Four new species of Phytocoris Fallén (Hemiptera, Miridae) from the Davis Mountains in Texas and further documentation of known species of Jeff Davis County.

A recent survey of the entomofauna of the Davis Mountains in the state of Texas has revealed four new species in the genus Phytocoris Fallén (Miridae, Mirinae, Mirini): Phytocorismcivorsp. nov. and Phytocorisschmitzisp. nov. found on Quercusgrisea Liebmann, and Phytocorismarquasp. nov. and Phytocorisrileyisp. nov. found attracted to lights. Descriptions, habitus, and genitalic images for the new species are included herein. Further, habitus and genitalic photographs of known Phytocoris species from the county are included to aid in identification.

Coupling Between Subregional Oscillators Within the Suprachiasmatic Nucleus Determines Free-Running Period in the Rat.

Rats housed in a 22-h light-dark cycle (11:11, T22) exhibit 2 distinct circadian locomotor activity (LMA) bouts simultaneously: one is entrained to the LD cycle and a second dissociated bout maintains a period greater than 24 h. These 2 activity bouts are associated with independent clock gene oscillations in the ventrolateral (vl-) and dorsomedial (dm-) suprachiasmatic nucleus (SCN), respectively. Previous results in our laboratory have shown that the vl- and dm-SCN oscillators are weakly coupled under T22 and that the period of the dissociated bout depends on coupling between the 2 subdivisions. Here, we sought to study the behavior of the T22 SCN pacemaker upon release into free-running conditions and compare it to the behavior of the system upon release from typical 24-h (12:12, T24) entrainment. T22-desynchronized rats or T24-entrained rats were released into constant darkness (DD). Activity rhythms in T22 rats rapidly resynchronized upon release into DD, and the free-running period (FRP) of the fused rhythm was longer than the FRP of T24 rats. We then asked whether the in vivo period changes were also present in the ex vivo SCN. Per1-luc rats were desynchronized in T22 for assessment of SCN Per1-luc ex vivo. Similar to behavioral FRP, the period of ex vivo SCN explanted from T22 rats was longer than that for T24 animals. Mathematical models supported the observed behavior of the dual oscillator system as the result of mutual coupling between the vl- and dm-SCN oscillators. This bidirectionally coupled model predicted both the FRP of the T22 system and its phase-shifting response to light. Together, these data support a model of pacemaker organization in which a light-sensitive vl-SCN oscillator is mutually coupled with a light-insensitive dm-SCN oscillator, and together they determine the period of the coupled system as a whole and its response to light pulses.

Systemic Bioavailability of Sublingual Atropine Ophthalmic Solution: a Phase I Study in Healthy Volunteers with Implications for Use as a Contingency Medical Countermeasure.

INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.

Decreased Naïve T-cell Production Leading to Cytokine Storm as Cause of Increased COVID-19 Severity with Comorbidities.

Aging, type 2 diabetes, and male gender are major risk factors leading to increased COVID-19 morbidity and mortality. Thymic production and the export of naïve T cells decrease with aging through the effects of androgens in males and in type 2 diabetes. Furthermore, with aging, recovery of naïve T-cell populations after bone marrow transplantation is delayed and associated with an increased risk of chronic graft vs. host disease. Severe COVID-19 and SARS infections are notable for severe T-cell depletion. In COVID-19, there is unique suppression of interferon signaling by infected respiratory tract cells with intact cytokine signaling. A decreased naïve T-cell response likely contributes to an excessive inflammatory response and increases the odds of a cytokine storm. Treatments that improve naïve T-cell production may prove to be vital COVID-19 therapies, especially for these high-risk groups.

A new species of the plant bug genus Rubrocuneocoris (Hemiptera: Heteroptera: Miridae: Phylinae) from Vietnam.

The genus Rubrocuneocoris Schuh is recognized from Vietnam for the first time, with a new species, R. vietnamensis n. sp.  The new species is described and documented with images of the habitus and male genitalic structures. Male and female genitalic structures are described for R. albescens Yasunaga. Species of Rubrocuneocoris described from Taiwan are herein transferred to Atractotomoidea Yasunaga and the following new combinations are accordingly proposed: Atractotomoidea falcis (Lin 2006) n. comb., A. maculosus (Lin 2006) n. comb., A. nodus (Lin 2006) n. comb., and A. trifidus (Lin 2006) n. comb. A revised checklist of Rubrocuneocoris is presented.

Contingency Medical Countermeasures for Mass Nerve-Agent Exposure: Use of Pharmaceutical Alternatives to Community Stockpiled Antidotes.

Having sufficient medical countermeasures (MCMs) available for the treatment of acetylcholinesterase-inhibiting nerve agent poisoned patients following a mass chemical exposure is a challenge for communities. After stockpiles containing auto-injectors are exhausted, communities need to be aware of alternative pharmaceutical options. The Department of Homeland Security Chemical Defense Program convened a federal interagency working group consisting of first responders, clinicians, and experts from the fields of medical toxicology, pharmacology, and emergency management. A literature review of pharmaceutical alternatives for treating nerve agent toxicity was performed. Pharmaceuticals that met the federal Public Health Emergency Medical Countermeasures Enterprise Product Specific Requirements were prioritized. Food and Drug Administration approval for one indication, market availability, and alignment to government procurement strategy were considered. This article summarizes the literature on comparative pharmacokinetics and efficacy against nerve agents (where available) of Food and Drug Administration approved drugs with muscarinic acetylcholine receptor antagonist and gamma-aminobutyric acid receptor agonist effects. This work is intended to serve as a resource of pharmaceutical options that may be available to communities (ie, emergency managers, planners, clinicians, and poison centers) when faced with a mass human exposure to a nerve agent and inadequate supplies of MCMs. (Disaster Med Public Health Preparedness. 2019;13:605-612).

Ilnacorahenryi, a new species of plant bug from Mexico (Heteroptera, Miridae, Orthotylinae, Orthotylini).

A new species of the plant bug genus Ilnacora, tribe Orthotylini, is described from Mexico. This species, unlike any other in the genus, is characterized by a predominantly black coloration, the absence of black scale-like setae on the pronotal disk, and unique male genitalia.

Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.

INTRODUCTION: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling. Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. However, TAAR1's influences on serotonin and glutamate neurotransmission will also be highlighted. Expert opinion: TAAR1 holds great promise as a therapeutic target for mental illness, addiction, and sleep disorders. A combination of preclinical and translationally driven studies has solidified TAAR1 as a key node in the regulation of dopaminergic signaling. Continued focus on the mechanisms underlying TAAR1's regulation of serotonin and glutamate signaling, as well as dopamine, will yield further disease-relevant insights.

Deletion of Trace Amine-Associated Receptor 1 Attenuates Behavioral Responses to Caffeine.

Trace amines (TAs), endogenous amino acid metabolites that are structurally similar to the biogenic amines, are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 full and partial agonists exhibit similar pro-cognitive, antidepressant- and antipsychotic-like properties in rodents and non-human primates, suggesting TAAR1 as a novel target for the treatment of neurological and psychiatric disorders. We previously reported that TAAR1 partial agonists are wake-promoting in rats and mice, and that TAAR1 knockout (KO) and overexpressing mice exhibit altered sleep-wake and EEG spectral composition. Here, we report that locomotor and EEG spectral responses to the psychostimulants modafinil and caffeine are attenuated in TAAR1 KO mice. TAAR1 KO mice and WT littermates were instrumented for EEG and EMG recording and implanted with telemetry transmitters for monitoring locomotor activity (LMA) and core body temperature (Tb). Following recovery, mice were administered modafinil (25, 50, 100 mg/kg), caffeine (2.5, 10, 20 mg/kg) or vehicle p.o. at ZT6 in balanced order. In WT mice, both modafinil and caffeine dose-dependently increased LMA for up to 6 h following dosing, whereas only the highest dose of each drug increased LMA in KO mice, and did so for less time after dosing. This effect was particularly pronounced following caffeine, such that total LMA response was significantly attenuated in KO mice compared to WT at all doses of caffeine and did not differ from Vehicle treatment. Tb increased comparably in both genotypes in a dose-dependent manner. TAAR1 deletion was associated with reduced wake consolidation following both drugs, but total time in wakefulness did not differ between KO and WT mice. Furthermore, gamma band EEG activity following both modafinil and caffeine treatment was attenuated in TAAR1 KO compared to WT mice. Our results show that TAAR1 is a critical component of the behavioral and cortical arousal associated with two widely used psychostimulants with very different mechanisms of action. Together with our previous findings, these data suggest that TAAR1 is a previously unrecognized component of an endogenous wake-modulating system.

Detection of ingested nitromethane and reliable creatinine assessment using multiple common analytical methods.

AIM: Nitromethane, found in fuels used for short distance racing, model cars, and model airplanes, produces a falsely elevated serum creatinine with standard creatinine analysis via the Jaffé method. Erroneous creatinine elevation often triggers extensive testing, leads to inaccurate diagnoses, and delayed or inappropriate medical interventions. Multiple reports in the literature identify "enzymatic assays" as an alternative method to detect the true value of creatinine, but this ambiguity does not help providers translate what type of enzymatic assay testing can be done in real time to determine if there is indeed false elevation. METHODS: We report seven cases of ingested nitromethane where creatinine was determined via Beckman Coulter® analyser using the Jaffé method, Vitros® analyser, or i-Stat® point-of-care testing. Nitromethane was detected and semi-quantified using a common clinical toxic alcohol analysis method, and quantified by headspace-gas chromatography-mass spectrometry. RESULTS: When creatinine was determined using i-Stat® point-of-care testing or a Vitros® analyser, levels were within the normal range. Comparatively, all initial creatinine levels obtained via the Jaffé method were elevated. Nitromethane concentrations ranged from 42 to 310 µg/mL. CONCLUSIONS: These cases demonstrate reliable assessment of creatinine through other enzymatic methods using a Vitros® analyser or i-STAT®. Additionally, nitromethane is detectable and quantifiable using routine alcohols gas chromatography analysis and by headspace-gas chromatography-mass spectrometry.

Sleep/Wake Physiology and Quantitative Electroencephalogram Analysis of the Neuroligin-3 Knockout Rat Model of Autism Spectrum Disorder.

Study Objectives: Neuroligin-3 (NLGN3) is one of the many genes associated with autism spectrum disorder (ASD). Sleep dysfunction is highly prevalent in ASD, but has not been rigorously examined in ASD models. Here, we evaluated sleep/wake physiology and behavioral phenotypes of rats with genetic ablation of Nlgn3. Methods: Male Nlgn3 knockout (KO) and wild-type (WT) rats were assessed using a test battery for ASD-related behaviors and also implanted with telemeters to record the electroencephalogram (EEG), electromyogram, body temperature, and locomotor activity. 24-h EEG recordings were analyzed for sleep/wake states and spectral composition. Results: Nlgn3 KO rats were hyperactive, exhibited excessive chewing behavior, and had impaired prepulse inhibition to an auditory startle stimulus. KO rats also spent less time in non-rapid eye movement (NREM) sleep, more time in rapid eye movement (REM) sleep, exhibited elevated theta power (4-9 Hz) during wakefulness and REM, and elevated delta power (0.5-4 Hz) during NREM. Beta (12-30 Hz) power and gamma (30-50 Hz) power were suppressed across all vigilance states. Conclusions: The sleep disruptions in Nlgn3 KO rats are consistent with observations of sleep disturbances in ASD patients. The EEG provides objective measures of brain function to complement rodent behavioral analyses and therefore may be a useful tool to study ASD.

Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology.

Study Objectives: Although recent innovations have enabled modification of the rat genome, it is unclear whether enhanced utility of rodents as human disease models will result. We compared electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD). Methods: Male contactin-associated protein-like 2 (Cntnap2) knockout (KO) and wild-type (WT) rats and male Cntnap2 KO and WT mice were implanted with telemeters to record EEG, electromyogram, body temperature, and locomotor activity. Animals were subjected to a test battery for ASD-related behaviors, followed by 24-hr EEG recordings that were analyzed for sleep-wake parameters and subjected to spectral analysis. Results: Cntnap2 KO rats exhibited severe motor seizures, hyperactivity, and increased consolidation of wakefulness and REM sleep. By contrast, Cntnap2 KO mice demonstrated absence seizure-like events, hypoactivity, and wake fragmentation. Although seizures observed in Cntnap2 KO rats were more similar to those in CDFE patients than in KO mice, neither model fully recapitulated the full spectrum of disease symptoms. However, KOs in both species had reduced spectral power in the alpha (9-12 Hz) range during wake, suggesting a conserved EEG biomarker. Conclusions: Deletion of Cntnap2 impacts similar behaviors and EEG measures in rats and mice, but with profound differences in nature and phenotypic severity. These observations highlight the importance of cross-species comparisons to understand conserved gene functions and the limitations of single- species models to provide translational insights relevant to human diseases.

Areas of endemism in the Nearctic: a case study of 1339 species of Miridae (Insecta: Hemiptera) and their plant hosts.

Areas of endemism are essential first hypotheses in investigating historical biogeography, but there is a surprising paucity of such hypotheses for the Nearctic region. Miridae, the plant bugs, are an excellent taxon to study in this context, because this group combines high species diversity, often small distribution ranges, a history of modern taxonomic revisions, and comprehensive electronic data capture and data cleaning that have resulted in an exceptionally error-free geospatial data set. Many Miridae are phytophagous and feed on only one or a small number of host plant species. The programs ndm/vndm are here used on plant bug and plant data sets to address two main objectives: (i) identify areas of endemism for plant bugs based on parameters used in a recent study that focused on Nearctic mammals; and (ii) discuss hypotheses on areas of endemism based on plant bug distributions in the context of areas identified by their host plant species. Given the narrow distribution ranges of many species of Miridae, the analytical results allow for tests of the prediction that areas of endemism for Miridae are smaller and more numerous, especially in the Western Nearctic, than are those of their host plants. Analyses of the default plant bug data set resulted in 45 areas of endemism, 35 of them north of Mexico and many located in the Western Nearctic; areas in the Nearctic are more numerous and smaller than those identified by mammals. The host plant data set resulted in ten areas of endemism, and even though the size range of areas is similar between the Miridae and plant data sets, the average area size is smaller in the Miridae data set. These results allow for the conclusion that the Miridae indeed present a valuable model system to investigate areas of endemism in the Nearctic.

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics.

BACKGROUND: Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy. METHODS: In the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt (Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models. RESULTS: RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy. CONCLUSIONS: These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.

Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition.

Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (Tb), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased Tb without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.

Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.

Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems.

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

Quantitative Electroencephalographic Analysis Provides an Early-Stage Indicator of Disease Onset and Progression in the zQ175 Knock-In Mouse Model of Huntington's Disease.

STUDY OBJECTIVES: Patients with Huntington's disease (HD) show a high prevalence of sleep disorders that typically occur prior to the onset of motoric symptoms and neurodegeneration. Our understanding of the pathophysiological alterations in premanifest HD is limited, hindering the ability to measure disease modification in response to treatment. We used a full-length knock-in HD model to determine early changes in the electroencephalogram (EEG) and sleep that may predict the onset and progression of the disease. METHODS: A 10-month longitudinal study was designed to determine the effect of the HD mutation on the EEG and sleep/wake changes in heterozygous (HET) and homozygous (HOM) zQ175 mice and wild-type (WT) littermates from 8 to 48 w of age. Mice were instrumented with tethered headmounts to record EEG/electromyography signals. Telemeters were implanted to continuously measure locomotor activity (LMA) and body temperature (Tb). Sleep deprivation (SDep) was performed at 8, 12, 16, 24, 32, and 48 w of age. RESULTS: The HD mutation disrupted the EEG field potential from 8-12 w in an age- and mutant huntington dose-dependent manner, prior to changes in sleep/wake states, LMA, and Tb. Prominent effects of the HD mutation on the EEG included a progressive reduction in low frequency power, a slowing of rapid eye movement peak theta frequency, and the emergence of state-dependent beta/gamma oscillations. There was no effect of genotype on the relative increase in nonrapid eye movement delta power or sleep time in response to SDep. CONCLUSIONS: The expression of the Huntington's disease (HD) mutation results in complex EEG alterations that occur prior to deficits in behavioral measures and are one of the earliest phenotypes uncovered in this mouse model. Despite these EEG changes, homeostatic responses to sleep loss were preserved in HET and HOM zQ175 mice. Greater insight into the localization and response of these EEG alterations to novel therapies may enable early intervention and improve outcomes for patients with HD.

Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.

Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep.