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Thin pancake-like neuronal networks cultured on top of a planar microelectrode array have been extensively tried out in neuroengineering, as a substrate for the mobile robot's control unit, i.e., as a cyborg's brain. Most of these attempts failed due to intricate self-organizing dynamics in the neuronal systems. In particular, the networks may exhibit an emergent spatial map of steady nucleation sites ("n-sites") of spontaneous population spikes. Being unpredictable and independent of the surface electrode locations, the n-sites drastically change local ability of the network to generate spikes. Here, using a spiking neuronal network model with generative spatially-embedded connectome, we systematically show in simulations that the number, location, and relative activity of spontaneously formed n-sites ("the vitals") crucially depend on the samplings of three distributions: (1) the network distribution of neuronal excitability, (2) the distribution of connections between neurons of the network, and (3) the distribution of maximal amplitudes of a single synaptic current pulse. Moreover, blocking the dynamics of a small fraction (about 4%) of non-pacemaker neurons having the highest excitability was enough to completely suppress the occurrence of population spikes and their n-sites. This key result is explained theoretically. Remarkably, the n-sites occur taking into account only short-term synaptic plasticity, i.e., without a Hebbian-type plasticity. As the spiking network model used in this study is strictly deterministic, all simulation results can be accurately reproduced. The model, which has already demonstrated a very high richness-to-complexity ratio, can also be directly extended into the three-dimensional case, e.g., for targeting peculiarities of spiking dynamics in cerebral (or brain) organoids. We recommend the model as an excellent illustrative tool for teaching network-level computational neuroscience, complementing a few benchmark models. [ABSTRACT FROM AUTHOR]

Stimulation-induced inhibition is one of the important effects of high-frequency stimulation (HFS) utilized by the therapy of deep brain stimulation (DBS) to treat certain neurological diseases such as epilepsy. In order to explore the stimulation sites to induce inhibition, this study investigated the activation effect of HFS of efferent fibers on the local inhibitory interneurons (IN). Antidromic HFS (A-HFS) of 100 Hz pulses was applied for 2 min at the efferent fibers—the alveus (i.e., the axons of pyramidal neurons) in the hippocampal CA1 region of anesthetized rats. Single unit spikes of INs in local feedback inhibitory circuits, as well as antidromically-evoked population spikes (APS) of pyramidal neurons, were recorded simultaneously in the CA1 region upstream of the stimulation site. Results showed that during the late 60 s of A-HFS, with a substantial suppression in APS amplitudes, the mean firing rate of INs was still significantly greater than the baseline level even when the A-HFS was applied with a weak pulse intensity of 0.08 ± 0.05 mA (9 rats). With a strong pulse intensity of 0.33 ± 0.08 mA (10 rats), the mean firing rate of INs was able to keep at a high level till the end of A-HFS. In addition, the mean latency of IN firing was significantly prolonged during the sustained A-HFS, indicating that alterations had been generated in the pathway to activate INs by the stimulations at efferent fibers. The results suggested that HFS at efferent fibers with various stimulation intensities can modulate the firing of local inhibitory neurons. The finding provides new clues for selecting stimulation sites to enhance inhibition in neural circuits by DBS. [ABSTRACT FROM AUTHOR]

We show that networks of excitatory neurons with stochastic spontaneous spiking activity and short-term synaptic plasticity can exhibit spontaneous repetitive synchronization in so-called population spikes. The major reason for this is that synaptic plasticity nonlinearly modulates the interaction between neurons. For large-scale two-dimensional networks, where the connection probability decreases exponentially with increasing distance between the neurons resulting in a small-world network connectome, a population spike occurs in the form of circular traveling waves diverging from seemingly non-stationary nucleation sites. The latter is in drastic contrast to the case of networks with a fixed fraction of steady pacemaker neurons, where the set of a few spontaneously formed nucleation sites is stationary. Despite the spatial non-stationarity of their nucleation, population spikes may occur surprisingly regularly. From a theoretical viewpoint, these findings show that the regime of nearly-periodic population spikes, which mimics respiratory rhythm, can occur strictly without stochastic resonance. In addition, the observed spatiotemporal effects serve as an example of transient chimera patterns. [ABSTRACT FROM AUTHOR]

Stimulation-induced inhibition is one of the important effects of high-frequency stimulation (HFS) utilized by the therapy of deep brain stimulation (DBS) to treat certain neurological diseases such as epilepsy. In order to explore the stimulation sites to induce inhibition, this study investigated the activation effect of HFS of efferent fibers on the local inhibitory interneurons (IN). Antidromic HFS (A-HFS) of 100 Hz pulses was applied for 2 min at the efferent fibers—the alveus (i.e., the axons of pyramidal neurons) in the hippocampal CA1 region of anesthetized rats. Single unit spikes of INs in local feedback inhibitory circuits, as well as antidromically-evoked population spikes (APS) of pyramidal neurons, were recorded simultaneously in the CA1 region upstream of the stimulation site. Results showed that during the late 60 s of A-HFS, with a substantial suppression in APS amplitudes, the mean firing rate of INs was still significantly greater than the baseline level even when the A-HFS was applied with a weak pulse intensity of 0.08 ± 0.05 mA (9 rats). With a strong pulse intensity of 0.33 ± 0.08 mA (10 rats), the mean firing rate of INs was able to keep at a high level till the end of A-HFS. In addition, the mean latency of IN firing was significantly prolonged during the sustained A-HFS, indicating that alterations had been generated in the pathway to activate INs by the stimulations at efferent fibers. The results suggested that HFS at efferent fibers with various stimulation intensities can modulate the firing of local inhibitory neurons. The finding provides new clues for selecting stimulation sites to enhance inhibition in neural circuits by DBS.

Dexpramipexole (DEX) has been described as the first-in-class F1Fo ATP synthase activator able to boost mitochondrial bioenergetics and provide neuroprotection in experimental models of ischemic brain injury. Although DEX failed in a phase III trial in patients with amyotrophic lateral sclerosis, it showed favorable safety and tolerability profiles. Recently, DEX emerged as a Nav1.8 Na+ channel and transient outward K+ (IA) conductance blocker, revealing therefore an unexpected, pleiotypic pharmacodynamic profile. In this study, we performed electrophysiological experiments in vitro aimed to better characterize the impact of DEX on voltage-dependent currents and synaptic transmission in the hippocampus. By means of patch-clamp recordings on isolated hippocampal neurons, we found that DEX increases outward K+ currents evoked by a voltage ramp protocol. This effect is prevented by the non-selective voltage-dependent K+ channel (Kv) blocker TEA and by the selective small-conductance Ca2+-activated K+ (SK) channel blocker apamin. In keeping with this, extracellular field recordings from rat hippocampal slices also demonstrated that the compound inhibits synaptic transmission and CA1 neuron excitability. Overall, these data further our understanding on the pharmacodynamics of DEX and disclose an additional mechanism that could underlie its neuroprotective properties. Also, they identify DEX as a lead to develop new modulators of K+ conductances. [ABSTRACT FROM AUTHOR]

Electrical pulse stimulation in the brain has shown success in treating several brain disorders with constant pulse frequency or constant inter-pulse interval (IPI). Varying IPI may offer a variety of novel stimulation paradigms and may extend the clinical applications. However, a lack of understanding of neuronal responses to varying IPI limits its informed applications. In this study, to investigate the effects of varying IPI, we performed both rat experiments and computational modeling by applying high-frequency stimulation (HFS) to efferent axon fibers of hippocampal pyramidal cells. Antidromically evoked population spikes (PSs) were used to evaluate the neuronal responses to pulse stimulations with different IPI patterns including constant IPI, gradually varying IPI, and randomly varying IPI. All the varying IPI sequences were uniformly distributed in the same interval range of 10 to 5 ms (i.e., 100 to 200 Hz). The experimental results showed that the mean correlation coefficient of PS amplitudes to the lengths of preceding IPI during HFS with random IPI (0.72 ± 0.04, n = 7 rats) was significantly smaller than the corresponding correlation coefficient during HFS with gradual IPI (0.92 ± 0.03, n = 7 rats, P < 0.001, t -test). The PS amplitudes induced by the random IPI covered a wider range, over twice as much as that induced by the gradual IPI, indicating additional effects induced by merely changing the appearance order of IPI. The computational modeling reproduced these experimental results and provided insights into these modulatory effects through the mechanism of non-linear dynamics of sodium channels and potassium accumulation in the narrow peri-axonal space. The simulation results showed that the HFS-induced increase of extracellular potassium ([K+] o ) elevated the membrane potential of axons, delayed the recovery course of sodium channels that were repeatedly activated and inactivated during HFS, and resulted in intermittent neuronal firing. Because of non-linear membrane dynamics, random IPI recruited more neurons to fire together following specific sub-sequences of pulses than gradual IPI, thereby widening the range of PS amplitudes. In conclusion, the study demonstrated novel HFS effects of neuronal modulation induced by merely changing the appearance order of the same group of IPI of pulses, which may inform the development of new stimulation patterns to meet different demands for treating various brain diseases. [ABSTRACT FROM AUTHOR]

An adverse effect of drug candidates, seizure is a serious issue in drug development. Improving evaluation systems for seizure liability is crucial for selecting good candidates. Firstly, in vitro electrophysiological measurement by a multielectrode array system in rat hippocampal brain slices was employed to confirm an increase in electrically evoked population spike (PS) area, the occurrence of multiple population spikes (MPSs), and thereby the seizure liability of five positive control chemicals: picrotoxin, 4-aminopyridine, pentylenetetrazole, penicillin G, and chlorpromazine. Aspirin, a negative control, did not affect PS area or generate MPSs. Furthermore, baclofen, an anticonvulsant drug, decreased PS area and inhibited the increase in PS area or occurrence of MPSs induced by picrotoxin. A comparative study of seizure liability among carbapenem antibiotics revealed that tienam > carbenin > omegacin and finibax. Despite leading to a strong decrease in PS area, physostigmine, cisplatin, and paroxetine still produced MPSs. Therefore, the increase in PS area or the occurrence of the MPS are considered significant evaluation parameters for seizure liability. In contrast, the in vitro electrophysiological measurement could not detect the seizure liability of diphenhydramine or fluvoxamine. A follow-up study of in vivo mouse behavioral change induced by intracerebroventricular administration of these drugs clearly detected convulsions. The in vitro electrophysiological study using hippocampal brain slices combined with in vivo behavior observation study of drug candidates administered by intracerebroventricular injection can implement to assess the seizure liability of even small amounts, especially in the early stages of drug development. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) traditionally utilizes electrical pulse sequences with a constant frequency, i.e., constant inter-pulse-interval (IPI), to treat certain brain disorders in clinic. Stimulation sequences with varying frequency have been investigated recently to improve the efficacy of existing DBS therapy and to develop new treatments. However, the effects of such sequences are inconclusive. The present study tests the hypothesis that stimulations with varying IPI can generate neuronal activity markedly different from the activity induced by stimulations with constant IPI. And, the crucial factor causing the distinction is the relative differences in IPI lengths rather than the absolute lengths of IPI nor the average lengths of IPI. In rat experiments in vivo, responses of neuronal populations to applied stimulation sequences were collected during stimulations with both constant IPI (control) and random IPI. The stimulations were applied in the efferent fibers antidromically (in alveus) or in the afferent fibers orthodromically (in Schaffer collaterals) of pyramidal cells, the principal cells of hippocampal CA1 region. Amplitudes and areas of population spike (PS) waveforms were used to evaluate the neuronal responses induced by different stimulation paradigms. During the periods of both antidromic and orthodromic high-frequency stimulation (HFS), the HFS with random IPI induced synchronous neuronal firing with large PS even if the lengths of random IPI were limited to a small range of 5–10 ms, corresponding to a frequency range 100–200 Hz. The large PS events did not appear during control stimulations with a constant frequency at 100, 200, or 130 Hz (i.e., the mean frequency of HFS with random IPI uniformly distributed within 5–10 ms). Presumably, nonlinear dynamics in neuronal responses to random IPI might cause the generation of synchronous firing under the situation without any long pauses in HFS sequences. The results indicate that stimulations with random IPI can generate salient impulses to brain tissues and modulate the synchronization of neuronal activity, thereby providing potential stimulation paradigms for extending DBS therapy in treating more brain diseases, such as disorders of consciousness and vegetative states.

BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal–dentate circuitry. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) traditionally utilizes electrical pulse sequences with a constant frequency, i.e., constant inter-pulse-interval (IPI), to treat certain brain disorders in clinic. Stimulation sequences with varying frequency have been investigated recently to improve the efficacy of existing DBS therapy and to develop new treatments. However, the effects of such sequences are inconclusive. The present study tests the hypothesis that stimulations with varying IPI can generate neuronal activity markedly different from the activity induced by stimulations with constant IPI. And, the crucial factor causing the distinction is the relative differences in IPI lengths rather than the absolute lengths of IPI nor the average lengths of IPI. In rat experiments in vivo , responses of neuronal populations to applied stimulation sequences were collected during stimulations with both constant IPI (control) and random IPI. The stimulations were applied in the efferent fibers antidromically (in alveus) or in the afferent fibers orthodromically (in Schaffer collaterals) of pyramidal cells, the principal cells of hippocampal CA1 region. Amplitudes and areas of population spike (PS) waveforms were used to evaluate the neuronal responses induced by different stimulation paradigms. During the periods of both antidromic and orthodromic high-frequency stimulation (HFS), the HFS with random IPI induced synchronous neuronal firing with large PS even if the lengths of random IPI were limited to a small range of 5–10 ms, corresponding to a frequency range 100–200 Hz. The large PS events did not appear during control stimulations with a constant frequency at 100, 200, or 130 Hz (i.e., the mean frequency of HFS with random IPI uniformly distributed within 5–10 ms). Presumably, nonlinear dynamics in neuronal responses to random IPI might cause the generation of synchronous firing under the situation without any long pauses in HFS sequences. The results indicate that stimulations with random IPI can generate salient impulses to brain tissues and modulate the synchronization of neuronal activity, thereby providing potential stimulation paradigms for extending DBS therapy in treating more brain diseases, such as disorders of consciousness and vegetative states. [ABSTRACT FROM AUTHOR]

Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP–spike (E–S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAβ increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.

Summary Ethnopharmacological relevance Sceletium tortuosum ( Mesembryanthemaceae ), a succulent plant indigenous to South Africa. is consumed in the form of teas, decoctions and tinctures and is sometimes smoked and used as snuff. In recent years, Sceletium has received a great deal of commercial interest for relieving stress in healthy people, and for treating a broad range of psychological, psychiatric and inflammatory conditions. Material and methods The whole extract (Zembrin®) was tested ex vivo in the hippocampus slice preparation after one week of daily oral administration of 5 and 10 mg/kg. Four alkaloids – mesembrine, mesembranol, mesembrenol and mesembrenone – were tested directly in vitro. All four were also tested in the presence of different glutamate receptor agonists. Results Zembrin® ex vivo as well as all alkaloids in vitro attenuated the amplitude of the population spike during electric stimulation as single shock as well as theta burst stimulation. Only Mesembranol and Mesembrenol having a hydroxyl group at position C6 instead of carbonyl group as in mesembrine and mesembrenone acted by attenuation of AMPA receptor mediated transmission as documented for the whole extract. Discussion The current experimental series revealed a new physiological effect of Zembrin ® on the electric activity of the hippocampus. Attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients. Administered doses of 5 and 10 mg/kg are in line with a dosage of 50 mg/subject as tested clinically. Conclusion We have discovered a new structure activity relationship for Sceletium alkaloids. Since attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients), Mesembrenol and Mesembranol may serve as new chemical leads for the development of new drugs for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability. [ABSTRACT FROM AUTHOR]

Abstract: The hippocampus is functionally differentiated along its longitudinal axis, with the dorsal and ventral segments preferentially involved in cognitive and emotional processing, respectively. Serotonergic modulation of hippocampal function has been extensively studied, but its relation to the dorsoventral axis has remained largely unknown. To examine the modulation of hippocampal output along the dorsoventral axis by endogenous serotonin (5‐HT) we compared the effect of the 5‐HT/noradrenaline (NA)‐releaser, 3,4‐methylenedioxymethamphetamine (MDMA), in transversal slices encompassing the entire rat hippocampus. Co‐release of 5‐HT and NA by MDMA resulted in a gradient of effects on evoked population spikes in the CA1 area along the dorsoventral axis of the hippocampus. Selective 5‐HT release decreased population spike amplitude in slices from dorsal hippocampus, whereas an increase was produced in the ventral hippocampus, indicating differential modulation of CA1 impulse flow along the dorsoventral axis by endogenous 5‐HT. Selective NA release increased population spike amplitude with no gradient indicating facilitatory effect of endogenous NA along the entire dorsoventral axis. Blockade of 5‐HT1A receptors prevented the inhibitory component of MDMA action and the emergence of the gradient, indicating that activation of 5‐HT1A receptors is required for differential modulation of CA1 impulse flow by endogenous 5‐HT. These findings suggest that a dorsoventral shift in CA1 output level may represent an integral component of 5‐HT action on hippocampal information processing. Given the preferential role of ventral hippocampus in emotional and anxiety‐related behavior, it can be proposed that serotonin tone encodes the emotional salience of the signal processed by hippocampus. [ABSTRACT FROM AUTHOR]

Studies using in vitro rat hippocampal slices addressed the mechanism of deprivation potentiation (DeP) of neuron population responses in field CA1 developing as a result of prolonged (60 or 120 min) cessation of rare (0.05 Hz) test stimuli of Schaffer collaterals (SC). The development of DeP was found to involve two independent mechanisms: pre- and postsynaptic, responsible for induction of the short-term and long-term components of DeP, respectively. These studies showed that the interaction of DeP and long-term post-tetanic potentiation (LTP) is competitive in nature, providing evidence of similarity in the mechanisms of the long-term phase of DeP and the phase of LTP associated with protein phosphorylation. Our investigation showed that the Ca-dependent mechanism of induction of the postsynaptic component of DeP does not involve NMDA receptors, but does involve purine P2 receptors. A common curve for the relationship between the efficiency of synaptic transmission and the use/non-use of synapses including DeP, long-term depression (LTD), and LTP zones is presented. [ABSTRACT FROM AUTHOR]