Memory is a dynamic brain function that is continually processed after encoding. Although psychologic concepts of mental schema are now well established, they have rarely been considered in animal studies. We used a behavior paradigm of multiple flavor-place paired associates (PAs) and showed that memory schema facilitates fast acquisition of new PAs in a single trial. The hippocampus is necessary for the encoding of new PAs and for memory retrieval within a certain time window—24 h following new PA consolidation. Whereas the anterior cingulate cortex (ACC) plays a critical role for dynamic PA learning and consolidation during training sessions, ACC is essential in schema representation and activation. New myelin generation is essential for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. Here, we show that newly formed OL progenitor cells and mature OLs are increased following repeated PA learning and that establishment of the memory schema is associated with enhanced myelin strength in the ACC region. Furthermore, to ensure that myelination is necessary for the acquisition of paired-associate learning, ACC lysolecithin-induced demyelination revealed impaired PA learning associated with decrease in ACC θ band power and reduced spike-field coherence and phase-locking in ACC.—Hasan, M., Kanna, M. S., Jun, W., Ramkrishnan, A. S., Iqbal, Z., Lee, Y., Li, Y. Schema-like learning and memory consolidation acting through myelination.
Drawing lithography technology has recently become a popular technique to fabricate (3D) microneedles. The conventional drawing process shows some limitations in fabricating dense, scale-up and small microneedles. In this study, we demonstrate a new drawing lithography process from a self-loading mold which is able to overcome these challenges. Different from the conventional molds which have difficult alignment and loading issues, a released SU-8 membrane is attached onto a SU-8 coated wafer to generate an innovative self-loading mold. The physically distinct SU-8 colloid in this mold successfully avoids the merging of the microneedle tips in the drawing process. Meanwhile, the same SU-8 colloid in mold can provide microneedles with uniform lengths on a large surface area. Furthermore, a low temperature drawing process with this improved technique prevents sharp tips from bending during the solidification stage. Remarkably, this new drawing lithography technology can fabricate microneedles with various lengths and they are strong enough to penetrate the outermost skin layer, namely the stratum corneum. The spacing between two adjacent microneedles is optimized to maximize the penetration rate through the skin. Histology images and drug diffusion testing demonstrate that microchannels are successfully created and the drugs can permeate the tissue under the skin. The fabricated microneedles are demonstrated to deliver insulin in vivo and lower blood glucose levels, suggesting future possible applications for minimally invasive transdermal delivery of macromolecules.
In summary, pulsed-HIFU may be an effective modality in the transsclera drug delivery with a high transporting rate and depth. In vivo studies are necessary to further evaluate its performance, including the drug penetration and its possible side effects.
Exposure to 2-MHz transcranial diagnostic ultrasound enhances the thrombolytic activity of intravenously administered tissue plasminogen activator (IV-tPA) in acute ischemic stroke (sonothrombolysis). However, rates of arterial recanalization vary widely, depending upon the clot burden, its location, and stroke subtype. We evaluated the influence of age and cholesterol level of the blood clots on sonothrombolysis in an in vitro model. To "age" the clots, serum was replaced by fresh blood periodically. We increased the cholesterol content of the clots by adding cholesterin to the blood. The clots were lysed by tPA and/or transcranial Doppler ultrasound sonication for 1 h. The extent of thrombolysis induced by various treatment protocols (controls, sonication, tPA, and sonothrombolysis) was evaluated with relative changes in the clot weights and in the clot structure by scanning electron microscopy (SEM) at end of the experiment. Sonothrombolysis induced significantly higher weight reduction in fresh clots (37.3 % in 2-h old clots versus 24.8 % in 10-h ones, p < 0.005) as well as the clots with higher cholesterol levels (41.7 versus 30.6 % in normal cholesterol clots, p < 0.005). SEM demonstrated patterns of clot dissolution among various treatment modalities. Sonothrombolysis induced better clot lysis in fresh thrombi with high cholesterol levels.
Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state.
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