Neuronal Network Oscillations Research Articles

Learning spiking neuronal networks with artificial neural networks: neural oscillations.

First-principles-based modelings have been extremely successful in providing crucial insights and predictions for complex biological functions and phenomena. However, they can be hard to build and expensive to simulate for complex living systems. On the other hand, modern data-driven methods thrive at modeling many types of high-dimensional and noisy data. Still, the training and interpretation of these data-driven models remain challenging. Here, we combine the two types of methods to model stochastic neuronal network oscillations. Specifically, we develop a class of artificial neural networks to provide faithful surrogates to the high-dimensional, nonlinear oscillatory dynamics produced by a spiking neuronal network model. Furthermore, when the training data set is enlarged within a range of parameter choices, the artificial neural networks become generalizable to these parameters, covering cases in distinctly different dynamical regimes. In all, our work opens a new avenue for modeling complex neuronal network dynamics with artificial neural networks.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

The computational power of the human brain.

At the end of the 20th century, analog systems in computer science have been widely replaced by digital systems due to their higher computing power. Nevertheless, the question keeps being intriguing until now: is the brain analog or digital? Initially, the latter has been favored, considering it as a Turing machine that works like a digital computer. However, more recently, digital and analog processes have been combined to implant human behavior in robots, endowing them with artificial intelligence (AI). Therefore, we think it is timely to compare mathematical models with the biology of computation in the brain. To this end, digital and analog processes clearly identified in cellular and molecular interactions in the Central Nervous System are highlighted. But above that, we try to pinpoint reasons distinguishing in silico computation from salient features of biological computation. First, genuinely analog information processing has been observed in electrical synapses and through gap junctions, the latter both in neurons and astrocytes. Apparently opposed to that, neuronal action potentials (APs) or spikes represent clearly digital events, like the yes/no or 1/0 of a Turing machine. However, spikes are rarely uniform, but can vary in amplitude and widths, which has significant, differential effects on transmitter release at the presynaptic terminal, where notwithstanding the quantal (vesicular) release itself is digital. Conversely, at the dendritic site of the postsynaptic neuron, there are numerous analog events of computation. Moreover, synaptic transmission of information is not only neuronal, but heavily influenced by astrocytes tightly ensheathing the majority of synapses in brain (tripartite synapse). At least at this point, LTP and LTD modifying synaptic plasticity and believed to induce short and long-term memory processes including consolidation (equivalent to RAM and ROM in electronic devices) have to be discussed. The present knowledge of how the brain stores and retrieves memories includes a variety of options (e.g., neuronal network oscillations, engram cells, astrocytic syncytium). Also epigenetic features play crucial roles in memory formation and its consolidation, which necessarily guides to molecular events like gene transcription and translation. In conclusion, brain computation is not only digital or analog, or a combination of both, but encompasses features in parallel, and of higher orders of complexity.

Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations.

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30-70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation-inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5'-triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.

Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.MethodsHere, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20–80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-β (Aβ) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO).ResultsGal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aβ42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aβ plaque load.ConclusionsWe report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

α2-Adrenergic modulation of Ih in adult-born granule cells in the olfactory bulb.

In the olfactory bulb (OB), a large population of axon-less inhibitory interneurons, the granule cells (GCs), coordinate network activity and tune the output of principal neurons, the mitral and tufted cells (MCs), through dendrodendritic interactions. Furthermore, GCs undergo neurogenesis throughout life, providing a source of plasticity to the neural network of the OB. The function and integration of GCs in the OB are regulated by several afferent neuromodulatory signals, including noradrenaline (NA), a state-dependent neuromodulator that plays a crucial role in the regulation of cortical function and task-specific decision processes. However, the mechanisms by which NA regulates GC function are not fully understood. Here, we show that NA modulates hyperpolarization-activated currents (Ih) via the activation of α2-adrenergic receptors (ARs) in adult-born GCs (abGCs), thus directly acting on channels that play essential roles in regulating neuronal excitability and network oscillations in the brain. This modulation affects the dendrodendritic output of GCs leading to an enhancement of lateral inhibition onto the MCs. Furthermore, we show that NA modulates subthreshold resonance in GCs, which could affect the temporal integration of abGCs. Together, these results provide a novel mechanism by which a state-dependent neuromodulator acting on Ih can regulate GC function in the OB.

Translating Pathological Brain Activity Primers in Parkinson's Disease Research.

Translational experimental approaches that help us better trace Parkinson's disease (PD) pathophysiological mechanisms leading to new therapeutic targets are urgently needed. In this article, we review recent experimental and clinical studies addressing abnormal neuronal activity and pathological network oscillations, as well as their underlying mechanisms and modulation. Our aim is to enhance our knowledge about the progression of Parkinson's disease pathology and the timing of its symptom's manifestation. Here, we present mechanistic insights relevant for the generation of aberrant oscillatory activity within the cortico-basal ganglia circuits. We summarize recent achievements extrapolated from available PD animal models, discuss their advantages and limitations, debate on their differential applicability, and suggest approaches for transferring knowledge on disease pathology into future research and clinical applications.

The dysfunction of mGluRIIs is involved in the disorder of hippocampal neural network in diabetic mice model.

Cognitive dysfunction is a high incidence of diabetes mellitus (DM). However, the relationship between DM-induced cognitive defect and neuronal network oscillations is still unknown. In this study, adult male C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ) to duplicate DM. After 12weeks, local field potentials were recorded in the perforant fiber pathway (PP) and dentate gyrus (DG) regions. Data showed that mice in the STZ group exhibited impairment of spatial learning and memory by the Morris Water Mazetest. The low gamma (LG) and high gamma (HG) power were increased in the PP and DG areas of the STZ group. Moreover, the phase synchronization and the information flow at theta and LG rhythms between the PP and DG areas were decreased, and the theta-LG phase-amplitude coupling strength was markedly reduced in the PPregion, DG region, and the PP-DG pathway in the STZ group. Additionally, the concentration of glutamate was increased by thehigh-performance liquid chromatography. Moreover, the NR2B and PSD95 expressions were markedly reduced, and the Akt/GSK-3β pathway was inhibited. Interestingly, the expressions of mGluRIIs (mGluR2 and mGluR3) were significantly decreased. The reduction of mGluRIIs may limit their function, such as restricting presynaptic glutamate release and reversing the dysfunction of NR2B via Akt/GSK-3β signaling pathway. In conclusion, our data suggest that DM alters the hippocampal neural network partly related to the dysfunction of mGluRIIs.

Review: Subjective Time Perception, Dopamine Signaling, and Parkinsonian Slowness.

The association between idiopathic Parkinson's disease, a paradigmatic dopamine-deficiency syndrome, and problems in the estimation of time has been studied experimentally for decades. I review that literature, which raises a question about whether and if dopamine deficiency relates not only to the motor slowness that is an objective and cardinal parkinsonian sign, but also to a compromised neural substrate for time perception. Why does a clinically (motorically) significant deficiency in dopamine play a role in the subjective perception of time's passage? After a discussion of a classical conception of basal ganglionic control of movement under the influence of dopamine, I describe recent work in healthy mice using optogenetics; the methodology visualizes dopaminergic neuronal firing in very short time intervals, then allows for correlation with motor behaviors in trained tasks. Moment-to-moment neuronal activity is both highly dynamic and variable, as assessed by photometry of genetically defined dopaminergic neurons. I use those animal data as context to review a large experimental experience in humans, spanning decades, that has examined subjective time perception mainly in Parkinson's disease, but also in other movement disorders. Although the human data are mixed in their findings, I argue that loss of dynamic variability in dopaminergic neuronal activity over very short intervals may be a fundamental sensory aspect in the pathophysiology of parkinsonism. An important implication is that therapeutic response in Parkinson's disease needs to be understood in terms of short-term alterations in dynamic neuronal firing, as has already been examined in novel ways—for example, in the study of real-time changes in neuronal network oscillations across very short time intervals. A finer analysis of a treatment's network effects might aid in any effort to augment clinical response to either medications or functional neurosurgical interventions in Parkinson's disease.

Formulation and Emulation of Quantum-Inspired Dynamical Systems With Classical Analog Circuits.

Quantum dynamical systems are capable of powerful computation but are hard to emulate on digital computers. We show that four novel analog circuit parts can emulate the phase-coherent unitary dynamics of such systems. These four parts are: a Planck capacitance analogous to a neuronal membrane capacitance; a quantum admittance element, together with the Planck capacitance, analogous to a neuronal quadrature oscillator; a quantum transadmittance element analogous to a complex neuronal synapse; and a quantum transadmittance mixer element analogous to a complex neuronal synapse with resonant modulation. These parts may be emulated classically, with paired real-value voltages on paired Planck capacitances corresponding to the real and imaginary portions of a probability amplitude; and appropriate paired real-value currents onto these Planck capacitances corresponding to diagonal (admittance), off-diagonal (transadmittance), or controlled off-diagonal (transadmittance mixer) Hamiltonian energy terms. The superposition of 2n simultaneously phase-coherent and symmetric probability-voltage amplitudes with O(n) of these parts, in a tensor-product architecture enables analog emulation of the quantum Fourier transform (QFT). Implementation of our circuits on an analog integrated circuit in a 0.18 μm process yield experimental results consistent with mathematical theory and computer simulations for emulations of NMR, Josephson junction, and QFT dynamics. Our results suggest that linear oscillatory neuronal networks with pairs of complex subthreshold/nonspiking sine and cosine neurons that are coupled together via complex synapses to other such complex neurons can architect quantum-inspired computation with classical analog circuits. Thus, an analog-circuit mapping between quantum and neural computation, both of which exploit analog computation for powerful operation, can enable future synergies between these fields.

Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer’s disease (AD). Resolution of inflammation follows neutralization of pathogens and is a response to limit damage and promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution is impaired in AD brains, we decided to test if intranasal administration of pro-resolving LMs in the AppNL-G-F/NL-G-F mouse model for AD could resolve inflammation and ameliorate pathology in the brain. A mixture of the pro-resolving LMs resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) and neuroprotectin D1 (NPD1) was administered to stimulate their respective receptors. We examined amyloid load, cognition, neuronal network oscillations, glial activation and inflammatory factors. The treatment ameliorated memory deficits accompanied by a restoration of gamma oscillation deficits, together with a dramatic decrease in microglial activation. These findings open potential avenues for therapeutic exploration of pro-resolving LMs in AD, using a non-invasive route.

Local inhibition in a model of the indirect pathway globus pallidus network slows and deregularizes background firing, but sharpens and synchronizes responses to striatal input.

The external segment of globus pallidus (GPe) is a network of oscillatory neurons connected by inhibitory synapses. We studied the intrinsic dynamic and the response to a shared brief inhibitory stimulus in a model GPe network. Individual neurons were simulated using a phase resetting model based on measurements from mouse GPe neurons studied in slices. The neurons showed a broad heterogeneity in their firing rates and in the shapes and sizes of their phase resetting curves. Connectivity in the network was set to match experimental measurements. We generated statistically equivalent neuron heterogeneity in a small-world model, in which 99% of connections were made with near neighbors and 1% at random, and in a model with entirely random connectivity. In both networks, the resting activity was slowed and made more irregular by the local inhibition, but it did not show any periodic pattern. Cross-correlations among neuron pairs were limited to directly connected neurons. When stimulated by a shared inhibitory input, the individual neuron responses separated into two groups: one with a short and stereotyped period of inhibition followed by a transient increase in firing probability, and the other responding with a sustained inhibition. Despite differences in firing rate, the responses of the first group of neurons were of fixed duration and were synchronized across cells.

Sex-dependent sensitivity to positive allosteric modulation of GABA action in an APP knock-in mouse model of Alzheimer's disease: Potential epigenetic regulation

Conflicting evidence suggest that perturbations of GABAergic neurotransmission play crucial roles in disrupting cortical neuronal network oscillations, memory, and cognitive deficits in Alzheimer's disease (AD). However, the role and impact of sex differences on GABAergic transmission in AD are not well understood. Using an APP knock-in mouse model of AD, APPNLGF mice, we studied the effects of acute diazepam administration on memory and anxiety-like behavior to unveil sex-dependent dysregulation of GABAergic neurotransmission. We also examined sex differences in GABAA receptor subunit mRNA and protein expression and the role of epigenetic regulation in hippocampus of APPNLGF mice. We found that diazepam elicited dose-dependent suppression of locomotion in wildtype and APPNLGF mice. However, a low dose, which had no significant effect in both male and female wildtype as well as female APPNLGF mice, significantly suppressed locomotion in male APPNLGF mice. Furthermore, this low dose of diazepam was more efficacious at eliciting anxiolytic-like effects in male than female APPNLGF mice. The same low dose of diazepam disrupted recognition memory exclusively in male APPNLGF mice. Biochemical analyses revealed that hippocampal α1 and α5 GABAA receptor subunits mRNA and protein expression were significantly higher in male than female APPNLGF mice and were regulated by histone H3 tri-methylation (H3K4me3) but not histone H3 acetylation. The higher sensitivity of APPNLGF males to diazepam-induced behavioral effects may potentially be due to epigenetic-dependent upregulation of hippocampal α1 and α5 GABAA receptor subunits expression compared to female APPNLGF mice. These findings suggest that dysregulation of GABAergic neurotransmission plays a significant role in memory and affective behavior, particularly in male APPNLGF mice.

Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond.

Self-organized neuronal oscillations rely on precisely orchestrated ensemble activity in reverberating neuronal networks. Chronic, non-malignant disorders of the brain are often coupled to pathological neuronal activity patterns. In addition to the characteristic behavioral symptoms, these disturbances are giving rise to both transient and persistent changes of various brain rhythms. Increasing evidence support the causal role of these “oscillopathies” in the phenotypic emergence of the disease symptoms, identifying neuronal network oscillations as potential therapeutic targets. While the kinetics of pharmacological therapy is not suitable to compensate the disease related fine-scale disturbances of network oscillations, external biophysical modalities (e.g., electrical stimulation) can alter spike timing in a temporally precise manner. These perturbations can warp rhythmic oscillatory patterns via resonance or entrainment. Properly timed phasic stimuli can even switch between the stable states of networks acting as multistable oscillators, substantially changing the emergent oscillatory patterns. Novel transcranial electric stimulation (TES) approaches offer more reliable neuronal control by allowing higher intensities with tolerable side-effect profiles. This precise temporal steerability combined with the non- or minimally invasive nature of these novel TES interventions make them promising therapeutic candidates for functional disorders of the brain. Here we review the key experimental findings and theoretical background concerning various pathological aspects of neuronal network activity leading to the generation of epileptic seizures. The conceptual and practical state of the art of temporally targeted brain stimulation is discussed focusing on the prevention and early termination of epileptic seizures.

Impact of TREM2 on hippocampal network oscillations in Tg2576 mice modeling amyloid-β pathology.

Loss of function mutations in gene encoding triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with the risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data for indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology in AD. However, mechanisms by which TREM2 contributes to increased predisposition to AD and influences its progression still remain ill-defined. We investigated the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal neuronal network oscillations in wild-type and Aβ overproducing Tg2576 mice by in vivo monitoring spontaneous and brainstem stimulation-induced local field potentials from CA1 region under urethane anesthesia. Functional impairment of TREM2, either in TREM2(Het) or TREM2(Hom), resulted in increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Furthermore, deficiency of TREM2 significantly reduced the power of stimulation-induced hippocampal theta oscillation in Tg2576 mice compared to wild-type mice. However, dysfunction of TREM2 did not influence hippocampal theta-phase gamma-amplitude coupling per se, given that both TREM2 intact and TREM2 total deficient Tg2576 mice had a comparable decrease in the phase-amplitude coupling between theta and gamma oscillations when compared to wild-type counterparts. Our findings indicate a TREM2-dependent microglial function in the hippocampal neuronal network oscillations in both physiological conditions and the setting of Aβ overproduction.

The Cellular Mechanisms of Dopamine Modulation on the Neuronal Network Oscillations in the CA3 Area of Rat Hippocampal Slices

Network oscillations at γ frequency band (30–80 Hz), generated by the interaction between inhibitory interneurons and excitatory neurons, have been proposed to be associated with higher brain functions such as learning and memory. Dopamine (DA), one of the major CNS transmitters, modulates hippocampal γ oscillations but the intracellular mechanisms involved remain elusive. In this study, we recorded kainate-induced γ oscillations in the CA3 area of rat hippocampal slices, and found that DA strongly enhanced γ power, which was largely blocked by dopamine receptor 1 (DR1) antagonist SCH23390, receptor tyrosine kinase (RTK) inhibitor UNC569 and ERK inhibitor U0126, partially blocked by D2/3R antagonist raclopride, PKA inhibitor H89 and PI3K inhibitor wortmannin, but not affected by AKT inhibitor TCBN or NMDAR antagonist D-AP5. Our results indicate that DA-mediated γ enhancement is involved in the activation of signaling pathway of DR1/2-RTK-ERK. Our data demonstrate a strong, rapid modulation of DA on hippocampal γ oscillations and provide a new insight into cellular mechanisms of DA-mediated γ oscillations.

The Control of Rat Hippocampal Gamma Oscillation Strength by BK Channel Activity

Neuronal network oscillations in the gamma frequency band (30–80 Hz, γ oscillations) are associated with the higher brain functions such as perception, attention, learning and memory. BK channels mediate rapid repolarization and fast afterhyperpolarization in neurons and control neuronal excitability, and potentially control hippocampal γ oscillations. In this study, we examined the effects of modulating BK channels on hippocampal γ oscillations in the absence or presence of Ca2+ influx through voltage-gated Ca2+ channels (VGCC) or Ca2+-permeable AMPA receptors (CP-AMPAR). We found that blocking BK channels enhanced γ power, without affecting oscillation frequency or regularity, suggesting that BK channel activity suppresses γ oscillations. Blocking either VGCC or CP-AMPAR itself enhanced γ power, and completely occluded the effect of BK channel blockers on γ oscillations, whereas blocking BK channels first could not prevent a further γ power increase upon blockade of either CP-AMPAR or VGCC. We propose that Ca2+ influx through VGCC or CP-AMPAR during γ oscillations, cause membrane BK channel activation and regulate hippocampal γ oscillation strength by negative feedback.

Comodulation of h- and Na+/K+ Pump Currents Expands the Range of Functional Bursting in a Central Pattern Generator by Navigating between Dysfunctional Regimes.

Central pattern generators (CPGs), specialized oscillatory neuronal networks controlling rhythmic motor behaviors such as breathing and locomotion, must adjust their patterns of activity to a variable environment and changing behavioral goals. Neuromodulation adjusts these patterns by orchestrating changes in multiple ionic currents. In the medicinal leech, the endogenous neuromodulator myomodulin speeds up the heartbeat CPG by reducing the electrogenic Na+/K+ pump current and increasing h-current in pairs of mutually inhibitory leech heart interneurons (HNs), which form half-center oscillators (HN HCOs). Here we investigate whether the comodulation of two currents could have advantages over a single current in the control of functional bursting patterns of a CPG. We use a conductance-based biophysical model of an HN HCO to explain the experimental effects of myomodulin. We demonstrate that, in the model, comodulation of the Na+/K+ pump current and h-current expands the range of functional bursting activity by avoiding transitions into nonfunctional regimes, such as asymmetric bursting and plateau-containing seizure-like activity. We validate the model by finding parameters that reproduce temporal bursting characteristics matching experimental recordings from HN HCOs under control, three different myomodulin concentrations, and Cs+ treated conditions. The matching cases are located along the border of an asymmetric regime away from the border with more dangerous seizure-like activity. We found a simple comodulation mechanism with an inverse relation between the pump and h-currents makes a good fit of the matching cases and comprises a general mechanism for the robust and flexible control of oscillatory neuronal networks.SIGNIFICANCE STATEMENT Rhythm-generating neuronal circuits adjust their oscillatory patterns to accommodate a changing environment through neuromodulation. In different species, chemical messengers participating in such processes may target two or more membrane currents. In medicinal leeches, the neuromodulator myomodulin speeds up the heartbeat central pattern generator by reducing Na+/K+ pump current and increasing h-current. In a computational model, we show that this comodulation expands the range of central pattern generator's functional activity by navigating the circuit between dysfunctional regimes resulting in a much wider range of cycle period. This control would not be attainable by modulating only one current, emphasizing the synergy of combined effects. Given the prevalence of h-current and Na+/K+ pump current in neurons, similar comodulation mechanisms may exist across species.

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations.

Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored. The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant. Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.