Daily acute intermittent hypoxia induced dynamic changes in dendritic mitochondrial ultrastructure and cytochrome oxidase activity in the pre-Bötzinger complex of rats

Exp Neurol. 2019 Mar;313:124-134. doi: 10.1016/j.expneurol.2018.12.008. Epub 2018 Dec 23.


Mitochondria, as primary energy generators and Ca2+ biosensor, are dynamically coupled to neuronal activities, and thus play a role in neuroplasticity. Here we report that respiratory neuroplasticity induced by daily acute intermittent hypoxia (dAIH) evoked adaptive changes in the ultrastructure and postsynaptic distribution of mitochondria in the pre-Bötzinger complex (pre-BötC). The metabolic marker of neuronal activity, cytochrome c oxidase (CO), and dendritic mitochondria were examined in pre-BötC neurons of adult Sprague-Dawley rats preconditioned with dAIH, which is known to induce long-term facilitation (LTF) in respiratory neural activities. We performed neurokinin 1 receptor (NK1R) pre-embedding immunocytochemistry to define pre-BötC neurons, in combination with CO histochemistry, to depict ultrastructural alterations and CO activity in dendritic mitochondria. We found that the dAIH challenge significantly increased CO activity in pre-BötC neurons. Darkly CO-reactive mitochondria at postsynaptic sites in the dAIH group were much more prevalent than those in the normoxic control. In addition, the length and area of mitochondria were significantly increased in the dAIH group, implying a larger surface area of cristae for ATP generation. There was a fine, structural remodeling, notably enlarged and branching mitochondria or tapered mitochondria extending into dendritic spines. Mitochondrial cristae were mainly in parallel-lamellar arrangement, indicating a high efficiency of energy generation. Moreover, flocculent or filament-like elements were noted between the mitochondria and the postsynaptic membrane. These morphological evidences, together with increased CO activity, demonstrate that dendritic mitochondria in the pre-BötC responded dynamically to respiratory plasticity. Hence, plastic neuronal changes are closely coupled to active mitochondrial bioenergetics, leading to enhanced energy production and Ca2+ buffering that may drive the LTF expression.

Keywords: Cytochrome oxidase; Dendrite; Immuno-electron microscope; Intermittent hypoxia; Mitochondria; Neuroplasticity; Pre-Bötzinger complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Dendrites / pathology*
  • Dendrites / ultrastructure
  • Dendritic Spines / pathology
  • Dendritic Spines / ultrastructure
  • Electron Transport Complex IV / metabolism*
  • Energy Metabolism
  • Hypoxia / enzymology*
  • Hypoxia / pathology*
  • Long-Term Potentiation
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure
  • Neuronal Plasticity
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-1 / biosynthesis
  • Respiratory Center / enzymology*


  • Receptors, Neurokinin-1
  • Adenosine Triphosphate
  • Electron Transport Complex IV