Abstract: Traumatic brain injury (mTBI) is associated with persistent sleep-wake disturbances in both humans and in animal models. The mechanism underlying this association is still unclear, but may in part be due to dysregulation of orexin (also known as hypocretin), a neuropeptide critical for optimal sleep and wakefulness, and deficient in human narcolepsy. Research from Dr. Lim's group has recently shown in mice that orexin is persistently diminished after TBI, due to a decrease in excitatory input to orexin neurons. Dietary supplementation with branched chain amino acids (BCAA), which are precursors to excitatory glutamate released by vesicles at the presynaptic nerve terminal, restores excitatory input to orexin neurons and also restores normalcy of sleep-wake patterns in mice with TBI. A recent pilot study from Dr. Lim's group, consisting of a randomized, double-blinded placebo-controlled clinical trial of BCAA supplementation in Veterans with TBI, revealed a significant improvement in self-reported sleep quality in the BCAA, but not placebo, group. Additional exploratory outcome measures will be discussed. In summary, data from mice have identified the mechanism, dosing, duration of action of BCAA restoration of sleep disturbances in TBI, and thus directly informed the translation of this promising therapy to interventions for humans with TBI.
Biography: Dr. Lim earned a combined MD/PhD degree from Emory University in Atlanta in 2006. Her PhD thesis identified a gene involved in pair bonding behavior in the monogamous prairie vole (Lim et al., Nature 2004) and was the recipient of the Society for Neuroscience Donald B. Lindsley Prize in 2005. She completed a neurology residency at Washington University in Saint Louis in 2010. There, she studied the role of orexin and the sleep-wake cycle in a mouse model of Alzheimer’s disease; these studies revealed that sleep and orexin modulate the deposition of amyloid plaques in the brain (Kang, Lim et al., Science 2009). She completed fellowship training in Sleep Medicine at the University of Pennsylvania, pursuing postdoctoral research that identified a novel dietary therapy composed of branched chain amino acids for the treatment of sleep-wake disturbances following mild traumatic brain injury (TBI) (Lim et al., Science Translational Medicine 2013), and she was awarded the Sleep Research Society Young Investigator Award for this work. Dr. Lim is currently an Assistant Professor at the VA Portland Health Care System and Oregon Health and Science University, and is supported by VA, DoD, NSF, and NIH to perform translational sleep research on rodent models and human subjects.
Lab website: www.computationalsleep.com