TRANSLATION OF BRAIN ACTIVITY INTO SLEEP

Abstract

Cytokines including tumor necrosis factor alpha (TNF) play a role in sleep regulation in health and disease. Hypothalamic and cerebral cortical levels of TNF mRNA or TNF protein have diurnal variations with higher levels associated with greater sleep propensity. Sleep loss is associated with enhanced brain TNF. Central or systemic TNF injections enhance sleep. Inhibition of TNF using the soluble TNF receptor, or anti-TNF antibodies, or a TNF siRNA reduces spontaneous sleep. Mice lacking the TNF 55 kD receptor have less spontaneous sleep. Injection of TNF into sleep regulatory circuits, e.g. the hypothalamus, promotes sleep. In normal humans, plasma levels of TNF co-vary with EEG slow wave activity (SWA) and in multiple disease states plasma TNF increases in parallel with sleep propensity. Downstream mechanisms of TNF-enhanced sleep include nitric oxide, adenosine, prostaglandins and activation of nuclear factor kappa B. Neuronal use induces cortical neurons to express TNF and if applied directly to cortical columns TNF induces a functional sleep-like state within the column. TNF mechanistically has several synaptic functions. TNF-sleep data led to the idea that sleep is a fundamental property of neuronal/glial networks such as cortical columns and is dependent upon past activity within such assemblies. This view of brain organization of sleep has profound implications for sleep function that are briefly reviewed herein.

Keywords: ATP; Cytokine; brain organization of sleep; interleukin-1; sleep function; tumor necrosis factor.

Figure 1

Cell activity drives oscillations between wake and sleep. Environmental and internal inputs induce cell activity; during waking this induces output 1 that is adaptive to the inputs. The waking-induced cell activity also induces release of extracellular ATP. The extracellular ATP provides a way for the brain to track prior activity; it induces via purine type 2 receptors (P2) release of cytokines, growth factors and neurotrophins that in turn activate nuclear factor kappa B to induce expression of glutamate and adenosine receptors. The change in receptor populations changes sensitivities of the neurons within the diffusible range of the extracellular ATP and this will result in output 2. Output 2, is delayed in time due to transcription and translation steps and thus is divorced, in time, from environmental inputs. Since that could cause non-adaptive behavior it requires a state (sleep) within which quiescence is imposed. Output 1, waking, has a positive feedback, whereas Output 2 has a negative feedback, onto cell input (e.g. reduced sensory input). The whole brain contains thousands of such neuronal/glial networks, e.g. cortical columns are a good example of a highly interconnected network. The synchrony of state between networks is a consequence of there being neuronal and chemical connections to other such networks (165) and from the influence of the activation systems projecting throughout the cortex; whole organism sleep is thus emerges from the activity-dependent local events.