Chronic sleep restriction impairs spatial memory in rats.

Although numerous experimental investigations have evaluated the neurobehavioral effects of either short periods of total sleep deprivation or selective rapid eye movement sleep deprivation, few studies have examined the effects of chronic sleep restriction (CSR). Long-Evans rats were deprived of sleep by the automated movement of activity wheels for 18 h/day for 5 consecutive days from 16:00 to 10:00 h, and were allowed 6 h/day of sleep opportunity (10:00-16:00 h; lights on from 10:00 to 22:00 h). Activity wheels were intermittently activated on a 3 s on : 12 s off schedule for the CSR condition, whereas a schedule of 36 min of continuous wheel movement in every 3 h was used for a cage movement control condition. A cross-over design was used with rats serving in both the CSR and the movement control conditions with 2 days of rest between conditions. Water maze acquisition training occurred at 16:00 h immediately after the 6-h sleep opportunity on each of the first 4 days, followed by a probe trial on day 5 to assess spatial memory recall. Although the rate of learning/acquisition was not affected by the daily 18 h of CSR, the day 5 recall of the platform location was impaired on three different probe trial measures. Thus, CSR impaired spatial memory, but did not affect the rate of learning/acquisition in the water maze.

Chronic ramelteon treatment in a mouse model of Alzheimer's disease.

Prior research has reported beneficial effects of melatonin in rodent models of Alzheimer's disease (AD). This study evaluated the effect of ramelteon (Rozerem, a melatonin receptor agonist) on spatial learning & memory and neuropathological markers in a transgenic murine model of AD (the B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J transgenic mouse strain; hereafter 'AD mice'). Three months of daily ramelteon treatment (~3mg/kg/day), starting at 3 months of age, did not produce an improvement in the cognitive performance of AD mice (water maze). In contrast to wild-type control mice, AD mice did not show any evidence of having learned the location of the escape platform. The cortex and hippocampus of AD mice contained significant quantities of beta-amyloid plaques and PARP-positive (poly ADP ribose polymerase) cells, indicating apoptosis. Six months of ramelteon treatment, starting at 3 months of age, did not produce any change in these neuropathological markers. The ability of long term melatonin treatment to improve cognition and attenuate neuropathology in AD mice did not generalize to this dosage of ramelteon.

Twenty-four hours, or five days, of continuous sleep deprivation or experimental sleep fragmentation do not alter thirst or motivation for water reward in rats.

Sleep disruption results in an increased demand for energy, which typically causes hyperphagia in an attempt to redress the energy metabolism imbalance. Therefore, experiments combining food reward and sleep disruption may underestimate the effect of sleep disruption due to their contradictory influences on behavior (for example on operant measures of attention). In contrast, water is not a central component of energy metabolism and thus thirst may not be affected by sleep disruption. However, little work has been done examining the effect of sleep disruption on thirst and motivation for water. The effect of total sleep deprivation (SD) and experimental sleep fragmentation (SF) on thirst and motivation for water was assessed. In experiment 1 (using 22 month old male Fisher-Norway rats) the amount of water consumed during a 15 min period immediately following a period of 24h SD or SF (in which water was not available) was measured, and, in a separate session, the amount of water consumed during the 24h of SD or SF was measured. Thereafter, the effect of 5 days SD or SF on motivation for water was assessed with the progressive ratio task (using water reward), which is widely used to assess motivation. Experiment 2 (using 6 month, and 22 month, old male Sprague- Dawley rats) followed an identical design except that the SF condition was dropped (due to a lack of any difference between the SD and SF conditions in experiment 1), and only the 6 month old rats experienced the full 5 day SD condition. Daily measurements of body weight and food consumption were recorded in experiment 2 in order to confirm previously published findings that food consumption goes up and body weight declines in sleep deprived rats. In both experiments the quantity of water rats consumed during a 15 min period immediately following the 24h period of sleep disruption, or consumed during the 24h period of SD or SF, did not change compared to control rats. Furthermore, 5 days of SD or SF had no effect on breakpoint in the progressive ratio task indicating that 5 days of SD or SF did not alter motivation for water reward. As previously reported, food consumption increased and body weight decreased during the 5 days of SD. in experiment 2. The findings indicate that although sleep disruption increases food consumption and decreases body weight, it does not alter thirst or motivation for water reward. Thus, water restriction is well suited for experiments examining the effect of sleep disruption on reward motivated behavioral tests in rats.

Physician, affective, and cognitive variables differentially predict 'initiation' versus 'maintenance' PSA screening profiles in diverse groups of men.

OBJECTIVES: To evaluate the relevance of demographic, physician, and psychological characteristics to PSA screening in ethnic subpopulations and ascertain whether the same characteristics distinguish men who have never had a PSA from those who screen infrequently and those who screen yearly (adhere). DESIGN AND METHODS: Stratified cluster-sampling was used to recruit 533 men (45-70 years) from four ethnic groups: African-American; European-American; immigrant Jamaican; and immigrant men from Trinidad and Tobago. Men provided demographic and structural (insurance, regular physician, annual exam, and physician recommendation), cognitive (risk and efficacy perceptions, knowledge), and emotional variables (cancer worry and embarrassment), and reported on PSA screening history. Multinomial logistic regression used these variables to predict three screening classifications (never screened, partially adherent, and adherent). RESULTS: Multinomial logistic regression showed that minority men were less likely to report either never screening or yearly screening, while younger men were more likely. Lack of a regular physician (OR=2.87, 95% CI 1.39-5.84), an annual exam (OR=1.73, 95% CI 0.91-3.28), and low recommendation (OR=3.76, 95% CI 2.13-6.66) were associated with being categorized as a never (vs. partially adherent) screener, but only annual exam (OR=0.26, 95% CI 0.10-0.63) was associated with yearly screening. Lower cancer worry was marginally associated with never screening (OR=0.59, 95% CI 0.38-1.04), while knowledge was associated with screening yearly over time (OR=0.46, 95% CI 0.28-0.77). CONCLUSIONS: Demographic, physician, and psychological variables are differentially associated with never, less than yearly, and yearly screening classifications. Minority men were unlikely to have never screened, but were also less likely to screen yearly. Physician variables were associated with the difference between not screening and partially adherent, but not between partially adherent and yearly screening suggesting that the role of physicians in PSA behaviour over time would benefit from further study.

24 hours of sleep deprivation in the rat increases sleepiness and decreases vigilance: introduction of the rat-psychomotor vigilance task.

A novel animal-analog of the human psychomotor vigilance task (PVT) was validated by subjecting rats to 24 h of sleep deprivation (SD) and examining the effect on performance in the rat-PVT (rPVT), and a rat multiple sleep latency test (rMSLT). During a three-phase (separate cohorts) crossover design, vigilance performance in the rPVT was compared with 24 h SD-induced changes in sleepiness assessed by polysomnographic evaluation and the rMSLT. Twenty-four hours of SD was produced by brief rotation of activity wheels at regular intervals in which the animals resided throughout the experiment. In the rPVT experiment, exercise controls (EC) experienced the same overall amount of locomotor activity as during SD, but allowed long periods of undisturbed sleep. After 24 h SD response latencies slowed, and lapses increased significantly during rPVT performance when compared with baseline and EC conditions. During the first 3 h of the recovery period following 24 h SD, polysomnographic measures indicated sleepiness. Latency to fall asleep after 24 h SD was assessed six times during the first 3 h after SD. Rats fell asleep significantly faster immediately after SD, than after non-SD baseline sessions. In conclusion, 24 h of SD in rats increased sleepiness, as indicated by polysomnography and the rMSLT, and impaired vigilance as measured by the rPVT. The rPVT closely resembles the human PVT test widely used in human sleep research and will assist investigation of the neurobiologic mechanisms that produce vigilance impairments after sleep disruption.

Microdialysis elevation of adenosine in the basal forebrain produces vigilance impairments in the rat psychomotor vigilance task.

STUDY OBJECTIVE: The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts potently in the basal forebrain (BF) to increase sleepiness. Here 300 microM of adenosine was dialyzed in the BF of rats, and the effect on vigilance was determined in the rat Psychomotor Vigilance Task (rPVT). DESIGN: Rats experienced all experimental conditions in a repeated-measures, cross-over design. PATIENTS OR PARTICIPANTS: Twelve young adult male Fischer-Norway rats. INTERVENTIONS: Sustained attention performance in the rPVT was evaluated following 2 hours of bilateral microdialysis perfusion of vehicle, adenosine (300 microM), or codialysis of 300 microM of adenosine with the A1 receptor antagonist 8-cyclopentyltheophylline. MEASUREMENTS AND RESULTS: During rPVT performance, response latencies and performance lapses increased significantly after adenosine dialysis when compared with baseline (no dialysis) or vehicle dialysis sessions. The codialysis of 8-cyclopentyltheophylline with adenosine completely blocked the effects produced by adenosine alone, resulting in performance equivalent to that of the vehicle sessions. CONCLUSIONS: Pharmacologic elevation of BF adenosine in rats produced vigilance impairments resembling the effect of sleep deprivation on vigilance performance in both man and rats. This effect of exogenous adenosine was completely blocked by codialysis with an adenosine A1 receptor antagonist. The results are consistent with the hypothesis that sleep loss induces elevations of BF adenosine that, acting via A1 receptors, lead to increased sleepiness and impaired vigilance.

Assessing sleepiness in the rat: a multiple sleep latencies test compared to polysomnographic measures of sleepiness.

Sleepiness following 6 h of sleep deprivation (SD) was evaluated with a rat multiple sleep latencies test (rMSLT), and the findings were compared to conventional polysomnographic measures of sleepiness. The 6 h of SD was produced by automated activity wheels, and was terminated at either the end of the light period or at the beginning of the dark period. The rMSLT consisted of 5 min wakefulness induced by sensory stimulation followed by 25 min of freedom to sleep. This procedure was repeated every 30 min for 3 h and was designed to minimize the amount of sleep lost due to the testing procedure. In separate rats, 6 h SD was followed by undisturbed recovery, allowing evaluation of conventional polysomnographic measures of sleepiness. Sleep onset latencies were reduced following SD, with recovery in the light (baseline = 8 min, 3 s versus post-SD = 1 min, 17 s) and dark period (baseline = 14 min, 17 s versus 7 min, 7 s). Sleep onset latencies were not altered by varying the duration criterion for the first sleep bout (i.e., sleep bout length criteria of 10, 20, 30, or 60 s were compared). Polysomnographic variables (non-rapid eye movement sleep episode duration, delta power, and number of awakenings) also provided reliable indirect measures of sleepiness, regardless of whether the recovery sleep occurred in the light or dark period. Evaluation of effect size indicated that the rMSLT was a strong measure of sleepiness, and was influenced by homeostatic, circadian, and illumination factors. The rMSLT provided a simple, objective, robust and direct measure of sleepiness that was as effective as conventional polysomnographic measures of sleepiness.

Demonstration of nondeclarative sequence learning in mice: development of an animal analog of the human serial reaction time task.

In this paper, we demonstrate nondeclarative sequence learning in mice using an animal analog of the human serial reaction time task (SRT) that uses a within-group comparison of behavior in response to a repeating sequence versus a random sequence. Ten female B6CBA mice performed eleven 96-trial sessions containing 24 repetitions of a 4-trial sequence. During the 12th session, the repeating sequence was replaced with the random sequence halfway through the session. Reaction time (RT) to respond to an illuminated nose-poke was recorded, and performance was compared at the halfway point in each session to test for any change in behavior. For learning effect, RTs decreased over the no-switch repeating-sequence sessions. For interference effect, behavior did not change appreciably at the halfway point during the last repeating-sequence session. However, RTs deteriorated significantly after the switch from repeating to random sequences halfway through session 12. The mice demonstrated a robust interference effect when switched from repeating to random sequences. This pattern of behavior in humans performing the SRT is interpreted as evidence of nondeclarative sequence learning. The similarity between the human and mouse SRTs will enable more direct comparisons of mouse-human nondeclarative memory behavior and will provide a useful behavioral end-point in mouse-models of basal ganglia dysfunction.

A new rat model of the human serial reaction time task: contrasting effects of caudate and hippocampal lesions.

There is often little correspondence between human and animal examples of nondeclarative memory. The serial reaction time task (SRT) is a sequence learning example of human nondeclarative memory that may be suitable for development as an animal model. The SRT is believed to be impaired by basal ganglia, not limbic system damage, but there is uncertainty whether limbic system pathology does in fact leave the SRT unimpaired. We therefore developed a new rat model that closely approximated the human SRT, using intracranial self-stimulation to promote rapid continuous responding to four adjacent nose pokes in a single test session. Intact rats that experienced repeated sequences demonstrated robust interference effects when switched to a random sequence of cued responses (at 4-, 8-, and 12-sequence lengths), unlike intact controls that experienced the random sequences only. The interference effect in the human task is a key measure for nondeclarative sequence learning. Rats with dorsal caudate lesions that experienced massed sequence repetitions showed an interference effect at the four-sequence length only. By contrast, rats with dorsal hippocampal lesions showed an interference effect at all sequence lengths. This new rat SRT model clarifies the basal ganglia-limbic system dichotomy suggested by human work.

Spatial working memory and the brainstem cholinergic innervation to the anterior thalamus.

The anteroventral thalamic nucleus (AV) has a role in spatial memory, but the influence of the prominent brainstem cholinergic projection to this region is unknown. Here, spatial memory in a 12-arm radial maze was examined after 0.15 microl bilateral AV infusions of scopolamine. In part one, rats visited six arms singly (the phase 1 arms) and, after a 10 min delay, were allowed free choice to both phase 1 arms and the remaining six baited arms (phase 2 arms). Scopolamine (10 microg) administered during the delay increased errors to both phase 1 and phase 2 arms, whereas PBS infusions increased phase 1 arm errors only. The PBS effect was the result of inserting the internal cannulas alone and not the infusion. The same dose of scopolamine (10 microg) infused before maze testing (part two: no phase 1 arms, no delay) also impaired spatial memory over and above the effects of both PBS and no-infusion, which did not differ markedly. Part two also showed that choice latency and choice strategies were unaffected by PBS and scopolamine. Cannulation and infusion procedures in both parts one and two did not produce any negative carryover effects across multiple control (no internal cannula) sessions, and a trypan blue manipulation indicated that infusions were restricted to the AV region. This study provides the first direct evidence that the brainstem cholinergic innervation to the limbic thalamus influences learning and memory, which may have important implications for human neurological conditions such as alcohol-related disorders and schizophrenia.