Magnitude and Mechanism of Phrenic Long-term Facilitation Shift Between Daily Rest Versus Active Phase

FUNCTION, 2023 · DOI: 10.1093/function/zqad041 · Published: August 8, 2023

Simple Explanation

This study investigates how the time of day (rest vs. active phase) and the duration of low-oxygen episodes affect a type of respiratory neuroplasticity called phrenic long-term facilitation (pLTF). pLTF is the persistent increase in phrenic nerve activity after acute intermittent hypoxia (AIH). The researchers found that the balance between serotonin and adenosine, two chemicals in the brain, plays a critical role. Depending on when AIH is administered and the duration of hypoxic episodes, pLTF can be driven more by serotonin or adenosine. These findings are important because AIH is being explored as a therapy for respiratory and motor impairments. Understanding how to optimize AIH protocols based on time-of-day and episode duration could improve its effectiveness.

Study Duration

Not specified

Participants

Young (3–4 mo old) male Sprague–Dawley rats

Evidence Level

Level 5, Animal Study

Key Findings

1
Basal spinal adenosine levels are significantly higher during the active phase compared to the rest phase in rats.
2
The mechanism driving pLTF shifts from serotonin-dominant (midrest) to adenosine-dominant (midactive) with a standard AIH protocol (3, 5-min moderate hypoxic episodes).
3
Shorter hypoxic episodes (15, 1-min) amplify serotonin-dependent pLTF during the rest phase but attenuate pLTF in the active phase due to elevated background adenosine.

Research Summary

The study demonstrates that the magnitude and mechanism of phrenic long-term facilitation (pLTF) are profoundly affected by the daily rest/active phase and the duration of hypoxic episodes within an acute intermittent hypoxia (AIH) protocol. Shifts in the serotonin/adenosine balance, influenced by fluctuations in spinal adenosine levels and the duration of hypoxic episodes, are responsible for these effects. The findings have significant implications for the design of future experiments, understanding the mechanisms of AIH-induced phrenic motor plasticity, and the development of AIH as a therapeutic modality.

Practical Implications

Optimizing AIH Therapy

The findings suggest that the time of day and AIH protocol (hypoxic episode duration) should be considered in clinical trials to maximize therapeutic benefits.

Understanding Neuroplasticity

The study provides insights into the complex interplay of neuromodulators and their impact on neuroplasticity, which can be applied to other motor systems.

Targeting Specific Mechanisms

The ability to elicit different mechanisms of plasticity (serotonin- vs. adenosine-dependent) opens the potential to target distinct outcomes, such as axonal growth or synaptogenesis, for more impactful therapeutics.

Study Limitations

1
Neuromodulators other than adenosine fluctuate during the sleep/wake cycle and could provide distinct influences on pLTF, including corticosterone, melatonin and orexin.
2
Hypoxia-evoked adenosine release in ventral C4 spinal cord was measured late in the rest or early active phase. It is important to verify if similar time-of-day effects occur in hypoxia-evoked spinal adenosine release.
3
Since all rats used in this study were male, we cannot comment on the generalizability of our findings to females.

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