Sleep occupies one-third of our adult lives and yet its function is still not known. In infants, sleep is even more prominent, as are the spontaneous myoclonic twitches that are a defining feature of active (or REM) sleep. Over the past decade, research in the Principal Investigator's laboratory has helped dispel the notion - which held sway until recently - that the brain plays no role in the control of infant sleep. Moreover, it is now widely accepted that sensory feedback (i.e., reafference) from twitching is closely monitored at all levels of the neuraxis. Of particular importance for this application is the recent discovery of oscillatory events-called spindle-bursts (SBs)-that are produced in primary sensory cortices in response to endogenously and exogenously generated sensory stimulation. It is thought that twitching, its associated reafference, and cortical SBs participate together in the development and maintenance of topographic organization. The Principal Investigator's laboratory has been engaged in this effort by monitoring neurophysiological activity in unanesthetized newborn rats as they cycle spontaneously between sleep and wakefulness and respond to specific peripheral tactile and proprioceptive stimulation. This application addresses two broad aims. First, a transient period during the first postnatal week in rats has been discovered when corpus callosotomy disinhibits spontaneous cortical activity and when recovery of function after callosotomy is possible. It is hypothesized that sleep-related twitching contributes to this recovery of function, just as it contributes to normal development. To test this hypothesis, neurophysiological and neuropharmacological approaches will be used, including the novel application of amperometry to unanesthetized infant rats for the measurement of real-time extracellular changes in cortical choline, glutamate, and GABA levels in relation to behavioral state, myoclonic twitching, and peripheral stimulation. Second, recent work suggests that SBs are differentially regulated depending on whether they are produced spontaneously (during active sleep) or evoked by peripheral proprioceptor stimulation. Because the ability of individuals to differentiate self-produced from externally produced sensory input relies upon the production of an efference copy, it is important to identify in newborn rats the neural circuitry that transmits spontaneous and evoked sensory information to somatosensory cortex.
This aim will be accomplished using a combination of methods, including surface EEG, amperometry, and selective unilateral inactivation of brain regions in the midbrain and forebrain. Preliminary results from the Principal Investigator's laboratory now demonstrate the feasibility of using amperometry in unanesthetized infant rats. The NIH Blueprint for Neuroscience emphasizes the need for more basic research to understand neurodevelopment, neurodegeneration, and neuroplasticity. This application is compatible with the Blueprint, focusing as it does on sleep, neural function, and brain plasticity across early infancy under normal conditions and after neural insult. Moreover, the approach that informs this work is contributing to a fundamental reconceptualization of infant sleep that will soon provide the foundation for a broader understanding of the function of sleep in both infants and adults.

Public Health Relevance

The NIH Blueprint for Neuroscience and the NIMH Blueprint for Change emphasize how basic, interdisciplinary research into the development of the brain and its response to injury is critical for advancing our understanding of the causes of the high rates of mental illness among children and adolescents. The current application focuses on the role that sensory feedback from sleep- related """"""""twitch"""""""" movements, which are especially prominent during the prenatal and early postnatal period, plays in the construction of the nervous system, especially as concerns the cerebral cortex and its interconnections. By understanding how the brain interprets these movements and how early injury and sensory disruption alter the brain's responses, we will begin to shed light on how early sensory experiences during sleep and wakefulness help to shape both normal and pathological outcomes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Freund, Lisa S
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Mukherjee, Didhiti; Sokoloff, Greta; Blumberg, Mark S (2018) Corollary discharge in precerebellar nuclei of sleeping infant rats. Elife 7:
Mukherjee, Didhiti; Yonk, Alex J; Sokoloff, Greta et al. (2017) Wakefulness suppresses retinal wave-related neural activity in visual cortex. J Neurophysiol 118:1190-1197
Blumberg, Mark S (2017) Development evolving: the origins and meanings of instinct. Wiley Interdiscip Rev Cogn Sci 8:
Del Rio-Bermudez, Carlos; Plumeau, Alan M; Sattler, Nicholas J et al. (2016) Spontaneous activity and functional connectivity in the developing cerebellorubral system. J Neurophysiol 116:1316-27
Tiriac, Alexandre; Blumberg, Mark S (2016) Gating of reafference in the external cuneate nucleus during self-generated movements in wake but not sleep. Elife 5:
Sokoloff, Greta; Uitermarkt, Brandt D; Blumberg, Mark S (2015) REM sleep twitches rouse nascent cerebellar circuits: Implications for sensorimotor development. Dev Neurobiol 75:1140-53
Sokoloff, Greta; Plumeau, Alan M; Mukherjee, Didhiti et al. (2015) Twitch-related and rhythmic activation of the developing cerebellar cortex. J Neurophysiol 114:1746-56
Blumberg, Mark S; Sokoloff, Greta; Tiriac, Alexandre et al. (2015) A valuable and promising method for recording brain activity in behaving newborn rodents. Dev Psychobiol 57:506-17
Blumberg, Mark S (2015) Developing Sensorimotor Systems in Our Sleep. Curr Dir Psychol Sci 24:32-37
Del Rio-Bermudez, Carlos; Sokoloff, Greta; Blumberg, Mark S (2015) Sensorimotor processing in the newborn rat red nucleus during active sleep. J Neurosci 35:8322-32

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