Rapid tolerance and locomotor sensitization in ethanol-naïve adolescent rhesus macaques

Background: Acute and chronic tolerance, as well as locomotor sensitization, have been linked to ethanol intake. This study examined the change in response between 2 acutely administered doses of ethanol in adolescent rhesus macaques, with the objective of investigating rapid tolerance and locomotor sensitization to the behavioral effects of ethanol, and whether these phenomena are related to voluntary ethanol consumption in nonhuman primates. Methods: Rhesus macaques (n = 109, 42 males, 67 females) were administered 2 sequential intravenous doses of ethanol (2.2 g/kg for males, 2.0 g/kg for females) separated by a period of 5 to 30 days. Following each injection, subjects underwent a 30‐minute behavior assessment. Behavioral data were summarized using factor analysis, and compared between the 2 doses using repeated measures ANOVA. The relationship between behavioral response measures and the number of days between doses was analyzed using regression analyses. Following the second ethanol dose, subjects were given free access to an aspartame‐sweetened 8.4% ethanol solution for 1 hour a day for 4 weeks. Percent change in behavioral response measures from dose 1 to dose 2 was analyzed for associations with ethanol consumption using multiple regression analyses. Results: Factor analysis yielded 3 factors: ataxia, stimulation, and jumping. From dose 1 to dose 2 there was a significant decrease in ataxia and a significant increase in stimulation. Peak blood ethanol concentration did not differ between doses. There were no significant associations between the number of days between doses and the magnitude of change in response for any of the behavioral measures. Percent change in stimulation from dose 1 to dose 2 was positively associated with subsequent oral ethanol consumption only in females tested in a social setting. Conclusions: Adolescent rhesus macaques develop rapid tolerance to the motor‐impairing effects of alcohol, while at the same time developing locomotor sensitization. These changes in response are not necessarily short lived, and may persist for some time following the first ethanol dose. Clear and consistent associations between rapid tolerance and locomotor sensitization and ethanol intake levels have yet to be demonstrated, however.     

Regenerative peripheral nerve interfaces for real-time,proportional control of a Neuroprosthetic hand

Introduction

Regenerative peripheral nerve interfaces (RPNIs) are biological constructs which amplify neural signals and have shown long-term stability in rat models. Real-time control of a neuroprosthesis in rat models has not yet been demonstrated. The purpose of this study was to: a) design and validate a system for translating electromyography (EMG) signals from an RPNI in a rat model into real-time control of a neuroprosthetic hand, and; b) use the system to demonstrate RPNI proportional neuroprosthesis control.

Methods

Animals were randomly assigned to three experimental groups: (1) Control; (2) Denervated, and; (3) RPNI. In the RPNI group, the extensor digitorum longus (EDL) muscle was dissected free, denervated, transferred to the lateral thigh and neurotized with the residual end of the transected common peroneal nerve. Rats received tactile stimuli to the hind-limb via monofilaments, and electrodes were used to record EMG. Signals were filtered, rectified and integrated using a moving sample window. Processed EMG signals (iEMG) from RPNIs were validated against Control and Denervated group outputs.

Results

Voluntary reflexive rat movements produced signaling that activated the prosthesis in both the Control and RPNI groups, but produced no activation in the Denervated group. Signal-to-Noise ratio between hind-limb movement and resting iEMG was 3.55 for Controls and 3.81 for RPNIs. Both Control and RPNI groups exhibited a logarithmic iEMG increase with increased monofilament pressure, allowing graded prosthetic hand speed control (R²?=?0.758 and R²?=?0.802, respectively).

Conclusion

EMG signals were successfully acquired from RPNIs and translated into real-time neuroprosthetic control. Signal contamination from muscles adjacent to the RPNI was minimal. RPNI constructs provided reliable proportional prosthetic hand control.

     

Deformation strain is the main physical driver for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation

Mesenchymal stem cells play a major role during bone remodelling and are thus of high interest for tissue engineering and regenerative medicine applications. Mechanical stimuli, that is, deformation strain and interstitial fluid‐flow‐induced shear stress, promote osteogenic lineage commitment. However, the predominant physical stimulus that drives early osteogenic cell maturation is not clearly identified. The evaluation of each stimulus is challenging, as deformation and fluid‐flow‐induced shear stress interdepend. In this study, we developed a bioreactor that was used to culture mesenchymal stem cells harbouring a strain‐responsive AP‐1 luciferase reporter construct, on porous scaffolds. In addition to the reporter, mineralization and vitality of the cells was investigated by alizarin red staining and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Quantification of the expression of genes associated to bone regeneration and bone remodelling was used to confirm alizarin red measurements. Controlled perfusion and deformation of the 3‐dimensional scaffold facilitated the alteration of the expression of osteogenic markers, luciferase activity, and calcification. To isolate the specific impact of scaffold deformation, a computational model was developed to derive a perfusion flow profile that results in dynamic shear stress conditions present in periodically loaded scaffolds. In comparison to actually deformed scaffolds, a lower expression of all measured readout parameters indicated that deformation strain is the predominant stimulus for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation.