Preventing the stabilization of a Ca ²⁺ channel at the surface of sensory neurons attenuates postsurgical pain.

We recently showed that a neurosteroid analogue, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3β-OH further using electroencephalography. We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3β-OH (30 and 60 mg kg^-1) administered intraperitoneally or intravenously to young adult male and female rats. We found dose-dependent sex differences in 3β-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3β-OH 30 mg kg^-1. However, at the higher dose (60 mg kg^-1, i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2-6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg^-1 i.v., female rats appeared more sensitive to 3β-OH with relatively small changes within delta (1-4 Hz) and alpha (8-13 Hz) bands. Finally, 3β-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg^-1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. Based on its behavioural effects and EEG signature, 3β-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats.

Temporal lobe epilepsy (TLE) is associated with cognitive, social, and emotional comorbidities that persist between seizures and remain poorly addressed by seizure-focused treatment. We examined whether these interictal deficits reflect altered ventral CA1/subiculum (vCA1/Sub) output and whether shifting principal-cell excitability can improve behavior despite persistent pathology. In pilocarpine-treated mice, vCA1/Sub principal neurons were depolarized and showed altered recruitment, alveus/oriens stimulation produced diminished hyperpolarizing responses, and parvalbumin- and somatostatin-immunopositive cell densities were reduced in stratum oriens. Epileptic mice did not demonstrate social discrimination above chance despite retained social approach and social-odor preference and showed increased open-field center avoidance. Multiplexed chemogenetic inhibition of vCA1/Sub principal cells improved social discrimination and center exploration, whereas stronger inhibition did not reproduce the social-memory benefit. Within individual mice, discrimination was higher in predicted retuned than off-optimal states, and performance across inferred excitability states followed an inverted-U-like relationship. Anxiety-related and social improvements covaried across epileptic mice, consistent with shared dependence on vCA1/Sub circuit state. In a separate EEG cohort, moderate inhibition suppressed local hippocampal activity during the behavior-aligned interval without detectably reducing spontaneous seizures or early interictal spikes. These findings identify excessive vCA1/Sub output as a modifiable contributor to socio-affective dysfunction in TLE and show that retuning a disease-altered circuit can improve interictal behavior without acute seizure suppression. Highlights: Chronic epilepsy shifts vCA1/Sub toward a depolarized, disinhibited output state Moderate vCA1/Sub inhibition improves social discrimination in epileptic mice Stronger inhibition does not reproduce the behavioral benefit vCA1/Sub inhibition improves behavior without acute seizure suppression

The potential contribution of the ion channels that control the excitability of the midline and intralaminar nuclei of the thalamus to the modulation of behaviors has not been well studied. In this study, we used both global genetic deletion (knock-out, KO) and thalamus-specific molecular knock-down (KD) approaches to investigate the role of thalamic Ca_V3.1 T-type calcium channels (T-channels) in fear learning and fear responses. Previously, we have shown that the dominant subtype of T-channels in the central medial nucleus of the thalamus (CMT) is the Ca_V3.1 isoform and that CMT neurons from Ca_V3.1 KO animals have decreased burst firing. By specifically knocking down Ca_V3.1 T-channels in the CMT using the shRNA approach, we also reduced burst firing without affecting the tonic firing mode of the transfected neurons. We report that global Ca_V3.1 KO animals showed stronger freezing behaviors during both the conditioning and testing phases of contextual fear conditioning, while CMT-specific Ca_V3.1 KD mice only had stronger fear responses during testing. In contrast, the cue-mediated fear responses were similar between Ca_V3.1 KO and Ca_V3.1 KD mice and the controls. Our findings validate thalamic Ca_V3.1 T-channels as a potential new target for the development or treatment of different psychiatric diseases, such as post-traumatic stress disorder, schizophrenia, anxiety, and substance abuse disorders.

SUMMARY: The dentate gyrus has often been posited to act as a gate that dampens highly active afferent input into the hippocampus. Effective gating is thought to prevent seizure initiation and propagation in the hippocampus and support learning and memory processes. Pathological changes to DG circuitry that occur in temporal lobe epilepsy (TLE) can increase DG excitability and impair its gating ability which can contribute to seizures and cognitive deficits. There is evidence that TLE pathologies and seizures may independently contribute to learning and memory deficits in TLE through distinct mechanisms. These two factors are difficult to untangle since TLE pathologies can drive seizures, and seizures can worsen TLE pathologies. Here we assessed whether chemogenetically increasing dentate granule cell (DGC) excitability was enough to break down the dentate gate in the absence of TLE pathologies. We found that increasing excitability specifically in DGCs caused seizures in non-epileptic mice. Importantly, due to the modulatory nature of DREADD effects, seizures were driven by intrinsic circuit activity rather than direct activation of DGCs. These seizures resulted in a spatial memory deficit when induced after training in the spatial object recognition task and showed stereotypical patterns of activity in miniscope calcium recordings. Our results provide direct support for the dentate gate hypothesis since seizures could be induced in non-epileptic animals by artificially degrading the dentate gate with chemogenetics in the absence of epilepsy pathologies.

Recent advances in neuroscience techniques and methods ushered in a new era in the research of neuronal function with unprecedented selectivity and temporal resolution. One of the main characteristics of these technical advances is the ability to selectively target and/or modulate specific neuronal subpopulations and circuits in both healthy and diseased brains. Although initially designed as tools to help researchers better understand the mechanisms underlying neuronal activity and complex behaviors, these novel approaches may also accelerate the process of drug discovery in many areas of neuroscience, and some may even potentially serve as novel therapeutic strategies. The application of different electrophysiological techniques is still considered essential in studying ion channel function and pharmacology, as well as network-level changes in brain activity. The cutting-edge methods for investigation of brain function include opto-and chemogenetics in freely behaving animals; both approaches enable highly selective control of neuronal activity using either a light stimulation (optogenetics) or a chemical ligand (chemogenetics) in both loss-and gain-of-function experiments. In this review paper, we aim to summarize recent scientific evidence on the state-of-the-art and provide information on these advances, taking into account both academic and pharmaceutical industry points of view.