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.

Paroxysmal slow-wave discharges in a model of absence seizure are coupled to gamma oscillations in the thalamocortical and limbic systems.

OBJECTIVE: Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if gamma (30-160 Hz) activity were cross-frequency modulated by the 2-6 Hz slow-wave discharges induced by GBL in the limbic system. We hypothesized that inactivation of the nucleus reuniens (RE), which projects to frontal cortex (FC) and hippocampus, would affect the cross-frequency coupling of gamma (γ) in different brain regions. METHODS: Local field potentials were recorded by electrodes implanted in the FC, ventrolateral thalamus (TH), basolateral amygdala (BLA), nucleus accumbens (NAC), and dorsal hippocampus (CA1) of behaving rats. At each electrode, the coupling between the γ amplitude envelope to the phase of the 2-6 Hz slow-waves (SW) was measured by modulation index (MI) or cross-frequency coherence (CFC) of γ amplitude with SW. In separate experiments, the RE was infused with saline or GABAA receptor agonist, muscimol, before the injection of GBL. RESULTS: Following GBL injection, an increase in MI and CFC of SW to γ1 (30-58 Hz), γ2 (62-100 Hz) and γ3 (100-160 Hz) bands was observed at the FC, hippocampus and BLA, with significant increase in SW-γ1 and SW-γ3 coupling at TH, and increase in peak SW-γ1 CFC at NAC. Strong SW-γ modulation was also found during baseline immobility high-voltage spindles. Muscimol inactivation of RE, as compared to saline infusion, significantly decreased SW-γ1 CFC in the FC, and peak frequency of the SW-γ1 CFC in the thalamus, but did not significantly alter SW-γ CFCs in the hippocampus, BLA or NAC. SIGNIFICANCE: The paroxysmal 2-6 Hz SW discharges, a hallmark of absence seizure, significantly modulate γ activity in the hippocampus, BLA and NAC, suggesting a modulation of limbic functions. RE inactivation disrupted the SW modulation of FC and TH, partly supporting our hypothesis that RE participates in the modulation of SW discharges.

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.

Medial Septum Modulates Consciousness and Psychosis-Related Behaviors Through Hippocampal Gamma Activity.

Abnormally high-amplitude hippocampal gamma activity (30-100 Hz) in behaving animals is seen after a hippocampal seizure, following injection of phencyclidine (PCP) or ketamine, and transiently in a delirium stage during induction of general anesthesia. High-amplitude hippocampal gamma activity in behaving rats is associated with hyperactive behavior and impairment in sensorimotor gating and sensory gating. The medial septum is necessary for the high-amplitude gamma activity and abnormal behaviors observed following a hippocampal seizure or injection of PCP/ketamine. Glutamatergic projection of the hippocampus to the nucleus accumbens (NAC) and dopaminergic transmission in NAC is necessary for abnormal behaviors. Large hippocampal gamma waves are suggested to contribute to seizure-induced automatism following temporal lobe seizures, and the schizophrenia-like symptoms induced by PCP/ketamine. Low-amplitude gamma activity is found during general anesthesia, associated with loss of consciousness in humans and loss of righting reflex in animals. Local inactivation or lesion of the medial septum, NAC, and brain areas connected to the septohippocampal-NAC system attenuates the increase in hippocampal gamma and associated behavioral disruptions induced by hippocampal seizure or PCP/ketamine. Inactivation or lesion of the septohippocampal-NAC system decreases the dose of anesthetic necessary for gamma decrease and loss of consciousness in animals. Thus, it is proposed that the septohippocampal-NAC system serves to control consciousness and the behavioral hyperactivity and neural dysfunctions during psychosis.

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.

Long-term potentiation of the nucleus reuniens and entorhinal cortex to CA1 distal dendritic synapses in mice.

The present study investigated the short-term and long-term synaptic plasticity of excitatory synapses formed by the nucleus reuniens (RE) and entorhinal cortex (EC) on the distal apical dendrites of CA1 pyramidal cells. RE-CA1 synapses are implicated in memory involving the hippocampus and medial prefrontal cortex. Current source density (CSD) analysis was used to identify excitatory and inhibitory currents following stimulation of RE or medial perforant path (MPP) in urethane-anesthetized mice in vivo. At the distal apical dendrites, RE evoked an initial excitatory sink followed by inhibitory sources at short (~ 30 ms) and long (150-200 ms) latencies, and often showing gamma (25-40 Hz) oscillations. Both RE-evoked and spontaneous gamma-frequency local field potentials displayed the same CSD depth profile. Paired-pulse facilitation (PPF) of the distal excitatory sink at 20-200 ms interpulse intervals was observed following RE stimulation, generally higher than that following MPP stimulation. Theta-frequency burst stimulation (TBS) of RE induced input-specific long-term potentiation (LTP) at the distal dendritic CA1 synapses, accompanied by reduction of PPF. After TBS of the MPP, the MPP-CA1 distal dendritic synapse could manifest LTP or long-term depression, but the non-tetanized RE-CA1 synapse was typically potentiated. Heterosynaptic potentiation of the RE to CA1 distal synapses may occur after repeated activity of EC afferents, or spread of MPP stimulus currents to coursing RE afferents. The results indicate a propensity of RE-CA1 distal excitatory synapses to show PPF, LTP and gamma oscillations, all of which may participate in memory processing by RE and EC.

Phasic modulation of hippocampal synaptic plasticity by theta rhythm.

Theta rhythm and long-term potentiation (LTP) are 2 remarkable discoveries. The theta rhythm is an oscillatory neural activity of 3-10 Hz in the hippocampus. LTP is implicated as a cellular basis of memory, but the function of theta oscillation in memory is not clear. This review suggests that theta rhythm bestows optimal conditions for hippocampal LTP and memory encoding. Theta rhythm in hippocampal CA1 is generated mainly by 2 oscillating dipoles-somatic-inhibition and phase-shifted, distal dendritic excitation, with a smaller contribution by rhythmic proximal (CA3) excitation and distal inhibition. Our recent study showed that LTP of the excitatory synapses on the basal or apical dendrites of CA1 pyramidal cells peaked twice in a theta cycle, at the rising (R) and the midcycle (M) phase of the theta rhythm recorded at the distal apical dendrites. In contrast, evoked population spike excitability peaked at a single phase near the midcycle. We infer that R and M peaks of LTP correspond to maximal dendritic depolarization and maximal somatic depolarization of CA1 pyramidal cells, respectively. A ∼50° phase shift between LTP-versus-theta-phase functions suggests independent LTP at the basal and apical dendrites. It is argued that theta phase-dependent LTP occurs under physiological conditions, by pairing presynaptic activity with oscillating postsynaptic depolarization. Place cells, showing intrinsic membrane potential oscillations, are ideal LTP participants. It is suggested that theta phase-dependent LTP contributes to memory encoding, and disruption of either theta oscillation or LTP may disrupt memory in various neurological disorders, including epilepsy and Alzheimer's disease. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity.

α-Thalassemia X-linked intellectual disability (ATR-X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2-type chromatin-remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX-cKO) causes deficits in long-term hippocampus-dependent spatial memory. Thus, we hypothesized that ATRX-cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane-anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired-pulse facilitation (PPF) at 50-ms interpulse interval, and by their long-term potentiation (LTP) induced by theta-frequency burst stimulation. Baseline single-pulse excitatory response at each synapse did not differ between ATRX-cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX-cKO mice. While basal dendritic LTP of the first-pulse excitatory response was not affected in ATRX-cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long-term spatial memory deficits in ATRX-cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR-X syndrome patients.

Long-lasting changes in hippocampal GABAB-receptor mediated inhibition following early-life seizures in kindling-prone but not kindling-resistant rats.

The hypotheses that hippocampal GABAB receptor dysfunction is a long-lasting consequence of early-life seizures, and its dependence on genetic background, were tested. Two strains of rats bred to be prone (FAST) or resistant (SLOW) to amygdala kindling were used. On postnatal day (PND) 10, control rats were injected with saline, and seizure rats with kainic acid to induce status epilepticus (SE) for 2 h. A significantly lower dose of kainic acid was found to induce SE in FAST as compared to SLOW rats. Population excitatory postsynaptic potentials (pEPSPs) and population spikes (PSs) were recorded in CA1 of hippocampal slices of adult rats in vitro, following stimulation of stratum radiatum. Input-output relation of the single-pulse pEPSP and PS did not show a significant difference between seizure and control rats, sex, or strain (FAST and SLOW). Paired-pulse PSs were significantly enhanced at 10-50 ms interpulse intervals, in FAST seizure male rats compared to FAST male controls, but not in other groups. In adult FAST but not SLOW rats, significantly lower suppression of pEPSPs at 250-300 ms following heterosynaptic burst stimulation was found in seizure rats compared to control rats; the heterosynaptic suppression of the pEPSP was blocked by selective GABAB receptor antagonist CGP55845A. The results provide evidence that an early-life SE has a long-lasting effect in decreasing GABAB receptor-mediated presynaptic inhibition in the hippocampus, in FAST but not in SLOW rats.

Long-lasting disruption of spatial memory by GABAB receptor antagonist induced seizures.

The objective of this project was to test whether a drug-induced model of temporal lobe seizures, namely seizures induced by a gamma aminobutyric acid (GABAB) receptor antagonist, CGP35348, result in long-term disruption of hippocampal memory function. Seizures were induced in experimental rats by intracerebroventricular (i.c.v.) injection of CGP35348 (0.64 µmol in 3 µL) for three consecutive days; control rats received no injection. Rats were first trained to criterion on an open radial arm maze (RAM) with 4 of the 8 arms baited, then received seizure and control treatment, and tested again on the RAM during the first week (days 1-5) and fourth week (days 22-29) after the last injection. An initial i.c.v. CGP35348 injection induced a mean of 4.4 seizures in the hippocampus, often accompanied with stages 3-5 convulsions, and sometimes with jumping; three daily CGP35348 injections induced 10.4 ±â€¯1.8 (n = 7 rats) seizures in total. In two separate experiments, seizure-treated rats performed worse than control rats in working memory (WM) during both the 1st and 4th weeks after seizures. Reference memory (RM) deficit during the 1st week after seizures was observed in only one experiment in which RM was acquired >2 weeks ago. The memory deficits were not accompanied by gross neuronal loss in the hippocampus. In conclusion, i.c.v. injection of a GABAB receptor antagonist in adult rats induced brief, multiple, focal hippocampal seizures that induced deficits in spatial memory for up to 4 weeks.

Generalized seizures evoked by nucleus accumbens stimulation induced an opiate-mediated suppression of psychosis relevant behaviors.

We have previously demonstrated that kindling of the nucleus accumbens (NAc) induced psychosis relevant behaviors only after one, but not after five, stage-5 seizures, suggesting that five stage-5 NAc-evoked seizures antagonized psychosis relevant behaviors in rats. We hypothesized that brain opioid receptors are responsible for seizure-induced reduction of psychosis relevant behaviors in NAc kindled rats. Rats received NAc kindling until a stage-4 seizure was induced, after which naloxone, a non-specific opioid receptor antagonist, at dose of 1 or 10 mg/kg i.p., or saline (0.3 mL) i.p., was injected 15 min before each kindled seizure. Duration of afterdischarge (AD) was not significantly different among naloxone- and saline-treated groups. However, duration of postictal behavioral depression induced by a stage-5 seizure was significantly shorter in 10 mg/kg naloxone-treated than saline-treated rats, for long (>36 s) AD duration. When tested 3-4 days after five stage-5 seizures, 10 mg/kg naloxone-treated rats, as compared to saline-treated rats, showed a statistically significant loss of gating of hippocampal auditory evoked potentials, and significant reduction of startle response amplitude, but non-significant differences in prepulse inhibition and methamphetamine-induced locomotion. It is inferred that stage-5 seizures, by releasing endogenous opiates, contribute to postictal behavioral depression, and some long-term seizure-induced antipsychotic effects.

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABAA receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors.

Long-Term Potentiation and Excitability in the Hippocampus Are Modulated Differently by θ Rhythm.

Oscillations in the brain facilitate neural processing and cognitive functions. This study investigated the dependence of long-term potentiation (LTP), a neural correlate of memory, on the phase of the hippocampal θ rhythm, a prominent brain oscillation. Multichannel field potentials and current source-sinks were analyzed in hippocampal CA1 of adult male rats under urethane anesthesia. A single burst (five pulses at 200 Hz) stimulation of stratum oriens (OR) induced LTP of the basal dendritic excitatory sink (ES), which was maximal when the burst was delivered at ∼340° and ∼160° of the distal dendritic θ rhythm. Apical dendritic sink evoked by stratum radiatum (RAD) stimulation also showed biphasic maxima at ∼30° and ∼210° of the distal dendritic θ rhythm, about 50° phase delay to basal dendritic LTP. By contrast, maximal population spike (PS) excitability, following single-pulse excitation of the basal or mid-apical dendrites, occurred at a θ phase of ∼140°, and maximal basal dendritic ES occurred at ∼20°; γ (30-57 Hz) activity recorded in CA1 RAD had maximal power at ∼300° of the distal dendritic θ rhythm, different from the phases of maximal LTP. LTP induced during the rising θ phase was NMDA receptor sensitive. It is suggested that the θ phase modulation of CA1 PS excitability is mainly provided by θ-rhythmic proximal inhibition, while dendritic LTP is also modulated by dendritic inhibition and excitation, specific to basal and apical dendrites. In summary, basal and apical dendritic synaptic plasticity and spike excitability are facilitated at different θ phases in a compartmental fashion.

Medial septum modulates hippocampal gamma activity and prepulse inhibition in an N-methyl-d-aspartate receptor antagonist model of schizophrenia.

We reviewed the participation of the septohippocampal system in an animal model of schizophrenia that was acutely induced by systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist such as phencyclidine, MK-801 and ketamine. The NMDA receptor antagonist-induced model of schizophrenia is characterized by behavioral and electrophysiological disruptions, including a decrease in prepulse inhibition of the acoustic startle response (PPI), hyperlocomotion, decrease in gating of hippocampal auditory evoked potentials and robust increase in hippocampal gamma (30-100Hz) oscillations. Similar disruptions were also induced by a single electrographic seizure in the hippocampus. The behavioral and electrophysiological disruptions induced by an NMDA receptor antagonist can be reduced by inactivation or lesion of GABAergic neurons in the medial septum, deep brain stimulation of the medial septum or nucleus accumbens, or positive modulation of GABAB receptors. Our results suggest a close association between high-amplitude hippocampal gamma oscillations and psychosis-relevant behaviors including PPI loss, behavioral hyperactivity and loss in auditory gating. Abnormal electrophysiology suggests a disruption of somatic and apical dendritic inhibition in the hippocampus, resulting in distorted sensory integration, and impaired cognitive and memory processing. The hippocampus is suggested to be a hub in a brain network that participates in psychosis-relevant behaviors, through its direct projection to the nucleus accumbens, or through indirect connections via the entorhinal, cingulate and prefrontal cortices.

Disruption of Hippocampal Multisynaptic Networks by General Anesthetics.

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function. METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal). RESULTS: Monosynaptic population excitatory postsynaptic potentials at the basal and apical dendrites of CA1 were significantly decreased at greater than or equal to 0.25% (n = 4) and greater than or equal to 1.0% (n = 6) isoflurane, respectively. The perforant path evoked multisynaptic response at CA1 was decreased by ~50% at greater than or equal to 0.25% isoflurane (n = 5). A decreased population excitatory postsynaptic potential was accompanied by increased paired-pulse facilitation. Population spike amplitude in relation to apical dendritic population excitatory postsynaptic potential was not significantly altered by isoflurane. Spontaneous hippocampal local field potential at 0.8 to 300 Hz was dose-dependently suppressed by isoflurane (n = 6), with local field potential power in the 50- to 150-Hz band showing the highest decrease with isoflurane dose, commensurate with the decrease in trisynaptic CA1 response. Low-dose pentobarbital (n = 7) administration decreased the perforant path evoked trisynaptic CA1 response and hippocampal local field potentials at 78 to 125 Hz. CONCLUSIONS: Hippocampal networks are sensitive to low doses of isoflurane and pentobarbital, possibly through both glutamatergic and γ-aminobutyric acid-mediated transmission. Network disruption could help explain the impairment of hippocampal-dependent cognitive functions with low-dose anesthetic.

Functional connectivity of the hippocampus to the thalamocortical circuitry in an animal model of absence seizures.

OBJECTIVE: Using the gamma-butyrolactone (GBL) rat model of absence seizures, this study investigated the functional connectivity of the hippocampus, thalamus and cerebral cortex before and during absence seizures. METHODS: Functional connectivity between the hippocampus, thalamus and sensory and motor cortecies, were examined by the temporal correlations of the resting state blood-oxygen-level-dependent (BOLD) signal. Functional connectivity between these regions was calculated at baseline, 5min after saline injection, and at 5, 20 and 52min after GBL injection. This time interval spans the onset of behaviours including chewing and staring spells associated with GBL-induced absence seizures, along with the onset and suppression of spike-and-wave discharges (SWDs). RESULTS: Overall there was an increase in functional connectivity across most regions. The functional connectivity generally decreased over time and it returned to baseline 52min post-GBL injection. Functional connectivity of the thalamus to the sensory and motor cortecies increased during absence seizure. The results revealed enhanced connectivity of the left dorsal hippocampus and the thalamus shortly after GBL injection, which coincided with the appearance of SWDs in this rat model. SIGNIFICANCE: Increased functional connectivity between the hippocampus and the thalamus suggests that the hippocampus participates in the GBL model of absence seizures. Involvement of the hippocampus during absence seizure has implications for studies into the mechanisms in cognitive impairments in patients with absence epilepsy.

Resting state functional network disruptions in a kainic acid model of temporal lobe epilepsy.

We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE) in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD) signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN). The limbic network includes the hippocampus, amygdala, piriform cortex, nucleus accumbens, and mediodorsal thalamus, whereas DMN involves the medial prefrontal cortex, anterior and posterior cingulate cortex, auditory and temporal association cortex, and posterior parietal cortex. The TLE model manifested a higher clustering coefficient, increased global and local efficiency, and increased small-worldness as compared to controls, despite having a similar characteristic path length. These results suggest extensive disruptions in the functional brain networks, which may be the basis of altered cognitive, emotional and psychiatric symptoms in TLE.