Maciej Olszewski

Epilepsy frequently develops as a result of brain insult, for example, brain injury or stroke. Currently, there are no tools allowing us to predict which trauma patients will eventually develop epilepsy. There is evidence that microRNAs levels are altered in the blood, making them attractive candidates for peripheral biomarkers of epilepsy. We analyzed white blood cell subpopulations containing miR-155-5p and miR-674-3p, in control and stimulated animals and in control and symptomatic or asymptomatic animals in the amygdala stimulation model. The first proposed early biomarker of epilepsy is the relative proportion of CD45RA ⁺ B cells containing miR-155-5p and/or miR-674-3p. Others are increased number of CD45RA ⁺ B cells containing either miR-155-5p or miR-155-5p and miR-674-3p together or decreased number of CD161 ⁺ NK cells not containing miR-155-5p nor miR-674-3p. Additionally, we found that the decreased number of CD4 ⁺ T cells can be used as a potential biomarker for identifying epileptic animals with symptomatic epilepsy.

Oscillatory rhythms in local field potentials (LFPs) are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS) to enhance locomotor recovery in patients with gait disorders. Theta band activity (6-12 Hz) is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined Mesencephalic Locomotor Region (MLR) during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold ≤ 60 µA). Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (> 60 µA), the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus, thought to be a part of the MLR) were relatively small. Controlled locomotion was best achieved at 10 - 20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites.

Rationale Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Objective This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130–180 Hz) in mice. Methods Local field potentials were recorded from the nucleus accumbens of freely moving mice. Results Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT_1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT_2A, 5-HT₇ and histamine H₃ receptors had no effect. Conclusions NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT_1A receptors.

Improved understanding of the actions of antipsychotic compounds is critical for a better treatment of schizophrenia. Abnormal oscillatory activity has been found in schizophrenia and in rat models of the disease. N-Methyl-d-aspartic acid receptor (NMDAR) antagonists, used to model certain features of schizophrenia, increase the frequency and power of high-frequency oscillations (HFO, 130–180 Hz) in the rat nucleus accumbens, a brain region implicated in schizophrenia pathology. Antipsychotics can be classified as first- and second-generation drugs, the latter often reported to have wider benefit in humans and experimental models. This prompted the authors to examine the pre- and post-treatment effects of clozapine, risperidone (second-generation drugs) and sulpiride and haloperidol (first-generation drugs) on ketamine and MK801-enhanced accumbal HFO. Both NMDAR antagonists increased HFO frequency. In contrast, clozapine and risperidone markedly and dose-dependently reduced the frequency of spontaneous and NMDAR-antagonist-enhanced HFO, whilst a moderate effect was found for sulpiride and a much weaker effect for haloperidol. Unexpectedly, we found reductions in HFO frequency were associated with an increase in its power. These findings indicate that modulation of accumbal HFO frequency may be a fundamental effect produced by antipsychotic compounds. Of the drugs investigated, first- and second-generation compounds could be dissociated by their potency on this measure. This effect may partially explain the differences in the clinical profile of these drugs.

Rationale The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-d-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130–180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT_2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear. Objective This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT_2A receptors mediate the effects observed. Methods LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally. Results LSD (0.03–0.3 mg/kg) and DOI (0.5–2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40–60 Hz), but not high gamma oscillations (70–90 Hz). MDL 11939 (1.0 mg/kg), a 5HT_2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT_2A receptor agonist, 0.1–1.5 mg/kg), but not CP 809101 (5H_2C receptor agonist, 0.1–3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg). Conclusions Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT_2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.

The effect of stimuli predicting danger (DS) and safety (SS) in Pavlovian aversive conditioning on hippocampal local field potentials (LFP) was studied in 25 partially restrained adult male rats (Long-Evans). DS lasting 5 s preceded tail-shock, while SS overlapping DS during DS last 3 s predicted omission of shock. The power spectra of LFPs during trials were analyzed in theta and delta frequency bands. In DS, theta frequency during the last 3 s was lower that in first 2 s. In danger and safety situation theta peak frequency was different for dorsal CA1 activity (5.99 Hz vs. 6.86 Hz, respectively), while delta peak frequency was different for ventral CA1 (1.56 Hz vs. 1.07 Hz) for the last 3 s of trial. Differences in theta frequency in danger and safety situation may reflect differences in sensory processing during induced emotional states and/or related differences in motor behavior.