Joan C. Hendricks

Rest in Drosophila Is a Sleep-like State

To facilitate the genetic study of sleep, we documented that rest behavior in Drosophila melanogaster is a sleep-like state. The animals choose a preferred location, become immobile for periods of up to 157 min at a particular time in the circadian day, and are relatively unresponsive to sensory stimuli. Rest is affected by both homeostatic and circadian influences: when rest is prevented, the flies increasingly tend to rest despite stimulation and then exhibit a rest rebound. Drugs acting on a mammalian adenosine receptor alter rest as they do sleep, suggesting conserved neural mechanisms. Finally, normal homeostatic regulation depends on the timeless but not the period central clock gene. Understanding the molecular features of Drosophila rest should shed new light on the mechanisms and function of sleep.

Different behaviors during paradoxical sleep without atonia depend on pontine lesion site.

Bilateral pontine tegmental lesions in cats release a state of paradoxical sleep (PS) without atonia that possess all other electrographic criteria of PS. PS without atonia has been previously considered as a unitary phenomenon, but the present work demonstrates that different behavioral syndromes result from different lesion placements. Five of 25 cats exhibited the minimal syndrome of increased proximal limb and head movements. The head was not raised; and coordinated behavior was not seen. The nuchal electromyogram (EMG) showed tone for 25-100% of such an episode. Selective destruction of the origin (n = 2) or caudally projecting fibers (n = 1), of the tegmentoreticular pathway released this minimal syndrome of unorganized limb and head movements. This pathway had previously been proposed to mediate atonia, but the present work demonstrates that additional damage is necessary to release tone completely as well as the elaborate behaviors discussed below. Eight cats raised their heads, righted their forequarters, and moved head, neck and forelimbs in movements resembling orienting, staring, reaching and attempting to stand. The lesions releasing such behavior were centered at P = 3.0, H = 2.0, V = -4.0, and damaged a region projecting to the superior colliculus. Two cats with slightly more ventral lesions did not exhibit the orienting behavior. Six cats demonstrated violent phasic behavior resembling attack punctuating tonic periods of quiet staring or searching movements. Attack resulted from damage extending rostroventrally into the midbrain at P = 2.0, H = 2.5, V = -4.5 (4/6) or from unilateral damage to a lateral pathway arising in the central amygdalar nucleus (2/6). In 4 cats, coordinated fore- and hindlimb activation resulted in locomotion during PS. Walking resulted from larger, more ventral lesions centered at P = 3.0, H = 2.0, V = -5.5. Considering the anatomy of the lesions in relationship to brain stem systems known to play a role in orienting, attack and locomotion, we conclude that inhibitory systems were damaged by these lesions and that PS without atonia is not simply a state during which neural activity of normal PS can be expressed behaviorally.

A Drosophila model for age-associated changes in sleep:wake cycles.

One of the most consistent behavioral changes that occurs with age in humans is the loss of sleep consolidation. This can be quite disruptive and yet little is known about its underlying basis. To better understand the effects of aging on sleep:wake cycles, we sought to study this problem in Drosophila melanogaster, a powerful system for research on aging and behavior. By assaying flies of different ages as well as monitoring individual flies constantly over the course of their lifetime, we found that the strength of sleep:wake cycles decreased and that sleep became more fragmented with age in Drosophila. These changes in sleep:wake cycles became faster or slower with manipulations of ambient temperature that decreased or increased lifespan, respectively, demonstrating that they are a function of physiological rather than chronological age. The effect of temperature on lifespan was not mediated by changes in overall activity level or sleep amount. Flies treated with the oxidative stress-producing reagent paraquat showed a breakdown of sleep:wake cycles similar to that seen with aging, leading us to propose that the accumulation of oxidative damage with age contributes to the changes in rhythm and sleep. Together, these findings establish Drosophila as a valuable model for studying age-associated sleep fragmentation and breakdown of rhythm strength, and indicate that these changes in sleep:wake cycles are an integral part of the physiological aging process.

A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis

In the fruit fly, Drosophila melanogaster, rest shares features with mammalian sleep, including prolonged immobility, decreased sensory responsiveness and a homeostatic rebound after deprivation. To understand the molecular regulation of sleep-like rest, we investigated the involvement of a candidate gene, cAMP response-element binding protein (CREB). The duration of rest was inversely related to cAMP signaling and CREB activity. Acutely blocking CREB activity in transgenic flies did not affect the clock, but increased rest rebound. CREB mutants also had a prolonged and increased homeostatic rebound. In wild types, in vivo CREB activity increased after rest deprivation and remained elevated for a 72-hour recovery period. These data indicate that cAMP signaling has a non-circadian role in waking and rest homeostasis in Drosophila.

Gender Dimorphism in the Role of cycle (BMAL1) in Rest, Rest Regulation, and Longevity in Drosophila melanogaster

The central clock is generally thought to provide timing information for rest/activity but not to otherwise participate in regulation of these states. To test the hypothesis that genes that are components of the molecular clock also regulate rest, the authors quantified the duration and intensity of consolidated rest and activity for the four viable Drosophila mutations of the central clock that lead to arrhythmic locomotor behavior and for the pdf mutant that lacks pigment dispersing factor, an output neuropeptide. Only the cycle (cyc 0¹) and Clock (Clk Jrk) mutants had abnormalities that mapped to the mutant locus, namely, decreased consolidated rest and grossly extended periods of activity. All mutants with the exception of the cyc 0¹ fly exhibited a qualitatively normal compensatory rebound after rest deprivation. This abnormal response in cyc 0¹ was sexually dimorphic, being reduced or absent in males and exaggerated in females. Finally, the cyc 0¹ mutation shortened the life span of male flies. These data indicate that cycle regulates rest and life span in male Drosophila.

The need for a simple animal model to understand sleep

Simple animal models have allowed biologists to apply the tools of modern molecular genetics to such complex behaviors as circadian rhythms and long-term memory consolidation. The mechanisms and molecules discovered in these simple animals are evolutionarily conserved in other species, including mammals. Sleep research lacks a simple animal model because criteria based on the electroencephalogram have been met only in birds and mammals. We argue that straightforward behavioral criteria could allow the identification of a sleep-like rest state that might be useful for molecular investigations to understand the regulation and function of sleep. Candidate model systems are discussed, leading to the conclusion that several species have complementary strengths. Specifically, techniques developed for larval zebrafish can be used to visualize neural firing patterns in the living animal, and the fruit fly Drosophila melanogaster has been used successfully for molecular and genetic dissection of complex behaviors. We conclude with a hypothesis that one putative function of sleep, the optimization of neural plasticity, would also have adaptive value in simple organisms and might therefore be evolutionarily conserved.

Brachycephalic airway syndrome.

The range of clinical syndromes and the pathophysiology of respiratory disorders in brachycephalic animals are presented. The problem of deciding which patients require surgical management is reviewed in the light of recent studies and the authors clinical experience. Newer information from related disorders in humans suggests that serious problems can be subclinical and difficult to diagnose. The index of suspicion and guidelines for providing surgical relief to veterinary patients may need to undergo revision.

Absence of shivering in the cat during paradoxical sleep without atonia

Abstract There is good evidence that in many species there is no effective thermoregulation in paradoxical sleep (PS), either to ambient or hypothalamic thermal stimuli. In the present work placement of pontine tegmental lesions released elaborate behaviors during PS without atonia. Regulation of brain temperature was not altered by these lesions, and shivering, piloerection, and curled posture in a cold room were lost during PS even when motor neurons were thus permanently disinhibited throughout PS. The lack of thermoregulation is considered as part of a pattern of suspension of homeostasis in highly activated states.

Exploring human/animal intersections: Converging lines of evidence in comparative models of aging

At a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the Universitys Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age‐related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research.

Veterinarians in biomedical research: building national capacity.

This Executive Summary provides the conclusions from the presentations and discussions at the conference Veterinarians in Biomedical Research-Building National Capacity, a meeting coordinated by the AAVMC and held at the National Institutes of Health (NIH), Bethesda, MD, August 1-4, 2007.