Crosstalk between the subiculum and sleep-wake regulation: A review.

The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non-rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep-wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep-wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second-order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep-wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep-deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness.

The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy.

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control.

Discriminating rapid eye movement sleep from wakefulness by analyzing high frequencies from single-channel EEG recordings in mice.

Rapid eye movement sleep (REMS) is characterized by the appearance of fast, desynchronized rhythms in the cortical electroencephalogram (EEG), similar to wakefulness. The low electromyogram (EMG) amplitude during REMS distinguishes it from wakefulness; therefore, recording EMG signal seems to be imperative for discriminating between the two states. The present study evaluated the high frequency components of the EEG signal from mice (80-500 Hz) to support REMS detection during sleep scoring without an EMG signal and found a strong positive correlation between waking and the average power of 80-120 Hz, 120-200 Hz, 200-350 Hz and 350-500 Hz. A highly negative correlation was observed with REMS. Furthermore, our machine learning approach demonstrated that simple EEG time-series features are enough to discriminate REMS from wakefulness with sensitivity of roughly 98 percent and specificity of around 92 percent. Interestingly, assessing only the higher frequency bands (200-350 Hz as well as 350-500 Hz) gives significantly greater predictive power than assessing only the lower end of the EEG frequency spectrum. This paper proposes an approach that can detect subtle changes in REMS reliably, and future unsupervised sleep-scoring approaches could greatly benefit from it.

Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons.

Toll-like receptors (TLR) are one of the main constituents of the innate immune system in mammals. They can detect conserved microbial structures (pathogen-associated molecular patterns) and host-derived ligands that are produced during cellular stress and damage (danger-associated molecular patterns) and may then initiate an intracellular signaling cascade leading to the expression of pro-inflammatory cytokines and immediate immune responses. Some TLR (TLR1, 2, 4, 5, and 6) are expressed on the cell surface while others (TLR3, 7, 8 and 9) are present on the surface of endosomes and their ligands require internalization before recognition is possible. Several TLR have also been detected in neurons where they may serve functions that are not related to immune responses. TLR2, 3, and 4 have been described in cortical neurons and, for TLR4, a seizure-promoting role in epilepsies associated with inflammation has been shown. TLR3, 7, and 8 expressed in neurons seem to influence the growth or withdrawal of neurites and robust activation of TLR8 in neurons may even induce neuronal death. The goal of the current study was to investigate the expression of TLR8 in the hippocampus of mice during postnatal development and in adulthood. We focused on three functionally distinct groups of GABAergic interneurons characterized by the expression of the molecular markers parvalbumin, somatostatin, or calretinin, and we applied double fluorescence immunohistochemistry and cell counts to quantify co-expression of TLR8 in the three groups of GABA-interneurons across hippocampal subregions. We found subregion-specific differences in the expression of TLR8 in these interneurons. During postnatal development, TLR8 was detected only in mice older than P5. While only a small fraction of hippocampal calretinin-positive interneurons expressed TLR8, most parvalbumin-positive interneurons in all hippocampal subregions co-expressed TLR8. Somatostatin-positive interneurons co-expressing TLR8 were mainly present in hippocampal sector CA3 but rare in the dentate gyrus and CA1. High expression of TLR8 in parvalbumin-interneurons may contribute to their high vulnerability in human temporal lobe epilepsy.

Occupational risk assessment of organophosphates with an emphasis on psychological and oxidative stress factors.

Organophosphate pesticides (OPPs) are widely used all over the world in domestic and industrial settings, but these chemicals affect the nervous system, induce suicidal thoughts, depression and anxiety, and impair sleep quality. The purpose of this study was to investigate the relationship between the main toxicity mechanisms of OPPs, oxidative stress and cholinesterase inhibition, and psychological parameters in chronic exposure to OPPs. This cross-sectional study was conducted on 56 male OPPs factory workers as the worker group and 47 unexposed individuals within the same age range as the control group. Psychological factors were assessed using validated questionnaires. The activity of plasma cholinesterase and oxidative stress biomarkers, total antioxidant capacity of plasma, lipid peroxidation (LPO), and protein carbonylation were determined in blood samples by spectrophotometer. Sleep quality score in the factory workers was lower, and depression and suicidal ideation scores were higher than those in the control group. These factory workers showed 35% lower levels of plasma cholinesterase activity than did the controls. Compared to the control group, a significant impairment in oxidative stress biomarkers was also observed in the workers. Meanwhile, there was a significant relationship between the duration of employment and the level of LPO as well as a significant correlation between the quality of sleep and plasma cholinesterase in the workers. In conclusion, long-term exposure to OPPs could cause oxidative damages and neurobehavioral effects. The close monitoring of workplace exposure to organophosphates pesticides and also their respective solvents along with the reduction of working hours are of the necessities to avoid the adverse impacts of exposure to these pesticides.

Silencing of Hippocampal Somatostatin Interneurons Induces Recurrent Spontaneous Limbic Seizures in Mice.

The hippocampus proper and the subiculum contain two major populations of somatostatin (SST)-containing interneurons, oriens-lacunosum moleculare (O-LM) cells projecting from the stratum oriens to the stratum lacunosum moleculare and bistratified cells with their cell bodies close to the pyramidal cell layer and axons terminating in the strata radiatum and oriens. Both types of interneurons innervate pyramidal cell dendrites and exert prominent feedback inhibition. We now investigated whether impairing this type of feed-back inhibition by selectively inhibiting GABA release from SST expressing interneurons in hippocampal sector CA1 and subiculum may be sufficient to induce spontaneous recurrent seizures. We injected transgenic mice expressing Cre-recombinase on the SST promoter unilaterally into the ventral CA1 sector and subiculum with an adeno-associated viral (AAV) vector expressing tetanus toxin light chain (TeLC) with its reading frame inverted in a flip-excision (FLEX) cassette. This treatment resulted in specific expression of TeLC and silencing of SST-containing interneurons. We continuously monitored the EEG and behavior of the mice for six weeks. Nine out of eleven mice within 10 days developed series of pre- or interictal spikes (IS, 21.4 ± 6.83 per week) and four mice exposed recurrent spontaneous seizures (SRS, 1.5 ± 0.29 per week). All 23 SRS observed were preceded by IS series. Our data demonstrate a critical role of feed-forward inhibition mediated by SST-containing interneurons suggesting that their sustained malfunctioning can be causatively involved in the development of TLE.

The effect of GABAergic neurotransmission on the seizure-related activity of the laterodorsal thalamic nuclei and the somatosensory cortex in a genetic model of absence epilepsy.

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARß3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARß3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARß3 in the LDN as well as reduction of GABAARα1, GABAARß3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.

Alteration of the neurogenesis and long term potential of olfactory bulb in an animal model of PTSD.

Failure of extinction of fear-conditioned traumatic memory is the main pathology behind post-traumatic stress disorder (PTSD). Functional and structural dysfunctions in the olfactory system are implicated by studies in PTSD patients. However, little is known regarding the neurobiological networks of trauma­related odor sensitivity in PTSD. Male Wistar rats were exposed with a female cat for 10 min and long-term stress was evaluated by behavioral tests, containing open field (OF) and elevated plus maze (EPM). To prove the PTSD model, the serum level of cortisol was evaluated and compared with the control group. Local field potential (LFP) was applied to compare the electrophysiology of the OB in two groups. To assess neurogenesis, the expression of nestin, and doublecortin were evaluated. Data from EPM revealed a significant increase in spent time in the closed arms in PTSD group. We observed a significant reduction in OF parameters in terms of the total distance traveled, the time spent in the central zone, and the number of crossing the central zone in PTSD group compared to the control group. The mean serum cortisol level was significantly higher in the PTSD group than the control group. In LFP recording, the slope and the amplitude of field excitatory postsynaptic potential (fEPSP) in the PTSD group were significantly higher than that of the control group. Our results also showed that the mRNA expression level of nestin as a neural progenitor marker and doublecortin, as an immature neuron marker, significantly decreased in the PTSD group compared to the control group. This study has shown that PTSD can disrupt the OB function through decreasing neurogenesis. More information on PTSD and OB would help us to establish a greater degree of accuracy on this matter.

Prolonged Sleep Apnea in Two Patients with a History of Opium Abuse -A Case Report.

INTRODUCTION: Obstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing (SDB). CASE REPORT: Two 53- and 51-year-old male cases with daytime sleepiness and opium abuse and severe sleep apnea and long respiratory events duration (200 and 275 seconds respectively) noted in polysomnography were reported at Ebn-e-Sina and Razavi hospitals, in Mashhad, Iran. After positive airway pressure (PAP) therapy respiratory events resolved and patients' daytime alertness improved. CONCLUSION: The long duration of sleep apnea could be the result of opium abuse. Therefore, drug history should be carefully considered in the evaluation of SDB patients. The PAP device was effective in the management of sleep respiratory events and the improvement of patient's complications.

Effects of garlic extract on spreading depression: In vitro and in vivo investigations.

OBJECTIVES: The potential use of garlic for prevention and treatment of different types of headaches has been suggested by several medieval literatures. Cortical spreading depression (CSD), a propagating wave of neuroglial depolarization, was established as a target for anti-migraine drugs. This study was designed to investigate the effect of garlic extract on CSD in adult rats. METHODS: CSD was induced by KCl microinjection in the somatosensory cortex. The effects of five different concentrations of garlic oil (1-500 µl/l) were tested on different characteristic features of CSD in necocortical slices. In in vivo experiments, the effects of garlic oil on electrophysiological and morphological changes induced by CSD were investigated. RESULTS: Garlic oil in a dose-dependent manner decreased the amplitude of CSD but not its duration and velocity in neocortical brain slices. Garlic oil at concentration of 500 µl/l reversibly reduced the amplitude of the field excitatory post-synaptic potentials and inhibited induction of long-term potentiation in the third layer of neocortical slices. In in vivo studies, systemic application of garlic oil (1 ml/l) for three consecutive days reduced the amplitude and repetition rate of CSD. Garlic oil also prevented of CSD-induced reactive astrocytosis in the neocortex. DISCUSSION: Garlic oil suppresses CSD, likely via inhibition of synaptic plasticity, and prevents its harmful effects on astrocyte. Further studies are required to identify the exact active ingredient(s) of garlic oil that inhibit CSD and may have the potential to use in treatment of CSD-related disorders.