Background Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice with genetic deficiency of forebrain acetylcholine show increased anesthetic sensitivity to isoflurane and ketamine and decreased gamma-frequency brain activity. Methods Male adult mice with heterozygous knockdown of vesicular acetylcholine transporter in the brain or homozygous knockout of the transporter in the basal forebrain were compared with wild-type mice. Hippocampal and frontal cortical electrographic activity and righting reflex were studied in response to isoflurane and ketamine doses. Results The loss-of-righting-reflex dose for isoflurane was lower in knockout (mean ± SD, 0.76 ± 0.08%, n = 18, P = 0.005) but not knockdown (0.78 ± 0.07%, n = 24, P = 0.021), as compared to wild-type mice (0.83 ± 0.07%, n = 23), using a significance criterion of P = 0.017 for three planned comparisons. Loss-of-righting-reflex dose for ketamine was lower in knockout (144 ± 39 mg/kg, n = 14, P = 0.006) but not knockdown (162 ± 32 mg/kg, n = 20, P = 0.602) as compared to wild-type mice (168 ± 24 mg/kg, n = 21). Hippocampal high-gamma (63 to 100 Hz) power after isoflurane was significantly lower in knockout and knockdown mice compared to wild-type mice (isoflurane-dose and mouse-group interaction effect, F[8,56] = 2.87, P = 0.010; n = 5 to 6 mice per group). Hippocampal high-gamma power after ketamine was significantly lower in both knockout and knockdown mice when compared to wild-type mice (interaction effect F[2,13] = 6.06, P = 0.014). The change in frontal cortical gamma power with isoflurane or ketamine was not statistically different among knockout, knockdown, and wild-type mice. Conclusions These findings suggest that forebrain cholinergic neurons modulate behavioral sensitivity and hippocampal gamma activity during isoflurane and ketamine anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

SUMMARYObjective-Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs.Methods-Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABA A receptor agonist muscimol.Results-As PDs developed following GBL injection, coherence of local field potentials at 2.5-6 Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40 -80 ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5-6 Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30-120 Hz hippocampal gamma power, and hastened the transition of PDs to 1-2 Hz slow waves.Significance-During GBL induced 2.5-6 Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the

The effects of acetylcholine on cortical activation were studied in wild-type (WT) mice, compared to knockout (KO) mice depleted of the vesicular acetylcholine transporter (VAChT) gene in the basal forebrain, and knockdown (KD) mice with heterogeneous depletion of VAChT gene in the brain. Cortical activation was assessed by comparing power spectra of local field potentials (LFPs) during activated states of rapid-eye-movement sleep (REM) or walk (WLK), with those during non-activated states of slow-wave sleep (SWS) or awake-immobility (IMM). Activation-induced suppression of delta (1-4 Hz) and beta (13-30 Hz) power in the hippocampus, and delta power in frontal cortex, were reduced in KO and KD mice compared to WT mice.Mean theta frequency was higher in KD than KO mice during WLK and REM, but not different between WT and KO mice. Peak theta (4-12 Hz) and integrated gamma (30-150 Hz) power were not significantly different among mouse groups. However, theta-peak-frequency selected gamma2 (62-100 Hz) power was lower in KO than WT or KD mice during WLK, and theta-peak-frequency selected theta power during REM decreased faster with high theta frequency in KO than WT/ KD mice. Theta power increase during REM compared to WLK was lower in KO and KD mice compared to WT mice. Theta-gamma cross-frequency coherence, a measure of synchronization of gamma with theta phase, was not different among mouse groups.However, during REM, SWS, and IMM, delta-gamma coherence was significantly higher and proximal-distal delta coherence in CA1 was lower in KO than WT/KD mice. We conclude that a deficiency in basal forebrain acetylcholine release not only enhances slow waves and suppresses theta-associated gamma waves during activation, but also increases delta-gamma cross-frequency coherence during nonactivated states, with a possible effect of disrupting cognitive processing during any brain state. K E Y W O R D S delta waves, delta-gamma coupling, rapid-eye-movement sleep, slow-wave sleep, theta rhythm, theta-gamma coupling, vesicular acetylcholine transporter 1 | INTRODUCTION Cortical (hippocampal and neocortical) activation is observed electrographically as a decrease of slow waves, or desynchronization

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It has been shown in previous studies (1) that in addition to agglutinating erythrocytes, mumps virus, under appropriate conditions, will hemolyze red blood cells. This hemolytic activity was destroyed by a variety of physical and chemical agents which left intact the capacity of the virus to agglutinate erythrocytes and to elute therefrom (2). These findings appeared to indicate that the hemolytic reaction involves some labile component of the virus that is not essential for hemagglutination or etution from erythrocytes. However, since both hemolysis and hemagglutination appeared to follow union between virus and red blood cell, the discovery of certain factors of mutual importance for these two reactions could be anticipated. In order to study the relationships between hemagglutination, virus elution, and hemolysis, the agglutination and lysis of red blood cells by mumps virus were observed under conditions affecting (a) the red cell receptors, (b) adsorption of virus on unmodified erythrocytes, and (c) elution of virus after its adsorption on the red blood cell. The results of these experiments are presented in this report. Materials and MethodsViruses.--The egg-adapted strain of mumps virus described in previous studies was employed (1, 2). The virus was cultivated in the amniotic sac of 7-to-8-day-old chick embryos. After incubation at 35°C., for 5 days, the amniotic fluid was harvested, placed in glass ampoules, sealed, and stored at --70°C. until required.The PR8 strain of influenza A virus and the Lee strain of influenza B virus were employed. These viruses were cultivated in the allantoic sac of 10-to-12-day-old embryos. The allantoic fluid was collected after 48 hours' incubation at 35°C. and handled in the same manner as the fluids infected with mumps virus.Red Blood Cells.--Blood specimens from the various animals were mixed with an equal volume of Alsever's solution and stored at 4°C. for use during periods up to I0 days. Unless otherwise noted, chicken erythrocytes were used in all tests. The cells were washed 3 times in 0.85 per cent NaCI solution buffered at pH 7.2 (0.025 ~t phosphate) and made up to the desired concentration in this buffered saline.