Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury.spinal cord injury | NT3 | chitosan | functional recovery | endogenous neurogenesis

Previous findings suggested the role of the prefrontal cortex, hippocampus, and cingulate gyrus in major depressive disorders (MDD), but the white matter microstructural abnormalities of the fibers connecting these brain structures are not known. The purpose of this study was to test the hypothesis that white matter abnormalities are present in association fibers of the uncinate fasciculus (UF) and cingulum bundle (CB) among MDD subjects. A total of 21 MDD subjects aged between 30 and 65 years and 21 age-matched healthy controls (HC) were recruited. All subjects were right-handed and without history of diabetes or other cardiac diseases. We extracted quantitative tract-specific measures based on diffusion tensor imaging tractography to examine both diffusivity and geometric properties of the UF and CB. Significantly decreased fractional anisotropy (FA) and increased radial diffusivity of the right UF were observed in MDD patients compared with HC (po0.05), while their geometric characteristics remained relatively unchanged. Among MDD subjects, depression severity had a significant negative correlation with normalized number of fibers (NNF) in the right UF (r ¼ À0.53, p ¼ 0.02). We also found significant age effect (oldoyoung) in HC group and laterality effect (L4R) in both groups in the FA measure of the CB. Our study demonstrates novel findings of white matter microstructural abnormalities of the right UF in MDD. In the MDD group, the severity of depression is associated with reduced NNF in the right UF. These findings have implications for both clinical manifestations of depression as well as its pathophysiology.

Background This represents the first graph theory based brain network analysis study in bipolar disorder, a chronic and disabling psychiatric disorder characterized by severe mood swings. Many imaging studies have investigated white matter in bipolar disorder with results suggesting abnormal white matter structural integrity, particularly in the fronto-limbic and callosal systems. However, many inconsistencies remain in the literature, and no study to-date has conducted brain network analyses using a graph-theoretic approach. Methods We acquired 64-direction diffusion-weighted MRI on 25 euthymic bipolar I disorder subjects and 24 gender and age equivalent healthy subjects. White matter integrity measures including fractional anisotropy and mean diffusivity were compared in the whole brain. Additionally, structural connectivity matrices based on whole brain deterministic tractography were constructed followed by the computation of both global and local brain network measures. We also designed novel metrics to further probe inter-hemispheric integration. Results Network analyses revealed that the bipolar brain networks exhibited significantly longer characteristic path length, lower clustering coefficient, and lower global efficiency relative to those of controls. Further analyses revealed impaired inter-hemispheric but relatively preserved intra-hemispheric integration. These findings were supported by whole brain white matter analyses that revealed significantly lower integrity in the corpus callosum in bipolar subjects. There were also abnormalities in nodal network measures in structures within the limbic system, especially the left hippocampus, the left lateral orbito-frontal cortex, and the bilateral isthmus cingulate. Conclusions These results suggest abnormalities in structural network organization in bipolar disorder, particularly in inter-hemispheric integration and within the limbic system.

Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI. Using weighted gene coexpression network analysis (WGCNA), we established gene modules/ programs corresponding to various pathological events at different times after SCI. These objective measures of gene module expression also revealed that enhanced new neurogenesis and angiogenesis, and reduced inflammatory responses were keys to conferring the effect of NT3-chitosan on regeneration.S pinal cord injury (SCI) is a debilitating medical condition that often leads to permanent impairment of sensory and motor functions. SCI is considered almost incurable because axons in the central nervous system (CNS), unlike those in the peripheral nervous system (PNS), are believed not to regenerate. The innate ability of mature CNS neurons to regenerate is much weaker than that of PNS neurons (1). In addition, myelin debris in the injured CNS is more inhibitory toward axonal growth compared to that in the PNS (2). Moreover, the mode of immune cell infiltration and microglia activation are different in CNS versus PNS, resulting in a different cellular microenvironment, which crucially influences the outcome, i.e., PNS axons regenerate, while CNS axons do not (3).Over the years, SCI research has focused on ways to promote the long-distance growth of CNS motor axons, mainly by neutralizing inhibitory myelin components and/or changing the neuronal intrinsic program to enable better regeneration (4). Unfortunately, however, although numerous studies have been carried out following this line of strategy, no major breakthroughs translatable to therapy have been achieved. In recent years, efforts toward promoting long distance axonal growth have been complemented with alternative approaches aimed at using exogenous stem cells to generate local new neurons that form nascent relay neural networks to pass ascending and descending neurotransmission signals with or without long-distance axonal growth (5-7).SCI is a complex medical condition. The primary lesion includes the physical traumatic wounding of both white and gray matter, breakdown of the vasculature system, and acute immune reactions, which is followed by secondary lesions, such as demyelination, additional immune cell infiltration, inflammation, glial scar formation, impaired neurotransmission, and neuronal apoptosis (8). Secondary lesions are intermingled with intrinsic repair processes, including remyelina...

Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions. We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.

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Objectives Late-life major depression (LLD) is characterized by distinct epidemiological and psychosocial factors, as well as medical co-morbidities that are associated with specific neuroanatomical differences. The purpose of this study was to use interregional correlations of cortical and subcortical volumes to examine cortical-subcortical structural network properties in subjects with LLD compared to healthy comparison subjects. Design Cross-sectional neuroimaging study Setting General community Participants We recruited 73 healthy elderly comparison subjects and 53 subjects with LLD who volunteered in response to advertisements. Measurements Brain network connectivity measures were generated by correlating regional volumes after controlling for age, gender, and intracranial volume using the Brain Connectivity Toolbox (www.brain-connectivity-toolbox.net). Results Results for overall network strength revealed that LLD networks showed a greater magnitude of associations for both positive and negative correlation weights compared to healthy elderly networks. LLD networks also demonstrated alterations in brain network structure when compared to healthy comparison subjects. LLD networks were also more vulnerable to targeted attacks compared to healthy elderly comparison subjects and this vulnerability was attenuated when controlling for white matter alterations. Conclusions Overall, this study demonstrates that cortical-subcortical network properties are altered in LLD and may reflect the underlying neuroanatomical vulnerabilities of the disorder.