Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

New cells are continuously added to the rodent olfactory bulb (OB), throughout development and in adults. These cells migrate tangentially from the subventricular zone along the rostral migratory stream to the OB, where they migrate radically from the center to periphery of the OB. Although different modalities of radial migration have been described in other brain regions, the mechanisms governing radial migration in the OB are still mostly unknown. Here, we identify a new modality of migration in which neuronal precursors migrate along blood vessels toward their destination. Our results show that half of the radially migrating cells associate with the vasculature in the granule cell layer of the OB, and in vivo time-lapse imaging demonstrates that they use blood vessels as a scaffold for their migration through an interaction with the extracellular matrix and perivascular astrocyte end feet. The present data provide evidence that a new modality of migration, vasophilic migration, is occurring in the adult brain and reveals a novel role of brain vasculature.

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZderived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB.

Fibrous substrates, functioning as a temporary extracellular matrix, can be easily prepared by 5 electrospinning which allows to obtain fibrous matrices suitable as internal filler for nerve guidance 6 channels. In this study, gelatin micro-or nano-fibres have been prepared by electrospinning 7 technique by tuning gelatin concentration and solution flow rate. The influence of gelatin fibre 8 diameter on cell adhesion and proliferation was tested in vitro using Schwann cells (SC) and dorsal 9 root ganglia (DRG) explant cultures. Cell adhesion was evaluated by quantifying cell spreading area, 10 actin cytoskeleton organization and focal adhesion complex formation. Nano-fibres showed to 11 promote cell spreading and actin cytoskeleton organization, resulting in higher cellular adhesion 12 and proliferation rate. Yet, cell migration and motility were quantified by transwell and time lapse 13 assays respectively and results showed that cells cultured on micro-fibres displayed higher motility 14 and migration rate. Finally, DRG axon outgrowth resulted to be higher on micro-fibres. These data 15 suggest that gelatin electrospun fibres topography can be adjusted in order to modulate SC and 16 axons organization and that both nano-and micro-fibres are promising fillers for the design of 17 devices for peripheral nerve repair. 18 19

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