C'mon get happy: reduced magnitude and duration of response during a positive-affect induction in depression.

BACKGROUND: Depression involves decreased positive affect. Whether this is due to a failure to achieve or maintain positive emotion in response to discrete stimuli is unclear. Understanding the nature of decreased positive affect could help to address how to intervene in the phenomenon, for example, how to structure interventions using positive and rewarding stimuli in depression. Thus, we examined the time course of affect following exposure to positive stimuli in depressed and healthy individuals. METHODS: Seventy-one adults with major depressive disorder and thirty-four never-depressed controls read a self-generated highly positive script and continuously rated their affect for 7 min. RESULTS: Both groups quickly achieved increased positive affect, however, compared to controls, depressed participants did not achieve the same level of positive affect, did not maintain their positive affect, spent less time rating their affect as happy, and demonstrated larger drops in mood. CONCLUSIONS: These data indicate that depressed and nondepressed individuals can generate positive reactions to happy scripts, but depressed individuals cannot achieve or sustain equivalent levels of positive affect. Interventions for depression might fruitfully focus on increasing depressed individuals' ability to maintain initial engagement with positive stimuli over a sustained period of time.

The Effects of the Combination of Mesenchymal Stromal Cells and Nanofiber-Hydrogel Composite on Repair of the Contused Spinal Cord.

A bone marrow-derived mesenchymal stromal cell (MSC) transplant and a bioengineered nanofiber-hydrogel composite (NHC) have been shown to stimulate nervous tissue repair in the contused spinal cord in rodent models. Here, these two modalities were combined to assess their repair effects in the contused spinal cord in adult rats. Cohorts of contused rats were treated with MSC in NHC (MSC-NHC), MSC in phosphate-buffered saline (MSC-PBS), NHC, or PBS injected into the contusion site at 3 days post-injury. One week after injury, there were significantly fewer CD68+ cells in the contusion with MSC-NHC and NHC, but not MSC-PBS. The reduction in CD86+ cells in the injury site with MSC-NHC was mainly attributed to NHC. One and eight weeks after injury, we found a greater CD206+/CD86+ cell ratio with MSC-NHC or NHC, but not MSC-PBS, indicating a shift from a pro-inflammatory towards an anti-inflammatory milieu in the injury site. Eight weeks after injury, the injury size was significantly reduced with MSC-NHC, NHC, and MSC-PBS. At this time, astrocyte, and axon presence in the injury site was greater with MSC-NHC compared with MSC-PBS. We did not find a significant effect of NHC on MSC transplant survival, and hind limb function was similar across all groups. However, we did find fewer macrophages at 1 week post-injury, more macrophages polarized towards a pro-regenerative phenotype at 1 and 8 weeks after injury, and reduced injury volume, more astrocytes, and more axons at 8 weeks after injury in rats with MSC-NHC and NHC alone compared with MSC-PBS; these findings were especially significant between rats with MSC-NHC and MSC-PBS. The data support further study in the use of an NHC-MSC combination transplant in the contused spinal cord.

The Effect of Inflammatory Priming on the Therapeutic Potential of Mesenchymal Stromal Cells for Spinal Cord Repair.

Mesenchymal stromal cells (MSC) are used for cell therapy for spinal cord injury (SCI) because of their ability to support tissue repair by paracrine signaling. Preclinical and clinical research testing MSC transplants for SCI have revealed limited success, which warrants the exploration of strategies to improve their therapeutic efficacy. MSC are sensitive to the microenvironment and their secretome can be altered in vitro by exposure to different culture media. Priming MSC with inflammatory stimuli increases the expression and secretion of reparative molecules. We studied the effect of macrophage-derived inflammation priming on MSC transplants and of primed MSC (pMSC) acute transplants (3 days) on spinal cord repair using an adult rat model of moderate-severe contusive SCI. We found a decrease in long-term survival of pMSC transplants compared with unprimed MSC transplants. With a pMSC transplant, we found significantly more anti-inflammatory macrophages in the contusion at 4 weeks post transplantation (wpt). Blood vessel presence and maturation in the contusion at 1 wpt was similar in rats that received pMSC or untreated MSC. Nervous tissue sparing and functional recovery were similar across groups. Our results indicate that macrophage-derived inflammation priming does not increase the overall therapeutic potential of an MSC transplant in the adult rat contused spinal cord.

Schwann cell delivery via a novel 3D collagen matrix conduit improves outcomes in critical length nerve gap repairs.

OBJECTIVE: The current clinical standard of harvesting a nerve autograft for repair of long-segment peripheral nerve injuries (PNIs) is associated with many potential complications. Guidance channels offer an alternative therapy. The authors investigate whether autologous Schwann cells (SCs) implanted within a novel collagen-glycosaminoglycan conduit will improve axonal regeneration in a long-segment PNI model. METHODS: Novel NeuraGen 3D collagen matrix conduits were implanted with autologous SCs to investigate axonal regeneration across a critical size defect (13 mm) in male Fischer rat sciatic nerve. Reversed sciatic nerve autografts served as positive controls, and conduits filled with serum only as negative controls. Electrophysiological assessments were made in vivo. Animals were killed at 4 or 16 weeks postinjury, muscle weights were measured, and grafts underwent immunohistochemical and morphometric analysis. RESULTS: SC survival was confirmed by the presence of green fluorescent protein-labeled SCs within regenerated fibers. Regeneration and elongation of myelinated axons in all segments of the graft were significantly enhanced at 16 weeks in the SC-filled conduits compared to the conduit alone and were statistically similar to those of the autograft. Nerves repaired with SC-filled conduits exhibited onset latencies and nerve conduction amplitudes similar to those of the contralateral controls and autograft (p < 0.05). Adding SCs to the conduit also significantly reduced muscle atrophy compared to conduit alone (p < 0.0001). CONCLUSIONS: Repair of long-segment PNI of rat sciatic nerve is significantly enhanced by SC-filled NeuraGen 3D conduits. Improvements in the total number of myelinated axons, axon diameter, and myelin thickness throughout SC-filled conduits allow for significant recovery in nerve conduction and a decrease in muscle atrophy.

Response to SSRI intervention and amygdala activity during self-referential processing in major depressive disorder.

There are conflicting reports on the impact of antidepressants on neural reactions for positive information. We thus hypothesized that there would be clinically important individual differences in neural reactivity to positive information during SSRI therapy. We further predicted that only those who responded to SSRIs would show increased amygdala reactivity to positive information following treatment to a level similar to that seen in healthy participants. Depressed individuals (n = 17) underwent fMRI during performance of a task involving rating the self-relevance of emotionally positive and negative cue words before and after receiving 12 weeks of SSRI therapy. At post-treatment, SSRI responders (n = 11) had increased amygdala activity in response to positive stimuli, and decreased activity in response to negative stimuli, compared to non-responders (n = 6). Results suggest that normalizing amygdala responses to salient information is a correlate of SSRI efficacy. Second line interventions that modulate amygdala activity, such as fMRI neurofeedback, may be beneficial in those who do not respond to SSRI medications.

Aligned Fingolimod-Releasing Electrospun Fibers Increase Dorsal Root Ganglia Neurite Extension and Decrease Schwann Cell Expression of Promyelinating Factors.

Researchers are investigating the use of biomaterials with aligned guidance cues, like those provided by aligned electrospun fibers, to facilitate axonal growth across critical-length peripheral nerve defects. To enhance the regenerative outcomes further, these aligned fibers can be designed to provide local, sustained release of therapeutics. The drug fingolimod improved peripheral nerve regeneration in preclinical rodent models by stimulating a pro-regenerative Schwann cell phenotype and axonal growth. However, the systemic delivery of fingolimod for nerve repair can lead to adverse effects, so it is necessary to develop a means of providing sustained delivery of fingolimod local to the injury. Here we created aligned fingolimod-releasing electrospun fibers that provide directional guidance cues in combination with the local, sustained release of fingolimod to enhance neurite outgrowth and stimulate a pro-regenerative Schwann cell phenotype. Electrospun fiber scaffolds were created by blending fingolimod into poly(lactic-co-glycolic acid) (PLGA) at a w/w% (drug/polymer) of 0.0004, 0.02, or 0.04%. We examined the effectiveness of these scaffolds to stimulate neurite extension in vitro by measuring neurite outgrowth from whole and dissociated dorsal root ganglia (DRG). Subsequently, we characterized Schwann cell migration and gene expression in vitro. The results show that drug-loaded PLGA fibers released fingolimod for 28 days, which is the longest reported release of fingolimod from electrospun fibers. Furthermore, the 0.02% fingolimod-loaded fibers enhanced neurite outgrowth from whole and dissociated DRG neurons, increased Schwann cell migration, and reduced the Schwann cell expression of promyelinating factors. The in vitro findings show the potential of the aligned fingolimod-releasing electrospun fibers to enhance peripheral nerve regeneration and serve as a basis for future in vivo studies.

The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord.

An injury to the spinal cord causes long-lasting loss of nervous tissue because endogenous nervous tissue repair and regeneration at the site of injury is limited. We engineered an injectable nanofiber-hydrogel composite (NHC) with interfacial bonding to provide mechanical strength and porosity and examined its effect on repair and neural tissue regeneration in an adult rat model of spinal cord contusion. At 28 days after treatment with NHC, the width of the contused spinal cord segment was 2-fold larger than in controls. With NHC treatment, tissue in the injury had a 2-fold higher M2/M1 macrophage ratio, 5-fold higher blood vessel density, 2.6-fold higher immature neuron presence, 2.4-fold higher axon density, and a similar glial scar presence compared with controls. Spared nervous tissue volume in the contused segment and hind limb function was similar between groups. Our findings indicated that NHC provided mechanical support to the contused spinal cord and supported pro-regenerative macrophage polarization, angiogenesis, axon growth, and neurogenesis in the injured tissue without any exogenous factors or cells. These results motivate further optimization of the NHC and delivery protocol to fully translate the potential of the unique properties of the NHC for treating spinal cord injury.

Laminin polymer treatment accelerates repair of the crushed peripheral nerve in adult rats.

Promoting axon growth after peripheral nerve injury may support recovery. Soluble laminin polymers formed at pH 4 (aLam) accelerate axon growth from adult dorsal root ganglion neurons in vitro. We used an adult rat model of a peripheral (peroneal) nerve crush to investigate whether an injection of aLam enhances axon growth and functional recovery in vivo. Rats that received an injection of aLam into the crush at 2 days post-injury show significant improvements in hind limb motor function at 2 and 5 weeks after injury compared with control rats that received phosphate-buffered saline. Functional improvement was not associated with changes in sensitivity to thermal or mechanical stimuli. Treatment with aLam decreased the occurrence of autophagia and abolished non-compliance with treadmill walking. Rats treated with aLam showed increased axon presence in the crush site at 2 weeks post-injury and larger axon diameter at 10 weeks post-injury compared with controls. Treatment with aLam did not affect Schwann cell presence or axon myelination. Our results demonstrated that aLam accelerates axon growth and maturity in a crushed peroneal nerve associated with expedited hind limb motor function recovery. Our data support the therapeutic potential of injectable aLam polymers for treatment of peripheral nerve crush injuries. STATEMENT OF SIGNIFICANCE: Incidence of peripheral nerve injury has been estimated to be as high as 5% of all cases entering a Level 1 trauma center and the majority of cases are young males. Peripheral nerves have some endogenous repair capabilities, but overall recovery of function remains limited, which typically has devastating effects on the individual, family, and society, as wages are lost and rehabilitation is extended until the nerves can repair. We report here that laminin polymers injected into a crush accelerated repair and recovery, had no adverse effects on sensory function, obliterated non-compliance for walking tests, and decreased the occurrence of autophagia. These data support the use of laminin polymers for safe and effective recovery after peripheral nerve injury.

Validation study of neurotrophin-3-releasing chitosan facilitation of neural tissue generation in the severely injured adult rat spinal cord.

It was previously reported that a tube holding chitosan carriers loaded with neurotrophin-3 (NT-3), after insertion into a 5 mm long transection gap in the adult rat spinal cord, triggered de novo neural tissue generation and functional recovery. Here, we report an effort to validate these findings using stringent blinding methodologies, which are crucial for robustness in reproducing biomedical studies. Radio frequency identification (RFID) chips were utilized to label rats that were randomly assigned into three experimental groups: transection with chitosan-NT-3 implant (C-NT3), transection only (T-controls), and laminectomy only (S-controls), blinding the experimenters to the treatments. Three months after surgery, animals only known by their RFID were functionally, electrophysiologically, and anatomically assessed. The data were then collected into the proper groups and statistically analyzed. Neural tissue with nestin-, Tuj1-, and NeuN-positive cells was found bridging the transection gap in C-NT3 rats, but not in T-controls. Motor- and somatosensory-evoked potentials were detected in C-NT3 rats and S-controls, but not in T-controls. Hind limb movement was significantly better in C-NT3 rats compared with T-controls. Our validation study indicates that C-NT3 implants facilitate neural tissue generation, at least in part, by eliciting endogenous neurogenesis. Our data support the use of C-NT3 implants for tissue remodeling in the injured spinal cord.

Biomaterials for revascularization and immunomodulation after spinal cord injury.

Spinal cord injury (SCI) causes immediate damage to the nervous tissue accompanied by loss of motor and sensory function. The limited self-repair competence of injured nervous tissue underscores the need for reparative interventions to recover function after SCI. The vasculature of the spinal cord plays a crucial role in SCI and repair. Ruptured and sheared blood vessels in the injury epicenter and blood vessels with a breached blood-spinal cord barrier (BSCB) in the surrounding tissue cause bleeding and inflammation, which contribute to the overall tissue damage. The insufficient formation of new functional vasculature in and near the injury impedes endogenous tissue repair and limits the prospect of repair approaches. Limiting the loss of blood vessels, stabilizing the BSCB, and promoting the formation of new blood vessels are therapeutic targets for spinal cord repair. Inflammation is an integral part of injury-mediated vascular damage, which has deleterious and reparative consequences. Inflammation and the formation of new blood vessels are intricately interwoven. Biomaterials can be effectively used for promoting and guiding blood vessel formation or modulating the inflammatory response after SCI, thereby governing the extent of damage and the success of reparative interventions. This review deals with the vasculature after SCI, the reciprocal interactions between inflammation and blood vessel formation, and the potential of biomaterials to support revascularization and immunomodulation in damaged spinal cord nervous tissue.

Soluble laminin polymers enhance axon growth of primary neurons in vitro.

A substrate of laminin polymers formed at pH 4 (acidic pH-induced laminin; aLam) promotes neurite growth of embryonic rat cortical neurons better than a substrate of similar but structurally different laminin polymers formed at neutral pH (neutral pH-induced laminin; nLam). We investigated the effects of these laminin polymers, used as soluble supplements, on neurite growth of cultured adult rat primary dorsal root ganglion neurons. When added to the culture medium, aLam was found to promote neurite growth about twofold better than nLam. Immunoblocking experiments revealed that aLam elicited neurite growth to a similar extent through the α1 or α3 integrin subunit, while nLam required the availability of the α1 integrin subunit to elicit neurite growth. With aLam, but not nLam, immunoblocking of the α1 or α3 subunit resulted in an increase in the protein level of the alternative subunit. The presence of a mature focal adhesion complex, which is associated with neurite growth, was elevated in neurons in the presence of aLam relative to nLam or culture medium. Our data indicated that the two types of laminin polymers promote neurite growth of adult rat primary sensory neurons to a different degree, likely through different ligand-receptor interactions. These findings support the potential of soluble laminin polymers as injectable therapeutics for eliciting axon growth after nervous system injury. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2372-2381, 2018.

Extracellular matrix components as therapeutics for spinal cord injury.

There is no treatment for people with spinal cord injury that leads to significant functional improvements. The extracellular matrix is an intricate, 3-dimensional, structural framework that defines the environment for cells in the central nervous system. The components of extracellular matrix have signaling and regulatory roles in the fate and function of neuronal and non-neuronal cells in the central nervous system. This review discusses the therapeutic potential of extracellular matrix components for spinal cord repair.

Biomaterials for spinal cord repair.

Spinal cord injury (SCI) results in permanent loss of function leading to often devastating personal, economic and social problems. A contributing factor to the permanence of SCI is that damaged axons do not regenerate, which prevents the re-establishment of axonal circuits involved in function. Many groups are working to develop treatments that address the lack of axon regeneration after SCI. The emergence of biomaterials for regeneration and increased collaboration between engineers, basic and translational scientists, and clinicians hold promise for the development of effective therapies for SCI. A plethora of biomaterials is available and has been tested in various models of SCI. Considering the clinical relevance of contusion injuries, we primarily focus on polymers that meet the specific criteria for addressing this type of injury. Biomaterials may provide structural support and/or serve as a delivery vehicle for factors to arrest growth inhibition and promote axonal growth. Designing materials to address the specific needs of the damaged central nervous system is crucial and possible with current technology. Here, we review the most prominent materials, their optimal characteristics, and their potential roles in repairing and regenerating damaged axons following SCi.