Emmanuel Moyse

Somatostatin and dementia in Parkinson's disease.

The concentrations of somatostatin in the cortex, hippocampus and caudate nucleus of subjects with Parkinsons disease were determined by radioimmunoassay. Somatostatin levels in the frontal cortex were significantly reduced in Parkinsonian subjects who were slightly or severely demented compared to controls and to non-demented Parkinsonians. Significant reductions were also observed in the hippocampus and entorhinal cortex of severely demented subjects.

Brain-derived neurotrophic factor (BDNF) and food intake regulation: A minireview

Neurotrophins, and in particular BDNF, play important roles in proliferation, differentiation and survival of neurons during development, as well as in the synaptic activity and plasticity in many groups of mature neurons. Several lines of evidence suggest that BDNF and its high affinity receptor TrkB contribute to food intake and body weight control. In rodents, pharmacological treatments with BDNF induce reduction in food intake, whereas genetic models with an altered BDNF/TrkB signalling display hyperphagia and obesity. Genetic studies in humans have shown that mutations in the BDNF or TrkB genes may account for certain types of obesity or other forms of eating disorders. Since circulating levels of BDNF correlate with eating disorders in humans and peripheral BDNF treatments reduce hyperphagia and hyperglycaemia in obese diabetic rodents, an endocrine role of BDNF appears plausible and requires further investigation. A central anorectic action of BDNF has also been documented, with a primary focus on the hypothalamus and a more recent highlight on the brainstem integrator of energy homeostasis, the dorsal vagal complex. In this review, we will briefly present neurotrophins and their receptors and focus on experimental evidence which point out BDNF as a signalling component of food intake regulation, with a particular emphasis on the localization of the central anorectic action of BDNF.

In vivo neurogenesis in the dorsal vagal complex of the adult rat brainstem.

The dorsal vagal complex (DVC) encompasses the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve (DMX) and the area postrema (AP), that altogether provide the major integrative center for the mammalian autonomic nervous system. The adult rat DVC has been reported to contain afferent-dependent concentration of the plasticity-promoting polysialylated form of neural cell adhesion molecule [J Neurosci 21 (2001) 4721; Eur J Neurosci 14 (2001) 1194]. This prompted us to assess the occurrence of neurogenesis in the DVC of adult rats. Cumulative in vivo labeling of cell proliferation with i.p. bromodeoxyuridine (BrdU) injections was combined with phenotypic markers and confocal microscopy on serial brainstem sections throughout the DVC extent. In basal condition, sparse BrdU+ nuclei were selectively detected in the DVC according to a discrete and reproducible pattern. Some of them were found to colocalize with the neuronal markers doublecortin, HuC/D, or neuronal-specific antigen (NeuN), demonstrating that neurogenesis does occur within the DVC of adult rat. In the NTS, 10% of the BrdU+ nuclei were also NeuN+. A comparable proportion of astrogliogenesis was found in the DVC. Nestin immunohistochemistry yielded a highly specific labeling pattern at the border between AP and NTS. These data may relate to the neural stem cells that have been reported in the floor of the IVth ventricle [J Neurosci 16 (1996) 7599]. In order to assess a possible modulation of neurogenesis by afferent input in vivo, unilateral vagotomy was performed prior to cumulative BrdU treatment. Such DVC deafferentation triggered a large increase of BrdU incorporation in the ipsilateral DVC, which was associated with microglial proliferation in the DMX and with increased genesis of neurons and astrocytes in the NTS. These findings establish DVC as a novel model of adult neurogenesis that is reactive to deafferentation.

Identification and localization of dopamine receptor subtypes in rat olfactory mucosa and bulb: a combined in situ hybridization and ligand binding radioautographic approach.

Olfactory bulb (OB) of mammals contains a large population of dopaminergic interneurons within the glomerular layer. Dopamine has been shown in vivo to modulate several aspects of olfactory information processing. The dopamine receptors of olfactory bulb and mucosa are assessed here at the levels of mRNAs and radioligand binding sites with presently available tools. D1A mRNA was found in OB glomerular-, plexiform-, mitral-cell and granular layers, but not in olfactory mucosa. D1B mRNA was absent in olfactory bulb and mucosa. D1-like binding sites were detected with two distinct radioligands, in glomerular-, plexiform-, mitral cell- and granular layers of OB but not in olfactory mucosa. We thus demonstrate the previously doubtful presence of D1-like receptors in OB. D2 mRNAs were localized in the glomerular and granular layers of OB and in olfactory mucosa; lesser amounts of D3 mRNAs were found in OB glomerular and granular layer, but not in olfactory mucosa. No D4 mRNA was detected in either structure. High densities of D2-like, [125I]Iodosulpride-labelled binding sites, were revealed within lamina propria of olfactory mucosa, and confirmed in the olfactory nerve- and glomerular layers of OB. A faint but significant density of [3H]7-hydroxy-dipropyl-aminotetralin (OH-DPAT) labelled, D3 binding sites was detected in olfactory nerve- and glomerular layers of OB, but not in olfactory mucosa. Competition of [125I]Iodosulpride specific binding by three D2/D3 selective drugs yielded kinetics typical of the D2 receptor subtype in olfactory bulb and mucosa. Olfactory nerve- and glomerular layers of OB are proved thus to contain a predominant contingent of D2 receptors and a minor population of D3 receptors, while olfactory mucosa expresses only D2 receptors.

Induction of apoptosis in rat olfactory neuroepithelium by synaptic target ablation

The olfactory system provides a useful in vivo model for studying the influence of synaptic targets on the survival of relay neurones. The bipolar sensory neurones located in the olfactory mucosa project synaptically onto the ipsilateral olfactory bulb, and their survival depends on the integrity of this connection. We demonstrate here that the retrograde neuronal degeneration induced by olfactory bulb removal involves apoptosis. As revealed by typical nucleosome-sized fragmentations of the genomic DNA, the apoptosis rate reaches a maximum 32 h after bulbectomy. A transient c-fos mRNA accumulation was detected, peaking 16 h after bulbectomy, suggesting that c-fos is involved in the early steps of programmed cell death.

Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding–electrophysiological study

Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D2 type in mammals. The present study assessed, in the frog, both the anatomical localization of D2-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [125I]iodosulpride-labelled D2 binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D2 antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity. In the frog olfactory bulb, both anatomical localization of D2-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio.

Glial fibrillary acidic protein (GFAP)‐positive radial‐like cells are present in the vicinity of proliferative progenitors in the nucleus tractus solitarius of adult rat

The dorsal vagal complex (DVC), an integrative center of autonomic functions located dorsally in the caudal brainstem, comprises the nucleus tractus solitarius (NTS), the area postrema (AP), and the dorsal motor nucleus of the vagus nerve (DMNX). Recently, this area of the brainstem was shown to retain, during adulthood, the expression of developmental markers, which is consistent with several forms of morphological and functional plasticity. These data led us to attempt to determine the structural organization and phenotypical characteristics of the astroglial compartment in the adult DVC. We report a strikingly high density of glial fibrillary acidic protein (GFAP) immunoreactive cells in the NTS and the DMNX compared to other brainstem structures. Furthermore, we observed a subpopulation of atypical GFAP+ cells in the NTS. These cells expressed vimentin and nestin and displayed unbranched processes that radiate rostrocaudally from cuboid cell bodies located in the 4th ventricle wall. Interestingly, these radiating cells were found in close association with neural progenitors whose proliferation was stimulated by intracerebroventricular injection of epidermal growth factor / basic fibroblast growth factor or lesion of the vagus nerve. Newly born neurons in the NTS identified by doublecortin (DCX) immunolabeling were also preferentially found in the vicinity of the radiating cells. Altogether, these results indicate that the adult NTS retains, during adulthood, astroglial cells that display morphological and phenotypical features seen during development. The overlap in the distribution of proliferative neural progenitors, newborn neurons, and radiating GFAP‐positive cells suggest a possible role of the glial compartment of the NTS in functional plasticity in this structure. J. Comp. Neurol. 501:353–368, 2007.

Neurogenesis and neural stem cells in the dorsal vagal complex of adult rat brain: new vistas about autonomic regulations--a review.

The dorsal vagal complex (DVC) of the brainstem is the major reflex center of autonomic nervous system. Several neuroplasticity effectors have been identified in the DVC of adult rat, such as PSA-NCAM, GAP-43, BDNF and its receptor TrkB; moreover, acute vagal stimulation was found to induce c-fos and to down-regulate western-blot-assayed tissular concentration of PSA-NCAM. Adult neurogenesis was first shown in rat DVC by BrdU incorporation combined with phenotypic labelling in situ; new neurons are generated in equal proportions with new astrocytes and at a lower rate than in olfactory bulb or hippocampus. Intrinsic proliferative cells were then detected within the DVC of adult rat by means of Ki-67 immunohistochemistry and western-blot of D-cyclins. The presence of neural stem cells within DVC was directly demonstrated by applying the in vitro neurosphere assay on microdissected adult DVC explants; DVC-derived neurospheres display lower proliferation rate and neurogenic potential than forebrain ones. Vagotomy in adult promotes massive and transient increase of neurogenic and microglial proliferations within DVC, the kinetics and location of which were analyzed by Ki-67 immunohistochemistry and cyclin D western blot. These mechanisms shed light on so far unknown plasticity potential in DVC, which brings novel cues about physiological adaptations of autonomic reflexes in adult mammals.

Localization of mu opioid receptors on the membranes of nerve endings and tanycytes in the guinea-pig median eminence by electron microscopic radioautography

The high density of opioid-containing nerve endings in the median eminence together with the absence of direct effects of opioids upon pituitary suggest a local action of opioids in the median eminence. The aim of this work was to address the occurrence of mu-opioid binding sites in the median eminence at the electron microscopic level, using the highly selective radioligand [125I]FK 33-824. mu-Opioid receptors were labeled in vitro on slightly prefixed slices of mediobasal hypothalamus. The labeling was essentially detected in the external part of the median eminence. Most of the silver grains overlaid membrane appositions. Two overall types of appositions were concerned: nerve terminal-nerve terminal or nerve terminal-tanycyte. Detailed analysis of the silver grain distribution indicated that mu receptors were observed on membranes of different types of nerve endings but also of tanycytes. All the binding sites were localized out of synaptic junctions since the median eminence is totally devoid of these structures. Our results suggest that in the median eminence, opioid peptides have a paracrine and/or autocrine action occurring at least via mu receptors located on nerve terminals but also on tanycytes.

A positive change in energy balance modulates TrkB expression in the hypothalamus and nodose ganglia of rats.

Brain-derived neurotrophic factor (BDNF) and its TrkB receptor play critical roles in the synaptic activity and plasticity of mature neurons and enhance adult neurogenesis. Furthermore, treatment with BDNF has been found to attenuate weight gain or even cause weight loss and appetite suppression in rats. The aim of this study was to look at the effect of nutrient intake on BDNF concentrations and cellular proliferation in the brain. Adult male Wistar rats were given one of three diets for 6 weeks: high-carbohydrate, high-fat or high-fat pair-fed diets. Rats were sacrificed at the end of the feeding period and BDNF concentrations in the dorsal vagal complex (DVC), hypothalamus and plasma were measured by ELISA on protein extracts of these samples. Cellular proliferation in the DVC was quantified by Ki-67 immunohistochemistry. Neither BDNF levels nor proliferation were modified by the diet. Secondly, using rats that received the same diets, real-time PCR was performed in the DVC, hypothalamus and nodose ganglia in order to compare TrkB receptor levels. The results showed significantly lower TrkB levels in the hypothalamus and nodose ganglia of fasted rats receiving the high-fat diet when compared to the other groups. These two complementary methodological approaches suggest that there is a relationship between long-term dietary intake and BDNF. More precisely, TrkB expression is more responsive to energy states than to diet composition. An increment in energy stores thus triggers decreased BDNF anorexigenic signaling at the receptor level in the hypothalamus and nodose ganglia, but not in the DVC.