Strain in the Midbrain: Impact of Traumatic Brain Injury on the Central Serotonin System.

Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.

Transcriptomic dynamics governing serotonergic dysregulation in the dorsal raphe nucleus following mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae.

Outcomes of Live Kidney Donors Who Develop End-Stage Renal Disease.

BACKGROUND: Kidney donors can develop end-stage renal disease (ESRD) after donation, but the outcomes of those who do remain poorly characterized. METHODS: Using United States Renal Data System and Scientific Registry for Transplant Research data, we compared access to kidney transplantation (KT), time from ESRD to listing, time from listing to KT, and post-KT graft failure and death between donors and matched nondonors with ESRD. RESULTS: Among 99 donors between April 1994 and November 2011 who developed ESRD, 78 initially received dialysis (of whom 37 listed for KT, 2 received live donor KT without listing, and 39 never listed for or received a KT), 20 listed preemptively (of whom 19 were subsequently transplanted), and 1 received a preemptive live donor KT without listing or ever receiving dialysis. Donors were listed earlier (median time to listing, 17 months vs 120 for nondonors; P < 0.001), received KT earlier (median waiting time, 2.8 months vs 21.5 for nondonors; P < 0.001), and received 13% live donor, 87% standard criteria, and 0% expanded criteria deceased donor KT (39%, 50%, and 11% in nondonors). Post-KT graft (adjusted hazard ratio, 1.9; 95% confidence interval, 0.9 to 4.1; P = 0.1) and patient (adjusted hazard ratio, 0.7; 95% confidence interval, 0.2 to 2.4; P = 0.5) survival were comparable in donors and nondonors. CONCLUSIONS: Our finding that 39 of 99 donors who developed ESRD never listed for a transplant warrants further study to ascertain why these donors with ESRD never gained access to the waiting list.

A microarray-based genotyping and genetic mapping approach for highly heterozygous outcrossing species enables localization of a large fraction of the unassembled Populus trichocarpa genome sequence.

Microarrays have demonstrated significant power for genome-wide analyses of gene expression, and recently have also revolutionized the genetic analysis of segregating populations by genotyping thousands of loci in a single assay. Although microarray-based genotyping approaches have been successfully applied in yeast and several inbred plant species, their power has not been proven in an outcrossing species with extensive genetic diversity. Here we have developed methods for high-throughput microarray-based genotyping in such species using a pseudo-backcross progeny of 154 individuals of Populus trichocarpa and P. deltoides analyzed with long-oligonucleotide in situ-synthesized microarray probes. Our analysis resulted in high-confidence genotypes for 719 single-feature polymorphism (SFP) and 1014 gene expression marker (GEM) candidates. Using these genotypes and an established microsatellite (SSR) framework map, we produced a high-density genetic map comprising over 600 SFPs, GEMs and SSRs. The abundance of gene-based markers allowed us to localize over 35 million base pairs of previously unplaced whole-genome shotgun (WGS) scaffold sequence to putative locations in the genome of P. trichocarpa. A high proportion of sampled scaffolds could be verified for their placement with independently mapped SSRs, demonstrating the previously un-utilized power that high-density genotyping can provide in the context of map-based WGS sequence reassembly. Our results provide a substantial contribution to the continued improvement of the Populus genome assembly, while demonstrating the feasibility of microarray-based genotyping in a highly heterozygous population. The strategies presented are applicable to genetic mapping efforts in all plant species with similarly high levels of genetic diversity.