Effects of exercise and pharmacological inhibition of histone deacetylases (HDACs) on epigenetic regulations and gene expressions crucial for neuronal plasticity in the motor cortex.

The objective of this study was to examine the effect of epigenetic treatment using an histone deacetylases (HDAC) inhibitor in addition to aerobic exercise on the epigenetic markers and neurotrophic gene expressions in the motor cortex, to find a more enriched brain pre-conditioning for motor learning in neurorehabilitation. ICR mice were divided into four groups based on two factors: HDAC inhibition and exercise. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately at 10 m/min for 60 min) were conducted five days a week for four weeks. NaB administration inhibited total HDAC activity and enhanced acetylation level of histones specifically in histone H4, accompanying the increase of transcription levels of immediate-early genes (IEGs) (c-fos and Arc) and neurotrophins (BDNF and NT-4) crucial for neuroplasticity in the motor cortex. However, exercise enhanced HDAC activity and acetylation level of histone H4 and H3 without the modification of transcription levels. In addition, there were no synergic effects between HDAC inhibition and the exercise regime on the gene expressions. This study showed that HDAC inhibition could present more enriched condition for neuroplasticity to the motor cortex. However, exercise-induced neurotrophic gene expressions could depend on exercise regimen based on the intensity, the term etc. Therefore, this study has a novelty suggesting that pharmacological HDAC inhibition could be an alternative potent approach to present a neuronal platform with enriched neuroplasticity for motor learning and motor recovery, however, an appropriate exercise regimen is expected in this approach.

Learning effects of dynamic postural control by auditory biofeedback versus visual biofeedback training.

Augmented sensory biofeedback (BF) for postural control is widely used to improve postural stability. However, the effective sensory information in BF systems of motor learning for postural control is still unknown. The purpose of this study was to investigate the learning effects of visual versus auditory BF training in dynamic postural control. Eighteen healthy young adults were randomly divided into two groups (visual BF and auditory BF). In test sessions, participants were asked to bring the real-time center of pressure (COP) in line with a hidden target by body sway in the sagittal plane. The target moved in seven cycles of sine curves at 0.23Hz in the vertical direction on a monitor. In training sessions, the visual and auditory BF groups were required to change the magnitude of a visual circle and a sound, respectively, according to the distance between the COP and target in order to reach the target. The perceptual magnitudes of visual and auditory BF were equalized according to Stevens' power law. At the retention test, the auditory but not visual BF group demonstrated decreased postural performance errors in both the spatial and temporal parameters under the no-feedback condition. These findings suggest that visual BF increases the dependence on visual information to control postural performance, while auditory BF may enhance the integration of the proprioceptive sensory system, which contributes to motor learning without BF. These results suggest that auditory BF training improves motor learning of dynamic postural control.

Distinct sites regulating grayanotoxin binding and unbinding to D4S6 of Na(v)1.4 sodium channel as revealed by improved estimation of toxin sensitivity.

Grayanotoxin (GTX) exerts selective effects on voltage-dependent sodium channels by eliminating fast sodium inactivation and causing a hyperpolarizing shift in voltage dependence of channel activation. In this study, we adopted a newly developed protocol that provides independent estimates of the binding and unbinding rate constants of GTX (k(on) and k(off)) to GTX sites on the sodium channel protein, important in the molecular analysis of channel modification. Novel GTX sites were determined in D2S6 (Asn-784) and D3S6 (Ser-1276) by means of site-directed mutagenesis; the results suggested that the GTX receptor consists of the S6 transmembrane segments of four homologous domains facing the ion-conducting pore. We systematically introduced at two sites in D4S6 (Na(v)1.4-Phe-1579 and Na(v)1.4-Tyr-1586) amino acid substituents with residues containing hydrophobic, aromatic, charged, or polar groups. Generally, substitutions at Phe-1579 increased both k(on) and k(off), resulting in no prominent change in dissociation constant (K(d)). It seems that the smaller the molecular size of the residue at Na(v)1.4-Phe-1579, the larger the rates of k(on) and k(off), indicating that this site acts as a gate regulating access of toxin molecules to a receptor site. Substitutions at Tyr-1586 selectively increased k(off) but had virtually no effect on k(on), thus causing a drastic increase in K(d). At position Tyr-1586, a hydrophobic or aromatic amino acid side chain was required to maintain normal sensitivity to GTX. These results suggest that the residue at position Tyr-1586 has a more critical role in mediating GTX binding than the one at position Phe-1579. Here, we propose that the affinity of GTX to Na(v)1.4 sodium channels might be regulated by two residues (Phe and Tyr) at positions Phe-1579 and Tyr-1586, which, respectively, control access and binding of GTX to its receptor.