Paraventricular Thalamus Dynamically Modulates Aversive Memory via Tuning Prefrontal Inhibitory Circuitry.

The impact of stress on the formation and expression of memory is well studied, especially on the contributions of stress hormones. But how stress affects brain circuitry dynamically to modulate memory is far less understood. Here, we used male C57BL6/J mice in an auditory fear conditioning as a model system to examine this question and focused on the impact of stress on dorsomedial prefrontal cortex (dmPFC) neurons which play an important role in probabilistic fear memory. We found that paraventricular thalamus (PVT) neurons are robustly activated by acute restraining stress. Elevated PVT activity during probabilistic fear memory expression increases spiking in the dmPFC somatostatin neurons which in turn suppresses spiking of dmPFC parvalbumin (PV) neurons, and reverts the usual low fear responses associated with probabilistic fear memory to high fear. This dynamic and reversible modulation allows the original memory to be preserved and modulated during memory expression. In contrast, elevated PVT activity during fear conditioning impairs synaptic modifications in the dmPFC PV-neurons and abolishes the formation of probabilistic fear memory. Thus, PVT functions as a stress sensor to modulate the formation and expression of aversive memory by tuning inhibitory functions in the prefrontal circuitry.SIGNIFICANCE STATEMENT The impact of stress on cognitive functions, such as memory and executive functions, are well documented especially on the impact by stress hormone. However, the contributions of brain circuitry are far less understood. Here, we show that a circuitry-based mechanism can dynamically modulate memory formation and expression, namely, higher stress-induced activity in paraventricular thalamus (PVT) impairs the formation and expression of probabilistic fear memory by elevating the activity of somatostatin-neurons to suppress spiking in dorsomedial prefrontal parvalbumin (PV) neurons. This stress impact on memory via dynamic tuning of prefrontal inhibition preserves the formed memory but enables a dynamic expression of memory. These findings have implications for better stress coping strategies as well as treatment options including better drug targets/mechanisms.

Sustained Delivery of Methylsulfonylmethane from Biodegradable Scaffolds Enhances Efficient Bone Regeneration.

Introduction: As a popular dietary supplement containing sulfur compound, methylsulfonylmethane (MSM) has been widely used as an alternative oral medicine to relieve joint pain, reduce inflammation and promote collagen protein synthesis. However, it is rarely used in developing bioactive scaffolds in bone tissue engineering. Methods: Three-dimensional (3D) hydroxyapatite/poly (lactide-co-glycolide) (HA/PLGA) porous scaffolds with different doping levels of MSM were prepared using the phase separation method. MSM loading efficiency, in vitro drug release as well as the biological activity of MSM-loaded scaffolds were investigated by incubating mouse pre-osteoblasts (MC3T3-E1) in the uniform and interconnected porous scaffolds. Results: Sustained release of MSM from the scaffolds was observed, and the total MSM release from 1% and 10% MSM/HA/PLGA scaffolds within 16 days was up to 64.9% and 68.2%, respectively. Cell viability, proliferation, and alkaline phosphatase (ALP) activity were significantly promoted by incorporating 0.1% of MSM in the scaffolds. In vivo bone formation ability was significantly enhanced for 1% MSM/HA/PLGA scaffolds indicated by the repair of rabbit radius defects which might be affected by a stimulated release of MSM by enzyme systems in vivo. Discussion: Finding from this study revealed that the incorporation of MSM would be effective in improving the osteogenesis activity of the HA/PLGA porous scaffolds.

The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model.

BACKGROUND: N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. METHODS: By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. RESULTS: In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. CONCLUSIONS: We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

In Vivo MRI and X-Ray Bifunctional Imaging of Polymeric Composite Supplemented with GdPO4 ·H2 O Nanobundles for Tracing Bone Implant and Bone Regeneration.

Homogeneous and monodisperse GdPO4 ·H2 O nanobundles are successfully synthesized via a solvothermal method. Then, GdPO4 ·H2 O are incorporated into the composite of hydroxyapatite and poly(lactic-co-glycolic acid) to obtain a biodegradable and traceable bone implant. After implanted, the GdPO4 ·H2 O/HA/PLGA implant and the newly formed bone can be easily traced and observed through the combination of magnetic resonance imaging and X-ray imaging.