title: Midbrain raphe stimulation improves behavioral and anatomical recovery from fluid-percussion brain injury.
abstract: The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In water-maze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Carballosa Gonzalez
authors.forename: Meghan O
authors.initials: MO
authors.lastname: Blaya
authors.forename: Ofelia F
authors.initials: OF
authors.lastname: Alonso
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hentall
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D011903:Raphe Nuclei / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function
chemical_list: D000242:Cyclic AMP