Why humans and other animals sleep is one of the remaining deep mysteries of physiology. One prominent theory in neuroscience is that sleep is when the brain replays memories “offline” to better encode them (“memory consolidation”). A prominent and competing theory is that sleep is important for re-balancing activity in brain networks that have been perturbed during learning while awake. Such “rebalancing” of brain activity involves homeostatic plasticity mechanisms that were first discovered at Brandeis University, and have been thoroughly studied by a number of Brandeis labs including the Turrigiano lab. Now, a study from the Turrigiano lab just published in the journal Cell shows that these homeostatic mechanisms are indeed gated by sleep and wake, but in the opposite direction from that theorized previously: homeostatic brain rebalancing occurs exclusively when animals are awake, and is suppressed by sleep. These findings raise the intriguing possibility that different forms of brain plasticity – for example those involved in memory consolidation and those involved in homeostatic rebalancing – must be temporally segregated from each other to prevent interference.

The requirement that neurons carefully maintain an average firing rate, much like the thermostat in a house senses and maintains temperature, has long been suggested by computational work. Without homeostatic (“thermostat-like”) control of firing rates, models of neural networks cannot learn and drift into states of epilepsy-like saturation or complete quiescence. For years, our understanding of neuronal homeostasis was limited almost exclusively to reduced preparations such as cell cultures and acute slices. In 2013, the Turrigiano Lab provided the first ­in vivo evidence for firing rate homeostasis in the mammalian brain: led by postdoctoral fellow, Keith Hengen, researchers recorded the activity of individual neurons in the visual cortex of freely behaving rat pups for 8h per day across a nine-day period during which vision through one eye was occluded. The activity of neurons initially dropped, but over the next 4 days, firing rates came back to basal levels despite the loss of vision. In essence, these experiments confirmed what had long been suspected – the activity of neurons in intact brains is indeed homeostatically governed.

Due to the unique opportunity to study a fundamental mechanism of brain plasticity in an unrestrained animal, Hengen et al. continued to probe the possibility of an intersection between an animal’s behavior and homeostatic plasticity. In order to truly evaluate possible circadian and behavioral influences on homeostasis of neuronal activity, it was necessary to follow individual cells without cessation for the entire 9-day experiment, rather than evaluate snapshots of each day. For this work, the researchers had to find creative computational solutions to recording many terabytes of data necessary to follow the activity of single neurons for more than 200 hours. Ultimately, these data revealed that individual neurons have a “set-point” for activity that is tightly regulated, despite dramatic changes to input and the environment. In an unpredicted twist, the homeostatic recovery occurred almost exclusively during periods of activity and was inhibited during sleep. Prior predictions either assumed no role for behavioral state, or that sleeping should account for homeostasis. To solidify this finding, the lab established evidence for a causal role for active waking by artificially enhancing natural waking periods during the homeostatic rebound. When animals were kept awake, homeostatic plasticity was further bolstered.

This finding opens doors onto a new field of understanding the behavioral, environmental, and circadian influences on homeostatic plasticity mechanisms in the brain. Some of the key questions that immediately beg to be answered include:

What it is about sleep that precludes the expression of homeostatic plasticity?

How is it possible that mechanisms requiring complex patterns of transcription, translation, trafficking, and modification can be modulated on the short timescales of behavioral state-transitions in rodents?

And finally, how generalizable is this finding? As homeostasis is bidirectional, does a shift in the opposite direction similarly require wake or does the change in sign allow for new rules in expression?

About this neuroscience research

Authors on the paper include postdoctoral fellow Keith Hengen, Neuroscience grad student Alejandro Torrado Pachedo, and Neuroscience undergraduate James McGregor ’14 (now in grad school at Emory).

NeuroscienceNews.com would like to thank Keith Hengen for submitting this research directly to us.

Source: Keith Hengen – Brandeis University

Image Source: Image is credited to Brandeis University.

Original Research: Abstract for “Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake” by Keith B. Hengen, Alejandro Torrado Pacheco, James N. McGregor, Stephen D. Van Hooser, and Gina G. Turrigiano in Cell. Published online March 17 2016 doi:10.1016/j.cell.2016.01.046

Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake



Highlights

•Individual neocortical neurons were followed continuously during visual deprivation

•Control neurons have stable mean firing rates across behavioral states

•Perturbation by visual deprivation reveals a cell-autonomous firing rate set point

•Homeostatic recovery of firing is enabled by wake and inhibited by sleep states

Summary

Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms.

“Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake” by Keith B. Hengen, Alejandro Torrado Pacheco, James N. McGregor, Stephen D. Van Hooser, and Gina G. Turrigiano in Cell. Published online March 17 2016 doi:10.1016/j.cell.2016.01.046

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