Compromise in inspiratory breathing following cervical spinal cord injury (SCI) is caused by damage to descending bulbospinal axons originating in the rostral ventral respiratory group (rVRG) and consequent denervation and silencing of phrenic motor neurons (PhMNs) that directly control diaphragm activation. In a rat model of high-cervical hemisection SCI, we performed systemic administration of an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential. PTEN antagonist peptide (PAP4) robustly restored diaphragm function, as determined with electromyography (EMG) recordings in living SCI animals. PAP4 promoted substantial, long-distance regeneration of injured rVRG axons through the lesion and back toward PhMNs located throughout the C3–C5 spinal cord. These regrowing rVRG axons also formed putative excitatory synaptic connections with PhMNs, demonstrating reconnection of rVRG-PhMN-diaphragm circuitry. Lastly, re-lesion throug...

Traumatic peripheral nerve injuries affect thousands of people every year. These injured nerves have the ability to regenerate, but the process is slow and full functional recovery is rare for most patients. Therapy in the form of treadmill exercise has...

The axon initial segment (AIS), a specific region for action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that the appropriate recruitment of the AIS macrocomplex is essential for synchr...

Peripheral axon regeneration is improved when the nerve lesion under consideration has recently been preceded by another nerve injury. This is known as the conditioning lesion effect (CLE). While the CLE is one of the most well robust and well character...

The genes that drive different aspects of developmental defects in Down syndrome (DS) are largely unknown. A potential driver of neurodevelopmental defects is Down syndrome cell adhesion molecule (Dscam), which is located in the Down Syndrome critical r...

Injury to the adult mammalian central nervous system (CNS) leads to permanent deficits in sensory and motor function. Dorsal root ganglion (DRG) neurons are essential for sensorimotor function as they receive and convey sensory information from the envi...

The ultrastructural organization of nodes of Ranvier has been investigated mainly by electron microscopy due to their small size (~1 µm). This technique, however, provides limited molecular specificity. On the other hand, the resolution power of convent...

Canonical and non-canonical Wnt signaling pathways are essential for development and maintenance of the central nervous system (CNS). Whereas the roles of canonical Wnt pathways in neuronal survival and axonal regeneration in adult CNS have been described, the functions of non-canonical Wnt pathways are not well understood. Furthermore, the role of non-canonical Wnt ligands in the adult retina has not been investigated. Non-canonical Wnt signaling shares receptors with canonical Wnt ligands but functions through calcium and JNK signaling pathways. Non-canonical ligands, such as the prototypic ligand Wnt5a, have varying effects in the developing CNS, including inhibiting or promoting axonal growth. To identify a role for non-canonical Wnt signaling in the developed retina after injury, we characterized the effect of Wnt5a on neurite outgrowth in cultured retinal ganglion cell (RGC) neurons and on axonal regeneration in the injured optic nerve in the mouse. Endogenous Wnt5a was upregulated after injury and e...

Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo . To identify genes affecting axon regeneration in Caenorhabditis elegans , we performed both an RNAi-based screen for defective motor axon regeneration in unc-70 /β-spectrin mutants and a candidate gene screen. From these screens, we identified at least 50 conserved genes with growth-promoting or growth-inhibiting functions. Through our analysis of mutants, we shed new light on certain aspects of regeneration, including the role of β-spectrin and membrane dynamics, the antagonistic activity of MAP kinase signaling pathways, and the role of stress in promoting axon regeneration. Many gene candidates had not previously been associated with axon regeneration and implicate new pathways of interest ...

Increased mTOR activity has been shown to enhance regeneration of injured axons by increasing neuronal protein synthesis, while PTEN signaling can block mTOR activity to attenuate protein synthesis. MicroRNAs (miR) have been implicated in regulation of PTEN and mTOR expression, and previous work in spinal cord showed an increase in miR-199a-3p after spinal cord injury (SCI) and increase in miR-21 in SCI animals that had undergone exercise. Pten mRNA is a target for miR-21 and miR-199a-3p is predicted to target mTor mRNA. Here, we show that miR-21 and miR-199a-3p are expressed in adult dorsal root ganglia (DRG) neurons and we used culture preparations to test functions of the rat miRs in adult DRG and embryonic cortical neurons. miR-21 increases and miR-199a-3p decreases in DRG neurons after in vivo axotomy. In both the adult DRG and embryonic cortical neurons, miR-21 promotes and miR-199a-3p attenuates neurite growth. miR-21 directly bound to Pten mRNA and miR-21 overexpression decreased Pten mRNA levels. ...