Midbrain control of breathing and blood pressure: The role of periaqueductal gray matter and mesencephalic collicular neuronal microcircuit oscillators.

Neural circuitry residing within the medullary ventral respiratory column nuclei and dorsal respiratory group interact with the Kölliker-Fuse and medial parabrachial nuclei to generate the core breathing rhythm and pattern during resting conditions. Triphasic eupnea consists of inspiratory [I], post-inspiratory [post-I], and late-expiratory [E2] phases. Mesencephalic zones exert modulatory influences upon respiratory rhythm-generating circuitry, sympathetic oscillators, and parasympathetic nuclei. The earliest evidence supporting the existence of midbrain control of breathing derives from studies conducted by Martin and Booker in 1878. These authors demonstrated electrical stimulation of the deep layers of the mesencephalic colliculi in the rabbit augmented ventilation and sequentially elicited chest wall tremors and tetany. Investigations performed during the past several decades would demonstrate stimlation of distributed zones within the midbrain reticular formation elicits starkly disparate effects upon respiratory phase switching. Schmid, Böhmer, and Fallert demonstrated electrical stimulation of the nucleus rubre and emanating axon bundles alternately elicits or inhibits the activity of medullary expiratory- or inspiratory-related units and phrenic nerve discharge with differential latency. A series of studies would later indicate the red nucleus mediates hypoxic ventilatory depression. Periaqueductal gray matter neurons exhibit extensive afferent and efferent interconnectivity with suprabulbar, brainstem, and spinal cord zones aptly positioning these units to modulate breathing, autonomic outflow, nociception locomotion, micturtion, and sexual behavior. Experimental stimulatory activation of the tectal colliculi and periaqueductal gray matter via electrical current or glutamate, D,L-homocysteinic acid, or bicuculline microinjections coordinately modulates neuromotor inspiratory bursting frequency and amplitude and discharge of pre-Bötzinger complex, ventrolateral medullary late-I and post-I, and ventrolateral nucleus tractus solitarius decrementing early-I and augmenting and decrementing late-I neurons, elicits expiratory outflow and vocalization, and blunt the Hering-Breuer reflex in unanesthetzed decerebrate and anesthetized preprations of the cat and rat. Stimulation of the mesencephalic colliuli or dorsal divisions of the PAG potently amplifes renal sympathetic neural efferent activity, dynamic arterial pressure magnitude, and myocardial contraction frequency and elicits various behavioral defense responses. Elicited physiological effects exhibit extensive locoregional heterogeneity and variably enlist requisite contributions from the dorsomedial hypothalamus and/or lateral parabrachial nuclei. Stimulation of the dorsal mesencephalon occasionally elicits dynamic increases of arterial pressure magnitude exhibiting prominent oscillatory variability coherent with phrenic nerve discharge, perhaps by generating intra-neuraxial hysteresis, serving to intermittently deliver blood to organ vascular beds under high pressure in order to prevent organ edema, microcirculatory dysfunction, and downregulation of vascular smooth muscle alpha adrenergic receptors. Chemosensitive mesencephalic caudal raphé units and projections of hypoxia-sensitive units in the caudal hypothalamus to the periaqueductal gray matter may imply the existence of a diencephalo-smesencephalic chemosensitive network modulating breathing and sympathetic discharge.