Cholinergic and behavior-dependent beta and gamma waves are coupled between olfactory bulb and hippocampus.

Olfactory oscillations may enhance cognitive processing through coupling with beta (ß, 15-30 Hz) and gamma (γ, 30-160 Hz) activity in the hippocampus (HPC). We hypothesize that coupling between olfactory bulb (OB) and HPC oscillations is increased by cholinergic activation in control rats and is reduced in kainic-acid-treated epileptic rats, a model of temporal lobe epilepsy. OB γ2 (63-100 Hz) power was higher during walking and immobility-awake (IMM) compared to sleep, while γ1 (30-57 Hz) power was higher during grooming than other behavioral states. Muscarinic cholinergic agonist pilocarpine (25 mg/kg ip) with peripheral muscarinic blockade increased OB power and OB-HPC coherence at ß and γ1 frequency bands. A similar effect was found after physostigmine (0.5 mg/kg ip) but not scopolamine (10 mg/kg ip). Pilocarpine increased bicoherence and cross-frequency coherence (CFC) between OB slow waves (SW, 1-5 Hz) and hippocampal ß, γ1 and γ2 waves, with stronger coherence at CA1 alveus and CA3c than CA1 stratum radiatum. Bicoherence further revealed a nonlinear interaction of ß waves in OB with ß waves at the CA1-alveus. Beta and γ1 waves in OB or HPC were segregated at one phase of the OB-SW, opposite to the phase of γ2 and γ3 (100-160 Hz) waves, suggesting independent temporal processing of ß/γ1 versus γ2/γ3 waves. At CA1 radiatum, kainic-acid-treated epileptic rats compared to control rats showed decreased theta power, theta-ß and theta-γ2 CFC during baseline walking, decreased CFC of HPC SW with γ2 and γ3 waves during baseline IMM, and decreased coupling of OB SW with ß and γ2 waves at CA1 alveus after pilocarpine. It is concluded that ß and γ waves in the OB and HPC are modulated by a slow respiratory rhythm, in a cholinergic and behavior-dependent manner, and OB-HPC functional connectivity at ß and γ frequencies may enhance cognitive functions.

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

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.

Aberrant slow waves in the hippocampus during activation in mice with low cholinergic tone.

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.

Forebrain Acetylcholine Modulates Isoflurane and Ketamine Anesthesia in Adult Mice.

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.

Positive allosteric modulator of GABAB receptor alters behavioral effects but not afterdischarge progression induced by partial hippocampal kindling.

Hippocampal seizures decreased the function of GABAB receptors, which may further increase seizure susceptibility and contribute to development of schizophrenia-like behaviors. Recent literature indicates that GABAB receptor agonist may normalize schizophrenia-like behaviors and prevent drug-induced behavioral sensitization. We hypothesized that positive modulation of GABAB receptor function during seizure induction will reduce seizure-induced schizophrenia-like behaviors. Using a partial hippocampal kindling model, afterdischarges were induced after injection of saline or dimethyl sulfoxide (vehicle-kindled rats), or a GABAB receptor positive allosteric modulator CGP7930, at 1 mg/kg i.p. (CGP1-kindled) or 5 mg/kg i.p. (CGP5-kindled). The increase in the primary afterdischarge duration during kindling was not different among the groups. However, the CGP5-kindled group showed a lower afterdischarge starting frequency as compared to vehicle-kindled or CGP1-kindled groups. Partial hippocampal kindling (21 afterdischarges) resulted in decreased prepulse inhibition and decreased gating of hippocampal auditory evoked potentials in vehicle-kindled and CGP1-kindled rats, as compared to saline-injected non-kindled rats, recorded 3-4 days after the last afterdischarge. However, CGP5-kindled rats showed normal prepulse inhibition and hippocampal auditory gating (compared to non-kindled rats), which was significantly higher than the respective measure in vehicle-kindled rats. CGP5-kindled group also showed methamphetamine-induced locomotion that was significant lower than the vehicle-kindled or CGP1-kindled group, but slightly higher than the saline-injected non-kindled rats. In conclusion, this study provides original data that a GABAB receptor positive allosteric modulator could therapeutically prevent or normalize some seizure-induced behavioral disruptions in a model of temporal lobe epilepsy.

The hippocampus participates in a pharmacological rat model of absence seizures.

OBJECTIVE: 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 GABAA 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 cognitive and memory deficits in some patients with absence seizures and absence status epilepticus.