The role of the hypothalamus in modulation of respiration

https://doi.org/10.1016/j.resp.2018.07.003Get rights and content

Highlights

  • The hypothalamus has many nuclei involved in respiratory control.

  • The hypothalamus modulates respiration in hypoxic and hypercapnic conditions.

  • The hypothalamus modulates respiration in awake and sleep states, and under stress.

  • Dysfunction of the hypothalamus causes abnormal breathing and hypoventilation.

Abstract

The hypothalamus is a higher center of the autonomic nervous system and maintains essential body homeostasis including respiration. The paraventricular nucleus, perifornical area, dorsomedial hypothalamus, and lateral and posterior hypothalamus are the primary nuclei of the hypothalamus critically involved in respiratory control. These hypothalamic nuclei are interconnected with respiratory nuclei located in the midbrain, pons, medulla and spinal cord. We provide an extensive review of the role of the above hypothalamic nuclei in the maintenance of basal ventilation, and modulation of respiration in hypoxic and hypercapnic conditions, during dynamic exercise, in awake and sleep states, and under stress. Dysfunction of the hypothalamus causes abnormal breathing and hypoventilation. However, the cellular and molecular mechanisms how the hypothalamus integrates and modulates autonomic and respiratory functions remain to be elucidated.

Introduction

The hypothalamus is the gray matter of the ventral portion of the diencephalon. Although the hypothalamus occupies less than 3% of the total brain tissue, the hypothalamus regulates a variety of autonomic brain functions that are often associated with specific regions of the hypothalamus. Probably, the best known function is neural control of endocrine function (Pang and Han, 2012). Other prominent functions of the hypothalamus include the control of sleep-wake cycle (Willie et al., 2001), circadian rhythms (Saper et al., 2005), thermoregulation (Nakamura, 2011), food intake (Yamanaka et al., 2003), energy homeostasis (Sakurai et al., 1998) and cardiovascular regulation (Dampney, 2016). Thus, the hypothalamus is seen as a major controller of body homeostasis. Moreover, as a part of the limbic system, the hypothalamus is involved in the mediation of important behavior such as flight or fight response (Dampney, 2015), reward seeking (Harris et al., 2005) and many more. Although modulation of respiration is directly or indirectly coupled with many of the above-mentioned homeostatic functions, the role of the hypothalamus in regulation of respiration is often underappreciated and, thus, the present review is exclusively focused on the respiratory functions of the hypothalamus.

Section snippets

Lesioning and transection experiments

First evidence demonstrating that the hypothalamus is a part of the central control system of respiration was provided by transection experiments. Removal of brain regions rostral to the diencephalon (i.e., decortication) increased ventilation in awake cats, suggesting that brain areas rostral to the diencephalon exert an inhibitory influence on respiration (Tenney and Ou, 1977). However, removal of the diencephalon including the hypothalamus caused a significant decrease in ventilation in

Respiratory nuclei of the hypothalamus

The more refined experimental approaches and conventional methods by electrophysiology, neuropharmacology and Fos brain mapping identified the paraventricular nucleus (PVN), perifornical area (PFA), dorsomedial hypothalamus (DMH) and lateral and posterior hypothalamus as primary nuclei of the hypothalamus that are involved in respiratory control.

Postnatal development

The increase in firing frequency and membrane depolarization elicited by hypoxia in hypothalamic neurons is age dependent. An increase in the density of Fos-expressing caudal hypothalamic neurons was not observed during hypoxia in rats less than 12 days old (Horn et al., 2000a), although significant differences were not found in the magnitude of the inward current responses to moderate or severe hypoxia between neonatal and juvenile caudal hypothalamic neurons (Horn et al., 1999). As mentioned

Implication of the hypothalamus in neurogenic breathing disorders

Dysfunction of the hypothalamus is linked to various neurogenic breathing disorders in humans. For instance, congenital central hypoventilation syndrome (CCHS) is a disorder of central respiratory control often characterized with mutation of PHOX2B gene in a subset of patients with hypothalamic dysfunction, resulting in alveolar hypoventilation and absence of ventilatory response to hypercapnia and hypoxia, especially during non-rapid eye movement sleep (Ize-Ludlow et al., 2007; Patwari et al.,

Conclusion and outlook

A number of studies have shown that the hypothalamus plays a vital role in modulation of respiration. Particularly, the PVN, PFA, DMH, lateral and caudal hypothalamus are the primary nuclei of the hypothalamus critically involved in respiratory control. Neurons in these regions have extensive interconnectivity and have substantial connection with other respiratory brain regions in the midbrain, pons, medulla and spinal cord. These regions of the hypothalamus are involved in the maintenance of

Conflict of interest

The authors declare no competing financial interests.

Acknowledgments

This work was supported by JSPS KAKENHI Grant Numbers 26460311, 15K00417, 17H05540, 17K08559 and 18K17783. The authors cordially thank Dr. Mathias Dutschmann for his critical reading of the manuscript.

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