Inhibiting neuronal AC1 for treating anxiety and headache in the animal model of migraine.

Migraines are a common medical condition. From a basic science point of view, the central mechanism for migraine and headache is largely unknown. In the present study, we demonstrate that cortical excitatory transmission is significantly enhanced in the anterior cingulate cortex (ACC)-a brain region which is critical for pain perception. Biochemical studies found that the phosphorylation levels of both the NMDA receptor GluN2B and AMPA receptor GluA1 were enhanced in ACC of migraine rats. Both the presynaptic release of glutamate and postsynaptic responses of AMPA receptors and NMDA receptors were enhanced. Synaptic long-term potentiation (LTP) was occluded. Furthermore, behavioral anxiety and nociceptive responses were increased, which were reversed by application of AC1 inhibitor NB001 within ACC. Our results provide strong evidence that cortical LTPs contribute to migraine-related pain and anxiety. Drugs that inhibit cortical excitation such as NB001 may serve as potential medicines for treating migraine in the future.

Age-related attenuation of cortical synaptic tagging in the ACC is rescued by BDNF or a TrkB receptor agonist in both sex of mice.

Long-term potentiation (LTP) is a key cellular mechanism for learning and memory, and recent studies in the hippocampus found that LTP was impaired in aged animals. Previous studies of cortical LTP have focused primarily on the homosynaptic plasticity in adult mice, while fewer studies have looked at heterosynaptic plasticity-such as synaptic tagging in aged mice. In the present study, we investigated synaptic tagging in adult and middle-aged mice's anterior cingulate cortex (ACC) using the 64-channel multielectrode dish (MED64) recording system. We found that synaptic tagging was impaired in the ACC of middle-aged male mice as compared to adult mice. Both the network late-phase LTP (L-LTP) and the recruitment of inactive responses were reduced in the ACC of middle-aged male mice. Similar results were found in female middle-aged mice, indicating that there is no gender difference. Furthermore, bath application of brain-derived neurotrophic factor (BDNF) or systemic treatment with newly developed TrkB receptor agonists R13, was shown to rescue both synaptic tagging, and L-LTP, in middle-aged mice. To determine the distribution of synaptic LTP within the ACC, a new visualization method was developed to map the Spatio-temporal variation of LTP in the ACC. Our results provide strong evidence that cortical potentiation and synaptic tagging show an age-dependent reduction, and point to the TrkB receptor as a potential drug target for the treatment of memory decline.

Physical activity intervention promotes working memory and motor competence in preschool children.

Objective: This study investigated the effects of 12 weeks of specifically designed physical activity intervention on working memory and motor competence in preschool children and explored the correlation between working memory changes and motor competence changes by the intervention. Methods: Four classes of preschool children were grouped into an intervention group and a control group. Children in the intervention group received a 12-week physical activity intervention, while children in the control group followed their daily routine as usual. Before and after the intervention period, children were assessed with the 1-back task and Movement Assessment Battery for Children, second edition (MABC-2) to measure their working memory and motor competence, respectively. Results: Regarding working memory, the accuracy on the 1-back task increased significantly in the intervention group relative to the control group. The intervention group demonstrated a greater decrease in response time from pre- to posttest than the control group, but the difference was not statistically significant. Regarding motor competence, children's manual dexterity, aiming and catching and total score increased significantly in the intervention group relative to the control group, while no significant difference in static and dynamic balance was observed between the two groups. Furthermore, the correlation results showed that changes in the efficacy and efficiency of working memory were positively related to changes in static and dynamic balance and the total score on the MABC-2. Conclusion: These findings demonstrated that 12 weeks of specifically designed physical activity intervention could improve preschool children's efficacy of working memory as well as manual dexterity, aiming and catching and global motor competence. The improvement in the efficacy and efficiency of working memory was positively related to the improvement in static and dynamic balance and global motor competence.

Enhancement of behavioral nociceptive responses but not itching responses by viewing mirror images in adult mice.

Can mice recognize themselves in a mirror? The answer is unclear. Previous studies have reported that adult mice - when shown itch-like videos - demonstrated itch empathy. However, this was proven to be unreproducible in other studies. In the present study, we wanted to examine whether adult mice were able to recognize their mirror image. In our testing, we found that mice spent more time in the central area in an open field with mirrors surrounding the chamber than those in a normal open field. In a similar open field test with four mice placed in four directions, mice showed similar behavioral responses to those with mirrors. These results indicate that mice are able to recognize images in the mirror, however, they cannot distinguish their own mirror images from the mirror images of other mice. To repeat the experiments of itch empathy, we compared the itch responses of mice in the mirrored environment, to those without. No significant difference in itching responses was detected. Differently, in the case of chemical pain (formalin injection), animals' nociceptive responses to formalin during Phase II were significantly enhanced in the mirrored open field. A new format of heat map was developed to help the analysis of the trace of mice in the open field. Our results suggest that mice do recognize the presence of mice in the mirror, and their nociceptive - but not itch - responses are enhanced.

Mapping thalamic-anterior cingulate monosynaptic inputs in adult mice.

The anterior cingulate cortex (ACC) is located in the frontal part of the cingulate cortex, and plays important roles in pain perception and emotion. The thalamocortical pathway is the major sensory input to the ACC. Previous studies have show that several different thalamic nuclei receive projection fibers from spinothalamic tract, that in turn send efferents to the ACC by using neural tracers and optical imaging methods. Most of these studies were performed in monkeys, cats, and rats, few studies were reported systematically in adult mice. Adult mice, especially genetically modified mice, have provided molecular and synaptic mechanisms for cortical plasticity and modulation in the ACC. In the present study, we utilized rabies virus-based retrograde tracing system to map thalamic-anterior cingulate monosynaptic inputs in adult mice. We also combined with a new high-throughput VISoR imaging technique to generate a three-dimensional whole-brain reconstruction, especially the thalamus. We found that cortical neurons in the ACC received direct projections from different sub-nuclei in the thalamus, including the anterior, ventral, medial, lateral, midline, and intralaminar thalamic nuclei. These findings provide key anatomic evidences for the connection between the thalamus and ACC.

NMDA Receptor-Dependent Synaptic Depression in Potentiated Synapses of the Anterior Cingulate Cortex of adult Mice.

Long-term potentiation (LTP) is an important molecular mechanism for chronic pain in the anterior cingulate cortex (ACC), a key cortical region for pain perception and emotional regulation. Inhibiting ACC LTP via various manipulations or pharmacological treatments blocks chronic pain. Long-term depression (LTD) is another form of synaptic plasticity in the ACC, which is also proved to be involved in the mechanisms of chronic pain. However, less is known about the interactive relationship between LTP and LTD in the ACC. Whether the synaptic depression could be induced after synaptic LTP in the ACC is not clear. In the present study, we used multi-channel field potential recording systems to study synaptic depression after LTP in the ACC of adult mice. We found that low frequency stimulus (LFS: 1 Hz, 15 min) inhibited theta burst stimulation (TBS)-induced LTP at 30 min after the induction of LTP. However, LFS failed to induce depression at 90 min after the induction of LTP. Furthermore, NMDA receptor antagonist AP-5 blocked the induction of synaptic depression after potentiation. The GluN2B-selective antagonist Ro25-6981 also inhibited the phenomenon in the ACC, while the GluN2A-selective antagonist NVP-AAM077 and the GluN2C/D-selective antagonist PPDA and UBP145 had no any significant effect. These results suggest that synaptic LTP can be depressed by LTD in a time dependent manner, and GluN2B-containing NMDA receptors play important roles in this form of synaptic depression.

Contagious itch can be induced in humans but not in rodents.

Itch contagion has been reported in human when people watch someone scratching in a video. The basic mechanism of contagious itch induced by scratching video is still being investigated. A recent study has reported that adult mice showed itch like responses after watching itch-like video or mice showing itching responses. However, such contagious itch behaviors failed to be reproduced by another study by repeating the same experiments of viewing itching mice. It is unclear if contagious itch induced by seeing itching video may be reproducible. In the present study, we used a four-iPad paradigm to repeat these experiments, and found that mice showed no significant itch-like responses after watching itching video of mice. To test if mice actually can see the video, we placed mirrors at the same location. Interestingly, mice showed altered activities in the open field with the mirrors. Finally, in healthy subjects, we found that viewing human itch video did cause itch sensation or responses. Our results indicate that the mouse model may not appropriate for studying contagious itch in humans.