Consciousness is comprised of a multitude of brain states that reflect varying degrees of exteroceptive awareness and rely on specialized functional neural networks that flexibly respond to the demands of the external world. Fast neural oscillations, such as those in beta (15-30 Hz) and low gamma (30-80 Hz) frequency bands, are prominent in mammalian salience- and attention-associated brain areas during goal-directed behaviors and reflect top-down and bottom-up information processing, respectively. However, how these oscillations vary on a millisecond scale across the attentional timespan, as well as how they are disturbed following sleep deprivation (SD), are not well understood. To investigate time-dependent and cognition-relevant changes in neuroelectric activity in mice, local field potential (LFP) electrodes are implanted in various attention- and salience-associated brain regions prior to inclusion in the behavioral protocols. Once trained, these intracerebral multi-site LFPs are measured during self-initiated attentional performance to assess near-instantaneous, moment-to-moment changes in oscillatory activity as animals switch between task-off and task-on behaviors. These recordings are done when mice are rested as well as when they are deprived of sleep. When mice are not sleep-deprived, preliminary findings reveal an enhancement of beta and low gamma oscillations as well as a robust reduction in high gamma power (>80 Hz) – which is associated with internally-focused cognitive operations and external disengagement – during correct trial performance. These findings highlight a possible reprioritization of task-related network activity to produce a signal-to-noise ratio that underlies optimal signal-driven performance as animals anticipate information-bearing cues. Current manipulations involve depriving mice of sleep prior to task performance to better understand how variations in fast oscillations during attentional effort are disturbed following sleep loss and correlate with SD-induced performance impairments. So far, these findings suggest rapid changes in neural dynamics as animals shift between behavioral states, including varying levels of exteroceptive awareness and external focus. Through these ongoing efforts, we endeavor to identify electrophysiological biomarkers of normal vigilance that can provide insights into attentional processing under normal conditions and inform potential treatments to mitigate oscillatory and behavioral disruptions caused by poor sleep. I01 BX004500 I01 BX002774 IK6 BX005714 R21 MH125242

Summary Attention is impaired in many neuropsychiatric disorders, as well as by sleep disruption, leading to decreased workplace productivity and increased risk of accidents. Thus, understanding the neural substrates is important. Here we test the hypothesis that basal forebrain neurons that contain the calcium‐binding protein parvalbumin modulate vigilant attention in mice. Furthermore, we test whether increasing the activity of basal forebrain parvalbumin neurons can rescue the deleterious effects of sleep deprivation on vigilance. A lever release version of the rodent psychomotor vigilance test was used to assess vigilant attention. Brief and continuous low‐power optogenetic excitation (1 s, 473 nm @ 5 mW) or inhibition (1 s, 530 nm @ 10 mW) of basal forebrain parvalbumin neurons was used to test the effect on attention, as measured by reaction time, under control conditions and following 8 hr of sleep deprivation by gentle handling. Optogenetic excitation of basal forebrain parvalbumin neurons that preceded the cue light signal by 0.5 s improved vigilant attention as indicated by quicker reaction times. By contrast, both sleep deprivation and optogenetic inhibition slowed reaction times. Importantly, basal forebrain parvalbumin excitation rescued the reaction time deficits in sleep‐deprived mice. Control experiments using a progressive ratio operant task confirmed that optogenetic manipulation of basal forebrain parvalbumin neurons did not alter motivation. These findings reveal for the first time a role for basal forebrain parvalbumin neurons in attention, and show that increasing their activity can compensate for disruptive effects of sleep deprivation.

Experimental evidence has implicated multiple neurotransmitter systems in either the direct or indirect modulation of cortical arousal and attention circuitry. In this review, we selectively focus on three such systems: 1) norepinephrine (NE)-containing neurons of the locus coeruleus (LC), 2) acetylcholine (ACh)-containing neurons of the basal forebrain (BF), and 3) parvalbumin (PV)-containing gamma-aminobutyric acid neurons of the BF. Whereas BF-PV neurons serve as a rapid and transient arousal system, LC-NE and BF-ACh neuromodulation are typically activated on slower but longer-lasting timescales. Recent findings suggest that the BF-PV system serves to rapidly respond to even subtle sensory stimuli with a microarousal. We posit that salient sensory stimuli, such as those that are threatening or predict the need for a response, will quickly activate the BF-PV system and subsequently activate both the BF-ACh and LC-NE systems if the circumstances require longer periods of arousal and vigilance. We suggest that NE and ACh have overlapping psychological functions with the main difference being the precise internal/environmental sensory situations/contexts that recruit each neurotransmitter system - a goal for future research to determine. Implications of dysfunction of each of these three attentional systems for our understanding of neuropsychiatric conditions are considered. Finally, the contemporary availability of research tools to selectively manipulate and measure the activity of these distinctive neuronal populations promises to answer longstanding questions, such as how various arousal systems influence downstream decision-making and motor responding.

Abstract Introduction The nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasome protein complex activates caspase-1 to convert the pro-forms of IL-18 and IL-1 beta (IL-1β) into their active forms and is involved in homeostatic sleep and sleep responses to pathogenic stimuli. Intermittent hypoxia (IH) is a hallmark of sleep disordered breathing (SDB) and both IL-18 receptors are associated with SDB in humans. Thus, we hypothesized that NLRP3 inflammasomes are involved in SDB-related sleep disturbances. Methods Sleep architecture was assessed by polysomnography in NLRP3 knockout (KO) and wild-type (WT) mice (N = 8 per group). A gas exchange mixer delivered house air serving as a control or chronic IH that involved 90 second episodic oxygen reductions that consisted of ambient oxygen (21%) with brief hypoxic conditions (~10%) that lasted for 3 seconds for the first 10 h of the light period for 5 consecutive days. Gene expression and protein levels in the brain and lungs were assayed using real-time polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Results In WT mice, significant increased non-rapid-eye movement (NREM) sleep amounts and NREM sleep electroencephalogram delta power (0.5-4 Hz) were found after 1 day of IH compared to control conditions (p < 0.001). After 5 days of IH, WT mice showed a significant attenuation in NREM sleep amounts and NREM sleep delta power (p < 0.001) and increased wake bout frequency (p = 0.006) when compared to control conditions. However, the IH-induced NREM sleep and NREM sleep delta power enhancements and reductions were attenuated (21-35%) in NLRP3 KO mice compared to WT mice. In WT mice, NLRP3, IL-1β, IL-18 and caspase-1 gene expression, IL-1β and IL-18 protein levels, and caspase-1 activity were significantly increased in the somatosensory cortices, NTS, and lungs after both 1 and 5 days of IH when compared to control conditions (p < 0.05 for all), although NLRP3 KO mice did not exhibit significant differences in molecules downstream of NLRP3 inflammasome activation. Conclusion Our findings indicate that altered NLRP3 inflammasome activation contributes to dysregulated sleep occurring from IH and likely is involved in sleep disturbances in SDB. Support (If Any) VA Career Development Aware IBX002823, VA Merit BX004500, NIH/NIMH 1R21MH125242, NIH/NHLBI R03 HL154284, and NIH/NHLBI R35 HL135818. JTM received partial salary compensation and funding from Merck Investigator Sponsored Programs but has no conflict of interest with this work.

Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. Rats were administered DORA-22 or the GABA receptor-targeting hypnotic eszopiclone early in the light period, then exposed to six hourly clean cage changes with measurements of NREM sleep onset latency. Both compounds initially promoted sleep (hours 1 and 2), with DORA-22 exhibiting a more rapid hypnotic onset; and exhibited extended efficacy, evident six hours after administration in a sleep latencies test. A common complaint concerning hypnotic use is lingering hypersomnolence, and this is a concern in pharmacotherapy of the elderly. A second study was designed to determine a minimal dose of DORA-22 which would initially promote sleep but exhibit minimal extended hypnotic effect.Animals were administered DORA-22, then exposed for six hours to a single cage previously dirtied by a conspecific, followed by return to home cage. EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1 mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.

Summary Attention is impaired in many neuropsychiatric disorders 1 and by sleep disruption, leading to decreased workplace productivity and increased risk of accidents 2–4 . Thus, understanding the underlying neural substrates is important for developing treatments. The basal forebrain (BF) is a brain region which degenerates in dementia 5–7 and is implicated in the negative effects of sleep disruption on vigilance and cognition 8,9 . Previous studies demonstrated that the BF controls cortical fast oscillations that underlie attention 10–12 and revealed the important role of cholinergic neurons 13–15 . However, the role of other neurochemically defined BF subtypes is unknown. Recent work has shown that one population of BF GABAergic neurons containing the calcium-binding protein parvalbumin (PV) control cortical fast oscillations and arousals from sleep 16–19 but their role in awake behavior is unclear. Thus, here we test the hypothesis that BF-PV neurons modulate vigilant attention in mice. A lever release version of the rodent psychomotor vigilance test (rPVT) was used to assess vigilant attention as measured by reaction time. Brief and continuous low power optogenetic excitation of BF-PV neurons (1s,473nm@5mW) that preceded the cue light signal by 0.5s improved vigilant attention as indicated by quicker reaction times. In contrast, both sleep deprivation (8h) and optogenetic inhibition of BF-PV neurons (1s,530nm@10mW) slowed reaction times. Importantly, BF-PV excitation rescued the reaction time deficits in sleep deprived mice. These findings reveal for the first time a role for BF-PV neurons in attention. HIGHLIGHTS Optogenetic methods tested the neural circuitry of vigilant attention in mice Excitation of basal forebrain parvalbumin neurons quickened reaction times Sleep deprivation or inhibition of parvalbumin neurons slowed reaction times Excitation of parvalbumin neurons rescued deficits produced by sleep deprivation

The ability to rapidly arouse from sleep is important for survival. However, increased arousals in patients with sleep apnea and other disorders prevent restful sleep and contribute to cognitive, metabolic, and physiologic dysfunction [1, 2]. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments that restore normal sleep. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system, including the brainstem parabrachial neurons, which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea [3]. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia [4], but which BF cell types mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here, we tested the role of BF parvalbumin (PV) neurons in arousal using optogenetic techniques in mice. Optical stimulation of BF-PV neurons produced rapid transitions to wakefulness from non-rapid eye movement (NREM) sleep but did not affect REM-wakefulness transitions. Unlike previous studies of BF glutamatergic and cholinergic neurons, arousals induced by stimulation of BF-PV neurons were brief and only slightly increased total wake time, reminiscent of clinical findings in sleep apnea [5, 6]. Bilateral optical inhibition of BF-PV neurons increased the latency to arousal produced by exposure to hypercarbia or auditory stimuli. Thus, BF-PV neurons are an important component of the brain circuitry that generates brief arousals from sleep in response to stimuli, which may indicate physiological dysfunction or danger to the organism.

Compensatory elevation in NREM sleep EEG delta power has been typically observed following prolonged wakefulness and widely used as a sleep homeostasis indicator. However, recent evidence in human and rodent chronic sleep restriction (CSR) studies suggests that NREM delta power is not progressively increased despite of accumulated sleep loss over days. In addition, there has been little progress in understanding how sleep EEG in different brain regions responds to CSR. Using novel high-density EEG electrode arrays in the mouse model of CSR where mice underwent 18-h sleep deprivation per day for 5 consecutive days, we performed an extensive analysis of topographical NREM sleep EEG responses to the CSR condition, including period-amplitude analysis of individual slow waves. As previously reported in our analysis of REM sleep responses, we found different patterns of changes: (i) progressive decrease in NREM sleep duration and consolidation, (ii) persistent enhancement in NREM delta power especially in the frontal and parietal regions, and (iii) progressive increases in individual slow wave slope and frontal fast oscillation power. These results suggest that multiple sleep-wake regulatory systems exist in a brain region-specific manner, which can be modulated independently, especially in the CSR condition.

Increases in broadband cortical electroencephalogram (EEG) power in the gamma band (30–80 Hz) range have been observed in schizophrenia patients and in mouse models of schizophrenia. They are also seen in humans and animals treated with the psychotomimetic agent ketamine. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. Here we report that tonic optogenetic manipulation of an ascending arousal system bidirectionally tunes cortical broadband gamma power, allowing on-demand tests of the effect on cortical processing and behavior. Constant, low wattage optogenetic stimulation of basal forebrain (BF) neurons containing the calcium-binding protein parvalbumin (PV) increased broadband gamma frequency power, increased locomotor activity, and impaired novel object recognition. Concomitantly, task-associated gamma band oscillations induced by trains of auditory stimuli, or exposure to novel objects, were impaired, reminiscent of findings in schizophrenia patients. Conversely, tonic optogenetic inhibition of BF-PV neurons partially rescued the elevated broadband gamma power elicited by subanesthetic doses of ketamine. These results support the idea that increased cortical broadband gamma activity leads to impairments in cognition and behavior, and identify BF-PV activity as a modulator of this activity. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity.

CACNA1I , a schizophrenia risk gene, encodes a subtype of voltage-gated T-type calcium channel Ca V 3.3. We previously reported that a patient-derived missense de novo mutation (R1346H) of CACNA1I impaired Ca V 3.3 channel function. Here, we generated Ca V 3.3-RH knock-in animals, along with mice lacking Ca V 3.3, to investigate the biological impact of R1346H (RH) variation. We found that RH mutation altered cellular excitability in the thalamic reticular nucleus (TRN), where Ca V 3.3 is abundantly expressed. Moreover, RH mutation produced marked deficits in sleep spindle occurrence and morphology throughout non-rapid eye movement (NREM) sleep, while Ca V 3.3 haploinsufficiency gave rise to largely normal spindles. Therefore, mice harboring the RH mutation provide a patient derived genetic model not only to dissect the spindle biology but also to evaluate the effects of pharmacological reagents in normalizing sleep spindle deficits. Importantly, our analyses highlighted the significance of characterizing individual spindles and strengthen the inferences we can make across species over sleep spindles. In conclusion, this study established a translational link between a genetic allele and spindle deficits during NREM observed in schizophrenia patients, representing a key step toward testing the hypothesis that normalizing spindles may be beneficial for schizophrenia patients.

The thalamic reticular nucleus (TRN) is implicated in schizophrenia pathology. However, it remains unclear whether alterations of TRN activity can account for abnormal electroencephalographic activity observed in patients, namely reduced spindles (10–15 Hz) during sleep and increased delta (0.5–4 Hz) and gamma-band activity (30–80 Hz) during wakefulness. Here, we utilized optogenetic and reverse-microdialysis approaches to modulate activity of the major subpopulation of TRN GABAergic neurons, which express the calcium-binding protein parvalbumin (PV), and are implicated in schizophrenia dysfunction. An automated algorithm with enhanced efficiency and reproducibility compared to manual detection was used for sleep spindle assessment. A novel, low power, waxing-and-waning optogenetic stimulation paradigm preferentially induced spindles that were indistinguishable from spontaneously occurring sleep spindles without altering the behavioral state, when compared to a single pulse laser stimulation used by us and others. Direct optogenetic inhibition of TRN-PV neurons was ineffective in blocking spindles but increased both wakefulness and cortical delta/gamma activity, as well as impaired the 40 Hz auditory steady-state response. For the first time we demonstrate that spindle density is markedly reduced by (i) optogenetic stimulation of a major GABA/PV inhibitory input to TRN arising from basal forebrain parvalbumin neurons (BF-PV) and; (ii) localized pharmacological inhibition of low-threshold calcium channels, implicated as a genetic risk factor for schizophrenia. Together with clinical findings, our results support impaired TRN-PV neuron activity as a potential cause of schizophrenia-linked abnormalities in cortical delta, gamma, and spindle activity. Modulation of the BF-PV input to TRN may improve these neural abnormalities.

The type 5 metabotropic glutamate receptor (mGluR5) represents a novel therapeutic target for schizophrenia and other disorders. Schizophrenia is associated with progressive abnormalities in cortical oscillatory processes including reduced spindles (8-15 Hz) during sleep and increased delta (0.5-4 Hz)- and gamma-band activity (30-80 Hz) during wakefulness. mGluR5 knockout (KO) mice demonstrate many schizophrenia-like behaviors, including abnormal sleep. To examine the effects of mGluR5 on the maintenance of the neocortical circuitry responsible for such neural oscillations, we analyzed sleep/wake electroencephalographic (EEG) activity of mGluR5 KO mice at baseline, after 6 h of sleep deprivation, and during a visual method of cortical entrainment (visual steady state response). We hypothesized mGluR5-KO mice would exhibit translationally relevant abnormalities in sleep and neural oscillations that mimic schizophrenia. Power spectral and spindle density analyses were performed across 24-h EEG recordings in mGluR5-KO mice and wild-type (WT) controls. Novel findings in mGluR5 KO mice include deficits in sleep spindle density, wake alpha power, and 40-Hz visual task-evoked gamma power and phase locking. Sigma power (10-15 Hz), an approximation of spindle activity, was also reduced during non-rapid eye movement sleep transitions. Our observations on abnormal sleep/wake are generally in agreement with previous reports, although we did not replicate changes in rapid eye movement sleep. The timing of these phenotypes may suggest an impaired circadian process in mGluR5 KO mice. In conclusion, EEG phenotypes in mGluR5 KO mice resemble deficits observed in patients with schizophrenia. These findings implicate mGluR5-mediated pathways in several translationally relevant phenotypes associated with schizophrenia, and suggest that agents targeting this receptor may have harmful consequences on sleep health and daily patterns of EEG power.NEW & NOTEWORTHY Metabotropic glutamate receptor type 5 (mGluR5) knockout (KO) mice show several translationally relevant abnormalities in neural oscillatory activity associated with schizophrenia. These include deficits in sleep spindle density, sigma and alpha power, and 40-Hz task-evoked gamma power. The timing of these phenotypes suggests an impaired circadian process in these mice. Previously reported rapid eye movement sleep deficits in this model were not observed. These findings suggest mGluR5-enhancing drugs may improve sleep stability and sleep spindle density, which could impact memory and cognition.

Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally affecting mnemonic function, yet many hypnotic drugs (e.g. benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine whether the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze and then administered DORA-22 (10, 30, or 100 mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a 6-hr time period (at time points 0 and 3 hr), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption-wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared with vehicle treatment for one dose (30 mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg) and time spent in platform location and number of platform crossings (10 mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.

Sleep facilitates learning and memory, and sleep loss/disruption such as experienced in insomnia may impact cognition. Of utmost importance is the development of hypnotics that improve the sleep profile of the insomniac, but minimally impair sleep dependent memory consolidation (SDMC) and “next day” cognition. Here, we evaluated if treatment in the rat with the dual orexin receptor antagonist DORA-22 (Merck & Co., Inc.) would improve insomnia-related sleep disruption, consequent hypersomnia, as well as memory impairment. To evaluate improvement of insomnia-related sleep disruption, animals were first administered doses of DORA-22 (vehicle 20% TPGS or DORA-22 doses of either 10, 30, or 100 mg/kg), and then exposed to 6 hours of a dirty cage change insomnia model. Recovery period hypersomnia following model exposure was also evaluated. In a second experiment, to evaluate DORA-22 improvement of insomnia-impaired SDMC, animals were first trained to learn the location of a platform in the Morris Water Maze, and then administered DORA-22 (above doses), followed by insomnia model exposure. Animals were then evaluated for memory of the platform location. Select doses of DORA-22 improved insomnia-related sleep disruption, producing an overall decrease in wake and increase in sleep. Furthermore, in the recovery period following model exposure, NREM and REM sleep latencies were decreased, indicating improved “next day” hypersomnia. Several water maze measures indicated improved probe trial performance due to DORA-22 treatment (select doses), including time and distance spent in the target quadrant and platform location, as well as number of platform crossings. Our rodent dirty cage change models successfully disrupted sleep, as well as produced hypersomnia and impaired sleep-dependent memory consolidation. DORA-22 treatment was hypnotically effective, including improvement of insomnia-related sleep disruption and attenuated measures of hypersomnia. Additionally,DORA-22 treatment improved insomnia-associated memory consolidation deficits. Merck Investigator Studies Program

Insomnia involves disruption of sleep initiation, maintenance and/or overall quality, and may interfere with cognition. Here, we evaluated memory impairment produced by rodent mild (acute) insomnia models. Insomnia models consisted of either single or repeated exposure to cages previously occupied (dirtied) by an unfamiliar rat for 5-7 days. Rats were trained in the Morris water maze to remember the platform location (acquisition), and were then exposed to: (a) 6 hr of undisturbed baseline; (b) dirty cage change-induced insomnia (animal placed into a cage dirtied by another rat for 6 hr); or (c) double-dirty cage change-induced insomnia (animal placed into a cage dirtied by another rat for 3 hr, and then another dirty cage 3 hr later). The animal's memory for the platform location was then evaluated in a probe trial. Double-dirty cage change-induced insomnia significantly disrupted sleep, although the effects of dirty cage change-induced insomnia were overall not significant. In the fourth hour of double-dirty cage change-induced insomnia (following the second cage change), sleep episode number and duration alterations indicated sleep fragmentation. Furthermore, power spectral analysis revealed diminished wake and, to a lesser extent, rapid eye movement theta power (indicated by trend difference) in the last 3 hr of exposure. Significant deficits were noted for measures of water maze performance following double-dirty cage change-induced insomnia, indicating impaired memory. In summary, one variant of the rodent insomnia model, double-dirty cage change-induced insomnia, disrupted sleep and attenuated memory consolidation, indicating this paradigm may be useful to evaluate the effects of hypnotics on memory consolidation.

Study Objectives:Sleep spindles are abnormal in several neuropsychiatric conditions and have been implicated in associated cognitive symptoms. Accordingly, there is growing interest in elucidating the pathophysiology behind spindle abnormalities using rodent models of such disorders. However, whether sleep spindles can reliably be detected in mouse electroencephalography (EEG) is controversial necessitating careful validation of spindle detection and analysis techniques. Methods:Manual spindle detection procedures were developed and optimized to generate an algorithm for automated detection of events from mouse cortical EEG. Accuracy and external validity of this algorithm were then assayed via comparison to sigma band (10-15 Hz) power analysis, a proxy for sleep spindles, and pharmacological manipulations. Results:We found manual spindle identification in raw mouse EEG unreliable, leading to low agreement between human scorers as determined by F1-score (0.26 ± 0.07). Thus, we concluded it is not possible to reliably score mouse spindles manually using unprocessed EEG data. Manual scoring from processed EEG data (filtered, cubed root-mean-squared), enabled reliable detection between human scorers, and between human scorers and algorithm (F1-score > 0.95). Algorithmically detected spindles correlated with changes in sigma-power and were altered by the following conditions: sleep-wake state changes, transitions between NREM and REM sleep, and application of the hypnotic drug zolpidem (10 mg/kg, intraperitoneal). Conclusions:Here we describe and validate an automated paradigm for rapid and reliable detection of spindles from mouse EEG recordings. This technique provides a powerful tool to facilitate investigations of the mechanisms of spindle generation, as well as spindle alterations evident in mouse models of neuropsychiatric disorders.

Slow-wave activity (SWA) is an oscillatory neocortical activity occurring in the electroencephalogram delta (δ) frequency range (~0.5-4 Hz) during nonrapid eye movement sleep. SWA is a reliable indicator of sleep homeostasis after acute sleep loss and is involved in memory processes. Evidence suggests that cortical neuronal nitric oxide synthase (nNOS) expressing neurons that coexpress somatostatin (SST) play a key role in regulating SWA. However, previous studies lacked selectivity in targeting specific types of neurons that coexpress nNOS-cells which are activated in the cortex after sleep loss. We produced a mouse model that knocks out nNOS expression in neurons that coexpress SST throughout the cortex. Mice lacking nNOS expression in SST positive neurons exhibited significant impairments in both homeostatic low-δ frequency range SWA production and a recognition memory task that relies on cortical input. These results highlight that SST+/nNOS+ neurons are involved in the SWA homeostatic response and cortex-dependent recognition memory.

There are advantages and limitations associated with a science, technology, engineering and math (STEM) education at small, liberal arts colleges relative to larger universities. While there may be increased opportunity for personal attention and access to faculty, students at liberal arts colleges may not always have the opportunity to gain experience with state-of-the-art equipment and technology. Herein, we describe a case study of an inter-institutional partnership between Stonehill College and two neuroscience research laboratories which are part of the Veterans Affairs Boston Healthcare System (VABHS). Both laboratories are affiliated with Harvard Medical School (HMS). We discuss the benefits as well as the challenges associated with the development and maintenance of this partnership. The experience with the use of sophisticated instrumentation and technology available in these laboratories may give students a competitive edge when applying to graduate school programs. However, we contend that the most important advantage of this research experience is the development of a sense of self-esteem and professional competence that will allow students to meet the many challenges that lie ahead in graduate school and beyond.