Marcos Frank, PhD

• University of California San Francisco, Department of Physiology, Postdoctoral Research
• Stanford University, PhD, Neuroscience Program
• University of California, BA, Santa Cruz

Among the many unanswered questions in biology, one of the most persistent and perplexing is why animals sleep. Despite great progress in our understanding of the regulation and neurobiology of sleep, as well as the consequences of sleep loss on human performance, why the brain needs sleep remains a mystery.

The mystery of sleep function only deepens when we consider the developing animal. Infant animals spend as much as 80% of their time in sleep, and rather than being a passive response to the environment, infant sleep is an actively regulated state. This suggests that whatever the function of sleep might be, it is something that begins very early in life.

In my laboratory, one way we investigate the mystery of sleep function is by examining the role of sleep in the development of central visual pathways. The visual system is uniquely suited for our studies because many of the basic processes of neural development were first described in this sensory system.

One critical step in visual system development is the establishment of rudimentary circuits in visual cortex; a process that requires endogenous neural activity instead of waking visual experience. Given the large amounts of sleep during this developmental period, we suspect that this activity is provided by the sleeping brain.

A second essential stage in visual system development occurs during narrow, ‘critical’ periods when the brain is exquisitely sensitive to changes in visual experience. The classic studies by Hubel and Wiesel showed that blocking vision in one eye during the critical period resulted in dramatic physiological and anatomical changes in visual cortex.

We have previously demonstrated that this well-described form of in vivo plasticity is enhanced by sleep, and we are currently investigating the underlying mechanisms responsible for this effect. We now know that critical cellular steps in this process include a sleep-dependent activation of several kinases and the phosphorylation of cortical AMPA receptors; key steps in potentiating post-synaptic responses.

We are also interested in determining the cellular basis for sleep homeostasis and, more specifically, the interactions between sleep regulation and sleep function. To this end we are investigating the role of glial cells in the accumulation and discharge of sleep pressure and synaptic plasticity in vivo. We have shown, for example, that astrocytes are key players in controlling sleepiness in mammals through the release of glio-transmitters. Because glia also influence synaptic plasticity, these cells are uniquely positioned to connect the regulation of sleep with one of its hypothesized functions.

We approach both questions using an arsenal of tools including measures of brain activityin vivo (electrical and intracellular calcium), proteins and genes (Western blots to RNA sequencing), combined with quantitative measurements of sleep and wakefulness. This provides us a powerful means of addressing the enduring mystery of sleep.

Interests

The regulation and function of sleep in developing and adult animals. The role of experience and offline processes in brain plasticity. The role of glia in sleep regulation and function.

Key Words

Neural development, sleep, synaptic plasticity, glia

Techniques

Chronic recording of single and multiple neuron activity combined with infusion of neuroactive compounds in freely moving animals, sleep/wake state analyses in developing and adult animals, measuring and manipulating synaptic plasticity in vivo, optogenetics, viral transfection of transgenes, transgenic animals, optical imaging of intrinsic cortical signals, 2-photon microscopy, calcium imaging in neurons and glia in vivo combined with electrophysiological recording. Additional techniques include immunohistochemistry, in situ hybridization, Western blot assays qPCR, microarrays and RNA sequencing.

• Ingiosi AM, Hayworth CR, Harvey DO, Singletary KG, Rempe MJ, Wisor JP, Frank MG: A role for astroglial calcium in mammalian sleep and sleep regulation. Current Biology 2020, 30(22):4373-4383.e7, ISSN 0960-9822, https://doi.org/10.1016/j.cub.2020.08.052.
• Dumoulin Bridi M, Aton SJ, Seibt J, Renouard L, Coleman T, Frank MG: Rapid eye movement sleep promotes cortical plasticity in the developing brain. ScienceAdvances 2015. (1):1-8.
• Frank MG, Cantera R: Sleep, clocks, and synaptic plasticity. Trends Neurosci 2014, 37(9):491-501.
• Frank MG: Astroglial regulation of sleep homeostasis. Curr Opin Neurobiol 2013, 23(5):812-818.
• Dumoulin MC, Aton SJ, Watson AJ, Renouard L, Coleman T, Frank MG: Extracellular signal-regulated kinase (ERK) activity during sleep consolidates cortical plasticity in vivo. Cerebral cortex 2013, 25: 507-15. PMID 24047601 DOI: 10.1093/cercor/bht250.
• Aton SJ, Broussard C, Dumoulin M, Seibt J, Watson A, Coleman T, Frank MG: Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons. Proceedings of the National Academy of Sciences of the United States of America 2013, 110(8):3101-3106.
• Seibt J, Dumoulin MC, Aton SJ, Coleman T, Watson A, Naidoo N, Frank MG: Protein synthesis during sleep consolidates cortical plasticity in vivo. Current biology 2012, 22(8):676-682.
• Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, Haydon PG, Frank MG: Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 2009, 61(2):213-219.
• Aton SJ, Seibt J, Dumoulin M, Jha SK, Steinmetz N, Coleman T, Naidoo N, Frank MG: Mechanisms of sleep-dependent consolidation of cortical plasticity. Neuron 2009, 61(3):454-466.
• Jha SK, Jones BE, Coleman T, Steinmetz N, Law C, Griffin G, Hawk J, Frank MG: Sleep-dependent plasticity requires cortical activity. Journal of Neuroscience 2005, 25(40):9266-9274.
• Frank MG, Issa NP, Stryker MP: Sleep enhances plasticity in the developing visual cortex. Neuron 2001, 30(1):275-287.
• Frank MG, Morrissette R, Heller HC: Effects of sleep deprivation in neonatal rats. Am J Physiol 1998, 275(44):R148-R157.