Multicomponent drug Neurexan mitigates acute stress-induced insomnia in rats.

The aim of this study was to determine whether the multicomponent drug Neurexan could mitigate acute insomnia after exposure to a psychosocial stressor. We administered Neurexan orally to rats and examined stress-induced insomnia using the male rat dirty cage exchange method. The neurocircuitry and electrophysiological correlates of the model are characterised, and it represents various human insomnia conditions. Male rats were randomly assigned in a crossover design to six treatment groups and electroencephalography (EEG) electrodes attached. Three groups were exposed to a cage inhabited by another male rat for a week and the other three groups received a clean cage. Prior to cage change, rats were given either no drug, vehicle control or Neurexan. Non-rapid eye movement (NREM) sleep, REM sleep, and waking were assessed manually via EEG recordings. Group means were compared for sleep latency and for the 2 h after cage change for: time in each state, state-specific episode duration/frequency, in addition to NREM delta, gamma and REM theta EEG spectral power. Rats administered Neurexan fell asleep faster than vehicle-treated rats and spent less time awake with shorter, albeit more waking episodes and increased NREM episodes after dirty cage exposure. Neurexan-treated rats given dirty cages were not statistically different on any outcomes from Neurexan-treated rats given clean cages, thereby mitigating the stressor. In the EEG power spectra analysed, changes between treatment groups were not detected. This research confirms that Neurexan treatment has somnogenic effects and ameliorates psychological stressor-induced acute insomnia.

Mechanistic Studies of the Palladium-Catalyzed Desulfinative Cross-Coupling of Aryl Bromides and (Hetero)Aryl Sulfinate Salts.

Pyridine and related heterocyclic sulfinates have recently emerged as effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with (hetero)aryl halides. These sulfinate reagents are straightforward to prepare, stable to storage and coupling reaction conditions, and deliver efficient reactions, thus offering many advantages, compared to the corresponding boron-derived reagents. Despite the success of these reactions, there are only scant details of the reaction mechanism. In this study, we use structural and kinetic analysis to investigate the mechanism of these important coupling reactions in detail. We compare a pyridine-2-sulfinate with a carbocyclic sulfinate and establish different catalyst resting states, and turnover limiting steps, for the two classes of reagent. For the carbocyclic sulfinate, the aryl bromide oxidative addition complex is the resting state intermediate, and transmetalation is turnover-limiting. In contrast, for the pyridine sulfinate, a chelated Pd(II) sulfinate complex formed post-transmetalation is the resting-state intermediate, and loss of SO2 from this complex is turnover-limiting. We also investigated the role of the basic additive potassium carbonate, the use of which is crucial for efficient reactions, and deduced a dual function in which carbonate is responsible for the removal of free sulfur dioxide from the reaction medium, and the potassium cation plays a role in accelerating transmetalation. In addition, we show that sulfinate homocoupling is responsible for converting Pd(OAc)2 to a catalytically active Pd(0) complex. Together, these studies shed light on the challenges that must be overcome to deliver improved, lower temperature versions of these synthetically important processes.

Performance on the mouse vibration actuating search task is compromised by sleep deprivation.

As we go about our daily routines we are continuously bombarded with environmental feedback that requires appraisal and response. Sleep loss can compromise the efficiency by which these cognitive processes function. Operationally, poor performance caused by insufficient sleep translates to increased health and safety risks in settings where attention and timely and/or accurate decisions to respond are critical (e.g., at work, on the road, etc.). Current rodent tasks that assess altered cognition after sleep deprivation (SD) do not accurately model the continuous multisensory feedback that informs goal-oriented behavior in humans. Herein, we describe the vibration actuating search task (VAST), which consists of a vibrating open field with pseudo-randomly selected entrance and target destination points. To successfully complete a trial, mice use feedback from rotary motor-induced floor vibrations to navigate from the entrance point to the target destination. Sets of 20 trials were conducted on 3 consecutive days, and before testing on the third day control mice were undisturbed while other mice were sleep deprived for 10 h. On the first 2 days mice learned the task with high success rates. Alternatively, VAST performance was compromised following SD as measured by increased failures in task completion, time to target, time spent immobile, and decreased speed as compared with undisturbed mice. The VAST enables the analysis of continuous feedback via multiple sensory modalities in mice and is applicable to a variety of operational settings.NEW & NOTEWORTHY The vibration actuating search task (VAST) is a novel performance assay that uses continuous auditory and haptic feedback to motivate and direct search behaviors in mice. The VAST is rapidly acquired by mice and performance is disrupted by sleep deprivation. The VAST has practical application in occupational settings. The cognitive aspects of the sensorimotor integration in the VAST may prove useful for rodent models of neurodegenerative disease.

Range position and climate sensitivity: The structure of among-population demographic responses to climatic variation.

Species' distributions will respond to climate change based on the relationship between local demographic processes and climate and how this relationship varies based on range position. A rarely tested demographic prediction is that populations at the extremes of a species' climate envelope (e.g., populations in areas with the highest mean annual temperature) will be most sensitive to local shifts in climate (i.e., warming). We tested this prediction using a dynamic species distribution model linking demographic rates to variation in temperature and precipitation for wood frogs (Lithobates sylvaticus) in North America. Using long-term monitoring data from 746 populations in 27 study areas, we determined how climatic variation affected population growth rates and how these relationships varied with respect to long-term climate. Some models supported the predicted pattern, with negative effects of extreme summer temperatures in hotter areas and positive effects on recruitment for summer water availability in drier areas. We also found evidence of interacting temperature and precipitation influencing population size, such as extreme heat having less of a negative effect in wetter areas. Other results were contrary to predictions, such as positive effects of summer water availability in wetter parts of the range and positive responses to winter warming especially in milder areas. In general, we found wood frogs were more sensitive to changes in temperature or temperature interacting with precipitation than to changes in precipitation alone. Our results suggest that sensitivity to changes in climate cannot be predicted simply by knowing locations within the species' climate envelope. Many climate processes did not affect population growth rates in the predicted direction based on range position. Processes such as species-interactions, local adaptation, and interactions with the physical landscape likely affect the responses we observed. Our work highlights the need to measure demographic responses to changing climate.

P2X7 receptors in body temperature, locomotor activity, and brain mRNA and lncRNA responses to sleep deprivation.

The ionotropic purine type 2X7 receptor (P2X7R) is a nonspecific cation channel implicated in sleep regulation and brain cytokine release. Many endogenous rhythms covary with sleep, including locomotor activity and core body temperature. Furthermore, brain-hypothalamic cytokines and purines play a role in the regulation of these physiological parameters as well as sleep. We hypothesized that these parameters are also affected by the absence of the P2X7 receptor. Herein, we determine spontaneous expression of body temperature and locomotor activity in wild-type (WT) and P2X7R knockout (KO) mice and how they are affected by sleep deprivation (SD). We also compare hypothalamic, hippocampal, and cortical cytokine- and purine-related receptor and enzyme mRNA expressions before and after SD in WT and P2X7RKO mice. Next, in a hypothesis-generating survey of hypothalamic long noncoding (lnc) RNAs, we compare lncRNA expression levels between strains and after SD. During baseline conditions, P2X7RKO mice had attenuated temperature rhythms compared with WT mice, although locomotor activity patterns were similar in both strains. After 6 h of SD, body temperature and locomotion were enhanced to a greater extent in P2X7RKO mice than in WT mice during the initial 2-3 h after SD. Baseline mRNA levels of cortical TNF-α and P2X4R were higher in the KO mice than WT mice. In response to SD, the KO mice failed to increase hypothalamic adenosine deaminase and P2X4R mRNAs. Further, hypothalamic lncRNA expressions varied by strain, and with SD. Current data are consistent with a role for the P2X7R in thermoregulation and lncRNA involvement in purinergic signaling.

Tumor necrosis factor enhances the sleep-like state and electrical stimulation induces a wake-like state in co-cultures of neurons and glia.

We characterise sleep-like states in cultured neurons and glia during development in vitro as well as after electrical stimulation, the addition of tumor necrosis factor alpha (TNF), and the combination of TNF plus electrical stimulation. We also characterise optogenetic stimulation-induced ATP release and neuronal interleukin-1 and TNF expression in vitro demonstrating the activity dependence of these putative sleep-regulatory substances. Action potential (AP) burstiness, expressed as the burstiness index (BI), synchronization of slow electrical potentials between recording electrodes (SYN), and slow wave (SW) power (0.25-3.75 Hz) determined using fast Fourier analyses emerged as network properties, maturing after 2 weeks in culture. Homologous in vivo measures are used to characterise sleep. Electrical stimulation reduced the BI, SYN and SW power values during and/or after the stimulus period. One day later, homeostasis was evident from rebounds of SYN and SW power values to above baseline levels; the magnitude of the rebound was stimulus pattern-dependent. The addition of TNF enhanced BI, SYN and SW power values, suggesting the induction of a deeper sleep-like state. Electrical stimulation reversed these TNF effects, suggesting the network state was more wake-like. The day after TNF plus electrical stimulation, the changes in SYN and SW power values were dependent upon the stimulus patterns the cells received the day before. We conclude that sleep and wake states in cultured in vitro networks can be controlled and they share molecular regulatory mechanisms with local in vivo networks. Further, sleep is an activity-dependent emergent local network property.

The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice.

Interleukin-1ß (IL1) is involved in sleep regulation and sleep responses induced by influenza virus. The IL1 receptor accessory protein (AcP) and an alternatively spliced isoform of AcP found primarily in neurons, AcPb, form part of the IL1 signaling complex. IL1-induced sleep responses depend on injection time. In rat cortex, both IL1 mRNA and AcPb mRNA peak at Zeitgeber Time (ZT) 0 then decline over the daylight hours. Sleep deprivation enhances cortical IL1 mRNA and AcPb mRNA levels, but not AcP mRNA. We used wild type (WT) and AcPb knockout (KO) mice and performed sleep deprivation between ZT10 and 20 or between ZT22 and 8 based on the time of day expression profiles of AcPb and IL1. We hypothesized that the magnitude of the responses to sleep loss would be strain- and time of day-dependent. In WT mice, NREMS and REMS rebounds occurred regardless of when they were deprived of sleep. In contrast, when AcPbKO mice were sleep deprived from ZT10 to 20 NREMS and REMS rebounds were absent. The AcPbKO mice expressed sleep rebound if sleep loss occurred from ZT22 to 8 although the NREMS responses were not as robust as those that occurred in WT mice. We also challenged mice with intranasal H1N1 influenza virus. WT mice exhibited the expected enhanced sleep responses. In contrast, the AcPbKO mice had less sleep after influenza challenge compared to their own baseline values and compared to WT mice. Body temperature and locomotor activity responses after viral challenge were lower and mortality was higher in AcPbKO than in WT mice. We conclude that neuron-specific AcPb plays a critical role in host defenses and sleep homeostasis.

Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylococcus aureus.

Macrophages take advantage of the antibacterial properties of copper ions in the killing of bacterial intruders. However, despite the importance of copper for innate immune functions, coordinated efforts to exploit copper ions for therapeutic interventions against bacterial infections are not yet in place. Here we report a novel high-throughput screening platform specifically developed for the discovery and characterization of compounds with copper-dependent antibacterial properties toward methicillin-resistant Staphylococcus aureus (MRSA). We detail how one of the identified compounds, glyoxal-bis(N4-methylthiosemicarbazone) (GTSM), exerts its potent strictly copper-dependent antibacterial properties on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species- and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface.

Dispersal, niche breadth and population extinction: colonization ratios predict range size in North American dragonflies.

Species' range sizes are shaped by fundamental differences in species' ecological and evolutionary characteristics, and understanding the mechanisms determining range size can shed light on the factors responsible for generating and structuring biological diversity. Moreover, because geographic range size is associated with a species' risk of extinction and their ability to respond to global changes in climate and land use, understanding these mechanisms has important conservation implications. Despite the hypotheses that dispersal behaviour is a strong determinant of species range areas, few data are available to directly compare the relationship between dispersal behaviour and range size. Here, we overcome this limitation by combining data from a multispecies dispersal experiment with additional species-level trait data that are commonly hypothesized to affect range size (e.g. niche breadth, local abundance and body size.). This enables us to examine the relationship between these species-level traits and range size across North America for fifteen dragonfly species. Ten models based on a priori predictions about the relationship between species traits and range size were evaluated and two models were identified as good predictors of species range size. These models indicated that only two species' level traits, dispersal behaviour and niche breadth were strongly related to range size. The evidence from these two models indicated that dragonfly species that disperse more often and further had larger North American ranges. Extinction and colonization dynamics are expected to be a key linkage between dispersal behaviour and range size in dragonflies. To evaluate how extinction and colonization dynamics among dragonflies were related to range size we used an independent data set of extinction and colonization rates for eleven dragonfly species and assessed the relationship between these populations rates and North American range areas for these species. We found a negative relationship between North American range size and species' extinction-to-colonization ratios. Our results indicate that metapopulation dynamics act to shape the extent of species' continental distributions. These population dynamics are likely to interact with dispersal behaviour, particularly at species range margins, to determine range limits and ultimately species range sizes.

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders.

Sleep and circadian rhythm disruptions are comorbid features of many pathologies and can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between sleep and/or circadian rhythm and alternative polyadenylation (APA), particularly in the context of other health challenges, are largely undescribed. APA is a process that generates various transcript isoforms from the same gene, resulting in effects on mRNA translation, stability, localization, and subsequent function. Here, we have identified unique APAs in rat brain that exhibit time-of-day-dependent oscillations in expression as well as APAs that are altered by sleep deprivation and the subsequent recovery period. Genes affected by APA usage include Mapt/Tau, Ntrk2, Homer1A, Sin3band Sorl. Sorl1 has two APAs which cycle with a 24 h period, one additional APA cycles with a 12 h period and one more that is reduced during recovery sleep. Finally, we compared sleep- or circadian-associated APAs with recently described APA-linked brain disorder susceptibility genes and found 46 genes in common.

Humanization of the mouse Tert gene reset telomeres to human length.

Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Terth/- mice, telomere length progressively declined, stabilizing below 10-kb. Terth/h mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Terth/h mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.

Corrigendum: Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

[This corrects the article DOI: 10.3389/fnsys.2022.1052441.].

Fibers in smaller fascicles have lower activation thresholds with cuff electrodes due to thinner perineurium and smaller cross-sectional area.

Objective. In nerve stimulation therapies, fibers in larger fascicles generally have higher activation thresholds, but the mechanisms are not well understood. We implemented and analyzed computational models to uncover the effects of morphological parameters on activation thresholds.Approach. We implemented finite element models of human vagus nerve stimulation to quantify the effects of morphological parameters on thresholds in realistic nerves. We also implemented simplified models to isolate effects of perineurium thickness, endoneurium diameter, fiber diameter, and fascicle location on current density, potential distributions (Ve), and activation thresholds across cuff geometries and stimulation waveforms. UsingVefrom each finite element model, we simulated activation thresholds in biophysical cable models of mammalian axons.Main results. Perineurium thickness increases with fascicle diameter, and both thicker perineurium and larger endoneurial diameter contributed to higher activation thresholds via lower peak and broader longitudinal potentials. Thicker perineurium caused less current to enter the fascicle transversely, decreasing peakVe. Thicker perineurium also inhibited current from leaving the fascicle, causing more constant longitudinal current density, broadeningVe. With increasing endoneurial diameter, intrafascicular volume increased faster than surface area, thereby decreasing intrafascicular current density and peakVe. Additionally, larger fascicles have greater cross-sectional area, thereby facilitating longitudinal intrafascicular current flow and broadeningVe. A large neighboring fascicle could increase activation thresholds, and for a given fascicle, fiber diameter had the greatest effect on thresholds, followed by fascicle diameter, and lastly, fascicle location within the epineurium. The circumneural cuff elicited robust activation across the nerve, whereas a bipolar transverse cuff with small contacts delivering a pseudo-monophasic waveform enabled more selective activation across fiber diameters and locations.Significance. Our computational studies provide mechanistic understanding of neural responses across relevant morphological parameters of peripheral nerves, thereby informing rational design of effective therapies.

FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function.

Sleep and circadian rhythms are observed broadly throughout animal phyla and influence neural plasticity and cognitive function. However, the few phylogenetically conserved cellular and molecular pathways that are implicated in these processes are largely focused on neuronal cells. Research on these topics has traditionally segregated sleep homeostatic behavior from circadian rest-activity rhythms. Here we posit an alternative perspective, whereby mechanisms underlying the integration of sleep and circadian rhythms that affect behavioral state, plasticity, and cognition reside within glial cells. The brain-type fatty acid binding protein, FABP7, is part of a larger family of lipid chaperone proteins that regulate the subcellular trafficking of fatty acids for a wide range of cellular functions, including gene expression, growth, survival, inflammation, and metabolism. FABP7 is enriched in glial cells of the central nervous system and has been shown to be a clock-controlled gene implicated in sleep/wake regulation and cognitive processing. FABP7 is known to affect gene transcription, cellular outgrowth, and its subcellular localization in the fine perisynaptic astrocytic processes (PAPs) varies based on time-of-day. Future studies determining the effects of FABP7 on behavioral state- and circadian-dependent plasticity and cognitive processes, in addition to functional consequences on cellular and molecular mechanisms related to neural-glial interactions, lipid storage, and blood brain barrier integrity will be important for our knowledge of basic sleep function. Given the comorbidity of sleep disturbance with neurological disorders, these studies will also be important for our understanding of the etiology and pathophysiology of how these diseases affect or are affected by sleep.

A Dichotomous Role for FABP7 in Sleep and Alzheimer's Disease Pathogenesis: A Hypothesis.

Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer's pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson's disease.

Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

Introduction: Insufficient sleep is pervasive worldwide, and its toll on health and safety is recapitulated in many settings. It is thus important to understand how poor sleep affects the brain and decision making. A robust literature documents the adverse effects of sleep deprivation on cognitive processes including cognitive flexibility, which is the capacity to appraise new feedback and make behavioral adjustments to respond appropriately. Animal models are often used to unravel the molecules, genes and neural circuits that are altered by sleep loss. Herein we take a translational approach to model the effects of sleep deprivation on cognitive rigidity, i.e., impaired cognitive flexibility in rats. Methods: There are several approaches to assess cognitive rigidity; in the present study, we employ a pairwise discrimination reversal task. To our knowledge this is the first time this paradigm has been used to investigate sleep deprivation. In this touchscreen operant platform, we trained rats to select one of two images to claim a sucrose pellet reward. If the non-rewarded image was selected the rats proceeded to a correction trial where both images were presented in the same position as before. This image presentation continued until the rat selected the correct image. Once rats reached performance criteria, the reward contingencies were reversed. In one group of rats the initial reversal session was preceded by 10 h of sleep deprivation. We compared those rats to controls with undisturbed sleep on the number of sessions to reach performance criteria, number of trials per session, response latencies, correct responses, errors, perseverative errors and perseveration bouts in the initial training and reversal phases. Results: We report that on reversal session one, sleep deprived rats completed a fraction of the trials completed by controls. On subsequent reversal sessions, the sleep deprived rats struggled to adapt to the reversed contingencies despite completing a similar number of trials, suggesting an effect of cognitive rigidity separate from fatigue. Discussion: We discuss the delayed performance dynamics incurred by sleep loss in the context of fatigue and the implications of using pairwise discrimination reversal as a model to further examine the effects of sleep loss on adaptive decision making.

The rat Lux Actuating Search Task (LAST) and effects of sleep deprivation on task reversal performance.

Sleep deprivation (SD) causes significant deficits in multiple aspects of cognition, including sustained attention and working memory. Investigating the neural processes underpinning these cognitive losses has proven challenging due to the confounds of current animal tasks; many employ appetitive or aversive stimuli to motivate behavior, while others lack task complexity that translates to human studies of executive function. We established the Lux Actuating Search Task (LAST) to circumvent these issues. The LAST is performed in a circular, open-field arena that requires rats to find an unmarked, quasi-randomly positioned target. Constant low-level floor vibrations motivate ambulation, while light intensity (determined by the rodent's proximity to the target destination) provides continuous visual feedback. The task has two paradigms that differ based on the relationship between the light intensity and target proximity: the Low Lux Target (LLT) paradigm and the High Lux Target paradigm (HLT). In this study, on days 1-6, the rats completed nine trials per day on one of the two paradigms. On day 7, the rats were either sleep deprived by gentle handling or were left undisturbed before undertaking the opposite (reversal) paradigm on days 7-9. Our results showed that SD significantly impeded the ability of Long Evans rats to learn the reversal paradigm, as indicated by increased times to target and increased failure percentages compared to rats whose sleep was undisturbed. Rats also showed reduced learning with the HLT paradigm, as the initial task or as the reversal task, likely due to the rodents' photophobia limiting their motivation to navigate toward a bright light, which is required to succeed.

Single prolonged stress blocks sleep homeostasis and pre-trauma sleep deprivation does not exacerbate the severity of trauma-induced fear-associated memory impairments.

Sleep is intimately linked to cognitive performance and exposure to traumatic stress that leads to post-traumatic stress disorder (PTSD) impairs both sleep and cognitive function. However, the contribution of pre-trauma sleep loss to subsequent trauma-dependent fear-associated memory impairment remains unstudied. We hypothesized that sleep deprivation (SD) prior to trauma exposure may increase the severity of a PTSD-like phenotype in rats exposed to single prolonged stress (SPS), a rodent model of PTSD. Rats were exposed to SPS alone, SD alone, or a combination of SPS+SD and measures of fear-associated memory impairments and vigilance state changes were compared to a group of control animals not exposed to SPS or SD. We found that SPS, and SPS+SD animals showed impaired fear-associated memory processing and that the addition of SD to SPS did not further exaggerate the effect of SPS alone. Additionally, the combination of SPS with SD results in a unique homeostatic sleep duration phenotype when compared to SD, SPS, or control animals. SPS exposure following SD represses homeostatic rebound and eliminates sleep-deprivation-induced increases in NREM sleep delta power. This work identifies a unique time frame where trauma exposure and sleep interact and identifies this window of time as a potential therapeutic treatment window for staving off the negative consequences of trauma exposure.

Floor vibrations for motivation and feedback in the rat vibration actuating search task.

Motivating rodents to perform cognitive tasks often relies on the application of aversive stimuli. The Vibration Actuating Search Task (VAST) is a novel open-field task in which gradient floor vibration provides motivation for the rodent to navigate in the direction of diminishing vibration to an unmarked target destination. Using floor vibration as a motivational stimulus may overcome several of the potential confounds associated with stimuli used in other tasks. In a series of three experiments, we determined whether (1) rats exhibit place preference for floor vibration over other aversive stimuli (i.e., water, foot shock, and bright light), (2) exposure to floor vibration is associated with a lower corticosterone response than exposure to these other stimuli, (3) rats successfully acquire the VAST, and (4) VAST performance is sensitive to 6 h of sleep deprivation (SD). Our results showed that rats exhibited place preference for vibration over water, foot shock, and bright light environments, and that corticosterone levels were lower in rats exposed to vibration than those exposed to water. VAST performance also significantly improved over two days of testing for some metrics, and SD impaired VAST performance. Overall, we conclude that (1) rats exhibit place preference for vibration over other stimuli commonly used to motivate task performance, (2) the vibrations employed by the VAST produce lower concentrations of circulating corticosterone than forced swimming, (3) rats can learn to use gradient floor vibration as a mode of performance feedback within two days of testing, and (4) VAST performance is substantially impaired by SD. Thus, the VAST is an effective and practical testbed for studying the mechanisms by which SD causes deficits in feedback-dependent decision making.

Optogenetic sleep enhancement improves fear-associated memory processing following trauma exposure in rats.

Sleep disturbances are commonly found in trauma-exposed populations. Additionally, trauma exposure results in fear-associated memory impairments. Given the interactions of sleep with learning and memory, we hypothesized that increasing sleep duration following trauma exposure would restore overall function and improve trauma-induced fear-associated memory dysfunction. Here, we utilized single prolonged stress, a validated rodent model of post-traumatic stress disorder, in combination with optogenetic activation of hypothalamic melanin-concentrating hormone containing cells to increase sleep duration. The goal of this work was to ascertain if post-trauma sleep increases are sufficient to improve fear-associated memory function. In our laboratory, optogenetic stimulation after trauma exposure was sufficient to increase REM sleep duration during both the Light and Dark Phase, whereas NREM sleep duration was only increased during the Dark Phase of the circadian day. Interestingly though, animals that received optogenetic stimulation showed significantly improved fear-associated memory processing compared to non-stimulated controls. These results suggest that sleep therapeutics immediately following trauma exposure may be beneficial and that post-trauma sleep needs to be further examined in the context of the development of post-traumatic stress disorder.