Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction.

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

Re-emergent Tremor in Parkinson's Disease: Evidence of Pathologic ß and Prokinetic γ Activity.

BACKGROUND: Re-emergent tremor is characterized as a continuation of resting tremor and is often highly therapy refractory. This study examines variations in brain activity and oscillatory responses between resting and re-emergent tremors in Parkinson's disease. METHODS: Forty patients with Parkinson's disease (25 males, mean age, 66.78 ± 5.03 years) and 40 age- and sex-matched healthy controls were included in the study. Electroencephalogram and electromyography signals were simultaneously recorded during resting and re-emergent tremors in levodopa on and off states for patients and mimicked by healthy controls. Brain activity was localized using the beamforming technique, and information flow between sources was estimated using effective connectivity. Cross-frequency coupling was used to assess neuronal oscillations between tremor frequency and canonical frequency oscillations. RESULTS: During levodopa on, differences in brain activity were observed in the premotor cortex and cerebellum in both the patient and control groups. However, Parkinson's disease patients also exhibited additional activity in the primary sensorimotor cortex. On withdrawal of levodopa, different source patterns were observed in the supplementary motor area and basal ganglia area. Additionally, levodopa was found to suppress the strength of connectivity (P < 0.001) between the identified sources and influence the tremor frequency-related coupling, leading to a decrease in ß (P < 0.001) and an increase in γ frequency coupling (P < 0.001). CONCLUSIONS: Distinct variations in cortical-subcortical brain activity are evident in tremor phenotypes. The primary sensorimotor cortex plays a crucial role in the generation of re-emergent tremor. Moreover, oscillatory neuronal responses in pathological ß and prokinetic γ activity are specific to tremor phenotypes. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Inhibition of fatty acid amide hydrolase reverses aberrant prefrontal gamma oscillations in the sub-chronic PCP model for schizophrenia.

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.

Interaction of acetylcholine and oxytocin neuromodulation in the hippocampus.

A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions.

Eltoprazine modulated gamma oscillations on ameliorating L-dopa-induced dyskinesia in rats.

AIM: Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats. METHODS: Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity. RESULTS: We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia. CONCLUSION: Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.

Esketamine increases neurotransmitter releases but simplifies neurotransmitter networks in mouse prefrontal cortex.

General anesthesia induces a profound but reversible unconscious state, which is accompanied by changes in various neurotransmitters in the cortex. Unlike the "brain silencing" effect of γ-aminobutyric acid (GABA) receptor potentiator anesthesia, ketamine anesthesia leads the brain to a paradoxical active state with higher cortical activity, which is manifested as dissociative anesthesia. However, how the overall neurotransmitter network evolves across conscious states after ketamine administration remains unclear. Using in vivo microdialysis, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and electroencephalogram (EEG) recording technique, we continuously measured the concentrations of six neurotransmitters and the EEG signals during anesthesia with esketamine, an S-enantiomer of ketamine racemate. We found that there was an increase in the release of five cortical neurotransmitters after the administration of esketamine. The correlation of cortical neurotransmitters was dynamically simplified along with behavioral changes until full recovery after anesthesia. The esketamine-increased gamma oscillation power was positively correlated only with the concentration of 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex. This study suggests that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.NEW & NOTEWORTHY In this study, we found that esketamine significantly increased the cortical concentration of multiple neurotransmitters in mice. However, esketamine dynamically simplified the overall network of cortical neurotransmitters at different behavioral states during the perianesthesia period. The concentration of 5-HT in the medial prefrontal cortex (mPFC) was highly correlated with the esketamine-increased gamma oscillation. These findings suggested that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.

Aberrant inhibitory processing in the somatosensory cortices of cannabis-users.

BACKGROUND: Delta-9 tetrahydrocannabinol (THC) is a major exogenous psychoactive agent, which acts as a partial agonist on cannabinoid (CB1) receptors. THC is known to inhibit presynaptic neurotransmission and has been repeatedly linked to acute decrements in cognitive function across multiple domains. Previous electrophysiological studies of sensory gating have shown specific deficits in inhibitory processing in cannabis-users, but to date these findings have been limited to the auditory cortices, and the degree to which these aberrations extend to other brain regions remains largely unknown. METHODS: We used magnetoencephalography (MEG) and a paired-pulse somatosensory stimulation paradigm to probe inhibitory processing in 29 cannabis-users (i.e. at least four times per month) and 41 demographically matched non-user controls. MEG responses to each stimulation were imaged in both the oscillatory and time domain, and voxel time-series data were extracted to quantify the dynamics of sensory gating, oscillatory gamma activity, evoked responses, and spontaneous neural activity. RESULTS: We observed robust somatosensory responses following both stimulations, which were used to compute sensory gating ratios. Cannabis-users exhibited significantly impaired gating relative to non-users in somatosensory cortices, as well as decreased spontaneous neural activity. In contrast, oscillatory gamma activity did not appear to be affected by cannabis use. CONCLUSIONS: We observed impaired gating of redundant somatosensory information and altered spontaneous activity in the same cortical tissue in cannabis-users compared to non-users. These data suggest that cannabis use is associated with a decline in the brain's ability to properly filter repetitive information and impairments in cortical inhibitory processing.

Theta-gamma coupling emerges from spatially heterogeneous cholinergic neuromodulation.

Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.

Angiotensin II induces cognitive decline and anxiety-like behavior via disturbing pattern of theta-gamma oscillations.

Hypertension is the most common chronic disease accompanied by cognitive decline and anxiety-like behavior. Angiotensin II (Ang II) induces hypertension by activating angiotensin II receptor subtype 1 (AT1R). The purpose of the study was to examine the potential underlying mechanism of alterations in cognition and anxiety-like behavior induced by Ang II. Adult C57 mice were intraperitoneal injected with either 1 mg/kg/d Ang II or saline individually for 14 consecutive days. Ang II resulted in cognitive decline and anxious like behavior in C57 mice. Moreover, Ang II disturbed bidirectional synaptic plasticity and neural oscillation coupling between high theta and gamma on PP (perforant pathway)-DG (dentate gyrus) pathway. In addition, Ang II decreased the expression of N-methyl-d-aspartate receptor (NR) 2A and NR 2B and increased the expression of GABAAR α1. The data suggest that Ang II disturb neural oscillations via altering excitatory and inhibitory (E/I) balance and eventually damage cognition and anxiety-like behavior in mice.

Test-retest reliability of tone- and 40 Hz train-evoked gamma oscillations in female rats and their sensitivity to low-dose NMDA channel blockade.

RATIONALE: Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40-Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical and clinical development of drug candidates engaging these circuits. However, there are few test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms. OBJECTIVE: We investigated the long-term psychometric stability of these measures in a rodent model. METHODS: Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025-0.15 mg/kg) to disrupt the evoked response. RESULTS: We found that 40-Hz ASSR showed good reliability (ICC=0.60-0.75), while the reliability of tone-evoked gamma ranged from poor to good (0.33-0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism. CONCLUSION: Overall, while both evoked gamma measures use NMDA transmission, 40-Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson's disease.

Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.

Spectral signatures of L-DOPA-induced dyskinesia depend on L-DOPA dose and are suppressed by ketamine.

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

VEGF Modulates the Neural Dynamics of Hippocampal Subregions in Chronic Global Cerebral Ischemia Rats.

Theta and gamma rhythms in hippocampus are important to cognitive performance. The cognitive impairments following cerebral ischemia is linked with the dysfunction of theta and gamma oscillations. As the primary mechanism for learning and memory, synaptic plasticity is in connection with these neural oscillations. Although vascular endothelial growth factor (VEGF) is thought to protect synaptic function in the ischemia rats to relieve cognitive impairment, little has been done on its effect of neural dynamics with this process. The present study investigated whether the alternation of neural oscillations in the hippocampus of ischemia rats is one of the potential neuroprotective mechanisms of VEGF. Rats were treated with the intranasal administration of VEGF at 72 h following chronic global cerebral ischemia procedure. Then local field potentials (LFPs) in hippocampal CA1 and CA3 regions were recorded and analyzed. Our results showed that VEGF can improve the power of theta and gamma rhythms in CA1 region after ischemia. Chronic global cerebral ischemia reduced the theta-gamma phase-amplitude coupling (PAC) not only within CA1 area but also in the pathway from CA3 to CA1, while VEGF alleviated the decreased coupling strength. Despite these notable differences, there were no obvious changes in the PAC within CA3 region. Surprisingly, the ischemia state did not affect the phase-phase interaction of hippocampus. In conclusion, our findings demonstrated that VEGF enhanced the theta-gamma PAC strength of CA3-CA1 pathway in ischemia rats, which may futher improve the information transmission within the hippocampus. These results illustrated the potential electrophysiologic mechanism of VEGF on cognitive improvement.

Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein.

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2-5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.

Ramelteon modulates gamma oscillations in the rat primary motor cortex during non-REM sleep.

Sleep disorders adversely affect daily activities and cause physiological and psychiatric problems. The shortcomings of benzodiazepine hypnotics have led to the development of ramelteon, a melatonin MT1 and MT2 agonist. Although the sleep-promoting effects of ramelteon have been documented, few studies have precisely investigated the structure of sleep and neural oscillatory activities. In this study, we recorded electrocorticograms in the primary motor cortex, the primary somatosensory cortex and the olfactory bulb as well as electromyograms in unrestrained rats treated with either ramelteon or vehicle. A neural-oscillation-based algorithm was used to classify the behavior of the rats into three vigilance states (e.g., awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep). Moreover, we investigated the region-, frequency- and state-specific modulation of extracellular oscillations in the ramelteon-treated rats. We demonstrated that in contrast to benzodiazepine treatment, ramelteon treatment promoted NREM sleep and enhanced fast gamma power in the primary motor cortex during NREM sleep, while REM sleep was unaffected. Gamma oscillations locally coordinate neuronal firing, and thus, ramelteon modulates neural oscillations in sleep states in a unique manner and may contribute to off-line information processing during sleep.

Measuring the effects of first antiepileptic medication in Temporal Lobe Epilepsy: Predictive value of quantitative-EEG analysis.

OBJECTIVE: To determine the quantitative EEG responses in a population of drug-naïve patients with Temporal Lobe Epilepsy (TLE) after Levetiracetam (LEV) initiation as first antiepileptic drug (AED). We hypothesized that the outcome of AED treatment can be predicted from EEG data in patients with TLE. METHODS: Twenty-three patients with TLE and twenty-five healthy controls were examined. Clinical outcome was dichotomized into seizure-free (SF) and non-seizure-free (NSF) after two years of LEV. EEG parameters were compared between healthy controls and patients with TLE at baseline (EEGpre) and after three months of AED therapy (EEGpre-post) and between SF and NSF patients. Receiver Operating Characteristic curves models were built to test whether EEG parameters predicted outcome. RESULTS: AED therapy induces an increase in EEG power for Alpha (p = 0.06) and a decrease in Theta (p < 0.05). Connectivity values were lower in SF compared to NSF patients (p < 0.001). Quantitative EEG predicted outcome after LEV treatment with an estimated accuracy varying from 65.2% to 91.3% (area under the curve [AUC] = 0.56-0.93) for EEGpre and from 69.9% to 86.9% (AUC = 0.69-0.94) for EEGpre-post. CONCLUSIONS: AED therapy induces EEG modifications in TLE patients, and such modifications are predictive of clinical outcome. SIGNIFICANCE: Quantitative EEG may help understanding the effect of AEDs in the central nervous system and offer new prognostic biomarkers for patients with epilepsy.

Ketamine normalizes high-gamma power in the anterior cingulate cortex in a rat chronic pain model.

Chronic pain alters cortical and subcortical plasticity, causing enhanced sensory and affective responses to peripheral nociceptive inputs. Previous studies have shown that ketamine had the potential to inhibit abnormally amplified affective responses of single neurons by suppressing hyperactivity in the anterior cingulate cortex (ACC). However, the mechanism of this enduring effect has yet to be understood at the network level. In this study, we recorded local field potentials from the ACC of freely moving rats. Animals were injected with complete Freund's adjuvant (CFA) to induce persistent inflammatory pain. Mechanical stimulations were administered to the hind paw before and after CFA administration. We found a significant increase in the high-gamma band (60-100 Hz) power in response to evoked pain after CFA treatment. Ketamine, however, reduced the high-gamma band power in response to evoked pain in CFA-treated rats. In addition, ketamine had a sustained effect on the high-gamma band power lasting up to five days after a single dose administration. These results demonstrate that ketamine has the potential to alter maladaptive neural responses in the ACC induced by chronic pain.

Chronic intermittent hypoxia transiently increases hippocampal network activity in the gamma frequency band and 4-Aminopyridine-induced hyperexcitability in vitro.

Chronic intermittent hypoxia (CIH) is the most distinct feature of obstructive sleep apnea (OSA), a common breathing and sleep disorder that leads to several neuropathological consequences, including alterations in the hippocampal network and in seizure susceptibility. However, it is currently unknown whether these alterations are permanent or remit upon normal oxygenation. Here, we investigated the effects of CIH on hippocampal spontaneous network activity and hyperexcitability in vitro and explored whether these alterations endure or fade after normal oxygenation. Results showed that applying CIH for 21 days to adult rats increases gamma-band hippocampal network activity and aggravates 4-Aminopyridine-induced epileptiform activity in vitro. Interestingly, these CIH-induced alterations remit after 30 days of normal oxygenation. Our findings indicate that hippocampal network alterations and increased seizure susceptibility induced by CIH are not permanent and can be spontaneously reverted, suggesting that therapeutic interventions against OSA in patients with epilepsy, such as surgery or continuous positive airway pressure (CPAP), could be favorable for seizure control.

Region-dependent regulation of acute ethanol on γ oscillation in the rat hippocampal slices.

BACKGROUND: Ethanol use disorders are a serious medical and public health problem in the world today. Acute ethanol intoxication can lead to cognitive dysfunction such as learning and memory impairment. Gamma oscillations (γ, 30-80 Hz) are synchronized rhythmic activity generated by population of neurons within local network, and closely related to learning and memory function. The hippocampus is a critical anatomic structure that supports learning and memory. On the grounds of structure and function, hippocampus can be divided into the intermediate (IH), the dorsal (DH), and ventral hippocampus (VH). The current study is the first to investigate the effects of acute ethanol on γ oscillations in these sub-regions of rat hippocampal slices. METHODS: The sustained γ oscillations were induced by 200 nM kainate (KA) in the CA3c of IH, DH, and VH. When KA-induced γ oscillation reached the steady state, ethanol (50 mM or 100 mM) was applied and the effects of ethanol on γ oscillation power was measured in the slices sequentially sectioned from ventral to dorsal hippocampus of adult rats. RESULTS: In the intermediate hippocampal slices, compared with control (KA only), ethanol (50 mM) caused 36.1 ± 3.9% decrease in γ power (p < 0.05, n = 10), while ethanol (100 mM) caused 55.3 ± 5.5% decrease in γ power (p < 0.001, n = 14). In the dorsal hippocampus, only ethanol (100 mM) caused 18.1 ± 8.6% decrease in γ power (p < 0.05, n = 12). However, in the ventral hippocampus, neither 50 mM nor 100 mM ethanol affected γ oscillation. CONCLUSIONS: Our results demonstrate that ethanol may produce the differential suppression of γ oscillations in a dose-dependent manner in different sub-regions of hippocampus, suggesting that the modulation of ethanol on hippocampal γ oscillation is region-dependent.