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Joshua T Gamse - One of the best experts on this subject based on the ideXlab platform.
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FGF activity asymmetrically regulates the timing of habenular neurogenesis in a Nodal-dependent manner
bioRxiv, 2018Co-Authors: Benjamin J. Dean, Joshua T Gamse, Shu-yu WuAbstract:The highly conserved habenular nuclei in the vertebrate Epithalamus function as an integrating center that relays information between the forebrain and the brain stem. These nuclei play crucial roles in modulating a broad variety of cognitive behaviors. Moreover, habenular nuclei has also attracted interest as a model for brain asymmetry, since many vertebrates exhibit left-right differences in habenular size and neural circuitry. Left-right (L/R) asymmetry is a shared feature of the central nervous system in vertebrates. Despite its prevalence and functional significance, few studies have addressed the molecular bases for the generation of the asymmetric brain structure, perhaps due to the absence of genetically accessible model animals showing robust brain asymmetry. Previous studies on zebrafish Epithalamus demonstrated that Nodal signaling directs the habenular asymmetry during the early stages of development by biasing the neurogenesis on the left-side. Here, we discover a novel regulatory module involving asymmetric activation of FGF signaling that determines the timing of habenular neurogenesis by regulating cell-cycle progression of neuronal progenitors, which seamlessly integrates the L/R patterning driven by Nodal and the spatiotemporal patterning of habenular neurons.
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dbx1b defines the dorsal habenular progenitor domain in the zebrafish Epithalamus
Neural Development, 2014Co-Authors: Benjamin J. Dean, Joshua T Gamse, Begum Erdogan, Shu-yu WuAbstract:Background The conserved habenular nuclei function as a relay system connecting the forebrain with the brain stem. They play crucial roles in various cognitive behaviors by modulating cholinergic, dopaminergic and serotonergic activities. Despite the renewed interest in this conserved forebrain region because of its importance in regulating aversion and reward behaviors, the formation of the habenular nuclei during embryogenesis is poorly understood due to their small size and deep location in the brain, as well as the lack of known markers for habenular progenitors. In zebrafish, the bilateral habenular nuclei are subdivided into dorsal and ventral compartments, are particularly large and found on the dorsal surface of the brain, which facilitates the study of their development.
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Pitx2c ensures habenular asymmetry by restricting parapineal cell number
Development, 2014Co-Authors: Laurence Garric, Joshua T Gamse, Brice Ronsin, Myriam Roussigné, Sabrina Booton, Pascale Dufourcq, Patrick BladerAbstract:Left-right (L/R) asymmetries in the brain are thought to underlie lateralised cognitive functions. Understanding how neuroanatomical asymmetries are established has been achieved through the study of the zebrafish Epithalamus. Morphological symmetry in the Epithalamus is broken by leftward migration of the parapineal, which is required for the subsequent elaboration of left habenular identity; the habenular nuclei flank the midline and show L/R asymmetries in marker expression and connectivity. The Nodal target pitx2c is expressed in the left Epithalamus, but nothing is known about its role during the establishment of asymmetry in the brain. We show that abrogating Pitx2c function leads to the right habenula adopting aspects of left character, and to an increase in parapineal cell numbers. Parapineal ablation in Pitx2c loss of function results in right habenular isomerism, indicating that the parapineal is required for the left character detected in the right habenula in this context. Partial parapineal ablation in the absence of Pitx2c, however, reduces the number of parapineal cells to wild-type levels and restores habenular asymmetry. We provide evidence suggesting that antagonism between Nodal and Pitx2c activities sets an upper limit on parapineal cell numbers. We conclude that restricting parapineal cell number is crucial for the correct elaboration of epithalamic asymmetry.
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Mediator subunit 12 coordinates intrinsic and extrinsic control of epithalamic development
Developmental Biology, 2013Co-Authors: Shu-yu Wu, Nancy Hernandez De Borsetti, Emily J. Bain, Christopher R. Bulow, Joshua T GamseAbstract:Abstract In the developing brain, the production of neurons from multipotent precursors must be carefully regulated in order to generate the appropriate numbers of various differentiated neuronal types. Inductive signals from extrinsic elements such as growth factors need to be integrated with timely expression of intrinsic elements such as transcription factors that define the competence of the cell. The transcriptional Mediator complex offers a mechanism to coordinate the timing and levels of intrinsic and extrinsic influences by acting as a rapid molecular switch for transcription of poised RNA pol II. The Epithalamus is a highly conserved region of the vertebrate brain that differentiates early and rapidly in the zebrafish. It includes the pineal and parapineal organs and the habenular nuclei. Mutation of the Mediator complex subunit Med12 impairs the specification of habenular and parapineal neurons and causes a loss of differentiation in pineal neurons and photoreceptors. Although FGF ligands and transcription factors for parapineal and photoreceptor development are still expressed in the pineal complex of med12 mutants, FGF signaling is impaired and transcription factor expression is reduced and/or delayed. We find that the timely expression of one of these transcription factors, tbx2b, is controlled by Med12 and is vital for parapineal specification. We propose that the Mediator complex is responsible for subtle but significant changes in transcriptional timing and amplitude that are essential for coordinating the development of neurons in the Epithalamus.
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failure in closure of the anterior neural tube causes left isomerization of the zebrafish Epithalamus
Developmental Biology, 2013Co-Authors: Po Nien Lu, Joshua T Gamse, Caroline Lund, Sataree Khuansuwan, Adelle Schumann, Marijah Harneytolo, Jennifer O LiangAbstract:Differences between the left and right sides of the brain are present in many animal species. For instance, in humans the left cerebral hemisphere is largely responsible for language and tool use and the right for processing spatial information. Zebrafish have prominent left–right asymmetries in their Epithalamus that have been associated with differential left and right eye use and navigational behavior. In wild-type (WT) zebrafish embryos, Nodal pathway genes are expressed in the left side of the pineal anlage. Shortly thereafter, a parapineal organ forms to the left of the pineal. The parapineal organ causes differences in gene expression, neuropil density, and connectivity of the left and right habenula nuclei. In embryos that have an open neural tube, such as embryos that are deficient in Nodal signaling or the cell adhesion protein N-cadherin, the left and right sides of the developing Epithalamus remain separated from one another. We find that the brains of these embryos often become left isomerized: both sides of the brain develop morphology and gene expression patterns that are characteristic of the left side. However, other aspects of epithalamic development, such as differentiation of specific neuronal cell types, are intact. We propose that there is a mechanism in embryos with closed neural tubes that prevents both sides from developing like the left side. This mechanism fails when the two sides of the Epithalamus are widely separated from one another, suggesting that it is dependent upon a signaling protein with limited range.
Marnie E. Halpern - One of the best experts on this subject based on the ideXlab platform.
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Disruption of Epithalamic Left–Right Asymmetry Increases Anxiety in Zebrafish
The Journal of Neuroscience, 2015Co-Authors: Lucilla Facchin, Erik R. Duboué, Marnie E. HalpernAbstract:Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish Epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left–right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish Epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the Epithalamus in the regulation of stress responses in zebrafish. SIGNIFICANCE STATEMENT The asymmetric Epithalamus of zebrafish has emerged as a valuable model to explore the formation and function of left–right differences in the brain. To probe the relationship between brain laterality and behavior, we examined the effects of left–right reversal of epithalamic asymmetry or symmetric development on behavior. In both cases, zebrafish showed increased measures of fear/anxiety, including reduced exploratory behavior and delayed exit from a confined space. Adults with reversed L-R asymmetry also have elevated cortisol levels relative to controls. The results reveal the importance of directional asymmetry of the dorsal diencephalon in the modulation of anxiety.
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Aversive cues fail to activate fos expression in the asymmetric olfactory-habenula pathway of zebrafish.
Frontiers in Neural Circuits, 2013Co-Authors: Tagide N. Decarvalho, Courtney M. Akitake, Christine Thisse, Bernard Thisse, Marnie E. HalpernAbstract:The dorsal habenular nuclei of the zebrafish Epithalamus have become a valuable model for studying the development of left-right (L-R) asymmetry and its function in the vertebrate brain. The bilaterally paired dorsal habenulae exhibit striking differences in size, neuroanatomical organization and molecular properties. They also display differences in their efferent connections with the interpeduncular nucleus (IPN) and in their afferent input, with a subset of mitral cells distributed on both sides of the olfactory bulb innervating only the right habenula. Previous studies have implicated the dorsal habenulae in modulating fear/anxiety responses in juvenile and adult zebrafish. It has been suggested that the asymmetric olfactory-habenula pathway (OB-Ha), revealed by selective labeling from an lhx2a:YFP transgene, mediates fear behaviors elicited by alarm pheromone. Here we show that expression of the fam84b gene demarcates a unique region of the right habenula that is the site of innervation by lhx2a:YFP-labeled olfactory axons. Upon ablation of the parapineal, which normally promotes left habenular identity; the fam84b domain is present in both dorsal habenulae and lhx2a:YFP-labeled olfactory bulb neurons form synapses on the left and the right side. To explore the relevance of the asymmetric olfactory projection and how it might influence habenular function, we tested activation of this pathway using odorants known to evoke behaviors. We find that alarm substance or other aversive odors, and attractive cues, activate fos expression in subsets of cells in the olfactory bulb but not in the lhx2a:YFP expressing population. Moreover, neither alarm pheromone nor chondroitin sulfate elicited fos activation in the dorsal habenulae. The results indicate that L-R asymmetry of the Epithalamus sets the directionality of olfactory innervation, however, the lhx2a:YFP olfactory-habenula pathway does not appear to mediate fear responses to aversive odorants.
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directional asymmetry of the zebrafish Epithalamus guides dorsoventral innervation of the midbrain target
Development, 2005Co-Authors: Joshua T Gamse, Christine Thisse, Bernard Thisse, Yung Shu Kuan, Michelle Macurak, Christian Brosamle, Marnie E. HalpernAbstract:The zebrafish Epithalamus, consisting of the pineal complex and flanking dorsal habenular nuclei, provides a valuable model for exploring how left-right differences could arise in the vertebrate brain. The parapineal lies to the left of the pineal and the left habenula is larger, has expanded dense neuropil, and distinct patterns of gene expression from the right habenula. Under the influence of Nodal signaling, positioning of the parapineal sets the direction of habenular asymmetry and thereby determines the left-right origin of habenular projections onto the midbrain target, the interpeduncular nucleus (IPN). In zebrafish with parapineal reversal, neurons from the left habenula project to a more limited ventral IPN region where right habenular axons would normally project. Conversely, efferents from the right habenula adopt a more extensive dorsoventral IPN projection pattern typical of left habenular neurons. Three members of the leftover-related KCTD (potassium channel tetramerization domain containing) gene family are expressed differently by the left and right habenula, in patterns that define asymmetric subnuclei. Molecular asymmetry extends to protein levels in habenular efferents, providing additional evidence that left and right axons terminate within different dorsoventral regions of the midbrain target. Laser-mediated ablation of the parapineal disrupts habenular asymmetry and consequently alters the dorsoventral distribution of innervating axons. The results demonstrate that laterality of the dorsal forebrain influences the formation of midbrain connections and their molecular properties.
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Leaning to the left: laterality in the zebrafish forebrain
Trends in Neurosciences, 2003Co-Authors: Marnie E. Halpern, Jennifer O Liang, Joshua T GamseAbstract:Abstract How the brain becomes lateralized is poorly understood. By contrast, much is known about molecular cues that specify the left–right axis of the body, fashioning the asymmetric morphology and positioning of the visceral organs. In zebrafish, the Nodal signaling pathway functions in visceral asymmetry and also in the embryonic brain, to bias laterality of the Epithalamus. Formation of an asymmetric pineal complex differentially influences adjacent diencephalic nuclei, the left and right habenulae, which acquire distinctive molecular and cellular features. Results from the genetically tractable zebrafish system provide a promising entry point for exploring how left–right biases are established and propagated in the developing vertebrate brain.
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The parapineal mediates left-right asymmetry in the zebrafish diencephalon
Development, 2003Co-Authors: Joshua T Gamse, Christine Thisse, Bernard Thisse, Marnie E. HalpernAbstract:The dorsal diencephalon (or Epithalamus) of larval zebrafish displays distinct left-right asymmetries. The pineal complex consists of the pineal organ anlage and an unpaired, left-sided accessory organ - the parapineal. The neighboring brain nuclei, the left and right dorsal habenulae, show consistent differences in their size, density of neuropil and gene expression. Mutational analyses demonstrate a correlation between the left-right position of the parapineal and the laterality of the habenular nuclei. We show that selective ablation of the parapineal organ results in the loss of habenular asymmetry. The left-sided parapineal therefore influences the left-right identity of adjacent brain nuclei, indicating that laterality of the dorsal diencephalon arises in a step-wise fashion.
Miguel L. Concha - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of directional asymmetry in the zebrafish Epithalamus
Seminars in Cell & Developmental Biology, 2009Co-Authors: Miguel L. Concha, Iskra A Signore, Alicia ColomboAbstract:Abstract The Epithalamus of zebrafish presents the best-studied case of directional asymmetry in the vertebrate brain. Epithalamic asymmetries are coupled to visceral asymmetry and include left-sided migration of a single midline structure (the parapineal organ) and asymmetric differentiation of paired bilateral nuclei (habenulae). The mechanisms underlying the establishment of epithalamic asymmetry involve the interplay between anti-symmetry and laterality signals to guide asymmetric parapineal migration. This event triggers the amplification of habenular asymmetries and the subsequent organisation of lateralised circuits in the interpeduncular nucleus. This review will summarise our current understanding on these processes and propose a sequential modular organisation of the events controlling the development of asymmetry along the parapineal–habenular–interpeduncular axis.
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Local tissue interactions across the dorsal midline of the forebrain establish CNS laterality
Neuron, 2003Co-Authors: Miguel L. Concha, Claire Russell, Jennifer C. Regan, Marcel Tawk, Samuel Sidi, Darren Gilmour, Marika Kapsimali, Lauro Sumoy, Kim Goldstone, Enrique AmayaAbstract:The mechanisms that establish behavioral, cognitive, and neuroanatomical asymmetries are poorly understood. In this study, we analyze the events that regulate development of asymmetric nuclei in the dorsal forebrain. The unilateral parapineal organ has a bilateral origin, and some parapineal precursors migrate across the midline to form this left-sided nucleus. The parapineal subsequently innervates the left habenula, which derives from ventral epithalamic cells adjacent to the parapineal precursors. Ablation of cells in the left ventral Epithalamus can reverse laterality in wild-type embryos and impose the direction of CNS asymmetry in embryos in which laterality is usually randomized. Unilateral modulation of Nodal activity by Lefty1 can also impose the direction of CNS laterality in embryos with bilateral expression of Nodal pathway genes. From these data, we propose that laterality is determined by a competitive interaction between the left and right Epithalamus and that Nodal signaling biases the outcome of this competition.
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asymmetry in the Epithalamus of vertebrates
Journal of Anatomy, 2001Co-Authors: Miguel L. Concha, Stephen W WilsonAbstract:The Epithalamus is a major subdivision of the diencephalon constituted by the habenular nuclei and pineal complex. Structural asymmetries in this region are widespread amongst vertebrates and involve dierences in size, neuronal organisation, neurochemistry and connectivity. In species that possess a photoreceptive parapineal organ, this structure projects asymmetrically to the left habenula, and in teleosts it is also situated on the left side of the brain. Asymmetries in size between the left and right sides of the habenula are often associated with asymmetries in neuronal organisation, although these two types of asymmetry follow dierent evolutionary courses. While the former is more conspicuous in fishes (with the exception of teleosts), asymmetries in neuronal organisation are more robust in amphibia and reptiles. Connectivity of the parapineal organ with the left habenula is not always coupled with asymmetries in habenular size and}or neuronal organisation suggesting that, at least in some species, assignment of parapineal and habenular asymmetries may be independent events. The evolutionary origins of epithalamic structures are uncertain but asymmetry in this region is likely to have existed at the origin of the vertebrate, perhaps even the chordate, lineage. In at least some extant vertebrate species, epithalamic asymmetries are established early in development, suggesting a genetic regulation of asymmetry. In some cases, epigenetic factors such as hormones also influence the development of sexually dimorphic habenular asymmetries. Although the genetic and developmental mechanisms by which neuroanatomical asymmetries are established remain obscure, some clues regarding the mechanisms underlying laterality decisions have recently come from studies in zebrafish. The Nodal signalling pathway regulates laterality by biasing an otherwise stochastic laterality decision to the left side of the Epithalamus. This genetic mechanism ensures a consistency of epithalamic laterality within the population. Between species, the laterality of asymmetry is variable and a clear evolutionary picture is missing. We propose that epithalamic structural asymmetries per se and not the laterality of these asymmetries are important for the behaviour of individuals within a species. A consistency of the laterality within a population may play a role in social behaviours between individuals of the species.
Dorothy E Oorschot - One of the best experts on this subject based on the ideXlab platform.
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total number of neurons in the habenular nuclei of the rat Epithalamus a stereological study
Journal of Anatomy, 2006Co-Authors: Rong Zhang, Dorothy E OorschotAbstract:The total number of neurons in the medial and lateral habenular nuclei of the rat Epithalamus was estimated using modern stereological counting methods and systematic random sampling techniques. Six to eight young adult male rats, and a complete set of serial 40-µm glycolmethacrylate sections for each rat, were used to quantify neuronal numbers. After a random start, a systematic subset (e.g. every third) of the serial sections was used to estimate the total volume of each nucleus using Cavalieri's method. The same set of sampled sections was used to estimate the number of neurons in a known subvolume (i.e. the numerical density Nv) by the optical disector method. Multiplication of the total volume by Nv yielded the total number of neurons. It was found that the right medial habenular nucleus consisted, on average, of 18 000 neurons (with a coefficient of variation of 0.18), while the right lateral habenular nucleus had 13 000 neurons on average (0.14). These total neuronal numbers provide important data for the transfer of information through these nuclei and for species comparisons.
Jennifer O Liang - One of the best experts on this subject based on the ideXlab platform.
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failure in closure of the anterior neural tube causes left isomerization of the zebrafish Epithalamus
Developmental Biology, 2013Co-Authors: Po Nien Lu, Joshua T Gamse, Caroline Lund, Sataree Khuansuwan, Adelle Schumann, Marijah Harneytolo, Jennifer O LiangAbstract:Differences between the left and right sides of the brain are present in many animal species. For instance, in humans the left cerebral hemisphere is largely responsible for language and tool use and the right for processing spatial information. Zebrafish have prominent left–right asymmetries in their Epithalamus that have been associated with differential left and right eye use and navigational behavior. In wild-type (WT) zebrafish embryos, Nodal pathway genes are expressed in the left side of the pineal anlage. Shortly thereafter, a parapineal organ forms to the left of the pineal. The parapineal organ causes differences in gene expression, neuropil density, and connectivity of the left and right habenula nuclei. In embryos that have an open neural tube, such as embryos that are deficient in Nodal signaling or the cell adhesion protein N-cadherin, the left and right sides of the developing Epithalamus remain separated from one another. We find that the brains of these embryos often become left isomerized: both sides of the brain develop morphology and gene expression patterns that are characteristic of the left side. However, other aspects of epithalamic development, such as differentiation of specific neuronal cell types, are intact. We propose that there is a mechanism in embryos with closed neural tubes that prevents both sides from developing like the left side. This mechanism fails when the two sides of the Epithalamus are widely separated from one another, suggesting that it is dependent upon a signaling protein with limited range.
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Leaning to the left: laterality in the zebrafish forebrain
Trends in Neurosciences, 2003Co-Authors: Marnie E. Halpern, Jennifer O Liang, Joshua T GamseAbstract:Abstract How the brain becomes lateralized is poorly understood. By contrast, much is known about molecular cues that specify the left–right axis of the body, fashioning the asymmetric morphology and positioning of the visceral organs. In zebrafish, the Nodal signaling pathway functions in visceral asymmetry and also in the embryonic brain, to bias laterality of the Epithalamus. Formation of an asymmetric pineal complex differentially influences adjacent diencephalic nuclei, the left and right habenulae, which acquire distinctive molecular and cellular features. Results from the genetically tractable zebrafish system provide a promising entry point for exploring how left–right biases are established and propagated in the developing vertebrate brain.