The importance of sleep in selecting neuronal circuitry; programmed cell death/apoptosis

Abstract Once a given brain region makes its initial synaptic connections, neurons making inappropriate ones must be removed. A key component of this removal is rapid eye movement (REM) sleep during which time all movement ceases except that of the eyes. However, the neuronal circuitry rapidly fires, releasing trophic factors including neurotransmitters and neuropeptides. Cells that have made correct synapses receive their trophic requirements; those that don’t die by apoptosis. Human fetuses are in REM sleep almost all the time, although some persists throughout life. Another major function of all phases of sleep, including REM and slow wave sleep, is to remove toxic molecules through channels that form the glymphatic system. Also memory consolidation occurs during sleep; ordinary memories during slow wave sleep and emotional memories during REM sleep. In birds and mammals, because of its enormous circuitry, the brain must eliminate incorrectly wired neurons. REM sleep stresses the neurons causing inappropriately connected ones to commit suicide. The mechanism through which neuronal death occurs is called apoptosis. This mechanism exists in all multicellular organisms. Apoptotic cells have several distinct features. Their cell bodies become dark and granular and their nuclear membranes and chromosomes are destroyed. Ultimately, the cell fragments into small vesicles that are engulfed by microglia without releasing various toxic compounds. Three families of proteins play key roles in apoptosis. Caspases are enzymes that when activated proteolyze almost all cellular proteins. Apaf-1 binds to a caspase, activating it. Members of the Bcl-2 family either negatively or positively regulate apoptosis. Intrinsic apoptosis occurs when damage to mitochondria occurs. Extrinsic apoptosis results when a neuron is deprived of trophic support. A cascade of events results from either form of apoptosis, beginning with oligomerization of Bcl-2 family members, leading to cytochrome C release and caspase activation.