Humans have been fascinated by sleep for millennia. After almost a century of scientific interrogation, significant progress has been made in understanding the neuronal regulation and functions of ...sleep. The application of new methods in neuroscience that enable the analysis of genetically defined neuronal circuits with unprecedented specificity and precision has been paramount in this endeavor. In this review, we first discuss electrophysiological and behavioral features of sleep/wake states and the principal neuronal populations involved in their regulation. Next, we describe the main modulatory drives of sleep and wakefulness, including homeostatic, circadian, and motivational processes. Finally, we describe a revised integrative model for sleep/wake regulation.
Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we ...identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.
Honeybee (Apis mellifera) foragers are among the first invertebrates for which sleep behavior has been described. Foragers (typically older than 21 days) have strong circadian rhythms; they are ...active during the day, and sleep during the night. We explored whether young bees (approximately 3 days of age), which are typically active around-the-clock with no circadian rhythms, also exhibit sleep behavior. We combined 24-hour video recordings, detailed behavioral observations, and analyses of response thresholds to a light pulse for individually housed bees in various arousal states. We characterized three sleep stages in foragers on the basis of differences in body posture, bout duration, antennae movements and response threshold. Young bees exhibited sleep behavior consisting of the same three stages as observed in foragers. Sleep was interrupted by brief awakenings, which were as frequent in young bees as in foragers. Beyond these similarities, we found differences in the sleep architecture of young bees and foragers. Young bees passed more frequently between the three sleep stages, and stayed longer in the lightest sleep stage than foragers. These differences in sleep architecture may represent developmental and/or environmentally induced variations in the neuronal network underlying sleep in honeybees. To the best of our knowledge, this is the first evidence for plasticity in sleep behavior in insects.
Circadian rhythms in behaviour and physiology are important for animal health and survival. Studies with individually isolated animals in the laboratory have consistently emphasized the dominant role ...of light for the entrainment of circadian rhythms to relevant environmental cycles. Although in nature interactions with conspecifics are functionally significant, social signals are typically not considered important time-givers for the animal circadian clock. Our results challenge this view. By studying honeybees in an ecologically relevant context and using a massive data set, we demonstrate that social entrainment can be potent, may act without direct contact with other individuals and does not rely on gating the exposure to light. We show for the first time that social time cues stably entrain the clock, even in animals experiencing conflicting photic and social environmental cycles. These findings add to the growing appreciation for the importance of studying circadian rhythms in ecologically relevant contexts.
Animals continuously alternate between sleep and wake states throughout their life. The daily organization of sleep and wakefulness is orchestrated by circadian, homeostatic, and motivational ...processes. Over the last decades, much progress has been made toward determining the neuronal populations involved in sleep/wake regulation. Here, we will discuss how the application of advanced
tools for cell type-specific manipulations now permits the functional interrogation of different features of sleep/wake state regulation: initiation, maintenance, and structural organization. We will specifically focus on recent studies examining the roles of wake-promoting neuronal populations.
Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and ...maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.
The social environment influences the circadian clock of diverse animals, but little is known about the functional significance, the specifics of the social signals, or the dynamics of socially ...mediated changes in the clock. Honey bees switch between activities with and without circadian rhythms according to their social task. Forager bees have strong circadian rhythms, whereas "nurse" bees typically care for the brood around-the-clock with no circadian rhythms in behavior or clock gene expression. Here we show that nurse-age bees that were restricted to a broodless comb inside or outside the hive showed robust behavioral and molecular circadian rhythms. By contrast, young nurses tended brood with no circadian rhythms in behavior or clock gene expression, even under a light-dark illumination regime or when placed with brood--but no queen--in a small cage outside the hive. This behavior is context-dependent because nurses showed circadian rhythms in locomotor activity shortly after removal from the hive, and in clock gene expression after ∼16 h. These findings suggest that direct interaction with the brood modulates the circadian system of honey bees. The dynamics of rhythm development best fit models positing that at least some pacemakers continue to oscillate and be entrained by the environment in nurses that are active around the clock. These cells set the phase to the clock network when the nurse is removed from the hive. These findings suggest that despite its robustness, the circadian system exhibits profound plasticity, enabling adjustment to rapid changes in the social environment.
Unlike most animals studied so far in which the activity with no circadian rhythms is pathological or linked to deteriorating performance, worker bees and ants naturally care for their sibling brood ...around the clock with no apparent ill effects. Here, we tested whether bumble-bee queens that care alone for their first batch of offspring are also capable of a similar chronobiological plasticity. We monitored locomotor activity of Bombus terrestris queens at various life cycle stages, and queens for which we manipulated the presence of brood or removed the ovaries. We found that gynes typically emerged from the pupae with no circadian rhythms, but after several days showed robust rhythms that were not affected by mating or diapauses. Colony-founding queens with brood showed attenuated circadian rhythms, irrespective of the presence of ovaries. By contrast, queens that lost their brood switched again to activity with strong circadian rhythms. The discovery that circadian rhythms in bumble-bee queens are regulated by the life cycle and the presence of brood suggests that plasticity in the circadian clock of bees is ancient and related to maternal behaviour or physiology, and is not a derived trait that evolved with the evolution of the worker caste.
Although considered an inactive state for centuries, sleep entails many active processes occurring at the cellular, circuit and organismal levels. Over the last decade, several key technological ...advances, including calcium imaging and optogenetic and chemogenetic manipulations, have facilitated a detailed understanding of the functions of different neuronal populations and circuits in sleep-wake regulation. Here, we present recent progress and summarize our current understanding of the circuitry underlying the initiation, maintenance and coordination of wakefulness, rapid eye movement sleep (REMS) and non-REMS (NREMS). We propose a de-arousal model for sleep initiation, in which the neuromodulatory milieu necessary for sleep initiation is achieved by engaging in repetitive pre-sleep behaviors that gradually reduce vigilance to the external environment and wake-promoting neuromodulatory tone. We also discuss how brain processes related to thermoregulation, hunger and fear intersect with sleep-wake circuits to control arousal. Lastly, we discuss controversies and lingering questions in the sleep field.
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