Alzheimer's disease ͉ hippocampus ͉ spatial memory

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain. Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Acupuncture and electro-acupuncture (EA) are now widely used to treat disorders like pain. We and others have shown previously that current frequency, intensity and treatment duration all significantly influence the anti-nociceptive effects of EA. There is evidence that stimulating sites also affect the antinociception, with EA applied ipsilaterally to the pain site being more effective under some pain states but contralateral EA under others. It was recently reported that local adenosine A1 receptors were responsible for ipsilateral acupuncture, but what mechanisms specifically mediate the anti-nociceptive effects of contralateral acupuncture or EA remains unclear. In the present study, we applied 100 Hz EA on the ipsi- or contra-lateral side of rats with inflammatory pain induced by intra-plantar injection of formalin, and reported distinct anti-nociceptive effects and mechanisms between them. Both ipsi- and contra-lateral EA reduced the paw lifting time in the second phase of the formalin test and attenuated formalin-induced conditioned place aversion. Contralateral EA had an additional effect of reducing paw licking time, suggesting a supraspinal mechanism. Lesions of rostral anterior cingulate cortex (ACC) completely abolished the anti-nociceptive effects of contra- but not ipsi-lateral EA. These findings were not lateralized effects, since injection of formalin into the left or right hind paws produced similar results. Overall, these results demonstrated distinct anti-nociceptive effects and mechanisms between different stimulating sides and implied the necessity of finding the best stimulating protocols for different pain states.

Supplemental Digital Content is Available in the Text.We comprehensively characterized the physiological properties of pain-related brain oscillations in freely moving rats and provided a foundation for the animal-to-human translation of experimental findings.

We have observed a ‘heat-sensitisation’ phenomenon in a large proportion of patients receiving suspended moxibustion treatment. Patients become thermally sensitised to moxibustion stimulation at certain locations on the body, indicated by sensations of strong warmth or heat penetrating into the body (heat penetration), warmth spreading around the stimulation site (heat expansion), warmth conducting in certain directions and reaching some body regions or even internal organs remote from stimulation sites (heat transmission), or other non-thermal sensations such as aching, heaviness, pressure etc. These heat-sensitised locations are not fixed, but may, during the progression of disease, dynamically change within a certain range centred on acupuncture points. Each condition seems to have its specific set of such sensitised acupuncture points and such phenomena are not commonly observed in other body regions or in healthy subjects. A number of clinical trials have shown that the appearance of heat sensitisation is correlated with better therapeutic effects in various diseases, indicating the clinical significance of such responses. Further investigation is required to elucidate the epidemiological characteristics and biological mechanisms of the heat sensitisation in suspended moxibustion.

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. However, how intrinsic excitability is regulated is still not fully understood. Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL exhibit higher neuronal threshold and are less prone to epileptogenesis. Finally, examination of human brain tissues reveals decreased CDYL and increased SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience-dependent gene regulation in controlling intrinsic excitability.

Objective To explore the effects of contralateral manual acupuncture (MA) on patients with chronic shoulder pain. Methods Eighty patients with chronic shoulder pain were randomly allocated to receive contralateral MA (n=38) for 4 weeks or to remain on a waiting list while receiving conventional orthopaedic therapy (n=42). Visual analogue scale (VAS) scores were taken as the primary outcome measure and used for a priori power calculation. Secondary outcome measures for the assessment of shoulder mobility and quality of life included the Jobe test, the Constant-Murley (CM) score, the Disabilities of the Arm, Shoulder and Hand (DASH) score, and the 36 item Short Form Health Survey (SF-36). Results Intention-to-treat (ITT) analysis demonstrated significant pain relief with contralateral acupuncture, with mean differences in VAS scores compared to the waiting list group of −19.4 (−28.0 to −10.8) at 2 weeks, −40.4 (−49.0 to −31.8) at 4 weeks, −41.1 (−49.7 to −32.5) at 8 weeks, and −40.9 (−49.5 to −32.3) at 16 weeks. CM and DASH scores were also improved at all time points (p<0.01). Shoulder mobility, physical functioning, social functioning and mental health components of the SF-36 were also improved by contralateral acupuncture at 8 weeks. No significant adverse effects were observed. Conclusions These results demonstrate beneficial effects of contralateral acupuncture in the treatment of chronic shoulder pain, both in terms of pain and function. Future research is required to compare directly the effects of local and contralateral acupuncture and to quantify the specific and non-specific effects. Trial Registration Number NCT01733914.

Proteins interact with each other to fulfill their functions. The importance of weak protein-protein interactions has been increasingly recognized. However, owing to technical difficulties, ultra-weak interactions remain to be characterized. Phosphorylation can take place via a K(D)≈25 mM interaction between two bacterial enzymes. Using paramagnetic NMR spectroscopy and with the introduction of a novel Gd(III)-based probe, we determined the structure of the resulting complex to atomic resolution. The structure accounts for the mechanism of phosphoryl transfer between the two enzymes and demonstrates the physical basis for their ultra-weak interaction. Further, molecular dynamics (MD) simulations suggest that the complex has a lifetime in the micro- to millisecond regimen. Hence such interaction is termed a fleeting interaction. From mathematical modeling, we propose that an ultra-weak fleeting interaction enables rapid flux of phosphoryl signal, providing a high effective protein concentration.