Divergent axonal projections are found throughout the central auditory system. Here, we evaluate these branched projections in terms of their types, distribution, and putative physiological roles. In general, three patterns of axon collateralization are found: intricate local branching, long-distance collaterals, and branched axons (BAs) involved in feedback-control loops. Local collaterals in the auditory cortex may be involved in local processing and modulation of neuronal firing, while long-range collaterals are optimized for wide-dissemination of information. Rarely do axons branch to both ascending and descending targets. Branched projections to two or more widely separated nuclei or areas are numerically sparse but widespread. Finally, branching to contralateral targets is evident at multiple levels of the auditory pathway and may enhance binaural computations for sound localization. These patterns of axonal branching are comparable to those observed in other modalities. We conclude that the operations served by BAs are area- and nucleus-specific and may complement the divergent unbranched projections of local neuronal populations.

This study evaluated the safety and efficacy of a novel hyper-crosslinked carbohydrate polymer (HCCP) for the repair of critical-sized bone defects in comparison to two alternative treatments: autologous bone and poly(lactide-co-glycolide) with hyaluronic acid (PLGA/HA). Bilateral critical-sized defects were created in the lateral femoral condyles of skeletally mature New Zealand White rabbits, and they were subsequently implanted with HCCP, PLGA/HA, or autologous bone in a randomized manner. Clinical and behavioral observations were made daily, and radiological and histopathological evaluations were performed at 4, 10, and 16 weeks postimplantation. Defects implanted with HCCP showed progressive bone regeneration and bridging of the defect without adverse histological events. No signs of infection or inflammation associated with the implant material were observed in all animals that received HCCP implantation. A radiographic assessment performed at 16 weeks post-implantation showed significantly higher bone density and volume in defects implanted with HCCP compared to PLGA/HA. No statistically significant difference was observed in bone density and volume between HCCP and autologous bone. These findings demonstrate that HCCP is biocompatible, osteoconductive, and capable of promoting bone regeneration in vivo; therefore, it is suitable for both tissue engineering and the repair of critical-sized bone defects.

Zinc finger (ZF), transcription activator-like effectors (TALE), and CRISPR/Cas9 therapies to regulate gene expression are becoming viable strategies to treat genetic disorders, although effective in vivo delivery systems for these proteins remain a major translational hurdle. We describe the use of a mesenchymal stem/stromal cell (MSC)-based delivery system for the secretion of a ZF protein (ZF-MSC) in transgenic mouse models and young rhesus monkeys. Secreted ZF protein from mouse ZF-MSC was detectable within the hippocampus 1 week following intracranial or cisterna magna (CM) injection. Secreted ZF activated the imprinted paternal Ube3a in a transgenic reporter mouse and ameliorated motor deficits in a Ube3a deletion Angelman Syndrome (AS) mouse. Intrathecally administered autologous rhesus MSCs were well-tolerated for 3 weeks following administration and secreted ZF protein was detectable within the cerebrospinal fluid (CSF), midbrain, and spinal cord. This approach is less invasive when compared to direct intracranial injection which requires a surgical procedure.