Beyond Dreams: Do Sleep-Related Movements Contribute to Brain Development?

Conventional wisdom has long held that the twitches of sleeping infants and adults are by-products of a dreaming brain. With the discovery of active (or REM) sleep in the 1950s and the recognition soon thereafter that active sleep is characterized by inhibition of motor outflow, researchers elaborated on conventional wisdom and concluded that sleep-related twitches are epiphenomena that result from incomplete blockade of dream-related cortical activity. This view persists despite the fact that twitching is unaffected in infants and adults when the cortex is disconnected from the brainstem. In 1966, Roffwarg and colleagues introduced the ontogenetic hypothesis, which addressed the preponderance of active sleep in early infancy. This hypothesis posited that the brainstem mechanisms that produce active sleep provide direct ascending stimulation to the forebrain and descending stimulation to the musculature, thereby promoting brain and neuromuscular development. However, this hypothesis and the subsequent work that tested it did not directly address the developmental significance of twitching or sensory feedback as a contributor to activity-dependent development. Here I review recent findings that have inspired an elaboration of the ontogenetic hypothesis. Specifically, in addition to direct brainstem activation of cortex during active sleep, sensory feedback arising from limb twitches produces discrete and substantial activation of somatosensory cortex and, beyond that, of hippocampus. Delineating how twitching during active sleep contributes to the establishment, refinement, and maintenance of neural circuits may aid our understanding of the early developmental events that make sensorimotor integration possible. In addition, twitches may prove to be sensitive and powerful tools for assessing somatosensory function in humans across the lifespan as well as functional recovery in individuals with injuries or conditions that affect sensorimotor function

Sleep Physiology: Setting the Right Tone

SummaryHumans prone to cataplexy experience sudden losses of postural muscle tone without a corresponding loss of conscious awareness. The brain mechanisms underlying this debilitating decoupling are now better understood, thanks to a new study using cataplectic mice

Brainstem Cholinergic Modulation of Muscle Tone in Infant Rats

In week-old rats, lesions of the dorsolateral pontine tegmentum (DLPT) and nucleus pontis oralis (PnO) have opposing effects on nuchal muscle tone. Specifically, pups with DLPT lesions exhibit prolonged bouts of nuchal muscle atonia (indicative of sleep) and pups with PnO lesions exhibit prolonged bouts of high nuchal muscle tone (indicative of wakefulness). Here we test the hypothesis that nuchal muscle tone is modulated, at least in part, by cholinergically mediated interactions between these two regions. First, in unanesthetized pups, we found that chemical infusion of the cholinergic agonist carbachol (22 mM, 0.1 µL) within the DLPT produced high muscle tone. Next, chemical lesions of the nucleus pontis oralis (PnO) were used to produce a chronic state of high nuchal muscle tone, at which time the cholinergic antagonist scopolamine (10 mM, 0.1 µL) was infused into the DLPT. Scopolamine effectively decreased nuchal muscle tone, thus suggesting that lesions of the PnO increase muscle tone via cholinergic activation of the DLPT. Using 2-deoxyglucose (2-DG) autoradiography, metabolic activation throughout the DLPT was observed after PnO lesions. Finally, consistent with the hypothesis that PnO inactivation produces high muscle tone, infusion of the sodium channel blocker, lidocaine (2%), into the PnO of unanesthetized pups produced rapid increases in muscle tone. We conclude that, even early in infancy, the DLPT is critically involved in the regulation of muscle tone and behavioral state and that its activity is modulated by a cholinergic mechanism that is directly or indirectly controlled by the PnO

The Development of Sleep-Wake Rhythms and the Search for Elemental Circuits in the Infant Brain

Despite the predominance of sleep in early infancy, developmental science has yet to play a major role in shaping concepts and theories about sleep and its associated ultradian and circadian rhythms. Here we argue that developmental analyses help us to elucidate the relative contributions of the brainstem and forebrain to sleep-wake control and to dissect the neural components of sleep-wake rhythms. Developmental analysis also makes it clear that sleep-wake processes in infants are the foundation for those of adults. For example, the infant brainstem alone contains a fundamental sleep-wake circuit that is sufficient to produce transitions among wakefulness, quiet sleep, and active sleep. In addition, consistent with the requirements of a flip-flop model of sleep-wake processes, this brainstem circuit supports rapid transitions between states. Later in development, strengthening bidirectional interactions between the brainstem and forebrain contribute to the consolidation of sleep and wake bouts, the elaboration of sleep homeostatic processes, and the emergence of diurnal or nocturnal circadian rhythms. The developmental perspective promoted here critically constrains theories of sleep-wake control and provides a needed framework for the creation of fully realized computational models. Finally, with a better understanding of how this system is constructed developmentally, we will gain insight into the processes that govern its disintegration due to aging and disease

Forebrain-independent generation of hyperthermic convulsions in infant rats

Febrile seizures are the most common type of convulsive events in children. It is generally assumed that the generalization of these seizures is a result of brainstem invasion by the initial limbic seizure activity. Using precollicular transection in 13-day-old rats to isolate the forebrain from the brainstem, we demonstrate that the forebrain is not required for generation of tonic-clonic convulsions induced by hyperthermia or kainate. Compared with sham-operated littermate controls, latency to onset of convulsions in both models was significantly shorter in pups that had undergone precollicular transection, indicating suppression of the brainstem seizure network by the forebrain in the intact animal. We have shown previously that febrile seizures are precipitated by hyperthermia-induced respiratory alkalosis. Here, we show that triggering of hyperthermia-induced hyperventilation and consequent convulsions in transected animals are blocked by diazepam. The present data suggest that the role of endogenous brainstem activity in triggering tonic-clonic seizures should be re-evaluated in standard experimental models of limbic seizures. Our work sheds new light on the mechanisms that generate febrile seizures in children and, therefore, on how they might be treated.Peer reviewe

Distinct Retinohypothalamic Innervation Patterns Predict the Developmental Emergence of Species-typical Circadian Phase Preference in Nocturnal Norway Rats and Diurnal Nile Grass Rats

How does the brain develop differently to support nocturnality in some mammals, but diurnality in others? To answer this question, one might look to the suprachiasmatic nucleus (SCN), which is entrained by light via the retinohypothalamic tract (RHT). However, because the SCN is more active during the day in all mammals studied thus far, it alone cannot determine circadian phase preference. In adult Norway rats (Rattus norvegicus), which are nocturnal, the RHT also projects to the ventral subparaventricular zone (vSPVZ), an adjacent region that expresses an in-phase pattern of SCN-vSPVZ neuronal activity. In contrast, in adult Nile grass rats (Arvicanthis niloticus), which are diurnal, an anti-phase pattern of SCN-vSPVZ neuronal activity is expressed. We hypothesized that these species differences result in part from a weak or absent RHT-to-vSPVZ projection in grass rats. Here, using a developmental comparative approach, we assessed species differences in behavior, hypothalamic activity, and RHT anatomy. We report that a robust retina-to-vSPVZ projection develops in Norway rats around the end of the second postnatal week when nocturnal wakefulness and the in-phase pattern of neuronal activity emerge. In grass rats, however, such a projection does not develop and the emergence of the anti-phase pattern during the second postnatal week is accompanied by increased diurnal wakefulness. When considered within the context of previously published reports on RHT projections in a variety of species, the current findings suggest that how and when the retina connects to the hypothalamus differentially shapes brain and behavior to produce animals that occupy opposing temporal niches

The Development of Day-night Differences in Sleep and Wakefulness in Norway Rats and the Effect of Bilateral Enucleation

The suprachiasmatic nucleus (SCN) exhibits circadian rhythmicity in fetal and infant rats, but little is known about the consequences of this rhythmicity for infant behavior. Here, in Experiment 1, we measured sleep and wakefulness in rats during the day and night in postnatal day (P)2, P8, P15 and P21 subjects. As early as P2, day-night differences in sleep-wake activity were detected. Nocturnal wakefulness began to emerge around P15 and was reliably expressed by P21. We hypothesized that the process of photic entrainment over the first postnatal week, which depends upon the development of connectivity between the retinohypothalamic tract (RHT) and the SCN, influences the later emergence of nocturnal wakefulness. To test this hypothesis, in Experiment 2 infant rats were enucleated bilaterally at P3 and P11, that is, before and after photic entrainment. Whereas pups enucleated at P11 and tested at P21 exhibited increased wakefulness at night, identical to sham controls, pups enucleated at P3 and tested at P21 exhibited the opposite pattern of increased wakefulness during the day. Pups tested at P28 and P35 exhibited this same pattern of increased daytime wakefulness. All together, these results suggest that prenatal and postnatal experience modulates the development of species-typical circadian sleep-wake patterns. Moreover, we suggest that visual system stimulation, via the RHT’s connections with the SCN, exerts an organizational influence on the developing circadian system and, consequently, contributes to the emergence of nocturnality in this species

Development of Twitching in Sleeping Infant Mice Depends on Sensory Experience

SummaryMyoclonic twitches are jerky movements that occur exclusively and abundantly during active (or REM) sleep in mammals, especially in early development [1–4]. In rat pups, limb twitches exhibit a complex spatiotemporal structure that changes across early development [5]. However, it is not known whether this developmental change is influenced by sensory experience, which is a prerequisite to the notion that sensory feedback from twitches not only activates sensorimotor circuits but modifies them [4]. Here, we investigated the contributions of proprioception to twitching in newborn ErbB2 conditional knockout mice that lack muscle spindles and grow up to exhibit dysfunctional proprioception [6–8]. High-speed videography of forelimb twitches unexpectedly revealed a category of reflex-like twitching—comprising an agonist twitch followed immediately by an antagonist twitch—that developed postnatally in wild-types/heterozygotes, but not in knockouts. Contrary to evidence from adults that spinal reflexes are inhibited during twitching [9–11], this finding suggests that twitches trigger the monosynaptic stretch reflex and, by doing so, contribute to its activity-dependent development [12–14]. Next, we assessed developmental changes in the frequency and organization (i.e., entropy) of more-complex, multi-joint patterns of twitching; again, wild-types/heterozygotes exhibited developmental changes in twitch patterning that were not seen in knockouts. Thus, targeted deletion of a peripheral sensor alters the normal development of local and global features of twitching, demonstrating that twitching is shaped by sensory experience. These results also highlight the potential use of twitching as a uniquely informative diagnostic tool for assessing the functional status of spinal and supraspinal circuits