Different roles of T-type calcium channel isoforms in hypnosis induced by an endogenous neurosteroid epipregnanolone.

BACKGROUND: Many neuroactive steroids induce sedation/hypnosis by potentiating γ-aminobutyric acid (GABAA) currents. However, we previously demonstrated that an endogenous neuroactive steroid epipregnanolone [(3ß,5ß)-3-hydroxypregnan-20-one] (EpiP) exerts potent peripheral analgesia and blocks T-type calcium currents while sparing GABAA currents in rat sensory neurons. This study seeks to investigate the behavioral effects elicited by systemic administration of EpiP and to characterize its use as an adjuvant agent to commonly used general anesthetics (GAs). METHODS: Here, we utilized electroencephalographic (EEG) recordings to characterize thalamocortical oscillations, as well as behavioral assessment and mouse genetics with wild-type (WT) and different knockout (KO) models of T-channel isoforms to investigate potential sedative/hypnotic and immobilizing properties of EpiP. RESULTS: Consistent with increased oscillations in slower EEG frequencies, EpiP induced an hypnotic state in WT mice when injected alone intra-peritoneally (i.p.) and effectively facilitated anesthetic effects of isoflurane (ISO) and sevoflurane (SEVO). The CaV3.1 (Cacna1g) KO mice demonstrated decreased sensitivity to EpiP-induced hypnosis when compared to WT mice, whereas no significant difference was noted between CaV3.2 (Cacna1h), CaV3.3 (Cacna1i) and WT mice. Finally, when compared to WT mice, onset of EpiP-induced hypnosis was delayed in CaV3.2 KO mice but not in CaV3.1 and CaV3.3 KO mice. CONCLUSION: We posit that EpiP may have an important role as novel hypnotic and/or adjuvant to volatile anesthetic agents. We speculate that distinct hypnotic effects of EpiP across all three T-channel isoforms is due to their differential expression in thalamocortical circuitry.

Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.

Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.

The T-type calcium channel isoform Cav3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile.

BACKGROUND: The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown. METHODS: We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Cav3.1 knock-out mice to investigate the molecular mechanisms of hypnosis induced by the neurosteroid analogue (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile (3ß-OH). RESULTS: Patch-clamp recordings showed that 3ß-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3ß-OH inhibited the spike firing mode more profoundly in WT than in Cav3.1 knockout mice. Furthermore, 3ß-OH significantly hyperpolarised neurones, reduced the amplitudes of low threshold spikes, and diminished rebound burst firing only in WT mice. We found that 80 mg kg-1 i.p. injections of 3ß-OH induced hypnosis in >60% of WT mice but failed to induce hypnosis in the majority of mutant mice. A subhypnotic dose of 3ß-OH (20 mg kg-1 i.p.) accelerated induction of hypnosis by isoflurane only in WT mice, but had similar effects on the maintenance of isoflurane-induced hypnosis in both WT and Cav3.1 knockout mice. In vivo recordings of LFPs showed that a hypnotic dose of 3ß-OH increased δ, θ, α, and ß oscillations in WT mice in comparison with Cav3.1 knock-out mice. CONCLUSIONS: The Cav3.1 T-channel isoform is critical for diminished thalamocortical excitability and oscillations that underlie neurosteroid-induced hypnosis.

Binge ethanol in adulthood exacerbates negative outcomes following juvenile traumatic brain injury.

Traumatic brain injuries (TBI) are a major public health problem with enormous costs in terms of health care dollars, lost productivity, and reduced quality of life. Alcohol is bidirectionally linked to TBI as many TBI patients are intoxicated at the time of their injury and we recently reported that, in accordance with human epidemiological data, animals injured during juvenile development self-administered significantly more alcohol as adults than did sham injured mice. There are also clinical data that drinking after TBI significantly reduces the efficacy of rehabilitation and leads to poorer long-term outcomes. In order to determine whether juvenile traumatic brain injury also increased the vulnerability of the brain to the toxic effects of high dose alcohol, mice were injured at 21days of age and then seven weeks later treated daily with binge-like levels of alcohol 5g/kg (by oral gavage) for ten days. Binge-like alcohol produced a greater degree of neuronal damage and neuroinflammation in mice that sustained a TBI. Further, mice that sustained a juvenile TBI exhibited mild learning and memory impairments in adulthood following binge alcohol and express a significant increase in hippocampal ectopic localization of newborn neurons. Taken together, these data provide strong evidence that a mild brain injury occurring early in life renders the brain highly vulnerable to the consequences of binge-like alcohol consumption.

Juvenile Traumatic Brain Injury Increases Alcohol Consumption and Reward in Female Mice.

Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.

Broadband and mid-infrared absorber based on dielectric-thin metal film multilayers.

We propose a periodic multilayer structure of dielectric and metal interlayers to achieve a near-perfect broadband absorber of mid-infrared radiation. We examine the influence of four factors on its performance: (1) the interlayer metal conductance, (2) the number of dielectric layers, (3) a nanopatterned antireflective layer, and (4) a reflective metallic bottom layer for backreflection. Absorption characteristics greater than 99% of the 300 K and 500 K blackbody spectra are found for the optimized structures. Incident angle and polarization dependence of the absorption spectra are examined. We also investigate the possibility of fabricating a nanopatterned antireflective layer to maximize absorption.

Suppression of long-range collective effects in meta-surfaces formed by plasmonic antenna pairs.

The collective effects in a periodic array of plasmonic double-antenna meta-molecules are studied. We experimentally observe that the collective behavior in this structure substantially differs from the one observed in their single-antenna counterparts. This behavior is explained using an analytical dipole model. We find that in the double-antenna case the effective dipole-dipole interaction is significantly modified and the transverse long-range interaction is suppressed, giving rise to the disappearance of Wood's anomalies. Numerical calculations also show that such suppression of long-range interaction results in an anomalous spatial dispersion of the electric-dipolar mode, making it insensitive to the angle of incidence. In contrast, the quadrupolar mode of the antenna pair experiences strong spatial dispersion. These results show that collective effects in plasmonic metamaterials are very sensitive to the design and topology of meta-molecules. Our findings envision the possibility of suppressing the spatial dispersion effects to weaken the dependence of the metamaterials' response on the incidence angle.