1) Fundamental neural substrates participating in central autonomic regulation of circulation and respiration

To study the cardiorespiratory regulation system is not only important in medical practice but also a pleasure in satisfying our curiosity to the life. There are many words related to the heart and the lung that express our emotion or feeling of awe to the life. For example, mechanisms of "beating heart" or "breathtaking" are a matter of curiosity from the ancient time.

We have revealed the neural circuit in the medulla oblongata that is critically important for the blood pressure regulation but formerly treated as the black box. The neurons in the rostral ventrolateral medulla (RVLM), so called sympathetic premotor neurons in the cardiovascular center, integrate a variety of information and determine the activities of the sympathetic preganglionic neurons in the spinal cord. We call the axons of the RVLM neurons as the final common pathway governing sympathetic activities. The RVLM neurons not only receive information from the sensors of blood pressure, oxygen concentration in the blood, and so on, but also act by themselves as a sensor for chemicals in the cerebrospinal fluid. Now we have substantial, although not complete, knowledge of the homeostatic mechanisms that stabilize circulation and respiration around homeostatic points during resting states.



2) Dynamic regulation: From homeostasis to homeodynamics

Our daily life, however, does not only involve calm, resting states. Life is full of perturbations that induce active conditions, such as movements, eating, and communicating. During such active periods, cardiorespiratory regulation must be adjusted for bodily demands, which differ from those during resting states, by modulating or resetting homeostatic set-points. Research on processes for such adjustment mechanisms has been sparse, despite its importance from the perspective of quality-of-life.

To explore neural mechanisms of state-dependent adjustments (homeodynamics) of central autonomic regulation, we recently focused on a stress-induced defense (fight-or-flight) response because stressors induce not only cognitive, emotional, and behavioral changes, but also autonomic changes. These changes include increased blood pressure, heart rate, muscular blood flow, respiratory frequency, and tidal volume, and suppression of the baroreceptor reflex and pain sensitivity. Although research on neural circuits underlying these changes has implicated the hypothalamus in the defense response against stressors, neurotransmitters in this multifaceted and coordinated response have not been revealed.

To solve the problem, we used genetically engineered mice because they are superior to the traditional pharmacological approach in their specificity. By using prepro-orexin knockout mice and orexin neuron-ablated mice, we found that orexin-containing neurons in the hypothalamus act as a master switch to activate multiple efferent pathways of the defense response. Orexin, but not its co-transmitters in the neurons, appeared to be important, at least for changes in circulation and respiration.



3) Future directions

Stressful, irregular, and unbalanced life style induces so called life style-related illness. We are trying to understand how these factors result in illness from the viewpoint of homeodynamics failure. In addition, it may be useful to understand parasympathetic activator system for prevention of life style-related illness.

We have developed various methods for measuring physiologic functions in mice to bridge over the gap between the knowledge of molecular and systemic levels. We will continue to provide sophisticated methods in mice physiology.

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