Orexin/hypocretin role in reward: implications for opioid and other addictions

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the ‘anti-reward’ effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.

A neuronal topography of visual and acoustic fear conditioning within the amygdala

The lateral amygdala (LA) receives information from auditory and visual sensory modalities, and uses this information to encode lasting memories that predict threat. One unresolved question about the amygdala is how multiple memories, derived from different sensory modalities, are organized at the level of neuronal ensembles. We previously showed that fear conditioning using an auditory conditioned stimulus (CS) was spatially allocated to a stable topography of neurons within the dorsolateral amygdala (LAd) (Bergstrom et al, 2011). Here, we asked how fear conditioning using a visual CS is topographically organized within the amygdala. To induce a lasting fear memory trace we paired either an auditory (2 khz, 55 dB, 20 s) or visual (1 Hz, 0.5 s on/0.5 s off, 35 lux, 20 s) CS with a mild foot shock unconditioned stimulus (0.6 mA, 0.5 s). To detect learning-induced plasticity in amygdala neurons, we used immunohistochemistry with an antibody for phosphorylated mitogen-activated protein kinase (pMAPK). Using a principal components analysis-based approach to extract and visualize spatial patterns, we uncovered two unique spatial patterns of activated neurons in the LA that were associated with auditory and visual fear conditioning. The first spatial pattern was specific to auditory cued fear conditioning and consisted of activated neurons topographically organized throughout the LAd and ventrolateral nuclei (LAvl) of the LA. The second spatial pattern overlapped for auditory and visual fear conditioning and was comprised of activated neurons located mainly within the LAvl. Overall, the density of pMAPK labeled cells throughout the LA was greatest in the auditory CS group, even though freezing in response to the visual and auditory CS was equivalent. There were no differences detected in the number of pMAPK activated neurons within the basal amygdala nuclei. Together, these results provide the first basic knowledge about the organizational structure of two different fear engrams within the amygdala and suggest they are dissociable at the level of neuronal ensembles within the LA

Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer : an opportunity for intervention

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

Shaping development through mechanical strain: The transcriptional basis of diet-induced phenotypic plasticity in a cichlid fish

Adaptive phenotypic plasticity, the ability of an organism to change its phenotype to match local environments, is increasingly recognized for its contribution to evolution. However, few empirical studies have explored the molecular basis of plastic traits. The East African cichlid fish Astatoreochromis alluaudi displays adaptive phenotypic plasticity in its pharyngeal jaw apparatus, a structure that is widely seen as an evolutionary key innovation that has contributed to the remarkable diversity of cichlid fishes. It has previously been shown that in response to different diets, the pharyngeal jaws change their size, shape and dentition: hard diets induce an adaptive robust molariform tooth phenotype with short jaws and strong internal bone structures, while soft diets induce a gracile papilliform tooth phenotype with elongated jaws and slender internal bone structures. To gain insight into the molecular underpinnings of these adaptations and enable future investigations of the role that phenotypic plasticity plays during the formation of adaptive radiations, the transcriptomes of the two divergent jaw phenotypes were examined. Our study identified a total of 187 genes whose expression differs in response to hard and soft diets, including immediate early genes, extracellular matrix genes and inflammatory factors. Transcriptome results are interpreted in light of expression of candidate genesmarkers for tooth size and shape, bone cells and mechanically sensitive pathways. This study opens up new avenues of research at new levels of biological organization into the roles of phenotypic plasticity during speciation and radiation of cichlid fishes.

The mechanical strength of phosphates under friction-induced cross-linking

Purpose: In the present study, we consider mechanical properties of phosphate glasses under high temperatureinduced and under friction-induced cross-linking, which enhance the modulus of elasticity. Design/methodology/approach: Two nanomechanical properties are evaluated, the first parameter is the modulus of elasticity (E) (or Young's modulus) and the second parameter is the hardness (H). Zinc meta-, pyro - and orthophosphates were recognized as amorphous-colloidal nanoparticles were synthesized under laboratory conditions and showed antiwear properties in engine oil. Findings: Young's modulus of the phosphate glasses formed under high temperature was in the 60-89 GPa range. For phosphate tribofilm formed under friction hardness and the Young's modulus were in the range of 2-10 GPa and 40-215 GPa, respectively. The degree of cross-linking during friction is provided by internal pressure of about 600 MPa and temperature close to 1000°C enhancing mechanical properties by factor of 3 (see Fig 1). Research limitations/implications: The addition of iron or aluminum ions to phosphate glasses under high temperature - and friction-induced amorphization of zinc metaphosphate and pyrophosphate tends to provide more cross-linking and mechanically stronger structures. Iron and aluminum (FeO4 or AlO4 units), incorporated into phosphate structure as network formers, contribute to the anion network bonding by converting the P=O bonds into bridging oxygen. Future work should consider on development of new of materials prepared by solgel processes, eg., zinc (II)-silicic acid. Originality/value: This paper analyses the friction pressure-induced and temperature–induced the two factors lead phosphate tribofilm glasses to chemically advanced glass structures, which may enhance the wear inhibition. Adding the coordinating ions alters the pressure at which cross-linking occurs and increases the antiwear properties of the surface material significantly.

Stretching-induced orientation to improve mechanical properties of electrospun pan nanocomposites

Partially aligned and oriented polyacrylonitrile(PAN)-based nanofibers were electrospun from PAN and SWNTs/PAN in the solution of dimethylformamide(DMF) to make the carbon nanofibers. The as-spun nanofibers were hot-stretched in an oven to enhance its orientation and crystallinity. Then it were stabilized at 250 square under a stretched stress, and carbonized at 1000 square in N-2 atmosphere by fixing the length of the stabilized nanofiber to convert them into carbon nanofibers. With this hot-stretched process and with the introduction of SWNTs, the mechanical properties will be enhanced correspondingly. The crystallinity of the stretched fibers confirmed by X-ray diffraction has also increased. For PAN nanofibers, the improved fiber alignment and crystallinity resulted in the increased mechanical properties, such as the modulus and tensile strength of the nanofibers. It was concluded that the hot-stretched nanofiber and the SWNTs/PAN nanofibers can be used as a potential precursor to produce high-performance carbon composites.

Dynamic matrix control on wind-induced vibration of spatial latticed structures [Chinese title = 空间网壳结构风振抑制的动态矩阵预测控制分析]

Ameliorated strategies were put forward to improve the model predictive control in reducing the wind induced vibration of spatial latticed structures. The dynamic matrix control (DMC) predictive method was used and the reference trajectory which is called the decaying functions was suggested for the analysis of spatial latticed structure (SLS) under wind loads. The wind-induced vibration control model of SLS with improved DMC model predictive control was illustrated, then the different feedback strategies were investigated and a typical SLS was taken as example to investigate the reduction of wind-induced vibration. In addition, the robustness and reliability of DMC strategy were discussed by varying the model configurations.