Distinct contributions of ventral CA1/amygdala co-activation to the induction and maintenance of synaptic plasticity.

The amygdala is known to modulate hippocampal synaptic plasticity. One role could be an immediate effect of basolateral amygdala (BLA) in priming synaptic plasticity in the hippocampus. Another role could be through associative synaptic co-operation and competition that triggers events involved in the maintenance of synaptic potentiation. We present evidence that the timing and activity level of BLA stimulation are important factors for the induction and maintenance of long-term potentiation (LTP) in ventral hippocampal area CA1. A 100 Hz BLA co-stimulation facilitated the induction of LTP, whereas 200 Hz co-stimulation attenuated induction. A 100 Hz BLA co-stimulation also caused enhanced persistence, sufficient to prevent synaptic competition. This maintenance effect is likely through translational mechanisms, as mRNA expression of primary response genes was unaffected, whereas protein level of plasticity-related products was increased. Further understanding of the neural mechanisms of amygdala modulation on hippocampus could provide insights into the mechanisms of emotional disorders.

Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease.

Clinical studies have shown that female brains are more predisposed to neurodegenerative diseases such as Alzheimer's disease (AD), but the cellular and molecular mechanisms behind this disparity remain unknown. In several mouse models of AD, synaptic plasticity dysfunction is an early event and appears before significant accumulation of amyloid plaques and neuronal degeneration. However, it is unclear whether sexual dimorphism at the synaptic level contributes to the higher risk and prevalence of AD in females. Our studies on APP/PS1 (APPSwe/PS1dE9) mouse model show that AD impacts hippocampal long-term plasticity in a sex-specific manner. Long-term potentiation (LTP) induced by strong tetanic stimulation (STET), theta burst stimulation (TBS) and population spike timing-dependent plasticity (pSTDP) show a faster decay in AD females compared with age-matched AD males. In addition, behavioural tagging (BT), a model of associative memory, is specifically impaired in AD females with a faster decay in memory compared with males. Together with the plasticity and behavioural data, we also observed an upregulation of neuroinflammatory markers, along with downregulation of transcripts that regulate cellular processes associated with synaptic plasticity and memory in females. Immunohistochemistry of AD brains confirms that female APP/PS1 mice carry a higher amyloid plaque burden and have enhanced microglial activation compared with male APP/PS1 mice. Their presence in the diseased mice also suggests a link between the impairment of LTP and the upregulation of the inflammatory response. Overall, our data show that synaptic plasticity and associative memory impairments are more prominent in females and this might account for the faster progression of AD in females.

Age-related changes in hippocampal-dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor.

The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal-dependent long-term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age-related decline. The p75 neurotrophin receptor (p75NTR ) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age-related alterations. However, the mechanisms by which p75NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75NTR were resistant to age-associated changes in long-term plasticity, associative plasticity, and associative memory. Our study shows that p75NTR is responsible for age-dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA-ROCK2-LIMK1-cofilin. p75NTR may thus represent an important therapeutic target for limiting the age-related memory and cognitive function deficits.

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-Dependent Regulation.

A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes-associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.

Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice.

Sleep plays an important role in the establishment of long-term memory; as such, lack of sleep severely impacts domains of our health including cognitive function. Epigenetic mechanisms regulate gene transcription and protein synthesis, playing a critical role in the modulation of long-term synaptic plasticity and memory. Recent evidences indicate that transcriptional dysregulation as a result of sleep deprivation (SD) may contribute to deficits in plasticity and memory function. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, a clinically approved drug for human use, has been shown to ameliorate cognitive deficits in several neurological disease models. To further explore the therapeutic effect of SAHA, we have examined its potential role in improving the SD-mediated impairments in long-term plasticity, associative plasticity, and associative memory. Here we show that SAHA preserves long-term plasticity, associative plasticity, and associative memory in SD hippocampus. Furthermore, we find that SAHA prevents SD-mediated epigenetic changes by upregulating histone acetylation, hence preserving the ERK-cAMP-responsive element-binding protein (CREB)/CREB-binding protein-brain-derived neurotrophic factor pathway in the hippocampus. These data demonstrate that modifying epigenetic mechanisms via SAHA can prevent or reverse impairments in long-term plasticity and memory that result from sleep loss. Thus, SAHA could be a potential therapeutic agent in improving SD-related memory deficits.

Transdermal Gene Delivery by Functional Peptide-Conjugated Cationic Gold Nanoparticle Reverses the Progression and Metastasis of Cutaneous Melanoma.

Permeability barrier imposed by stratum corneum makes an extreme challenge for the topical delivery of plasmid DNA (pDNA), which is widely used in gene therapy. Existing techniques to overcome the skin barrier for bio-macromolecules delivery rely on sophisticated mechanical devices. It is still a big challenge to treat the skin cancer, for example, melanoma, that initiates in the dermal layer by topical gene therapy. To facilitate the skin penetration of pDNA deeply into the melanoma tissues, we here present a cell-penetrating peptide and cationic poly(ethyleneimine) conjugated gold nanoparticle (AuPT) that can compact the pDNAs into cationic nanocomplexes and penetrate through the intact stratum corneum without any additional enhancement used. Moreover, the AuPT is highly efficient in stimulating the intracellular uptake and nuclear targeting of the pDNAs in cells, which guarantees the effective transfection. This study provides evidence that penetrating peptide conjugated cationic gold nanoparticle offers a promising vehicle for both the skin penetration and transfection of pDNAs, possessing great potential in topical gene therapy.

Sustained release of piroxicam from solid lipid nanoparticle as an effective anti-inflammatory therapeutics in vivo.

This study aims to investigate the solid lipid nanoparticle (SLN) as a novel vehicle for the sustained release and transdermal delivery of piroxicam, as well as to determine the anti-inflammation effect of piroxicam-loaded SLN. SLN formulation was optimized and the particle size, polydispersity index, zeta potential (ZP), encapsulation efficiency, drug release, and morphological properties were characterized. The transdermal efficiency and mechanism of the piroxicam-loaded SLNs were investigated in vitro. With the inflammation induced edema model in rat, the anti-inflammatory efficiency of piroxicam-enriched SLNs (Pir-SLNs) was evaluated. The SLN formulation was optimized as: lecithin 100 mg, glycerin monostearate 200 mg, and Tween (1%, w/w). The particle size is around 102 ± 5.2 nm with a PDI of 0.262. The ZP is 30.21 ± 2.05 mV. The prepared SLNs showed high entrapment efficiency of 87.5% for piroxicam. There is no interaction between piroxicam and the vehicle components. The presence of polymorphic form of lipid with higher drug content in the optimized Pir-SLNs enables the Pir-SLNs to release the drug with a sustained manner. Pir-SLNs with oleic acid as enhancer can radically diffuse into both the stratum corneum and dermal layer, as well as penetrate through the hair follicles and sebaceous glands with significantly higher density than the other control groups. Pir-SLNs promptly inhibited the inflammation since the 3rd hour after the treatment by decreasing the PGE2 level. SLN was demonstrated to be a promising carrier for encapsulation and sustained release of piroxicam. Pir-SLN is a novel topical preparation with great potential for anti-inflammation application.

Porous microspheres as promising vehicles for the topical delivery of poorly soluble asiaticoside accelerate wound healing and inhibit scar formation in vitro &in vivo.

Asiaticoside is a natural compound possessing diverse pharmacological effects with great potential for clinical use. However, the low solubility and oil-water partition coefficient of asiaticoside lead to reduced effect and limited application. This study aims to construct a porous microsphere for the sustained release of asiaticoside to improve its absorption and enhance the therapeutic effects. Parameters of the formulations, including the drug to polymer ratio, solvent amounts of the inner and external phases, the stirring speed for preparation, and the drug entrapment efficiency were investigated and optimized. Particle size, morphology, pores structure, and Fourier transform infrared spectrum of the microsphere were characterized. The release kinetics and cellular uptake profiles of the asiaticoside-microspheres were examined. The therapeutic effects of asiaticoside-microspheres on wound healing and skin appendages regeneration were investigated in vitro & in vivo. Results showed that the optimized asiaticoside-microspheres possess spherical spongy structure with cylindrical holes. Asiaticoside can be loaded in the microsphere with high efficiency and released with sustained manner. The cellular uptake of asiaticoside from the microspheres was increased with 9.1 folds higher than that of free solution. Asiaticoside-microspheres expressed the strong promotion in the proliferation, migration of keratinocytes and wound scratching healing in vitro. More importantly, they significantly accelerated the re-epithelization, collagen synthesis and pro-angiogenesis in the rat full-skin wound healing. Porous microsphere was shown a novel carrier for the sustained delivery of poorly soluble asiaticoside, with absorption and therapeutic effects improved. Asiaticoside-microsphere is a promising topical preparation with excellent regenerative effects for the wound therapy.