Tumor necrosis factor α: Activity dependent expression and promotion of cortical column sleep in rats

Abstract

Cortical surface evoked potentials (SEPs) are larger during sleep and characterize a sleep-like state in cortical columns. Since tumor necrosis factor alpha (TNF) may be involved in sleep regulation and is produced as a consequence of waking activity, we tested the hypothesis that direct application of TNF to the cortex will induce a sleep-like state within cortical columns and enhance SEP amplitudes. We found that microinjection of TNF onto the surface of the somatosensory cortex enhanced whisker stimulation-induced SEP amplitude relative to a control heat-inactivated TNF microinjection. We also determined if whisker stimulation enhanced endogenous TNF expression. TNF immunoreactivity (IR) was visualized after 2 h of bilateral deflection of a single whisker bilaterally. The number of TNF-IR cells increased in layers II-IV of the activated somatosensory barrel column. In two separate studies, unilateral deflection of multiple whiskers for 2 h increased the number of TNF-IR cells in layers II-V in columns that also exhibited enhanced Fos-IR. TNF-IR also colocalized with NeuN-IR suggesting that TNF expression was in neurons. Collectively these data are consistent with the hypotheses that TNF is produced in response to neural activity and in turn enhances the probability of a local sleep-like state as determined by increases in SEP amplitudes.

Biochemical Regulation of Sleep and Sleep Biomarkers

“…These SRSs act within complex biochemical cascades, e.g., Figure 1, to form the sleep homeostat, a network of molecules that regulate sleep over different time scales. 4,11 Interleukin-1 Beta and tumor necrosis Factor Alpha IL1 and TNF are cytokines. They are released in response to many stimuli including sleep loss, tissue injury, and infection.…”

“…Further, enhanced afferent activity (e.g., by repeatedly twitching a single whisker), as well as local micro-injection of TNF, induce columns to switch to the sleep-like state. 11 Such data suggest that whole animal sleep may be a consequence of the fraction of individual local neuronal/glial networks in the sleep-like state. Thus, if sleep is a fundamental property of local networks semi-autonomously oscillating between states, sleepiness may be an emergent property dependent upon the number of local networks in a sleep-like state but not necessarily a consequence of the same networks being in a sleeplike state every time sleepiness manifests.…”

Delta Wave Power: An Independent Sleep Phenotype or Epiphenomenon?

“…Sleep regulatory substances, such as TNF, applied directly to cortical columns enhance ERPs suggesting that TNF directly enhances the probability of neuronal assemblies being in the functional sleep state. 29 Further, TNF applied in this localized fashion to the cortex enhances local EEG SWA. 23 The release of sleep regulatory substances, including TNF, IL1, nitric oxide, and adenosine, increases as a result of neuronal activity within neuronal networks (reviewed 30 ).…”

“…For example, TNF production is enhanced in cortical columns if afferent activity is increased and if TNF is applied to a cortical column, it induces a sleep-like state in the column. 29 TNF can cause synaptic up-scaling (via AMPA receptors 40 ) or down-scaling (via adenosine A1 receptors 41 ). In the Krueger/Obal theory, organism sleep is an emergent property of the synchronization of the sleep-like state of multiple networks.…”

Naturalistic Field Studies of Sleep and Performance

“…reviewed the theory of local sleep as a function of neuronal assemblies. Krueger, Rector and Churchill (2008) reviewed the role of cytokines in local sleep. Krueger (2008) reviewed the humoral regulation of sleep and implications for sleep as a use dependent process.…”