BDNF regulation in the rat dorsal vagal complex during stress-induced anorexia.

The dorsal vagal complex (DVC) is the satiety reflex-integrating center of adult mammals. Immobilization stress (IS) is known to elicit anorexia and to up-regulate BDNF expression in adult rat forebrain; intra-DVC delivery of BDNF was shown to elicit anorexia. Therefore, we addressed here whether IS would increase BDNF signaling in rat DVC by using PCR and western-blot on microdissected tissue extracts. Significant variations of BDNF expression in DVC after IS include exon V mRNA increase at 3 h, decreases of both protein and exon III mRNA at 24 h, and exon I mRNA decrease at 72 h. At the receptor level, IS elicited a highly significant induction of both full-length and truncated-1 TrkB mRNAs at 24 h after IS. In vivo recruitment of BDNF signaling in DVC during stress thus differs from hypothalamus, the relevance of which to anorexia is discussed.

Effects of aging and caloric restriction on brainstem satiety center signals in rats.

Age-related increases of body weight and adiposity, indicating dysregulation of food intake/energy expenditure, can be prevented in rodents by long-term 40% caloric restriction. The dorsal vagal complex (DVC), the brainstem center mediating the satiety reflex, has recently emerged as a determinant effector of long-term feeding adaptation. To study the effects of aging and caloric restriction on satiety circuits, leptin and brain-derived neurotrophic factor (BDNF) signaling systems were studied in 2- and 19-month-old ad libitum-fed (AL) and 19-month-old calorie-restricted (CR) rats. Age-induced hyperleptinemia in AL rats was correlated with elevated DVC BDNF immunoreactive concentrations and satiety threshold stability, suggesting functional desensitization of the DVC to these signals. To better understand this phenomenon, mRNA levels of receptor and post-receptor signaling effectors were measured by real-time RT-PCR. Aging selectively increased BDNF receptors and suppressor of cytokine signaling-3 (SOCS-3) mRNA levels. Caloric restriction prevented age-related increases of serum leptin, DVC BDNF and SOCS-3 mRNA levels, but not those of BDNF receptors. In CR rats, prevention of leptin resistance-promoting SOCS-3 induction was also observed at the protein level. This study suggests that leptin post-receptor targets and BDNF signaling play a role in the establishment of age-related DVC dysfunction.

Neuropeptide Y receptor subtypes in the dorsal vagal complex under acute feeding adaptation in the adult rat.

Neuropeptide Y (NPY), Peptide YY (PYY) and pancreatic polypeptides (PPs) belong to the same peptide family called the Y or NPY family. Central and peripheral injections of these peptides are implicated in the regulation of food intake at the level of the hypothalamus (central effects; increased food intake) and dorsal vagal complex (DVC) (peripheral effects; decreased food intake). The DVC of the brainstem is a satiety reflex key region, which includes the nucleus tractus solitarius (NTS), area postrema (AP) and dorso motor nucleus of the vagus (DMX). NPY binding sites were quantified on serial DVC sections using in vitro receptor autoradiography in two feeding adaptation models: fasting and inflammatory anorexia. Receptor autoradiography revealed that Y(1), Y(2), Y(4) and Y(5) receptor subtypes are present in all nuclei of the DVC. Additionally, we also observed significant amount of specific labelling remaining even after having blocked all known NPY receptor subtypes targeted by radioligands such as [(125)I][Leu(31), Pro(34)]PYY, [(125)I]PYY3-36 and [(125)I]hPP. This binding is referred as an atypical NPY site. Lipopolysaccharide (LPS) injection and food deprivation (24-48h) did not induce any change in the expression of NPY Y(1), Y(2,) Y(4) and Y(5) receptors at the level of the NTS and DMX. However, a significant decrease in [(125)I]PYY3-36/Y(2) and [(125)I]hPP/Y(4)- and Y(5)-insensitive binding sites (residual or atypical site) was observed in the AP. Together, these data could suggest that residual or atypical NPY binding site in the AP is modulated by food deprivation and may be physiologically relevant and implicated in feeding behaviors.

Microenvironmental determinants of adult neural stem cell proliferation and lineage commitment in the healthy and injured central nervous system.

The discovery of neural stem cells (NSC) which ensure continuous neurogenesis in the adult mammalian brain, has led to a conceptual revolution in basic neuroscience and to high hopes for clinical nervous tissue repair. However, several research issues remain to address before neural stem cells can be harnessed for regenerative therapies. The presence of NSC in a nervous structure is demonstrated in vitro by primary culture of dissociated adult nervous tissue in the presence of the specific mitogens EGF and bFGF. This leads to spherical masses of proliferating cells endowed with capacities for self-renewal and, after growth factor removal, differentiation into the three characteristic cell types of nervous tissue (neurons, astrocytes, oligodendrocytes). In vivo, neurogenesis per se, i.e. production of new neurons, occurs only in a small subset of NSC-endowed structures. The production of oligodendrocytes, i.e. myelinating glial cells, is similarly restricted. Such in vivo restrictions were formally demonstrated to arise from the tissular microenvironnement, which led to the emerging concept of "neurogenic niche". In this context, major challenges now consist in identifying the nature of tissue-specific extracellular signals that determine lineage commitment of NSC progeny, understanding why NSCs display weak in vivo reactivity to lesions compared to other stem cell types in adults, and identifying the factors behind the very high resistance to tumorigenesis displayed by NSCs. Altogether, the current data offer hope for the future use of adult NSCs in regenerative therapies, provided that tissue-specific signals are identified in view of counteracting the intrinsic repression of new cell genesis and/or stimulating endogenous NSC recruitment to lesion sites.