraventricular infusions of the acetylcholinesterase inhibitor physostigmine (10 micrograms bilaterally), the cholinergic agonist carbachol (1 microgram bilaterally), and the muscarinic agonist oxotremorine-M (0.1 micrograms bilaterally) activated lordosis in ovariectomized females primed with low doses of estrogen. In contrast, the putative M1 agonist McN-A-343 failed to significantly increase lordosis following intraventricular infusions (1, 10, 20 micrograms bilaterally). According to biochemical results, the ability of these agents to activate lordosis in female rats was related to their affinities for M2 binding sites not M1 binding sites. In a final experiment, estrogen treatment of ovariectomized rats did not alter muscarinic subtype binding in several brain areas as measured by the M1-selective ligand [3H] pirenzepine and the M2-selective ligand [3H] oxotremorine-M. The results of these experiments confirm that muscarinic systems contribute to the regulation of lordosis in female rats and indicate that M2 binding sites rather than M1 binding sites may be a critical component of this regulation.

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats

Article

Feb 1992

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P less than 0.10) to reduce the amnesia.

Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice

Article

Feb 1990

The effects of galanthamine, a long-acting acetylcholinesterase inhibitor, on passive avoidance and a modified Morris swim task were studied in mice. Lesions of the nucleus basalis magnocellularis (nBM) produced significant decreases in cortical choline acetyltransferase (ChAT) activity and profound deficits on the 24-h retention of a passive avoidance response and the reversal phase of the swim task. Galanthamine, administered 4 h before testing, improved performance of the two tasks in a dose-dependent fashion. In both tasks, galanthamine produced a U-shaped dose-response curve: the optimal dose was 3.0 mg/kg, IP on passive avoidance and 2.0 mg/kg on the swim task. The improvements in performance were not due to differences in motor activity or sensitivity to electric footshock. Behavioral tolerance did not occur from repeated doses of galanthamine; in fact, prior doses of galanthamine appeared to have a priming effect on later performance. In contrast to the effects in nBM-lesioned mice, galanthamine impaired performance of control mice on both tasks. Several characteristics of galanthamine suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease: 1) its ability to attenuate cognitive deficits in nBM-lesioned mice, 2) its relatively long half-life, and 3) its lack of tolerance effects in mice during 2 weeks of repeated dosing.

A comparison of the effects of two inhibitors on brain cholinesterase

Article

Jul 1987
NEUROPHARMACOLOGY

In the present paper various routes of administration (i.m., i.v. and i.c.v.) of physostigmine are compared and the effect of two drugs producing inhibition of cholinesterase, physostigmine and metrifonate, on the activity of cholinesterase in the brain of the rat and on levels of acetylcholine (ACh) and choline (Ch). After intramuscular administration of physostigmine (500 μg/kg), the activity of cholinesterase in brain was maximally inhibited (76%) at 5 min and recovered to 50% at 40 min. At 5 min, areas of the brain such as the striatum and medulla oblongata showed 49 and 67% inhibition, respectively. Levels of physostigmine in brain peaked at 5 min (1.28 nmol/g). With the exception of the cerebellum, there was a direct correlation between the concentration of physostigmine and inhibition of cholinesterase in a given area.

Relation of brain regional physostigmine concentration to cholinesterase activity and acetylcholine and choline levels in rat

Article

Aug 1986

The relationship between physostigmine (Phy) concentration, acetylcholine (ACh), choline (Ch) and cholinesterase (ChE) activity was examined in whole rat brain after the administration of [3H]Phy (650 microgram/kg i.m.). Cholinesterase inhibition was found to be inversely related to Phy levels. Maximal inhibition (80%) was seen at 5 min and by 2 hrs ChE activity had returned to control levels. Acetylcholine levels in whole brain peaked at 30 min at a concentration (80 nmol/g) 2.3 times higher than controls (33 nmol/g). Choline levels were not significantly altered. The regional distribution of Phy concentration and ChE activity was studied in six areas of the brain following i.m. administration of three different dosages of ( 3H]Phy. Physostigmine concentration and ChE activity showed a dose dependency in each area examined except in SP (medial septum). Striatum (ST) showed the greatest relative increase of ACh up to 30 min, when compared to other areas. Choline levels were not changed in any area with the exception of ST at 5 min where a decrease was seen. There was a relationship between ChE activity, Phy concentration and ACh levels in all areas examined with exception of the medulla oblongata (MO). Our results indicate that even though ChE was inhibited practically uniformly in all brain areas, the percent increase with respect to control animals and the relative increase of ACh varied widely from area to area. This finding has clinical implications in cases in which cholinomimetic therapy is used to elevate ACh levels in specific brain areas which show a cholinergic deficit.

The effects of physostigmine on acetylcholinesterase activity of CSF, plasma and brain. A comparison of intravenous and intra ventricular administration in beagle dogs

Article

Nov 1986
NEUROPHARMACOLOGY

The effects of various doses of physostigmine (Phy) on the activity of acetylcholinesterase (AChE) in plasma, cerebrospinal fluid (CSF) and brain were studied in beagle dogs. Two routes of administration were compared: intravenous (i.v.) and intracerebroventricular (i.c.v.). With intracerebroventricular administration, over 90% inhibition of the activity of AChE in CSF was reached within 5 min of injection at all doses (10-120 micrograms). Even at the smallest dose (10 micrograms), 50% inhibition of activity of the enzyme in CSF was still present at 90 min. The activity of AChE in plasma was only minimally inhibited by intraventricular administration of physostigmine. A different response was obtained following intravenous administration of physostigmine (250-1000 micrograms). The activity of AChE in plasma was inhibited but the activity of AChE in CSF was increased (36-80% at 180 min). This increase was dose-dependent and was blocked by pretreatment with atropine (1.5 mg i.v.) which suggests the involvement of a muscarinic receptor mechanism. The time course of the accumulation and regional distribution of [3H]physostigmine in brain also varied with the route of administration. At 5 min, with intravenous administration, physostigmine (1000 micrograms) reached greater concentrations and caused greater inhibition of AChE in the cortex. With intraventricular administration, physostigmine (80 micrograms) reached greater concentrations in two regions adjacent to the ventricular surface: the striatum and hippocampus. These regions also showed greater inhibition of the activity of AChE. Moderate to severe symptoms of cholinergic hyperactivity were seen only with the largest intraventricular dose (120 micrograms). This study suggests that intraventricular administration of physostigmine, a reversible inhibitor of cholinesterase (ChE), may offer distinct advantages over intravenous administration. Inhibition of acetylcholinesterase in CSF was more pronounced and persisted longer when physostigmine was administered directly into the CSF than when given intravenously. The implications of this study for a cholinergic therapy of Alzheimer's disease are discussed.

The Cholinergic Synapse and the Site of Memory

Article

Dec 1971

J. ANTHONY DEUTSCH

A simple hypothesis can explain the results obtained to date if we disregard those results when we wait 30 minutes after original learning to inject. The hypothesis is that, as a result of learning, the postsynaptic endings at a specific set of synapses become more sensitive to transmitter. This sensitivity increases with time after initial learning and then declines. The rate at which such sensitivity increases depends on the amount of initial learning. If the curve of transmission plotted against time is displaced upward with anticholinesterases then the very low portions will show facilitation, and the high portions will cause block (Fig. 8). The middle portions will appear unaffected (unless special experimental tests are made). If the curve of transmission is displaced down with anticholinergics, then the middle portion will appear unaffected and only the very early or late components will show block. The results are evidence that synaptic conductance is altered as a result of learning. So far it seems (i) that cholinergic synapses are modified as a result of learning and that it probably is the postsynaptic membrane that becomes increasingly more sensitive to acetylcholine with time after learning, up to a certain point. (ii) After this point, sensitivity declines, leading to the phenomenon of forgetting. (iii) There is also good evidence that there is an initial phase of declining sensitivity to cholinesterase or increasing sensitivity to anticholinergics. This could reflect the existence of a parallel set of synapses with fast decay that serve as a shortterm store. (iv) Increasing the amount of learning leads to an increase in conductance in each of a set of synapses without an increase in their number. (v) Both original learning and extinction are subserved by cholinergic synapses.

Nerve growth factor produces a temporary facilitation of recovery from entorhinal cortex lesions

Article

Mar 1983
BRAIN RES

Mature rats with entorhinal cortex lesions are impaired on learning a series of complex maze problems. A single, bilateral injection of NGF into the dorsal hippocampus caused an improvement during the initial maze learning, but it did not result in permanent recovery from the effects of the brain lesions. It is possible that chronic administration of NGF may have conferred more long-lasting functional recovery.

Alzheimer disease: Evidence for selective loss of cholinergic neurons in the Nucleus Basalis

Article

Aug 1981

The nucleus basalis of Meynert provides diffuse cholinergic input to the neocortex. When compared with an age- and sex-matched control, the nucleus basalis from a patient with Alzheimer disease demonstrated substantial reduction of neurons. Loss of this neuronal population may represent an anatomical correlate of the well-documented cholinergic derangement in Alzheimer disease.

Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: Selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase

Article

Sep 1995

One consistent finding in senile dementia of the Alzheimer's type is that the brain has reduced ability to synthesize acetylcholine. This has been related, in part, to memory dysfunctions. Although a cholinergic deficit is not singularly responsible for symptoms of dementia, treatment strategies have been designed to facilitate cholinergic activity by inhibiting acetylcholinesterase (AChE). To minimize toxicity, however, a cholinesterase inhibitor selective for only AChE would be an ideal treatment. The purpose of this study was to determine the selectivity of physostigmine, metrifonate, methanesulfonyl fluoride and tetrahydroaminoacridine (tacrine) toward AChE as compared with butyrylcholinesterase (BChE) in human cortex. The results show that methanesulfonyl fluoride is selective as an inhibitor of AChE as compared with BChE. Physostigmine inhibited AChE more than BChE. Metrifonate was found to inhibit BChE more than AChE. Tetrahydroaminoacridine inhibited both enzymes in a complex way.

Neuromodulation and Cortical Function - Modeling the Physiological-Basis of Behavior

Article

Mar 1995
BEHAV BRAIN RES

Michael E Hasselmo

Neuromodulators including acetylcholine, norepinephrine, serotonin, dopamine and a range of peptides alter the processing characteristics of cortical networks through effects on excitatory and inhibitory synaptic transmission, on the adaptation of cortical pyramidal cells, on membrane potential, on the rate of synaptic modification, and on other cortical parameters. Computational models of self-organization and associative memory function in cortical structures such as the hippocampus, piriform cortex and neocortex provide a theoretical framework in which the role of these neuromodulatory effects can be analyzed. Neuromodulators such as acetylcholine and norepinephrine appear to enhance the influence of synapses from afferent fibers arising outside the cortex relative to the synapses of intrinsic and association fibers arising from other cortical pyramidal cells. This provides a continuum between a predominant influence of external stimulation to a predominant influence of internal recall (extrinsic vs. intrinsic). Modulatory influence along this continuum may underlie effects described in terms of learning and memory, signal to noise ratio, and attention.

A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group

Article

Apr 1994

To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. Outpatients at 33 US centers. Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale--Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P < or = .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P < or = .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P < or = .002) and ADAS-Cog and FCCA (P < or = .001), as well as caregiver-global and quality-of-life assessments (P < or = .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.

Ameliorative effects of the centrally active cholinesterase inhibitor, NIK-247, on impairment of working memory in rats

Article

Feb 1993
PHYSIOL BEHAV

Using a three-panel runway task, the effects of NIK-247 on impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia were investigated in rats; these effects were compared with those of the well-known cholinesterase inhibitors, tetrahydroaminoacridine (THA) and physostigmine. Intraperitoneal injection of scopolamine (0.56 mg/kg) significantly increased the number of errors (pushes made on the two incorrect panels of the three-panel gates located at four choice points). NIK-247 (3.2-18 mg/kg PO), THA (1-10 mg/kg PO), and physostigmine (0.1 and 0.32 mg/kg IP) dose-dependently reduced the increase in errors induced by scopolamine. NIK-247 (32 mg/kg) was also effective in reducing the increase in errors produced by lesions of the dorsal hippocampus. A 5-min period of cerebral ischemia markedly increased the number of errors. NIK-247 (3.2 and 10 mg/kg), given immediately after blood flow recirculation and again 20 min before the runway test carried out 24 h after ischemia, significantly reduced the increase in errors expected to occur after ischemia. Tetrahydroaminoacridine (3.2 mg/kg) and physostigmine (0.1 mg/kg) similarly reversed the increased errors in ischemic rats. These results suggest that NIK-247 alleviates the impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia, possibly through activation of the central cholinergic system.

Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX, Maelicke A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49: 1-6

Article

Feb 1996

Similar to the gamma-aminobutyric acidA receptor and the N-methyl-D-aspartate subtype of glutamate receptor, neuronal nicotinic acetylcholine receptors are subject to positive modulatory control by allosterically acting ligands. Exogenous ligands such as galanthamine and the neurotransmitter 5-hydroxytryptamine, when applied in submicromolar concentrations with nicotinic agonists, significantly increase the frequency of opening of nicotinic receptor channels and potentiate agonist-activated currents. Because these effects have been shown to be blocked by the monoclonal antibody FK1, they are mediated by binding sites that are located on alpha subunits of nicotinic receptors and distinct from those for acetylcholine and acetylcholine-competitive ligands. At higher concentrations, the potentiating effect of these ligands decreases and is eventually overcome by an inhibition of the agonist-induced response. The sensitizing actions of galanthamine, 5-hydroxytryptamine, and related compounds, at submicromolar concentrations, may reflect the existence of cross-talk between adjacent neuroreceptors and synapses in the central nervous system and thus suggests the formation of transiently active chemical networks in the vertebrate brain.

Effects of Postoperative Housing Conditions on Functional Recovery in Rats with Lesions of the Hippocampus, Subiculum, or Entorhinal Cortex

Article

Feb 1997

In order to study the effects of differential housing conditions on recovery from damage to different components of the hippocampal formation, 85 rats received bilateral lesions of the hippocampus, entorhinal cortex, or subiculum or sham surgery and then were housed for 30 days in either an enriched environment or an impoverished environment. Rats were subsequently tested on a battery of tasks for assessing locomotor activity in their home cage, reactivity to novelty, spatial working and reference memory in the Morris water maze, and learning in the Hebb-Williams maze. Rats with the hippocampus removed showed impairments in most of the tasks we used (home-cage and novelty-induced locomotor activity, water maze, and Hebb-Williams maze). Most of the deficits induced by lesions to the entorhinal cortex were similar to those induced by the removal of the hippocampus. Some differences appear to be among the deficits induced by the lesions of these structures when assessing the home-cage locomotor activity, the reactions to novelty, and one aspect of the Hebb-Williams maze learning. Lesions to the subiculum induced only an impairment in the probe trial of the water-maze task. Confirming and extending previous findings in rats with various (but nonexcitotoxic) lesions of the hippocampus, an enriched environment had a beneficial effect on several of the deficits observed in the tasks we used. Further, only the rats with hippocampal lesions benefitted from having been housed in the enriched environment. However, their facilitated recovery was not observed in all tasks. After damage to different components of the hippocampal formation, the beneficial effects induced by the enriched housing conditions were shown to be both lesion-locus- and task-dependent.

Extension of a New Two-Trial Memory Task in the Rat: Influence of Environmental Context on Recognition Processes

Article

Apr 1997

A two-trial memory task, based on place or object exploration in a Y-maze, was developed to study recognition processes in young and aged Sprague-Dawley rats (Dellu et al., 1992). This paradigm avoids the use of electric shocks or deprivations that may have nonspecific effects, and the task does not require learning of a rule, i.e., involves essentially working memory. A number of behavioral parameters in several animals could be recorded automatically, thus allowing a detailed analysis of behavior and a simultaneous testing of several animals. We extended this task in order to evaluate the role of contextual information in recognition memory. When the contextual environment during acquisition and retrieval trials was unchanged, place recognition remained intact despite interpolated explorations. When the contextual environment during acquisition and retrieval trials was changed, object recognition was impaired. It was clearly shown that the correct choice between two discrete cues (e.g., small objects) is conditional on more diffuse environmental cues. Thus, it can be hypothesized that at least two kinds of recognition processes can be assessed in animals: an automatic process, based on a discrimination between familiarity and novelty, and a second process, more cognitively based and more effortful. In conclusion, the two-trial task in the Y-maze is sensitive, specific, and fast. It allows the study of both spatial and nonspatial memory, allows the study of different levels (automatic vs controlled) of cognitive processes and their neuroanatomical substrates, and may be profitably employed in aging studies and neuropharmacological research in general.

Persistent short term memory deficits in Hebb-Williams maze performance are shown by rats with unilateral entorhinal cortex lesions

Article

Mar 1997

The spatial abilities of adult, male Sprague-Dawley rats in the Hebb-Williams maze were examined at 6 months after unilateral electrolytic entorhinal cortex lesions. Compared with sham-operated rats, their performance was impaired in both initial entry and repeat entry errors over 12 consecutive problems, using immediate starting replacement for the 6 trials per problem. The configurations of the 12 maze problems are independent, and deficits were seen over the entire course of the testing. This study indicates that Hebb-Williams maze performance deficits after unilateral entorhinal cortex lesion are persistent and can be seen up to 6 months after injury.

Free recall and recognition in a network model of the hippocampus: Simulating effects of scopolamine on human memory function

Article

Jan 1998
BEHAV BRAIN RES

Free recall and recognition are simulated in a network model of the hippocampal formation, incorporating simplified simulations of neurons, synaptic connections, and the effects of acetylcholine. Simulations focus on modeling the effects of the acetylcholine receptor blocker scopolamine on human memory. Systemic administration of scopolamine is modeled by blockade of the cellular effects of acetylcholine in the model, resulting in memory impairments replicating data from studies on human subjects. This blockade of cholinergic effects impairs the encoding of new input patterns (as measured by delayed free recall), but does not impair the delayed free recall of input patterns learned before the blockade. The impairment is selective to the free recall but not the recognition of items encoded under the influence of scopolamine. In the model, scopolamine blocks strengthening of recurrent connections in region CA3 to form attractor states for new items (encoding impaired) but allows recurrent excitation to drive the network into previously stored attractor states (retrieval spared). Neuron populations representing items (individual words) have weaker recurrent connections than neuron populations representing experimental context. When scopolamine further weakens the strength of recurrent connections it selectively prevents the subsequent reactivation of item attractor states by context input (impaired free recall) without impairing the subsequent reactivation of context attractor states by item input (spared recognition). This asymmetry in the strength of attractor states also allows simulation of the list-strength effect for free recall but not recognition. Simulation of a paired associate learning paradigm predicts that scopolamine should greatly enhance proactive interference due to retrieval of previously encoded associations during storage of new associations.

Tetrahydroaminoacridine, a cholinesterase inhibitor, and D -cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation

Article

Jun 1998
NEUROREPORT

The present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D-cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions.

Potent acetylcholinesterase inhibitors: Design, synthesis, and structure - Activity relationships of bis-interacting ligands in the galanthamine series

Article

Nov 1998
BIOORGAN MED CHEM

New galanthamine derivatives, especially bis-interacting ligands 3-5 and 7-9 were prepared in order to interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase activities, and the structure-activity relationships of bis-interacting ligands are reported. Compounds 4d-e were found to be more potent than galanthamine and tacrine in inhibiting AChE.

Cholinesterase Inhibitors: A Therapeutic Strategy for Alzheimer Disease

Article

May 1999

To provide a review of acetylcholinesterase inhibitors (AChEIs) tested as therapeutic agents for Alzheimer disease (AD). MEDLINE searches (January 1986-July 1998) identified pertinent literature. Selected references from these articles, as well as abstracts from recent meetings and package insert literature from approved compounds, were also used as source material. AChEIs were reviewed with regard to chemical structure, mechanism of inhibition, substrate specificity, pharmacokinetics/pharmacodynamics, safety/tolerability, and efficacy. Cholinergic deficits, leading to cognitive impairment, are a significant aspect of neurodegeneration in AD. AChEIs reduce the degradation of acetylcholine, thus enhancing cholinergic transmission. In addition to the two agents approved by the Food and Drug Administration, tacrine and donepezil, six other compounds of diverse chemical structure and mechanism of inhibition including physostigmine, metrifonate, rivastigmine, and galantamine are under investigation as potential therapy for AD. These compounds are structurally diverse, possess unique patterns of specificities for the various forms of cholinesterase enzymes, use distinct mechanisms of enzyme inhibition, present unique adverse event profiles, and offer relatively similar mean gains in cognitive abilities to patients with AD in controlled clinical trials. Relative to placebo, new AChEIs in development provide modest improvements in cognition for patients with mild to moderate AD, with improved tolerability profiles and more convenient dosing relative to tacrine. The availability of a wide array of AChEIs soon to be accessible to patients with AD will provide additional options to those who cannot tolerate or do not respond to drugs currently used for AD.

Effect of the acetylcholinesterase inhibitor galantamine on learning and memory in prolonged alcohol intake rat model of acetylcholine deficit

Article

Jun 1999
METHOD FIND EXP CLIN

Different cholinomimetics are used in conditions of CNS acetylcholine (ACh) deficit. In this study, we examined the effect of the acetylcholinesterase inhibitor galanthamine in a prolonged alcohol intake model of ACh deficit in male Wistar rats. After 16 weeks of alcohol intake and a 2-week pause, rats administered galanthamine (2.5 mg/kg/day i.p.) showed an improved speed of learning and short-term memory in the shuttle box test as compared to the saline-injected alcoholic group (p < 0.05). Four weeks later, significant improvement in the passive avoidance memory of alcoholic galanthamine-treated rats was noted in the eight-arm radial maze (14 day test duration) as compared to the saline-injected alcoholic group (p < 0.05). During the first week in the shuttle box test, the nonalcoholic galanthamine-treated animals exhibited significantly impaired performance as compared to the untreated nonalcoholic control, while four weeks later, in the eight-arm radial maze, both groups did not differ. Our results show that galanthamine improves the speed of learning, short-term memory and spatial orientation of rats in conditions of prolonged alcohol intake.

Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 54: 2269-2276

Article

Jul 2000

To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. After 5 months, the galantamine-placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses). Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. Treatment discontinuations due to adverse events were low in all galantamine groups (6 to 10%) and comparable with the discontinuation rate in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild. Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

Raskind MA, Peskind ER, Wessel T, Yuan W. Calantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 54: 2261-2268

Article

Jul 2000

Galantamine is a reversible, competitive cholinesterase inhibitor that also allosterically modulates nicotinic acetylcholine receptors. These mechanisms of action provided the rationale for a therapeutic trial of galantamine in AD. A 6-month, multicenter, double-blind trial was undertaken in 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Eligible patients then entered a 6-month, open-label study of the 24 mg/d dose. Primary efficacy measures were the 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable. Galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 (p < 0.001 in both cases). Both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05). Therapeutic response to galantamine was not affected by APOE genotype. At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months. The most common adverse events, which were predominantly gastrointestinal, decreased in frequency during long-term treatment. There was no evidence of hepatotoxicity. Galantamine is effective and safe in AD. At 6 months, galantamine significantly improved cognition and global function. Moreover, cognitive and daily function were maintained for 12 months with the 24 mg/d dose.

Oscillatory Activity in Entorhinal Neurons and Circuits: Mechanisms and Function

Article

Jul 2000

Layers II and V of the entorhinal cortex (EC) occupy a privileged anatomical position in the temporal lobe memory system that allows them to gate the main flow of information in and out of the hippocampus, respectively. In vivo studies have shown that layer II of the EC is a robust generator of theta as well as gamma activity. Theta may also be present in layer V, but the layer V network is particularly prone to genesis of short-lasting high-frequency oscillations ("ripples"). Interestingly, in vitro studies have shown that EC layers II and V, but not layer III, have the potential to act as independent pacemakers of population oscillatory activity. Moreover, it has also been shown that subgroups of principal neurons both within layers II and V, but not layer III, are endowed with autorhythmic properties. These are characterized by subthreshold oscillations where the depolarizing phase is driven by the activation of "persistent" Na+ channels. We propose that the oscillatory properties of layer II and V neurons and local circuits are responsible for setting up the proper temporal dynamics for the coordination of the multiple sensory inputs that converge onto EC and thus help to generate sensory representations and memory encoding.

Two‐Phase Computational Model Training Long‐Term Memories in the Entorhinal‐Hippocampal Region

Article

Jul 2000

The computational model described here is driven by the hypothesis that a major function of the entorhinal cortex (EC)-hippocampal system is to alter synaptic connections in the neocortex. It is based on the following postulates: (1) The EC compares the difference between neocortical representations (primary input) and feedback information conveyed by the hippocampus (the "reconstructed input"). The difference between the primary input and the reconstructed input (termed "error") initiates plastic changes in the hippocampal networks (error compensation). (2) Comparison of the primary input and reconstructed input requires that these representations are available simultaneously in the EC network. We suggest that compensation of time delays is achieved by predictive structures, such as the CA3 recurrent network and EC-CA1 connections. (3) Alteration of intrahippocampal connections gives rise to a new hippocampal output. The hippocampus generates separated (independent) outputs, which, in turn, train long-term memory traces in the EC (independent components, IC). The ICs of the long-term memory trace are generated in a two-step manner, the operations of which we attribute to the activities of the CA3 (whitening) and CA1 (separation) fields. (4) The different hippocampal fields can perform both nonlinear and linear operations, albeit at different times (theta and sharp phases). We suggest that long-term memory is represented in a distributed and hierarchical reconstruction network, which is under the supervision of the hippocampal output. Several of these model predictions can be tested experimentally.

Cholinergic modulation of the hippocampus during encoding and retrieval

Abstract

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