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Ventral Midbrain (ventral + midbrain)
Selected AbstractsVentral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signalingDEVELOPMENTAL DYNAMICS, Issue 5 2008Jennifer L. Fogel Abstract Although Hedgehog (HH) signaling plays a critical role in patterning the ventral midbrain, its role in early midbrain specification is not known. We examined the midbrains of sonic hedgehog (Shh) and smoothened (Smo) mutant mice where HH signaling is respectively attenuated and eliminated. We show that some ventral (Evx1+) cell fates are specified in the Shh,/, mouse in a Ptc1 - and Gli1 -independent manner. HH-independent ventral midbrain induction was further confirmed by the presence of a Pax7 -negative ventral midbrain territory in both Shh,/, and Smo,/, mice at and before embryonic day (E) 8.5. Midbrain signaling centers are severely disrupted in the Shh,/, mutant. Interestingly, dorsal markers are up-regulated (Wnt1, Gdf7, Pax7), down-regulated (Lfng), or otherwise altered (Zic1) in the Shh,/, midbrain. Together with the increased cell death seen specifically in Shh,/, dorsal midbrains (E8.5,E9), our results suggest specific regulation of dorsal patterning by SHH, rather than a simple deregulation due to its absence. Developmental Dynamics 237:1359-1372, 2008. © 2008 Wiley-Liss, Inc. [source] Rab23 GTPase is expressed asymmetrically in Hensen's node and plays a role in the dorsoventral patterning of the chick neural tubeDEVELOPMENTAL DYNAMICS, Issue 11 2007Naixin Li Abstract The mouse Rab23 protein, a Ras-like GTPase, inhibits signaling through the Sonic hedgehog pathway and thus exerts a role in the dorsoventral patterning of the spinal cord. Rab23 mouse mutant embryos lack dorsal spinal cord cell types. We cloned the chicken Rab23 gene and studied its expression in the developing nervous system. Chick Rab23 mRNA is initially expressed in the entire neural tube but retracts to the dorsal alar plate. Unlike in mouse, we find Rab23 in chick already expressed asymmetrically during gastrulation. Ectopic expression of Rab23 in ventral midbrain induced dorsal genes (Pax3, Pax7) ectopically and reduced ventral genes (Nkx2.2 and Nkx6) without influencing cell proliferation or neurogenesis. Thus, in the developing brain of chick embryos Rab23 acts in the same manner as described for the caudal spinal cord in mouse. These data indicate that Rab23 plays an important role in patterning the dorso-ventral axis by dorsalizing the neural tube. Developmental Dynamics 236:2993,3006, 2007. © 2007 Wiley-Liss, Inc. [source] Impact of basic FGF expression in astrocytes on dopamine neuron synaptic function and developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Caroline Forget Abstract Behavioural sensitization to amphetamine (AMPH) requires action of the drug in the ventral midbrain where dopamine (DA) neurons are located. In vivo studies suggest that AMPH sensitization requires enhanced expression of basic fibroblast growth factor (bFGF) in the nucleus of midbrain astrocytes. One idea is that the AMPH-induced increase in bFGF expression in astrocytes leads to enhanced secretion of this peptide and to long-term plasticity in DA neurons. To study directly the effects of astrocytic expression of bFGF on DA neurons, we established a cell-culture model of mesencephalic astrocytes and DA neurons. Immunolabelling showed that even in the absence of a pharmacological stimulus, the majority of mesencephalic astrocytes in culture express bFGF at a nuclear level. Arguing against the idea that bFGF was secreted, bFGF was undetectable in the extracellular medium (below 10 pg/mL). However, supplementing culture medium with exogenous bFGF at standard concentrations (20 ng/mL) led to a dramatic change in the morphology of astrocytes, increased spontaneous DA release, and inhibited synapse formation by individual DA neurons. RNA interference (siRNA) against bFGF mRNA, caused a reduction in DA release but produced no change in synaptic development. Together these data demonstrate that under basal conditions (in the absence of a pharmacological stimulus such as amphetamine) bFGF is not secreted even though there is abundant nuclear expression in astrocytes. The effects of bFGF seen here on DA neurons are thus likely to be mediated through more indirect glial,neuronal interactions, leading to enhanced DA release without a necessary change in synapse number. [source] Membrane-associated guidance cues direct the innervation of forebrain and midbrain by dorsal raphe-derived serotonergic axonsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Audrey Petit Abstract Unlike many neurons that extend an axon precisely to a single target, individual dorsal raphe 5-HT neurons project to multiple brain regions and their axon terminals often lack classical synaptic specializations. It is not known how 5-HT axon collaterals select between multiple target fields, or even if 5-HT axons require specific guidance cues to innervate their targets. Nor is it known how these axon collaterals are restrained within specific innervation target regions. To investigate this, we challenged explants of dorsal raphe with co-explants, or cell membrane preparations of ventral midbrain, striatum or cerebral cortex. We provide evidence for membrane-associated cues that promote 5-HT axon growth into each of these three target regions. The axon growth-promoting activity was heat-, protease- and phosphatidylinositol-phospholipase-C (PI-PLC)-sensitive. Interestingly, 5-HT axons specifically lost the ability to grow in heterotypic explants, or membrane carpets, following contact with ventral midbrain or striatal, but not cortical, explants or membranes. This inductive activity associated with striatal and ventral midbrain membranes was sensitive to both high salt extraction and PI-PLC treatment. By contrast, the activity that inhibited 5-HT axon growth onto heterotypic membranes was sensitive only to high salt extraction. These results provide evidence that a glycosylphosphatidylinositol (GPI)-linked membrane protein promotes 5-HT axon growth, and that short-range membrane-bound, as well as GPI-linked, molecules contribute to the guidance of 5-HT axon collaterals. These findings suggest that 5-HT axon collaterals acquire a target-induced growth-inhibitory response to alternative targets, increasing their selectivity for the newly innervated field. [source] Glutamate receptor stimulation induces a persistent rhythmicity of the GABAergic inputs to rat midbrain dopaminergic neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2001Nicola Berretta Abstract The substantia nigra pars compacta and the ventral tegmental area are part of a complex network in the basal ganglia involved in behaviours as diverse as motor planning, generation of pleasure and drug addiction. Here we report that in the dopaminergic neurons of the rat ventral midbrain a brief coactivation of group I metabotropic and NMDA glutamate receptors may transform a temporally dispersed synaptic GABAergic input into a rhythmic pattern (range 4.5,22.5 Hz), probably through a mechanism involving electrotonic couplings. The plastic and long-lasting modification in the temporal code of the inhibitory synaptic activity induced by glutamate may be a key element in determining the function of midbrain dopaminergic neurons in both normal and pathological behaviour. [source] Confirmation of Correlations and Common Quantitative Trait Loci Between Neurotensin Receptor Density and Hypnotic Sensitivity to EthanolALCOHOLISM, Issue 12 2001V. Gene Erwin Background: In previous studies, genetic correlations were observed between hypnotic sensitivity to ethanol and high-affinity neurotensin receptor (NTS1) binding. Provisional quantitative trait loci (QTLs) were identified for these traits, and some of these QTLs were found on common chromosomal regions. In continued efforts to examine the relationship between NTS1 binding capacity and hypnotic sensitivity to ethanol, studies were designed to confirm correlations between NTS1 densities in the brain, duration of ethanol-induced loss of righting reflex (LORR), and blood ethanol concentrations at regain of righting reflex (BECRR). Another purpose of the study was to confirm QTLs for these traits. Methods: ILS X ISS F 2 mice and HAS X LAS F 2 rats as well as the progenitors were tested for LORR, BECRR, and NTS1 densities. Phenotypic correlations were calculated between LORR and BECRR and between these measures and NTS1 densities in striatum from both mice and rats. The F 2 mice were genotyped by using polymorphic markers for five previously reported QTLs for LORR to confirm QTLs for BECRR and NTS1 densities in striatum, ventral midbrain, and frontal cortex. Results: Phenotypic correlations were found between LORR and BECRR (r=,0.66 to ,0.74, p < 10,9) and between these measures and NTS1 densities in striatum (r= 0.28,0.38, p < 10,2) from both mice and rats. QTLs for LORR and BECRR (lod score = 2,6) were found in common regions of chromosomes 1, 2, and 15. By using the combined results from a previous LSXSS RI study and the current results, a suggestive QTL (lod score = 3.1) for striatal NTS1 receptor densities was found on chromosome 15 at approximately 60 cM, in the same region as the chromosome 15 LORR/BECRR QTL. Conclusions: The results are in agreement with previously reported correlations and QTLs for NTS1 receptor densities and measures of hypnotic sensitivity to ethanol in mice and extend those correlations to another species, the rat. These findings support a role for NTS1 in genetically mediated differences in hypnotic sensitivity to ethanol. [source] Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and deathMOVEMENT DISORDERS, Issue 3 2008Kambiz N. Alavian PhD Abstract Since mesencephalic dopaminergic neurons are associated to one of the most prominent human neurodegenerative ailments, Parkinson's disease, the molecular mechanism underlying their development and adult cellular properties has been the subject of intense investigations. Throughout life, transcription factors determine the fate of this neuronal population and control essential processes such as localization in the ventral midbrain, their neurotransmitter phenotype, their target innervations and synapse formation. Studies of transcription factors, such as Nurr1, Pitx3, Engrailed-1/2, and Lmx1a/b, have not only revealed importance of these genes during development, but also roles in the long-term survival and maintenance of these neurons. In this review, we will discuss the function of these transcription factors throughout the life of mesencephalic dopaminergic neurons and their value in the study of the disease mechanism. © 2007 Movement Disorder Society [source] Proteome analysis of ventral midbrain in MPTP-treated normal and L1cam transgenic micePROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 6 2008Madeleine Diedrich Abstract Treatment of mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene hydrochloride (MPTP) is a well established animal model for Parkinson's disease (PD), while overexpression of L1 cell adhesion molecule (L1cam) has been proposed to attenuate the degeneration of dopaminergic neurons induced by MPTP. To gain insight into the role of L1cam in the pathomechanism of PD, we investigated protein expression patterns after MPTP-treatment in both C57BL/6 (wild-type) and transgenic mice overexpressing L1cam in astrocytes. Our results showed that during the acute phase, proteins in functional complexes responsible for mitochondrial, glycolysis, and cytoskeletal function were down-regulated in MPTP-treated wild-type mice. After a recovery phase, proteins that were down-regulated in the acute phase reverted to normal levels. In L1cam transgenic mice, a much higher number of proteins was altered during the acute phase and this number even increased after the recovery phase. Many proteins involved in oxidative phosphorylation were still down-regulated and glycolysis related protein were still up-regulated. This pattern indicates a lasting severely impaired energy production in L1cam mice after MPTP treatment. [source] Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: Relevance to selective neuronal vulnerabilityTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 5 2007Nicholas M. Kanaan Abstract Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. Although aging is a primary risk factor for PD, its role in DA neuron degeneration remains unknown. Neurodegeneration in PD is not uniform throughout the ventral midbrain: the ventral tier of the substantia nigra (vtSN) is most vulnerable, whereas the dorsal tier (dtSN) and ventral tegmental area (VTA) are relatively resistant. We studied young (9,10 years old), middle-aged (14,17 years old), and old-aged (22,29 years old) rhesus monkeys to identify factors potentially underlying selective vulnerability and their association with aging. We focused on markers relevant to the ubiquitin-proteasome (UPS) and lysosome systems. Unbiased stereological counting was performed on tyrosine hydroxylase-positive (TH+) neurons and TH+ neurons containing Marinesco bodies (TH+MB) or lipofuscin (TH+lipo), markers of UPS or lysosomal activity, respectively. TH+ neuron numbers were inversely correlated with advancing age specifically in the vtSN, not the dtSN or VTA. TH intensity decreased throughout the ventral midbrain with increasing age, an effect exacerbated in the vtSN. TH+MB neurons were localized in the vulnerable vtSN of old monkeys. The number of MBs per cell increased with age, and TH intensity of TH+MB neurons decreased in middle age. Conversely, TH+lipo neurons were primarily found in the resistant dtSN and VTA. These data suggest that particular age-related changes localize to DAergic subregions relevant to degenerative patterns in PD. Furthermore, the results begin to characterize the nature of the link between aging and PD, and they support the concept that aged monkeys represent a valuable model for studying specific events preceding PD. J. Comp. Neurol. 502:683,700, 2007. © 2007 Wiley-Liss, Inc. [source] Abnormal activity in reward brain circuits in human narcolepsy with cataplexyANNALS OF NEUROLOGY, Issue 2 2010Aurélie Ponz PhD Objective Hypothalamic hypocretins (or orexins) regulate energy metabolism and arousal maintenance. Recent animal research suggests that hypocretins may also influence reward-related behaviors. In humans, the loss of hypocretin-containing neurons results in a major sleep-wake disorder called narcolepsy-cataplexy, which is associated with emotional disturbances. Here, we aim to test whether narcoleptic patients show an abnormal pattern of brain activity during reward processing. Methods We used functional magnetic resonance imaging in 12 unmedicated patients with narcolepsy-cataplexy to measure the neural responses to expectancy and experience of monetary gains and losses. We statistically compared the patients' data with those obtained in a group of 12 healthy matched controls. Results and Interpretation Our results reveal that activity in the dopaminergic ventral midbrain (ventral tegmental area) was not modulated in narcolepsy-cataplexy patients during high reward expectancy (unlike controls), and that ventral striatum activity was reduced during winning. By contrast, the patients showed abnormal activity increases in the amygdala and in dorsal striatum for positive outcomes. In addition, we found that activity in the nucleus accumbens and the ventral-medial prefrontal cortex correlated with disease duration, suggesting that an alternate neural circuit could be privileged over the years to control affective responses to emotional challenges and compensate for the lack of influence from ventral midbrain regions. Our study offers a detailed picture of the distributed brain network involved during distinct stages of reward processing and shows for the first time, to our knowledge, how this network is affected in hypocretin-deficient narcoleptic patients. ANN NEUROL 2010;67:190,200 [source] | |||||||||||||