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Published on: October 25, 2016
Mild Traumatic Brain Injury Affects Orexin/Hypocretin Physiology Differently in Male and Female Mice
Rebecca T Somach1,2,3, Ian D Jean1, Anthony M Farrugia1,2
1Department of Anesthesiology and Critical Care Medicine, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Abstract:
Traumatic brain injury (TBI) is known to affect the physiology of neural circuits in several brain regions, which can contribute to behavioral changes after injury. Disordered sleep is a behavior that is often seen after TBI, but there is little research into how injury affects the circuitry that contributes to disrupted sleep regulation. Orexin/hypocretin neurons (hereafter referred to as orexin neurons) located in the lateral hypothalamus normally stabilize wakefulness in healthy animals and have been suggested as a source of dysregulated sleep behavior. Despite this, few studies have examined how TBI affects orexin neuron circuitry. Further, almost no animal studies of orexin neurons after TBI have included female animals. Here, we address these gaps by studying changes to orexin physiology using ex vivo acute brain slices and whole-cell patch clamp recording. We hypothesized that orexin neurons would have reduced afferent excitatory activity after injury. Ultimately, this hypothesis was supported but there were additional physiological changes that occurred that we did not originally hypothesize. We studied physiological properties in orexin neurons approximately 1 week after mild traumatic brain injury (mTBI) in 6-8-week-old male and female mice. mTBI was performed with a lateral fluid percussion injury between 1.4 and 1.6 atmospheres. Mild TBI increased the size of action potential afterhyperpolarization in orexin neurons from female mice, but not male mice and reduced the action potential threshold in male mice, but not in female mice. Mild TBI reduced afferent excitatory activity and increased afferent inhibitory activity onto orexin neurons. Alterations in afferent excitatory activity occurred in different parameters in male and female animals. The increased afferent inhibitory activity after injury is more pronounced in recordings from female animals. Our results indicate that mTBI changes the physiology of orexin neuron circuitry and that these changes are not the same in male and female animals.
Insights
Mild traumatic brain injury (mTBI) alters orexin neuron circuitry, affecting wakefulness regulation. These changes differ between male and female mice, impacting sleep disorders after brain injury.
Area of Science:
- Neuroscience
- Neurophysiology
- Traumatic Brain Injury Research
Background:
- Traumatic brain injury (TBI) disrupts neural circuits, leading to behavioral changes like disordered sleep.
- Orexin neurons in the lateral hypothalamus regulate wakefulness but their function after TBI is understudied, especially in females.
Purpose of the Study:
- To investigate the physiological changes in orexin neurons and their afferent circuitry following mild traumatic brain injury (mTBI).
- To examine sex-based differences in orexin neuron responses to mTBI.
Main Methods:
- Used ex vivo acute brain slices and whole-cell patch clamp recordings in male and female mice 1 week after mTBI.
- Induced mTBI using lateral fluid percussion injury.
Main Results:
- mTBI altered action potential properties differently in male and female mice.
- mTBI reduced excitatory and increased inhibitory afferent activity onto orexin neurons.
- Sex-specific alterations in afferent activity and increased inhibition were observed, particularly in females.
Conclusions:
- mTBI significantly alters orexin neuron physiology and circuitry.
- These alterations are sex-dependent, suggesting different mechanisms for sleep dysregulation after TBI in males and females.
