Brainstem integration of arousal, sleep, cardiovascular, and respiratory control

The brainstem contains several critical areas involved in control of behavioral arousal, wake-sleep cycle, cardiovascular function, and respiration. Sleep and arousal are associated with profound changes in arterial pressure, heart rate, and respiration. Reciprocally, signals from brainstem areas controlling these functions promote arousal from sleep. These interactions involve neurons distributed throughout the rostrocaudal extent of the brainstem (figure 1). These neurons primarily utilize the excitatory amino-acid l-glutamate or the inhibitory amino acid γ-aminobutyric acid (GABA) and their activity is modulated in a state-dependent manner by cholinergic, monoaminergic, and peptidergic neurons in the brainstem and hypothalamus. Recent studies in rodents using optogenetic and other approaches for selective activation or inactivation of specific groups of brainstem neurons, identified by their unique expression of neurochemical markers, have led to a reevaluation of classical concepts on the brainstem mechanisms controlling arousal, wake-sleep cycle,^1–3 cardiovascular function^4–6 and respiration.^7,8 Some of the findings are supported by clinico-pathological correlations in humans and provide insight into the brainstem pathophysiology of disorders such as multiple system atrophy (MSA), obstructive sleep apnea, congenital central hypoventilation syndrome, sudden infantile death syndrome, and sudden unexpected death in epilepsy.