Acetylcholine neuromodulation in normal and abnormal learning and memory: vigilance control in waking, sleep, autism, amnesia, and Alzheimer's disease

This article provides a unified mechanistic neural explanation of how learning, recognition, and cognition break down during Alzheimer's disease, medial temporal amnesia, and autism. It also clarifies whey there are often sleep disturbances during these disorders. A key mechanism is how acetylcholine modules vigilance control in cortical layer

Cholinergic, but not dopaminergic or noradrenergic, enhancement sharpens visual spatial perception in humans

The neuromodulator acetylcholine modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target-flanker distance. We found that cholinergic enhancement with the cholinesterase inhibitor donepezil improved target detection, and modeling suggested that this was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions. In Experiment 2, we tested whether these effects were selective to the cholinergic system or would also be observed following enhancements of related neuromodulators dopamine or norepinephrine. Unlike cholinergic enhancement, dopamine (bromocriptine) and norepinephrine (guanfacine) manipulations did not improve performance or systematically alter the spatial profile of perceptual interactions between targets and distractors. These findings reveal mechanisms by which cholinergic signaling influences visual spatial interactions in perception and improves processing of a visual target among distractors, effects that are notably similar to those of spatial selective attention

Neurosystems: brain rhythms and cognitive processing

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.098352 - Wellcome Trust; 5R01NS067199 - NINDS NIH HH

Effet de la stimulation cholinergique sur la perception visuelle chez le rat et l'humain : études comportementales et électrophysiologiques

Le système cholinergique joue un rôle important dans de nombreuses fonctions cognitives telles que l'attention et l'apprentissage perceptuel. La stimulation pharmacologique du système cholinergique par le donépézil, un inhibiteur de l’acétylcholinestérase, est un moyen efficace pour améliorer les fonctions cognitives et le traitement cortical via les récepteurs muscariniques et nicotiniques. En effet, le donépézil permet l'accumulation d'acétylcholine dans la fente synaptique. Toutefois, l’effet de la stimulation pharmacologique du système cholinergique sur le traitement visuel complexe et l’apprentissage perceptuel n’est pas encore bien défini. L'objectif de cette thèse est d'étudier, d'une part, l'effet de la combinaison d’un entrainement visuel répétitif avec une stimulation cholinergique sur les capacités visuelles chez le rat et l’humain et, d'autre part, l’effet de la stimulation pharmacologique du système cholinergique sur la restauration des capacités visuelles dans un modèle de déficit visuel chez les rats. Nos résultats ont montré qu’un entrainement visuel/cholinergique entraînait : 1) une potentialisation à long terme de la réponse visuelle corticale chez le rat, 2) une récupération plus rapide des capacités visuelles chez la rat suite un écrasement du nerf optique 3) une amélioration de la performance dans une tâche perceptivo-cognitive de haut niveau plus rapide et conservée dans le temps chez les jeunes sujets sains. Le patron d’électroencéphalographie chez le sujet humain pratiquant une tâche d’attention visuelle n’est cependant pas modifié par l’administration d’une dose unique de donépézil. Ensembles, ces résultats soulignent le bénéfice considérable de la combinaison d’une stimulation du système cholinergique lors de l’entrainement visuel répétitif afin d'obtenir des améliorations de la perception visuelle. Cela présente une avenue très intéressante pour la réhabilitation chez les humains.The cholinergic system plays an important role in many cognitive functions such as attention and perceptual learning. Pharmacological stimulation of the cholinergic system via donepezil, an acetylcholinesterase inhibitor, is an efficient tool for enhancing cognitive functions and cortical processing via muscarinic and nicotinic receptors. In fact, donepezil allows the build-up of acetylcholine in the synaptic cleft. However, whether pharmacological manipulation of the cholinergic system has an effect on complex visual processing and perceptual learning remains unclear. The goal of this thesis is to investigate on the one hand the effect of combining repetitive visual training with cholinergic enhancement on visual capacities in rats and humans and on the other hand the effect of the pharmacological stimulation of the cholinergic system on visual restoration in a model of visual deficit in rats. Our results showed that cholinergic potentiation induces 1) a long-term potentiation of visual cortical response following repetitive visual stimulation, 2) a faster recovery of brightness discrimination in rats with an optic nerve crush, 3) a faster progression of and a sustained performance in a highly demanding perceptual-cognitive task for healthy young humans. However, the EEG pattern for subjects performing a visual attention task is not modified by a single administration of donepezil. Together these results underline the substantial benefice of combining cholinergic enhancement with visual training in order to obtain visual perception improvements, which presents an interesting avenue for visual rehabilitation paradigm in humans

Effects of cholinesterase inhibition on brain function

Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work - both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmine-induced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section

Chronic Olanzapine Treatment Eliminates Cognitive Deficits Produced by Neonatal Quinpirole Treatment.

This study evaluated the effects of chronic olanzapine treatment on cognitive performance and neurochemical function in a rodent model of schizophrenia. Animals were neonatally treated with quinpirole, a dopamine D2 receptor agonist, or saline. Quinpirole treatment produces an increase of dopamine D2 receptor sensitivity that extends into adulthood, known as D2 receptor priming, similar to a phenomenon that occurs in schizophrenia. These same rats were treated in adulthood for 28 days with olanzapine, an atypical antipsychotic, or saline. Dopamine D2- primed rats demonstrated significant deficits on a cognitive task that were alleviated by olanzapine treatment. Brain tissue analysis revealed that D2-primed animals demonstrated a significant decrease in the neurotrophins nerve growth factor (NGF) in the hippocampus and brain-derived neurotrophic factor (BDNF) in the frontal cortex. Olanzapine treatment alleviated the decrease in NGF. The results suggest that olanzapine eliminates cognitive impairment and may have neuroprotective properties in the hippocampus of D2-primed rats

Processing complex sounds passing through the rostral brainstem : The new early filter model

The rostral brainstem receives both “bottom-up” input from the ascending auditory system and “top-down” descending corticofugal connections. Speech information passing through the inferior colliculus of elderly listeners reflects the periodicity envelope of a speech syllable. This information arguably also reflects a composite of temporal-fine-structure (TFS) information from the higher frequency vowel harmonics of that repeated syllable. The amplitude of those higher frequency harmonics, bearing high frequency TFS information, correlates positively with the word recognition ability of elderly listeners under reverberatory conditions. Also relevant is that working memory capacity, which is subject to age-related decline, constrains the processing of sounds at the level of the brainstem. Turning to the effects of a visually presented sensory or memory load on auditory processes, there is a load-dependent reduction of that processing, as manifest in the auditory brainstem responses evoked by to-be-ignored clicks. Wave V decreases in amplitude with increases in the visually presented memory load. A visually presented sensory load also produces a load-dependent reduction of a slightly different sort: The sensory load of visually presented information limits the disruptive effects of background sound upon working memory performance. A new early filter model is thus advanced whereby systems within the frontal lobe (affected by sensory or memory load) cholinergically influence top-down corticofugal connections. Those corticofugal connections constrain the processing of complex sounds such as speech at the level of the brainstem. Selective attention thereby limits the distracting effects of background sound entering the higher auditory system via the inferior colliculus. Processing TFS in the brainstem relates to perception of speech under adverse conditions. Attentional selectivity is crucial when the signal heard is degraded or masked: e.g., speech in noise, speech in reverberatory environments. The assumptions of a new early filter model are consistent with these findings: A subcortical early filter, with a predictive selectivity based on acoustical (linguistic) context and foreknowledge, is under cholinergic top-down control. A limited prefrontal capacity limitation constrains this top-down control as is guided by the cholinergic processing of contextual information in working memory.Peer reviewe

Role of prefrontal cortex and cholinergic modulation in attentional performance in rats

The present thesis investigates the role of the prefrontal cortex and cholinergic modulation in attentional performance, and to a lesser extent, inhibitory response control, in rats. A greater understanding of these functions is important for the effective treatment of attentional and impulsive control deficits, present in a range of neuropsychiatric disorders. For this field to progress, the assessment of attentional performance in a similar manner across humans and animals is crucial. In the present thesis, attentional performance was assessed on the novel, touchscreen-based rodent continuous performance task (rCPT), which assesses sustained, focused attention in essentially an identical manner to CPTs commonly used in the clinic. Findings were compared to performance on the well-characterised 5-choice serial reaction time task (5-CSRTT), which assesses sustained, spatial divided attention and shares some, but not all characteristics of CPTs. The series of experiments described in this thesis contributes to the understanding of the role of the prefrontal cortex and cholinergic modulation in attentional performance; they also highlight differences between the two tasks in behaviour, brain functions and networks. Excitotoxic lesions of the medial prefrontal cortex (mPFC) and a range of cholinergic systemic pharmacology validated the role of the prefrontal cortex and cholinergic modulation in rCPT performance. A chemogenetic study also validated the role of the ascending cholinergic basal forebrain system in 5-CSRTT performance. These findings support 1. the idea of the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function; 2. a double dissociation of mPFC sub-regions on attentional performance, in which the prelimbic cortex (PL) appears to play a role in rCPT performance, compared with a role of the anterior cingulate cortex (ACC) in 5-CSRTT performance; and 3. a role of ascending cholinergic projections from the basal forebrain to the ACC in 5-CSRTT performance. These findings also establish the development of a successful flanker distractor probe in rodents on the rCPT. This thesis concludes with an important comparison of the attentional and impulsivity measures in the rCPT compared to the 5-CSRTT, to help provide guidelines as to which task is most appropriate to use for particular research questions

L’effet d’une potentialisation cholinergique sur la régionalisation et la synchronisation corticale d’un conditionnement visuel

Cette thèse démontre qu’une potentialisation cholinergique durant un conditionnement visuel typique permet de raffiner la réponse et la connectivité des neurones des aires corticales visuelles ainsi que des aires associatives supérieures via un phénomène plastique. Afin de déterminer cet effet sur un conditionnement visuel monoculaire sur la réponse corticale, nous avons utilisé un système d’imagerie calcique à large champ sur des souris adultes exprimant le rapporteur calcique GCaMP6s. La potentialisation cholinergique était causée par l’administration de donepezil (DPZ), un inhibiteur de l’acétylcholinestérase qui dégrade l’acétylcholine. Cette technique, possédant de bonnes résolutions spatiale et temporelle, a permis l’observation de l’activité neuronale dans les couches supra granulaires du cortex visuel primaire (V1), des aires secondaires (A, AL, AM, LM, PM, RL) ainsi que dans le cortex retrosplénial (RSC). Il a été alors possible de mesurer les modifications d’activité neuronale de ces aires au repos et lors de la présentation de stimulations visuelles, composées de réseaux sinusoïdaux d’orientation et de contraste varié. La réponse corticale des animaux naïfs est similaire en matière d’amplitude et de sensibilité au contraste pour chacune des orientations de stimulations visuelles présentées. Le conditionnement visuel accompagné de l’administration de DPZ diminue significativement la réponse neuronale évoquée par le stimulus conditionné dans la majorité des aires observés alors qu’il ne modifie pas la réponse à la stimulation non conditionnée. Cet effet n’est pas présent sans potentialisation cholinergique. Il est intéressant de noter qu’un effet sur la corrélation d’activation est observé exclusivement dans les aires de la voie visuelle ventrale. Finalement, le conditionnement monoculaire diminue la corrélation au repos entre les aires visuelles monoculaire et binoculaire de chacun des hémisphères, un effet qui disparaît lors de l’administration du DPZ durant le conditionnement. En conclusion, nos résultats démontrent une diminution de l’amplitude et de l’étalement de la réponse corticale dans les couches supra-granulaires de PM et de V1 en réponse à notre traitement. Nous suggérons que ces résultats démontrent une diminution de la réponse excitatrice causée par l’augmentation de l’activité inhibitrice en réponse à la stimulation conditionnée.The cholinergic system of the basal forebrain modulates the visual cortex and enhances visual acuity and discrimination when activated during visual conditioning. As wide-field calcium imaging provides cortical maps with a fine regional and temporal resolution, we used this technique to determine the effects of the cholinergic potentiation of visual conditioning on cortical activity and connectivity in the visual cortex and higher associative areas. Mesoscopic calcium imaging was performed in head-fixed GCaMP6s adult mice during resting state or monocular presentation of conditioned (0.03 cpd, 30°, 100% contrast) or non-conditioned 1Hz-drifting gratings (30°, 50 and 75% contrast; 90°, 50, 75 and 100% contrast), before and after conditioning. The conditioned stimulus was presented 10 min daily for a week. Donepezil (DPZ, 0.3 mg/kg, s.c.), a cholinesterase inhibitor that potentiates cholinergic transmission, or saline were injected prior to each conditioning session and compared to a sham-conditioned group. Cortical maps were established, then amplitude, duration, and latency of the peak response, as well as size of activation were measured in the primary visual cortex (V1), secondary visual areas (AL, A, AM, PM, LM, RL), the retrosplenial cortex (RSC) , and higher cortical areas. Visual stimulation increased calcium signaling in all primary and secondary visual areas, but no other cortices (except RSC). The cortical responses were sensitive to contrast but not to grating orientation. There were no significant effects of sham-conditioning or conditioning alone, but DPZ treatment during conditioning significantly decreased the evoked neuronal activity response for the conditioned stimulus in V1, AL, PM, and LM. The size of activated area and signal-to-noise ratio were affected in some cortical areas. There was no effect for the non-conditioned stimuli. Interestingly, signal correlation appeared only between V1 and the ventral visual pathway and RSC and was decreased by DPZ administration. The resting state activity was slightly correlated and rarely affected by treatments, except between binocular and monocular V1 in both hemispheres. In conclusion, despite the previously observed enhancement of the cortical response of layer 4 after visual conditioning with cholinergic potentiation, mesoscale cortical calcium imaging showed that cholinergic potentiation diminished the cortical activation in layer 2/3 and sharpened the responses to the conditioned visual stimulus in V1 and PM, via a layer-dependent effect

THE ROLE OF ACETYLCHOLINE IN ATTENTION AND LAPSES IN ATTENTION IN RATS USING THE MODE AND DEVIATION FROM MODE OF REACTION TIME LATENCY

Attention Deficit-Hyperactivity Disorder (ADHD) is currently the neurodevelopmental disorder most commonly diagnosed in children in the United States, and one of the defining characteristics of ADHD is inattention. Inattention is marked by increased lapses in attention, and when assessed clinically, it has been highly correlated with reaction-time variability (RTV). Evidence from the human/clinical literature has shown an inherently higher RTV to be the primary quantitative indicator of an ADHD diagnosis. Reaction-time distributions are characterized by an asymmetrical rightward skew, and because of the prevalence of this presentation, it has been theorized that the distribution peak and skew represent separate phenomena, or attention and lapses in attention respectively. By separating out the motor component of reaction time and employing parameters that closely parallel those used in clinical assessments of attention, the two-choice serial reaction time task (2-CSRTT) yields a measure in rodents, initiation time (IT), akin to human reaction time. Similar to the analysis of human reaction time using an ex-Gaussian approach, the peak and skew of IT distributions can be dissociated and separately analyzed using the mode and deviation from mode (distribution mean minus the mode), thus rendering a rodent variability measure indicative of lapses in attention. The effects of attentional stress are cumulative and can be induced via manipulations of both environmental and external factors. The current studies utilized both by decreasing signal salience and blocking the neurotransmitter, acetylcholine. Additionally, in order to separate high performing rats from low performers, a median split based on training IT devmode was introduced as a third independent variable. Lapses significantly increased when salience was reduced but remained unaffected by scopolamine HBr for all rats, as no main effect of baseline performance was observed following the median split. However, a three-way interaction effect was observed and under less salient conditions, lapses in attention increased for low performing rats following the blockade of acetylcholine transmission. The current findings, therefore, implicate acetylcholine in the facilitation and regulation of higher order attentional processes, such as sustaining attention and maintaining vigilance, and indicate an increased sensitivity to attentional stress in low performers