Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD

Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5mg/kg) or water vehicle provided Monday-Friday from postnatal days 28-55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability.P50 DA005312 - NIDA NIH HHS; R01 DA011716 - NIDA NIH HHS; P50 DA05312 - NIDA NIH HH

Immediate Adaptations to Post-Stroke Walking Performance Using a Wearable Robotic Exoskeleton

Objective To examine the immediate effects of a hip-assistive wearable robotic exoskeleton on clinical walking performance, walking energetics, gait kinematics, and corticomotor excitability in individuals with stroke. Design Randomized cross-over trial. Setting Research laboratory of a rehabilitation hospital. Participants Twelve individuals (4F/8M, mean age 57.8±7.2) with chronic hemiparetic stroke. Interventions Honda’s Stride Management Assist (SMA) exoskeleton, which provides torque-based flexion and extension assistance at the hip joints during walking. Main Outcome Measures The primary outcome measure was change in self-selected walking speed with the device off vs. with the device on. Secondary outcome measures included changes in clinical endurance, energy expenditure, kinematics, and corticomotor excitability of lower limb muscles. Results In a single session using the device, participants exhibited adaptations over most outcome measures. Self-selected walking speed and peak treadmill speed increased, while oxygen consumption rate decreased during overground and treadmill endurance tests. More symmetric walking patterns were observed during treadmill walking. Changes in corticomotor excitability were highly variable among participants, with a non-significant increase in excitability for the paretic rectus femoris. Conclusions The SMA hip exoskeleton causes immediate positive adaptations in walking performance in individuals with stroke when the device is in use

PLATELET FUNCTION ASSESSMENT IN A MICROFABRICATED DEVICE

Introduction Although platelets are small and simple in shape, they are complicated in their physiologhy. Their alpha granules and dense bodies secrete a large number of agents that are involved in haemostasis, and the glycoproteins on thei r surfaces form the linkages with proteins like fibrinogen, fibronectin, collagen and von Willebrand factor that are necessary for adhesion and aggregation A simple way to test platelet function is to immobilize substrates on a flow channel, induce flow over the substrate, and measure the percentage of surface covered by platelet adhesion. The use of several substrates can allow the assessment of a variety of platelet functions. A practical platelet analyzer should 1) be capable of distinguishing multiple aspects of platelet behavior, 2) require a small amount of blood, 3) examine platelet function under shear flow conditions, 4) be relatively simple to use, and 5) be relatively easy to manufacture. Modern micromanufacturing methods are readily available for the construction of the microchannels that can be filled with volumes of blood on the order of ?L. However, a technique is still needed to coat these channels with the appropriate protein substrates. Recently, a process called layer-by-layer assembly (Lvov et al., 2000) has been developed that allows well-controlled protein coatings to be adsorbed onto charged surfaces. The process takes advantage of the charge already on the surface to lay down, in alternating layers, positively and negatively charged ions. The combination of layer-bylayer assembly and micromanufacturing can thus form a basis for the device being sought. Key questions to be answered are whether it is possible to assemble the needed substrates and whether the platelet adhesion patterns behave as expected. For example, the amount of adhesion should be dependent on the substrate and the fluid shear stress. Because fibrinogen is a key protein in both platelet adhesion and platelet aggregation, this was selected as the first protein to be examined. Methods The microchannels were first created as ridges on a silicon wafer. The photopolymer SU-8 was spun onto the wafer and exposed through a mask under ultraviolet light to allow the polymer to cure. Afterwards, the wafer was deve loped in SU-8 developer, leaving SU-8 ridges only where the surface was exposed to light. The cured wafer was then used as a mold for polydimethylsiloxane (PDMS), an optically clear polymer that cures at room temperature in three days. The raised portions on the silicon then become microchannels in the PDMS. The PDMS microchannels were coated by the layer-by-layer selfassembly technique to provide controlled nanometer-thick layers of fibrinogen. A plexiglass plate was created to cover the channels, and inlet and outlet ports were incorporated into the cover to allow the injection of blood. A syringe injector (Cole Parmer) was used to inject platelet rich plasma at a controlled flow rate. Anticoagulated platelet rich plasma labeled with both acridine orange and a fluorescin isothiocynate-tagged anti-GpIIb/IIIa-antibody was passed through the microchannels. Several experimental runs for different shear rates were carried out. To estimate shear, Couette flow was assumed in the microchannels. Control experiments were performed on bare PDMS surfaces. Images were recorded with a fluorescent microscope. For each image, background subtraction was applied, followed by a thresholding technique to distinguish dark areas (platelets) from light areas (substrate with no adhesion). From these steps, the extent o

Coordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of THVTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of THVTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input

Activation of Prefrontal Cortical Parvalbumin Interneurons Facilitates Extinction of Reward-Seeking Behavior

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility

Sequence Specific Motor Performance Gains after Memory Consolidation in Children and Adolescents

Memory consolidation for a trained sequence of finger opposition movements, in 9- and 12-year-old children, was recently found to be significantly less susceptible to interference by a subsequent training experience, compared to that of 17-year-olds. It was suggested that, in children, the experience of training on any sequence of finger movements may affect the performance of the sequence elements, component movements, rather than the sequence as a unit; the latter has been implicated in the learning of the task by adults. This hypothesis implied a possible childhood advantage in the ability to transfer the gains from a trained to the reversed, untrained, sequence of movements. Here we report the results of transfer tests undertaken to test this proposal in 9-, 12-, and 17-year-olds after training in the finger-to-thumb opposition sequence (FOS) learning task. Our results show that the performance gains in the trained sequence partially transferred from the left, trained hand, to the untrained hand at 48-hours after a single training session in the three age-groups tested. However, there was very little transfer of the gains from the trained to the untrained, reversed, sequence performed by either hand. The results indicate sequence specific post-training gains in FOS performance, as opposed to a general improvement in performance of the individual, component, movements that comprised both the trained and untrained sequences. These results do not support the proposal that the reduced susceptibility to interference, in children before adolescence, reflects a difference in movement syntax representation after training

Solid stress facilitates spheroid formation: potential involvement of hyaluronan

When neoplastic cells grow in confined spaces in vivo, they exert a finite force on the surrounding tissue resulting in the generation of solid stress. By growing multicellular spheroids in agarose gels of defined mechanical properties, we have recently shown that solid stress inhibits the growth of spheroids and that this growth-inhibiting stress ranges from 45 to 120 mmHg. Here we show that solid stress facilitates the formation of spheroids in the highly metastatic Dunning R3327 rat prostate carcinoma AT3.1 cells, which predominantly do not grow as spheroids in free suspension. The maximum size and the growth rate of the resulting spheroids decreased with increasing stress. Relieving solid stress by enzymatic digestion of gels resulted in gradual loss of spheroidal morphology in 8 days. In contrast, the low metastatic variant AT2.1 cells, which grow as spheroids in free suspension as well as in the gels, maintained their spheroidal morphology even after stress removal. Histological examination revealed that most cells in AT2.1 spheroids are in close apposition whereas a regular matrix separates the cells in the AT3.1 gel spheroids. Staining with the hyaluronan binding protein revealed that the matrix between AT3.1 cells in agarose contained hyaluronan, while AT3.1 cells had negligible or no hyaluronan when grown in free suspension. Hyaluronan was found to be present in both free suspensions and agarose gel spheroids of AT2.1. We suggest that cell–cell adhesion may be adequate for spheroid formation, whereas solid stress may be required to form spheroids when cell–matrix adhesion is predominant. These findings have significant implications for tumour growth, invasion and metastasis

Parallel Alterations of Functional Connectivity during Execution and Imagination after Motor Imagery Learning

BACKGROUND: Neural substrates underlying motor learning have been widely investigated with neuroimaging technologies. Investigations have illustrated the critical regions of motor learning and further revealed parallel alterations of functional activation during imagination and execution after learning. However, little is known about the functional connectivity associated with motor learning, especially motor imagery learning, although benefits from functional connectivity analysis attract more attention to the related explorations. We explored whether motor imagery (MI) and motor execution (ME) shared parallel alterations of functional connectivity after MI learning. METHODOLOGY/PRINCIPAL FINDINGS: Graph theory analysis, which is widely used in functional connectivity exploration, was performed on the functional magnetic resonance imaging (fMRI) data of MI and ME tasks before and after 14 days of consecutive MI learning. The control group had no learning. Two measures, connectivity degree and interregional connectivity, were calculated and further assessed at a statistical level. Two interesting results were obtained: (1) The connectivity degree of the right posterior parietal lobe decreased in both MI and ME tasks after MI learning in the experimental group; (2) The parallel alterations of interregional connectivity related to the right posterior parietal lobe occurred in the supplementary motor area for both tasks. CONCLUSIONS/SIGNIFICANCE: These computational results may provide the following insights: (1) The establishment of motor schema through MI learning may induce the significant decrease of connectivity degree in the posterior parietal lobe; (2) The decreased interregional connectivity between the supplementary motor area and the right posterior parietal lobe in post-test implicates the dissociation between motor learning and task performing. These findings and explanations further revealed the neural substrates underpinning MI learning and supported that the potential value of MI learning in motor function rehabilitation and motor skill learning deserves more attention and further investigation