Cortical Acetylcholine Research Articles

Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.

Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention

Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1–3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10–20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.

Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer's Disease-Could BCHE Genotyping Be Helpful in Alzheimer's Therapy?

Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century since the first AD patient was diagnosed. Drugs increasing the availability of neurotransmitters at synapses in the brain are used clinically in the treatment of AD dementia, and cholinesterase inhibitors (ChEIs) are the mainstay of the therapy. A detrimental effect on cognitive function has been reported in patients with pharmacological inhibition of acetylcholinesterase (AChE) by ChEIs and reduced butyrylcholinesterase (BChE) activity due to the single nucleotide polymorphisms. The BChE K-variant (rs1803274), the most common genetic variant of the BCHE gene, was thought to reduce enzyme activity reflecting the lower clinical response to rivastigmine in AD patients. During ChEIs therapy, patients carrying reduced-activity BChE do not present such improved attention like patients with the wild-type enzyme. On the other hand, alterations in the BCHE gene causing enzyme activity reduction may delay AD onset in patients at risk by preserving the level of cortical acetylcholine (ACh). Based on our previous results, we conclude that SNPs localized outside of the coding sequence, in 5’UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene, but not solely K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity. Therefore, we suspect that not BChE-K itself, but these coexisting SNPs (rs1126680 and rs55781031), could be associated with deleterious changes in cognitive decline in patients treated with ChEIs. Based on the results, we suggest that SNPs (rs1126680) and/or (rs55781031) genotyping should be performed to identify subjects at risk for lowered efficacy ChEIs therapy, and such patients should be treated with a lower rivastigmine dosage. Finally, our sequence analysis of the N-terminal end of N-BChE revealed evolutionarily conserved amino acid residues that can be involved in disulfide bond formation and anchoring of N-BChE in the cell membrane.

Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders.

The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), which is currently the only D1 PAM for which published in vivo data is available. In vitro studies showed selective potentiation of the human D1 receptor without significant allosteric agonist effects. Due to a species difference in affinity for DETQ, transgenic mice expressing the human D1 receptor (hD1 mice) were used in vivo. In contrast to D1 agonists, DETQ increased locomotor activity over a wide dose-range without inverted U-shaped dose response or tachyphylaxis. DETQ also reversed hypo-activity in mice with dopamine depletion due to reserpine pretreatment, suggesting potential for treatment of motor symptoms in Parkinson's disease. Potential pro-cognitive effects were supported by improved performance in the novel object recognition task, enhanced release of cortical acetylcholine and histamine, and increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB. In addition, DETQ enhanced wakefulness in EEG studies and decreased immobility in the forced-swim test. Together, these results provide support for potential utility of D1 PAMs in the treatment of several neuropsychiatric disorders. LY3154207, a close analog of DETQ, is currently in phase 2 clinical trials.

The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice

Diminished dopamine D1 stimulation may contribute to cognitive impairment in Alzheimer’s and Parkinson’s diseases, schizophrenia, and other neuropsychiatric disorders. However, orthosteric D1 receptor (D1R) agonists produce receptor desensitization and an inverted U-shaped dose-response curve, but positive allosteric modulators (PAMs) do not. We examined the cognitive effects of DETQ, a D1R PAM, in mice genetically modified to express the human D1 receptor (“hD1 mice”). Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, dosed seven days (subchronic), followed by withdrawal, produced a prolonged deficit in novel object recognition (NOR) memory, which was reversed by acute treatment with DETQ, with no evidence for an inverted U-shaped response. This was blocked by the D1R antagonist, SCH391660. Single doses of D1R agonists, SKF38393 and SKF82958, and the acetylcholinesterase inhibitor, rivastigmine, alone and the combination of subeffective doses of both DETQ and rivastigmine, also restored NOR in both subchronic PCP-treated in hD1 mice. DETQ increased cortical and hippocampal acetylcholine efflux after both acute and subchronic dosing in hD1 mice. Subchronic but not acute DETQ, inhibited glutamate and GABA efflux. DETQ-induced acetylcholine efflux was absent in subchronic PCP-treated mice, indicating that restoration of NOR in subchronic PCP-treated mice does not require cortical acetylcholine efflux. This is additional evidence that DETQ stimulates D1R without producing an inverted-U-shaped response curve and increases neurotransmitter release in the mPFC and HIP without causing tolerance. The ability of D1 PAMs to improve cognition in humans with neuropsychiatric disorders without evidence of tolerance or an inverted-U-shaped response curve needs to be established clinically.

From eyes-closed to eyes-open: Role of cholinergic projections in EC-to-EO alpha reactivity revealed by combining EEG and MRI.

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system.

5-HT1A parital agonism and 5-HT7 antagonism restore episodic memory in subchronic phencyclidine-treated mice: role of brain glutamate, dopamine, acetylcholine and GABA.

The effect of atypical antipsychotic drugs (AAPDs), e.g., lurasidone, to improve cognitive impairment associated with schizophrenia (CIAS), has been suggested to be due, in part, to enhancing release of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in cortex and hippocampus. The present study found acute lurasidone reversed the cognitive deficit in novel object recognition (NOR) in subchronic (sc) phencyclidine (PCP)-treated mice, an animal model for CIAS. This effect of lurasidone was blocked by pretreatment with the 5-HT1AR antagonist, WAY-100635, or the 5-HT7R agonist, AS 19. Lurasidone significantly increased medial prefrontal cortex (mPFC) ACh, DA, and Glu efflux, all of which were blocked by WAY-100635, with similar effects in the dorsal striatum (dSTR), except for the absence of an effect on Glu increase. AS 19 inhibited Glu, but not DA efflux, in the dSTR. The selective 5-HT7R antagonist, SB-26970, increased mPFC DA, 5-HT, Glu, and, importantly, also GABA efflux and striatal DA, NE, 5-HT, and Glu efflux, indicating tonic inhibition of the release of these neurotransmitters by 5-HT7R stimulation. These results provide new evidence that GABA release in the mPFC is tonically inhibited by 5-HT7R stimulation and suggest that a selective 5-HT7R antagonist might be clinically useful to enhance cortical GABAergic release. All SB-269970 effects were blocked by AS 19 or WAY-100635, suggesting 5-HT1AR agonism is necessary for the release of these neurotransmitters by SB-269970. Lurasidone increased ACh, DA, and NE but not Glu efflux in mPFC and dSTR DA and Glu efflux in 5-HT7 KO mice. We conclude that lurasidone-induced Glu efflux in mPFC requires 5-HT7R antagonism while its effects on cortical ACh and DA efflux are mainly due to 5-HT1AR stimulation.

TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABAA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia

GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABAA α2,3 subtype-selective GABAA partial agonist and α1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABAA antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABAA agonists may be of benefit to treat CIAS.

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Cholinergic Modulation of Frontoparietal Cortical Network Dynamics Supporting Supramodal Attention.

A critical function of attention is to support a state of readiness to enhance stimulus detection, independent of stimulus modality. The nucleus basalis magnocellularis (NBM) is the major source of the neurochemical acetylcholine (ACh) for frontoparietal cortical networks thought to support attention. We examined a potential supramodal role of ACh in a frontoparietal cortical attentional network supporting target detection. We recorded local field potentials (LFPs) in the prelimbic frontal cortex (PFC) and the posterior parietal cortex (PPC) to assess whether ACh contributed to a state of readiness to alert rats to an impending presentation of visual or olfactory targets in one of five locations. Twenty male Long-Evans rats underwent training and then lesions of the NBM using the selective cholinergic immunotoxin 192 IgG-saporin (0.3 μg/μl; ACh-NBM-lesion) to reduce cholinergic afferentation of the cortical mantle. Postsurgery, ACh-NBM-lesioned rats had less correct responses and more omissions than sham-lesioned rats, which changed parametrically as we increased the attentional demands of the task with decreased target duration. This parametric deficit was found equally for both sensory targets. Accurate detection of visual and olfactory targets was associated specifically with increased LFP coherence, in the beta range, between the PFC and PPC, and with increased beta power in the PPC before the target's appearance in sham-lesioned rats. Readiness-associated changes in brain activity and visual and olfactory target detection were attenuated in the ACh-NBM-lesioned group. Accordingly, ACh may support supramodal attention via modulating activity in a frontoparietal cortical network, orchestrating a state of readiness to enhance target detection.SIGNIFICANCE STATEMENT We examined whether the neurochemical acetylcholine (ACh) contributes to a state of readiness for target detection, by engaging frontoparietal cortical attentional networks independent of modality. We show that ACh supported alerting attention to an impending presentation of either visual or olfactory targets. Using local field potentials, enhanced stimulus detection was associated with an anticipatory increase in power in the beta oscillation range before the target's appearance within the posterior parietal cortex (PPC) as well as increased synchrony, also in beta, between the prefrontal cortex and PPC. These readiness-associated changes in brain activity and behavior were attenuated in rats with reduced cortical ACh. Thus, ACh may act, in a supramodal manner, to prepare frontoparietal cortical attentional networks for target detection.

Daytime sleepiness in dementia with Lewy bodies is associated with neuronal depletion of the nucleus basalis of Meynert

IntroductionExcessive daytime sleepiness is a commonly reported clinical feature of dementia with Lewy bodies (DLB) that can occur early in the disease. Cholinergic depletion is known to be severe in DLB, even when dementia severity is mild. The nucleus basalis of Meynert serves as a primary source of cortical acetylcholine, and has a role in facilitating cortical activation and arousal. We sought to determine whether daytime sleepiness at the initial evaluation of patients with DLB was associated with neuronal loss in the nucleus basalis of Meynert. MethodsAutopsy-confirmed patients who met clinical criteria for probable DLB at their initial evaluation and who were administered the informant-completed Epworth Sleepiness Scale were included in the study (n = 40). Each patient had a dementia at baseline (80% with mild severity) and two or more features of parkinsonism, visual hallucinations, fluctuations, or probable REM sleep behavior disorder. Quantitative digital pathology of the nucleus basalis of Meynert was performed in the DLB group and in 20 non-DLB autopsy controls. ResultsDLB had greater neuronal depletion in the nucleus basalis of Meynert (p < 0.0001) than pathologic controls. Sleepiness was present in 58% of the DLB group and those with daytime sleepiness had significantly lower neuron counts in the nucleus basalis of Meynert than their non-sleepy counterparts (p = 0.001). Regression modeling revealed that sleepiness was a stronger predictor of neuronal loss in the nucleus basalis of Meynert than visual hallucinations, fluctuations or dementia severity (p = 0.003). ConclusionsExcessive daytime sleepiness in early DLB is indicative of a more profound loss of basal forebrain cholinergic integrity.

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3h with 0.3mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate.

Cholinergic Control of Information Coding

Specific forms of firing rate correlations can limit efficient information coding in neuronal populations. How this is mitigated is an important topic of current research. A novel study shows that increasing cortical acetylcholine (ACh) levels alter specific aspects of the population correlation structure, which in turn improves population-coding abilities.

Relationship between the changes in M1 excitability after motor learning and arousal state as assessed by short-latency afferent inhibition

To examine the factors that influence the inter-individual differences in the changes in primary motor cortex (M1) excitability seen after motor learning, we investigated the relationship between the amplitude of transcranial magnetic stimulation-induced motor evoked potentials (MEP) and short-latency afferent inhibition (SAI) after motor learning, based on the working hypothesis that SAI can be used to evaluate cortical acetylcholine (ACh) activity. To confirm this working hypothesis, we manipulated the arousal state of the subjects using a vigilance task, the outcomes of which might be correlated with cortical ACh activity, and investigated the effects of arousal state on SAI. As a result, we showed that SAI was significantly affected by arousal state. Consequently, we concluded that the subjects’ arousal state during motor learning tasks is one of factors to influence on inter-individual differences in the changes in M1 excitability seen after motor learning tasks.

Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia

BackgroundDopamine (DA) D4 receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D4 agonist, PD168077, at a sub-effective dose, together with a sub-effective dose of lurasidone, an atypical APD which is a weak D4 receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate D4Rs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D4 antagonists at clinical dosages, including clozapine, and risperidone. The D4 antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats. MethodsThe purpose of this study was to determine the effects of a selective D4 agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis. Results and discussionPD168077 alone, and in combination with sub-effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D4 receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D4 agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D4 antagonists.

Paradoxical Emergence: Administration of Subanesthetic Ketamine during Isoflurane Anesthesia Induces Burst Suppression but Accelerates Recovery.

Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery. Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection. A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 ± 24.11% vs. isoflurane after ketamine injection: 84.36 ± 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 ± 335 s vs. ketamine: 494 ± 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 ± 0.16 pmol vs. ketamine recovery: 0.75 ± 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued. Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but-paradoxically-accelerates the recovery of consciousness, possibly through cholinergic mechanisms.

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention.

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans.

Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention.

The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity.

Neural Correlates of Wakefulness, Sleep, and General Anesthesia: An Experimental Study in Rat.

Significant advances have been made in our understanding of subcortical processes related to anesthetic- and sleep-induced unconsciousness, but the associated changes in cortical connectivity and cortical neurochemistry have yet to be fully clarified. Male Sprague-Dawley rats were instrumented for simultaneous measurement of cortical acetylcholine and electroencephalographic indices of corticocortical connectivity-coherence and symbolic transfer entropy-before, during, and after general anesthesia (propofol, n = 11; sevoflurane, n = 13). In another group of rats (n = 7), these electroencephalographic indices were analyzed during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Compared to wakefulness, anesthetic-induced unconsciousness was characterized by a significant decrease in cortical acetylcholine that recovered to preanesthesia levels during recovery wakefulness. Corticocortical coherence and frontal-parietal symbolic transfer entropy in high γ band (85 to 155 Hz) were decreased during anesthetic-induced unconsciousness and returned to preanesthesia levels during recovery wakefulness. Sleep-wake states showed a state-dependent change in coherence and transfer entropy in high γ bandwidth, which correlated with behavioral arousal: high during wakefulness, low during SWS, and lowest during REM sleep. By contrast, frontal-parietal θ connectivity during sleep-wake states was not correlated with behavioral arousal but showed an association with well-established changes in cortical acetylcholine: high during wakefulness and REM sleep and low during SWS. Corticocortical coherence and frontal-parietal connectivity in high γ bandwidth correlates with behavioral arousal and is not mediated by cholinergic mechanisms, while θ connectivity correlates with cortical acetylcholine levels.

PM430. Blonanserin reversed phencyclidine-induced novel object recognition deficit and induced cortical dopamine and acetylcholine efflux through dopamine D3 receptor antagonism

PM430. Blonanserin reversed phencyclidine-induced novel object recognition deficit and induced cortical dopamine and acetylcholine efflux through dopamine D3 receptor antagonism