Dorsal mesencephalic modulation of breathing and autonomic outflow

Elements in the medullary ventral respiratory column nuclei and dorsal respiratory group interact with the Kolliker-Fuse and medial parabrachial nuclei to generate the breathing rhythm and pattern. 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 this derives from studies performed by Martin and Booker in 1878. These authors demonstrated augmentation of ventilation in response to electrical stimulation of the mesencephalic colliculi in the rabbit. A series of studies performed during the past several decades revealed a critical contribution of the red nucleus in mediating hypoxic ventilatory depression. Stimulation of distributed zones within the midbrain elicited seemingly disparate effects upon respiratory phase timing and transitioning. The works of Schmid and Bohmer demonstrated monosynaptic modulation of medullary inspiratory and expiratory related units in response to stimulation within midbrain zones corresponding with the red nucleus and rubrospinal tract. A plethora of studies have since generated strong evidence demonstrating and underscoring a critical contribution of the mesencephalic colliculi and periaqueductal gray matter in coordinately amplifying the respiratory output and sympathetic tone, blunting the Hering Breuer reflex and barosensitivity, and generating defense reaction behavioral responses to imminent environmental dangers. The lateral and ventrolateral divisions of the periaqueductal gray matter play critical roles in coordinating vocalization with breathing in an integrated circuit with the parabrachial nuclei. Authors have critically highlighted extensive and specific locoregional heterogeneity of effects elicited from periaqueductal gray matter stimulation. Studies have also made significant strides into elucidating the mechanistic basis and monosynaptic and polysynaptic propriobulbar and bulbospinal circuitry mediating periaqueductal gray matter and collicular modulation of breathing and autonomic outflow. The periaqueductal gray matter thus modulates and shapes neural respiratory frequency and amplitude, respiratory phase transitions, and autonomic outflow and appropriately coordinates defense reaction behavioral responses. The data collectively inspire fruitful new avenues of investigation in order to more thoroughly elucidate the mechanistic underpinnings of coordinate effects of the mesencephalic periaqueductal gray matter modulating the cardiovascular and respiratory outputs. We discuss and review the literature evaluating the role of the periaqueductal gray matter in modulating the respiratory and cardiovascular outputs.