PROJECT SUMMARY/ABSTRACT
Migraine-like headaches are among the most frequent complaints following mild traumatic brain injury (mTBI),
yet the mechanisms underlying these headaches are unknown. A possible clue is that sleep disruption is also
a common complaint after mTBI. Sleep disruption is a frequently-reported migraine trigger, while sleep is a
widely effective migraine abortive. Based on the clinical connections between mTBI, headache and sleep
disruption, we hypothesize that sleep disruption contributes to the development of post-traumatic headache
(PTH) following mTBI.
A mechanism that may link mTBI, sleep and PTH is the impairment of the glymphatic system, which is a
recently characterized brain-wide network of perivascular spaces that support the rapid exchange of
cerebrospinal and interstitial fluid. Glymphatic pathway function is greatest during sleep. It is suppressed
during waking by central noradrenergic tone and is reduced by mTBI. We propose that the impairment of
glymphatic function following mTBI may contribute to the development and persistence of PTH symptoms. In
support of this, our preliminary data demonstrate that treatment with the centrally-active a1-adrenergic
antagonist prazosin improves both glymphatic function and ameliorates PTH symptoms in mice. This proposal
will extend these findings by comparing the effects of repetitive impact and blast mTBI on glymphatic function,
testing whether treatment with prazosin can restore post-traumatic glymphatic function. Using well established
mouse models of mTBI and validated behavioral measures of PTH symptoms (light aversion and mechanical
facial allodynia), we will then define the role of glymphatic dysfunction in the development of PTH symptoms by
testing whether these symptoms are exacerbated in a transgenic mouse model in which glymphatic function is
constitutively impaired and whether increasing post-traumatic glymphatic function pharmacologically with
prazosin improves PTH symptoms. In a second set of experiments, we will test whether targeting sleep
provides a pathway for improving post-traumatic glymphatic impairment and ameliorating PTH symptoms. In
these studies we will define whether the effect of sleep augmentation on PTH behaviors is independent of
glymphatic function. In our final studies, we will evaluate whether peripheral or central alpha1 or beta
adrenergic signaling is a key driver of post-traumatic glymphatic impairment, and whether targeting these
processes can improve PTH-associated behaviors either through effect on glymphatic function or through
modulation of post-traumatic sleep.
The results of this study will provide a novel perspective on the mechanisms underlying development of PTH
that will potentially support targeting sleep disruption and glymphatic function as therapeutic strategies for
mTBI patients.