Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.

Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders.

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat.

Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI.

Axonal regeneration of different tracts following transplants of human glial restricted progenitors into the injured spinal cord in rats.

The goal of this study was to compare the efficacy of human glial restricted progenitors (hGRPs) in promoting axonal growth of different tracts. We examined the potential of hGRPs grafted into a cervical (C4) dorsal column lesion to test sensory axons, and into a C4 hemisection to test motor tracts. The hGRPs, thawed from frozen stocks, were suspended in a PureCol matrix and grafted acutely into a C4 dorsal column or hemisection lesion.

Therapy induces widespread reorganization of motor cortex after complete spinal transection that supports motor recovery.

Reorganization of the somatosensory system and its relationship to functional recovery after spinal cord injury (SCI) has been well studied. However, little is known about the impact of SCI on organization of the motor system. Recent studies suggest that step-training paradigms in combination with spinal stimulation, either electrically or through pharmacology, are more effective than step training alone at inducing recovery and that reorganization of descending corticospinal circuits is necessary.

Attention enhancing effects of methylphenidate are age-dependent.

The psychostimulant methylphenidate (MPH, Ritalin®) is used to treat a variety of cognitive disorders. MPH is also popular among healthy individuals, including the elderly, for its ability to focus attention and improve concentration, but these effects have not been shown to be comparable between aged and adult subjects. Thus, we tested whether MPH would improve performance in sustained attention in both adult and aged rats.

A combination therapy of neural and glial restricted precursor cells and chronic quipazine treatment paired with passive cycling promotes quipazine-induced stepping in adult spinalized rats.

Introduction: In order to develop optimal treatments to promote recovery from complete spinal cord injury (SCI), we examined the combination of: (1) a cellular graft of neural and glial restricted precursor (NRP/GRP) cells, (2) passive exercise, and (3) chronic quipazine treatment on behavioral outcomes and compared them with the individual treatment elements. NRP/GRP cells were transplanted at the time of spinalization.

Methods: Daily passive exercise began 1 week after injury to give sufficient time for the animals to recover.

Forelimb locomotor rating scale for behavioral assessment of recovery after unilateral cervical spinal cord injury in rats.

Background: Cervical spinal cord injury (SCI) models in rats have become increasingly useful because of their translational potential. The goal of this study was to design, develop and validate a quick and reliable forelimb locomotor rating scale for adult rats with unilateral cervical SCI injury.

New Method: Adult female rats were subjected to a C5 unilateral mild contusion (n=10), moderate contusion (n=10) or hemisection injury (n=9).

Implications of poly(N-isopropylacrylamide)-g-poly(ethylene glycol) with codissolved brain-derived neurotrophic factor injectable scaffold on motor function recovery rate following cervical dorsolateral funiculotomy in the rat.

Object: In a follow-up study to their prior work, the authors evaluated a novel delivery system for a previously established treatment for spinal cord injury (SCI), based on a poly(N-isopropylacrylamide) (PNIPAAm), lightly cross-linked with a polyethylene glycol (PEG) injectable scaffold. The primary aim of this work was to assess the recovery of both spontaneous and skilled forelimb function following a cervical dorsolateral funiculotomy in the rat. This injury ablates the rubrospinal tract (RST) but spares the dorsal and ventral corticospinal tract and can severely impair reaching and grasping abilities.

Serotonergic pharmacotherapy promotes cortical reorganization after spinal cord injury.

Cortical reorganization plays a significant role in recovery of function after injury of the central nervous system. The neural mechanisms that underlie this reorganization may be the same as those normally responsible for skilled behaviors that accompany extended sensory experience and, if better understood, could provide a basis for further promoting recovery of function after injury. The work presented here extends studies of spontaneous cortical reorganization after spinal cord injury to the role of rehabilitative strategies on cortical reorganization.

Role of cortical reorganization on the effect of 5-HT pharmacotherapy for spinal cord injury.

Cortical reorganization or expansion of the intact cortical regions into the deafferented cortex after complete spinal transection in neonatally spinalized rats was shown to be essential for increases in weight-supported stepping at adulthood. The novel somatotopic organization identified in these animals can be induced by exercise or spinal transplants that bridge the site of injury. However, the role of cortical reorganization in increased weight-supported (WS) stepping after pharmacotherapy is unknown.

Skilled hindlimb reaching task in rats as a platform for a brain-machine interface to restore motor function after complete spinal cord injury.

Behavioral tasks utilized as models for decoding neural activity for use in brain-machine interfaces are constrained primarily to forelimb tasks or locomotion. We present here our methodology for training adult rats in a novel skilled hindlimb 'reaching' task in which the animal is trained to make different types of hindlimb movements. 6 adult Long-Evans rats were trained to make variable duration (<1 or >1.

Experimental strategies for investigating psychostimulant drug actions and prefrontal cortical function in ADHD and related attention disorders.

Amphetamine-like psychostimulant drugs have been used for decades to treat a variety of clinical conditions. Methylphenidate (MPH)-Ritalin(R) , a compound that blocks reuptake of synaptically released norepinephrine (NE) and dopamine (DA) in the brain, has been used for more than 30 years in low dose, long-term regimens to treat attention deficit-hyperactive disorder (ADHD) in juveniles, adolescents, and adults. Now, these agents are also becoming increasingly popular among healthy individuals from all walks of life (e.

Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors.

Background: Psychostimulants improve a variety of cognitive and behavioral processes in patients with attention-deficit/hyperactivity disorder (ADHD). Limited observations suggest a potentially different dose-sensitivity of prefrontal cortex (PFC)-dependent function (narrow inverted-U-shaped dose-response curves) versus classroom/overt behavior (broad inverted U) in children with ADHD. Recent work in rodents demonstrates that methylphenidate (MPH; Ritalin) elicits a narrow inverted-U-shaped improvement in performance in PFC-dependent tests of working memory.

Amphetamine-enhanced motor training after cervical contusion injury.

Individually, motor training, pharmacological interventions, and housing animals in an enriched environment (EE) following spinal cord injury (SCI) result in limited functional improvement but, when combined, may enhance motor function. Here, we tested amphetamine (AMPH)-enhanced skilled motor training following a unilateral C3-C4 contusion injury on the qualitative components of reaching and on skilled forelimb function, as assessed using single-pellet and staircase reaching tasks. Kinematic analysis evaluated the quality of the reach, and unskilled locomotor function was also tested.

Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.

Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration.

PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury.

Secondary degeneration leads to an expansion of the initial tissue damage sustained during a spinal cord injury (SCI). Dampening the cellular inflammatory response that contributes to this progressive tissue damage is one possible strategy for neuroprotection after acute SCI. We initially examined whether treatment with a PEGylated form of rat interferon-beta (IFN-beta) would modulate the expression of several markers of inflammation and neuroprotection at the site of a unilateral cervical level 5 contusion injury.

Exercise induces cortical plasticity after neonatal spinal cord injury in the rat.

Exercise-induced cortical plasticity is associated with improved functional outcome after brain or nerve injury. Exercise also improves functional outcomes after spinal cord injury, but its effects on cortical plasticity are not known. The goal of this investigation was to study the effect of moderate exercise (treadmill locomotion, 3 min/d, 5 d/week) on the somatotopic organization of forelimb and hindlimb somatosensory cortex (SI) after neonatal thoracic transection.

Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury.

Evaluation of locomotor training after spinal cord injury (SCI) has primarily focused on hind limb recovery, with evidence of functional and molecular changes in response to exercise. Since trauma at a cervical (C) level is common in human SCI, we used a unilateral C4 contusion injury model in rats to determine whether forced exercise (Ex) would affect spinal cord biochemistry, anatomy, and recovery of fore and hind limb function. SCI was created with the Infinite Horizon spinal cord impactor device at C4 with a force of 200 Kdyne and a mean displacement of 1600-1800 microm in adult female Sprague-Dawley rats that had been acclimated to a motorized exercise wheel apparatus.

Stem cell delivery by lumbar puncture as a therapeutic alternative to direct injection into injured spinal cord.

Object: Using cellular transplants to treat spinal cord injury is a promising therapeutic strategy, but transplants grafted directly into the injury site can further damage the already compromised cord. To avoid additional trauma and to simplify translation to the clinic, it is advantageous to use less invasive delivery methods.

Methods: The authors compared the efficacy of intrathecal cell delivery at the lumbar region (lumbar puncture [LP]) to direct injection into a thoracic contusion injury using a mixed population of lineage-restricted neural precursor cells.

Effect of cervical dorsolateral funiculotomy on reach-to-grasp function in the rat.

Cervical spinal cord injury (SCI) can severely impair reaching and grasping ability, and several descending systems, including the rubrospinal tract and corticospinal tract, have been implicated in the control of reach-to-grasp movements. The primary aim of this study was to characterize further the forelimb deficits associated with a cervical dorsolateral funiculotomy, which ablates the rubrospinal tract but spares the dorsal and ventral corticospinal tract in the rat. Adult female rats that preferred to use their right forelimb to reach for single pellets received a lesion to the right cervical dorsolateral funiculus between the C3-4 dorsal roots.

Aspiration of a cervical spinal contusion injury in preparation for delayed peripheral nerve grafting does not impair forelimb behavior or axon regeneration.

A peripheral nerve graft model was used to examine axonal growth after a unilateral cervical (C) contusion injury in adult rats and to determine if manipulation of an injury site prior to transplantation affects spontaneous behavioral recovery. After a short delay (7 d) the epicenter of a C4 contusion was exposed and aspirated without harming the cavity walls followed by apposition with one end of a pre-degenerated tibial nerve to the rostral cavity wall. After a longer delay (28 d) the aspirated cavity was treated with GDNF to promote regeneration by chronically injured neurons.

Combining motor training with transplantation of rat bone marrow stromal cells does not improve repair or recovery in rats with thoracic contusion injuries.

Previous studies have demonstrated that either transplantation of bone marrow stromal cells (MSC) or physical exercise regimens can elicit limited functional recovery following spinal cord injury, presumably through different mechanisms. The present study examined whether transplantation of MSC derived from transgenic Fischer alkaline phosphatase (AP) rats, in combination with exercise, would have synergistic effects leading to recovery of function that is greater than either alone. Adult female Sprague-Dawley rats received a moderate thoracic contusion injury and were divided into three groups: operated controls (Op-Control), MSC transplant recipients (MSC), and MSC transplant recipients plus exercise (MSC+Ex).

Role of the 5-HT2C receptor in improving weight-supported stepping in adult rats spinalized as neonates.

Loss of descending serotonergic (5-HT) projections after spinal cord injury (SCI) contributes to motor deficits and upregulation of receptors on partially denervated serotonergic targets in the spinal cord. Serotonergic agonists acting on these upregulated receptors are potential therapeutic agents that could ameliorate motor deficits. However, modification of 5-HT receptors following complete spinal cord injury results in different effects by 5-HT2C receptor agonists and antagonists.

Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord.

This study evaluates functional recovery after transplanting human bone marrow-derived stromal cells (BMSCs) into contusion models of spinal cord injury (SCI). The authors used a high-throughput process to expand BMSCs and characterized them by flow cytometry, ELISA, and gene expression. They found that BMSCs secrete neurotrophic factors and cytokines with therapeutic potential for cell survival and axon growth.

Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation.

Cell transplantation as a treatment for spinal cord injury is a promising therapeutic strategy whose effective clinical application would be facilitated by non-invasive delivery protocols. Cells derived from the bone marrow are particularly attractive because they can be obtained easily, expanded to large numbers and potentially used for autologous as well as allogeneic transplantation. In this study we tested the feasibility of a novel minimally invasive method--lumbar puncture (LP)--for transplanting bone marrow stromal stem cells (MSC) into a clinically relevant spinal cord contusion model.