Innovative scaffold fabrication, angiogenesis promotion, and dynamic tissue culture techniques have been utilized to improve delivery of media into the core of large tissue constructs in tissue engineering. We have developed here an intra-tissue perfusion (ITP) system, which incorporates an array of seven micron-sized needles as a delivery conduit, to improve mass transfer into the core of thick liver tissues slices (>>300 microm mass transport limit). The ITP system improves the uniformity and distribution of media throughout the tissue, resulting in improved cell viability over the static-cultured controls. The ITP-cultured thick liver slices also exhibit improved phase I and phase II metabolic functions and albumin and urea synthetic functions after 3-day culture, which is the minimal period required by the U.S. Food and Drug Administration (FDA) for studying drug-drug interaction. This ITP system can also be used for culturing other thick tissue constructs of larger dimensions for various in vitro and in vivo applications, including bridging integration of the in vitro cultured constructs into living host tissues.
Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.
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.
The anterior cingulate cortex (ACC) is located in the frontal part of the cingulate cortex, and plays important roles on pain perception and emotion. The thalamocortical pathway is the major sensory input to the ACC. Previous studies 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 subnuclei 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.
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