Adi Cymerblit-Sabba

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in Rats In Vivo

In epilepsy, the cortical network fluctuates between the asymptomatic interictal state and the symptomatic ictal state of seizures. Despite their importance, the network dynamics responsible for the transition between the interictal and ictal states are largely unknown. Here we used multielectrode single-unit recordings from the hippocampus to investigate the network dynamics during the development of seizures evoked by various chemoconvulsants in vivo. In these experiments, we detected a typical network dynamics signature that preceded seizure initiation. The preictal state preceding pilocarpine-, kainate-, and picrotoxin-induced seizures was characterized by biphasic network dynamics composed of an early desynchronization phase in which the tendency of neurons to fire correlated action potentials decreased, followed by a late resynchronization phase in which the activity and synchronization of the network gradually increased. This biphasic network dynamics preceded the initiation both of the initial seizure and of recurrent spontaneous seizures that followed. During seizures, firing of individual neurons and interneuronal synchronization further increased. These findings advance our understanding of the network dynamics leading to seizure initiation and may in future help in the development of novel seizure prediction algorithms.

Development of hypersynchrony in the cortical network during chemoconvulsant-induced epileptic seizures in vivo.

The prevailing view of epileptic seizures is that they are caused by increased hypersynchronous activity in the cortical network. However, this view is based mostly on electroencephalography (EEG) recordings that do not directly monitor neuronal synchronization of action potential firing. In this study, we used multielectrode single-unit recordings from the hippocampus to investigate firing of individual CA1 neurons and directly monitor synchronization of action potential firing between neurons during the different ictal phases of chemoconvulsant-induced epileptic seizures in vivo. During the early phase of seizures manifesting as low-amplitude rhythmic β-electrocorticography (ECoG) activity, the firing frequency of most neurons markedly increased. To our surprise, the average overall neuronal synchronization as measured by the cross-correlation function was reduced compared with control conditions with ~60% of neuronal pairs showing no significant correlated firing. However, correlated firing was not uniform and a minority of neuronal pairs showed a high degree of correlated firing. Moreover, during the early phase of seizures, correlated firing between 9.8 ± 5.1% of all stably recorded pairs increased compared with control conditions. As seizures progressed and high-frequency ECoG polyspikes developed, the firing frequency of neurons further increased and enhanced correlated firing was observed between virtually all neuronal pairs. These findings indicated that epileptic seizures represented a hyperactive state with widespread increase in action potential firing. Hypersynchrony also characterized seizures. However, it initially developed in a small subset of neurons and gradually spread to involve the entire cortical network only in the later more intense ictal phases.

Prenatal Enriched Environment improves emotional and attentional reactivity to adulthood stress

Environmental factors seem to play a key role in brain and behavioral development, both in humans and animals. Different environmental manipulations, either pre- or post-natal, have been shown to exert long-term physiological and behavioral effects. While studies in the field of Enriched Environment mainly focus on the post weaning period and provide enrichment as a post adverse-experience manipulation, the preceding effects of prenatal Enriched Environment have rarely been investigated. In this study, we investigated the effects of prenatal Enriched Environment (through the entire pregnancy) followed by adulthood acute stress. In the prenatal Enriched Environment offspring, we found anxiety and depressive-like behaviors with poor attentional performance. Surprisingly, when prenatal Enriched Environment was followed by adulthood stress, we observed a dramatic restoration of these behavioral deficits. Our results suggest that prenatal Enriched Environment may substrate resiliency to adulthood stress.

Termination of Chemoconvulsant-Induced Seizures by Synchronous and Asynchronous Electrical Stimulation of the Hippocampus In-Vivo

BACKGROUND Neurostimulation has been proposed as a potential new treatment modality for pharmacoresistant epilepsy. Yet the effect of the different stimulation parameters on the efficacy of stimulation is not sufficiently known. OBJECTIVE Investigate the effect of different stimulation parameters on the efficacy of neurostimulation in terminating acute chemoconvulsant-induced hippocampal seizures in-vivo. METHODS Seizures were induced in rats in-vivo either by systemic or local intra hippocampal application of chemoconvulsants, and bipolar electrical stimulation was applied during seizures by stimulating the perforant pathway of the hippocampus. The stimulus intensity, frequency, and duration were altered. RESULTS Increasing the stimulus intensity and train duration increased the probability for seizure termination. The efficacy of stimulus intensity peaked at 250-300 μA. Low stimulation frequencies (≤13 Hz) were inefficient in terminating seizures. Increasing the stimulation frequency (up to 250 Hz) enhanced seizure termination, reaching a plateau effect at frequencies of 50-100 Hz. When we simultaneously applied the same stimulation frequency in two adjacent electrodes (synchronous stimulation) the probability for seizure termination did not significantly change. In contrast when the two stimulating electrodes were simultaneously activated with different asynchronous stimulation frequencies (30 and 100 Hz or 60 and 200 Hz, asynchronous stimulation) the probability for terminating seizures more than doubled. Similar results were also observed with local intra hippocampal-induced seizures. CONCLUSIONS Asynchronous stimulation paradigms enhanced the antiepileptic efficacy of neurostimulation, possibly by desynchronizing and functionally subdividing the network.

Methylphenidate and environmental enrichment ameliorate the deleterious effects of prenatal stress on attention functioning

Abstract Either pre- or post-natal environmental factors seem to play a key role in brain and behavioral development and to exert long-term effects. Increasing evidence suggests that exposure to prenatal stress (PS) leads to motor and learning deficits and elevated anxiety, while enriched environment (EE) shows protective effects. The dopaminergic system is also sensitive to environmental life circumstances and affects attention functioning, which serves as the preliminary gate to cognitive processes. However, the effects of methylphenidate (MPH) on the dopaminergic system and attentional functioning, in the context of these life experiences, remain unclear. Therefore, we aimed to examine the effects of EE or PS on distinct types of attention, along with possible effects of MPH exposure. We found that PS impaired selective attention as well as partial sustained attention, while EE had beneficial effects. Both EE and MPH ameliorated the deleterious effects of PS on attention functioning. Considering the possible psychostimulant effect of MPH, we examined both anxiety-like behavior as well as motor learning. We found that PS had a clear anxiogenic effect, whereas EE had an anxiolytic effect. Nevertheless, the treatment with both MPH and/or EE recovered the deleterious effects of PS. In the motor-learning task, the PS group showed superior performance while MPH led to impaired motor learning. Performance decrements were prevented in both the PS + MPH and EE + MPH groups. This study provides evidence that peripubertal exposure to EE (by providing enhanced sensory, motor, and social opportunities) or MPH treatments might be an optional therapeutic intervention in preventing the PS long-term adverse consequences.

Plant-derived nanoparticle treatment with cocc 30c ameliorates attention and motor abilities in sleep-deprived rats

Sleep is an essential physiological process that underlies crucial cognitive functions as well as emotional reactivity. Thus, sleep deprivation (SD) may exert various deleterious effects. In this study, we aimed to examine the adverse behavioral and hormonal effects of SD and a potential treatment with Plant-derived nanoparticle treatment - cocc 30c. The study was a 4-arm trial with randomization and double-blinding of verum and placebo treatments. SD was induced by using the Multiple Platform Method for 48 h. The effects of SD were evaluated behaviorally (pre-pulse inhibition (PPI), startle response and rotor-rod) at baseline as well as at 6, 12, 24h, and 14 days post deprivation. cocc 30c treatment was administrated Per Os every three hours starting immediately after baseline tests and for a period of 24h. On day 14, blood samples were taken and serum levels of corticosterone, testosterone, serotonin and leptin were tested. We found that cocc 30c improved PPI 12 and 24h post deprivation, likewise, cocc 30c improved motor learning. On day 14 SD led to increased startle response that was ameliorated by cocc 30c. Likewise, SD led to increased levels of corticosterone and serotonin while decreasing testosterone and leptin. Interestingly, cocc 30c treatment has moderated these hormonal alterations. We conclude that the treatment with cocc 30c recovers both short-term behavioral and the long-term hormonal modulations following SD.

In the letter to the editor from Fudge and Helmreich, the authors related to our recent publication (Cymerblit-Sabbaet al., 2015).

In the Letter to the Editor from Fudge and Helmreich, the uthors related to our recent publication (Cymerblit-Sabba t al., 2015) in which we referred to their results (Saul et al., 012). First, we would like to emphasize that the stress protocol sed in Saul et al. (2012) is different (i.e., type of stressors nd intensity) from ours. This difference is part of the ratioale that led us to conduct a systematic study which allows comparison of different developmental time points, in rder to examine whether there is a unique hyper-sensitive eriod for the exposure to stress. Thus, we utilized simiar stress protocols in the different time points examined. mportantly, we conducted behavioural examinations in the pen field that included: freezing duration, anxiety index, ctivity and velocity measures. Additionally, we measured tartle response and corticosterone level. We found consisent anxiety-like effects across all measures at the same evelopmental time points (i.e. PND 35—55). While Saul t al. (2012) showed that the exposure to stress in both adoescence and young adulthood led to increased time spent in he centre of the open field, there are numerous papers that eferred to the peripheral area of the open field as a meaure of anxiety, and time (or distance) spent in the centre rea as non-anxiety behaviour (Bailey and Crawley, 2009; estakova et al., 2013). We find their attempt to explain he tendency towards the central part of the open-field ccording to the test starting point (centre/corner) intersting and creative. Yet, one should expect that a naive at would show similar exploration patterns based on the entre/corner start location. This is not the case in their esults; hence, the interpretation of the start location effect n the stress groups is ambiguous. Therefore, as we viewed he results in Saul et al. (2012), they drew their concluions by referring only to the hypo-activity effect in both dolescence and young adulthood groups. However, hypoctivity is less indicative of anxiety behaviour, since there S