Habenular Nuclei

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Joshua T Gamse - One of the best experts on this subject based on the ideXlab platform.

  • FGF activity asymmetrically regulates the timing of Habenular neurogenesis in a Nodal-dependent manner
    bioRxiv, 2018
    Co-Authors: Benjamin J. Dean, Joshua T Gamse, Shu-yu Wu
    Abstract:

    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.

  • Distinct requirements for Wntless in Habenular development.
    Developmental biology, 2015
    Co-Authors: Yung Shu Kuan, Joshua T Gamse, Sara Roberson, Courtney M. Akitake, Lea Fortuno, Cecilia B. Moens, Marnie E Halpern
    Abstract:

    Secreted Wnt proteins play pivotal roles in development, including regulation of cell proliferation, differentiation, progenitor maintenance and tissue patterning. The transmembrane protein Wntless (Wls) is necessary for secretion of most Wnts and essential for effective Wnt signaling. During a mutagenesis screen to identify genes important for development of the Habenular Nuclei in the dorsal forebrain, we isolated a mutation in the sole wls gene of zebrafish and confirmed its identity with a second, independent allele. Early embryonic development appears normal in homozygous wls mutants, but they later lack the ventral Habenular Nuclei, form smaller dorsal habenulae and otic vesicles, have truncated jaw and fin cartilages and lack swim bladders. Activation of a reporter for β-catenin-dependent transcription is decreased in wls mutants, indicative of impaired signaling by the canonical Wnt pathway, and expression of Wnt-responsive genes is reduced in the dorsal diencephalon. Wnt signaling was previously implicated in patterning of the zebrafish brain and in the generation of left–right (L–R) differences between the bilaterally paired dorsal Habenular Nuclei. Outside of the epithalamic region, development of the brain is largely normal in wls mutants and, despite their reduced size, the dorsal habenulae retain L–R asymmetry. We find that homozygous wls mutants show a reduction in two cell populations that contribute to the presumptive dorsal habenulae. The results support distinct temporal requirements for Wls in Habenular development and reveal a new role for Wnt signaling in the regulation of dorsal Habenular progenitors.

  • kctd12 and ulk2 partner to regulate dendritogenesis and behavior in the Habenular Nuclei
    PLOS ONE, 2014
    Co-Authors: Patrick S Pagemccaw, Joshua T Gamse
    Abstract:

    The Habenular Nuclei of the limbic system regulate responses, such as anxiety, to aversive stimuli in the environment. The habenulae receive inputs from the telencephalon via elaborate dendrites that form in the center of the Nuclei. The kinase Ulk2 positively regulates dendritogenesis on Habenular neurons, and in turn is negatively regulated by the cytoplasmic protein Kctd12. Given that the habenulae are a nexus in the aversive response circuit, we suspected that incomplete Habenular dendritogenesis would have profound implications for behavior. We find that Ulk2, which interacts with Kctd12 proteins via a small proline-serine rich domain, promotes branching and elaboration of dendrites. Loss of Kctd12 results in increased branching/elaboration and decreased anxiety. We conclude that fine-tuning of Habenular dendritogenesis during development is essential for appropriate behavioral responses to negative stimuli.

  • dbx1b defines the dorsal Habenular progenitor domain in the zebrafish epithalamus
    Neural Development, 2014
    Co-Authors: Benjamin J. Dean, Joshua T Gamse, Begum Erdogan, Shu-yu Wu
    Abstract:

    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.

  • Subnuclear development of the zebrafish Habenular Nuclei requires ER translocon function
    Developmental biology, 2011
    Co-Authors: Caleb A. Doll, Marnie E Halpern, Jarred T. Burkart, Kyle D. Hope, Joshua T Gamse
    Abstract:

    Abstract The dorsal Habenular Nuclei (Dh) of the zebrafish are characterized by significant left–right differences in gene expression, anatomy, and connectivity. Notably, the lateral subnucleus of the Dh (LsDh) is larger on the left side of the brain than on the right, while the medial subnucleus (MsDh) is larger on the right compared to the left. A screen for mutations that affect Habenular laterality led to the identification of the sec61a-like 1(sec61al1) gene. In sec61al1c163 mutants, more neurons in the LsDh and fewer in the MsDh develop on both sides of the brain. Generation of neurons in the LsDh occurs more rapidly and continues for a longer time period in mutants than in WT. Expression of Nodal pathway genes on the left side of the embryos is unaffected in mutants, as is the left sided placement of the parapineal organ, which promotes neurogenesis in the LsDh of WT embryos. Ultrastructural analysis of the epithalamus indicates that ventricular precursor cells, which form an epithelium in WT embryos, lose apical-basal polarity in sec61al1c163 mutants. Our results show that in the absence of sec61al1, an excess of precursor cells for the LsDh exit the ventricular region and differentiate, resulting in formation of bilaterally symmetric Habenular Nuclei.

Marnie E Halpern - One of the best experts on this subject based on the ideXlab platform.

  • Development and connectivity of the Habenular Nuclei.
    Seminars in cell & developmental biology, 2017
    Co-Authors: Sara Roberson, Marnie E Halpern
    Abstract:

    Accumulating evidence has reinforced that the Habenular region of the vertebrate dorsal forebrain is an essential integrating center, and a region strongly implicated in neurological disorders and addiction. Despite the important and diverse neuromodulatory roles the Habenular Nuclei play, their development has been understudied. The emphasis of this review is on the dorsal Habenular Nuclei of zebrafish, homologous to the medial Nuclei of mammals, as recent work has revealed new information about the signaling pathways that regulate their formation. Additionally, the zebrafish dorsal habenulae have become a valuable model for probing how left-right differences are established in a vertebrate brain. Sonic hedgehog, fibroblast growth factors and Wingless-INT proteins are all involved in the generation of progenitor cells and ultimately, along with Notch signaling, influence Habenular neurogenesis and left-right asymmetry. Intriguingly, a genetic network has emerged that leads to the differentiation of dorsal Habenular neurons and, through localized chemokine signaling, directs the posterior outgrowth of their newly emerging axons towards their postsynaptic target, the midbrain interpeduncular nucleus.

  • Distinct requirements for Wntless in Habenular development.
    Developmental biology, 2015
    Co-Authors: Yung Shu Kuan, Joshua T Gamse, Sara Roberson, Courtney M. Akitake, Lea Fortuno, Cecilia B. Moens, Marnie E Halpern
    Abstract:

    Secreted Wnt proteins play pivotal roles in development, including regulation of cell proliferation, differentiation, progenitor maintenance and tissue patterning. The transmembrane protein Wntless (Wls) is necessary for secretion of most Wnts and essential for effective Wnt signaling. During a mutagenesis screen to identify genes important for development of the Habenular Nuclei in the dorsal forebrain, we isolated a mutation in the sole wls gene of zebrafish and confirmed its identity with a second, independent allele. Early embryonic development appears normal in homozygous wls mutants, but they later lack the ventral Habenular Nuclei, form smaller dorsal habenulae and otic vesicles, have truncated jaw and fin cartilages and lack swim bladders. Activation of a reporter for β-catenin-dependent transcription is decreased in wls mutants, indicative of impaired signaling by the canonical Wnt pathway, and expression of Wnt-responsive genes is reduced in the dorsal diencephalon. Wnt signaling was previously implicated in patterning of the zebrafish brain and in the generation of left–right (L–R) differences between the bilaterally paired dorsal Habenular Nuclei. Outside of the epithalamic region, development of the brain is largely normal in wls mutants and, despite their reduced size, the dorsal habenulae retain L–R asymmetry. We find that homozygous wls mutants show a reduction in two cell populations that contribute to the presumptive dorsal habenulae. The results support distinct temporal requirements for Wls in Habenular development and reveal a new role for Wnt signaling in the regulation of dorsal Habenular progenitors.

  • Neurotransmitter map of the asymmetric dorsal Habenular Nuclei of zebrafish
    Genesis (New York N.Y. : 2000), 2014
    Co-Authors: Tagide N. Decarvalho, Marnie E Halpern, Christine Thisse, Bernard Thisse, A. Subedi, Jason R. Rock, Brian D. Harfe, Elim Hong
    Abstract:

    The role of the Habenular Nuclei in modulating fear and reward pathways has sparked a renewed interest in this conserved forebrain region. The bilaterally paired Habenular Nuclei, each consisting of a medial/dorsal and lateral/ventral nucleus, can be further divided into discrete subdomains whose neuronal populations, precise connectivity and specific functions are not well understood. An added complexity is that the left and right habenulae show pronounced morphological differences in many non-mammalian species. Notably, the dorsal habenulae of larval zebrafish provide a vertebrate genetic model to probe the development and functional significance of brain asymmetry. Previous reports have described a number of genes that are expressed in the zebrafish habenulae, either in bilaterally symmetric patterns or more extensively on one side of the brain than the other. The goal of our study was to generate a comprehensive map of the zebrafish dorsal Habenular Nuclei, by delineating the relationship between gene expression domains, comparing the extent of left-right asymmetry at larval and adult stages, and identifying potentially functional subnuclear regions as defined by neurotransmitter phenotype. While many aspects of Habenular organization appear conserved with rodents, the zebrafish habenulae also possess unique properties that may underlie lateralization of their functions.

  • Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Elim Hong, Christine Thisse, Bernard Thisse, Kirankumar Santhakumar, Courtney A. Akitake, Sang Jung Ahn, Claire Wyart, Jean-marie Mangin, Marnie E Halpern
    Abstract:

    The habenulo-interpeduncular pathway, a highly conserved cholinergic system, has emerged as a valuable model to study left-right asymmetry in the brain. In larval zebrafish, the bilaterally paired dorsal Habenular Nuclei (dHb) exhibit prominent left-right differences in their organization, gene expression, and connectivity, but their cholinergic nature was unclear. Through the discovery of a duplicated cholinergic gene locus, we now show that choline acetyltransferase and vesicular acetylcholine transporter homologs are preferentially expressed in the right dHb of larval zebrafish. Genes encoding the nicotinic acetylcholine receptor subunits α2 and β4 are transcribed in the target interpeduncular nucleus (IPN), suggesting that the asymmetrical cholinergic pathway is functional. To confirm this, we activated channelrhodopsin-2 specifically in the larval dHb and performed whole-cell patch-clamp recording of IPN neurons. The response to optogenetic or electrical stimulation of the right dHb consisted of an initial fast glutamatergic excitatory postsynaptic current followed by a slow-rising cholinergic current. In adult zebrafish, the dHb are divided into discrete cholinergic and peptidergic subNuclei that differ in size between the left and right sides of the brain. After exposing adults to nicotine, fos expression was activated in subregions of the IPN enriched for specific nicotinic acetylcholine receptor subunits. Our studies of the newly identified cholinergic gene locus resolve the neurotransmitter identity of the zebrafish Habenular Nuclei and reveal functional asymmetry in a major cholinergic neuromodulatory pathway of the vertebrate brain.

  • Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Elim Hong, Christine Thisse, Bernard Thisse, Kirankumar Santhakumar, Courtney A. Akitake, Sang Jung Ahn, Claire Wyart, Jean-marie Mangin, Marnie E Halpern
    Abstract:

    The habenulo-interpeduncular pathway, a highly conserved cholinergic system, has emerged as a valuable model to study left-right asymmetry in the brain. In larval zebrafish, the bilaterally paired dorsal Habenular Nuclei (dHb) exhibit prominent left-right differences in their organization, gene expression, and connectivity, but their cholinergic nature was unclear. Through the discovery of a duplicated cholinergic gene locus, we now show that choline acetyltransferase and vesicular acetylcholine transporter homologs are preferentially expressed in the right dHb of larval zebrafish. Genes encoding the nicotinic acetylcholine receptor subunits alpha 2 and beta 4 are transcribed in the target interpeduncular nucleus (IPN), suggesting that the asymmetrical cholinergic pathway is functional. To confirm this, we activated channelrhodopsin-2 specifically in the larval dHb and performed whole-cell patch-clamp recording of IPN neurons. The response to optogenetic or electrical stimulation of the right dHb consisted of an initial fast glutamatergic excitatory postsynaptic current followed by a slow-rising cholinergic current. In adult zebrafish, the dHb are divided into discrete cholinergic and peptidergic subNuclei that differ in size between the left and right sides of the brain. After exposing adults to nicotine, fos expression was activated in subregions of the IPN enriched for specific nicotinic acetylcholine receptor subunits. Our studies of the newly identified cholinergic gene locus resolve the neurotransmitter identity of the zebrafish Habenular Nuclei and reveal functional asymmetry in a major cholinergic neuromodulatory pathway of the vertebrate brain.

Stephen W Wilson - One of the best experts on this subject based on the ideXlab platform.

  • Nodal signalling imposes left-right asymmetry upon neurogenesis in the Habenular Nuclei.
    Development, 2009
    Co-Authors: Myriam Roussigné, Isaac H. Bianco, Stephen W Wilson, Patrick Blader
    Abstract:

    The habenulae are evolutionarily conserved bilateral Nuclei in the epithalamus that relay input from the forebrain to the ventral midbrain. In zebrafish, the habenulae display left-right (L/R) asymmetries in gene expression and axonal projections. The elaboration of Habenular asymmetries requires the presence of a second asymmetric structure, the parapineal, the laterality of which is biased by unilateral Nodal signalling. Here we show that neurons are present earlier in the left habenula than in the right, but, in contrast to other Habenular asymmetry phenotypes, this asymmetry in neurogenesis is not dependent on the parapineal. Embryos in which the L/R asymmetry in Nodal signalling is abolished display symmetric neurogenesis, revealing a requirement for this pathway in asymmetrically biasing neurogenesis. Our results provide evidence of a direct requirement for unilateral Nodal activity in establishing an asymmetry per se, rather than solely in biasing its laterality.

  • The Habenular Nuclei: a conserved asymmetric relay station in the vertebrate brain
    Philosophical Transactions of the Royal Society B, 2008
    Co-Authors: Isaac H. Bianco, Stephen W Wilson
    Abstract:

    The dorsal diencephalon, or epithalamus, contains the bilaterally paired Habenular Nuclei and the pineal complex. The habenulae form part of the dorsal diencephalic conduction (DDC) system, a highly conserved pathway found in all vertebrates. In this review, we shall describe the neuroanatomy of the DDC, consider its physiology and behavioural involvement, and discuss examples of neural asymmetries within both Habenular circuitry and the pineal complex. We will discuss studies in zebrafish, which have examined the organization and development of this circuit, uncovered how asymmetry is represented at the level of individual neurons and determined how such left–right differences arise during development.

Sara Roberson - One of the best experts on this subject based on the ideXlab platform.

  • Development and connectivity of the Habenular Nuclei.
    Seminars in cell & developmental biology, 2017
    Co-Authors: Sara Roberson, Marnie E Halpern
    Abstract:

    Accumulating evidence has reinforced that the Habenular region of the vertebrate dorsal forebrain is an essential integrating center, and a region strongly implicated in neurological disorders and addiction. Despite the important and diverse neuromodulatory roles the Habenular Nuclei play, their development has been understudied. The emphasis of this review is on the dorsal Habenular Nuclei of zebrafish, homologous to the medial Nuclei of mammals, as recent work has revealed new information about the signaling pathways that regulate their formation. Additionally, the zebrafish dorsal habenulae have become a valuable model for probing how left-right differences are established in a vertebrate brain. Sonic hedgehog, fibroblast growth factors and Wingless-INT proteins are all involved in the generation of progenitor cells and ultimately, along with Notch signaling, influence Habenular neurogenesis and left-right asymmetry. Intriguingly, a genetic network has emerged that leads to the differentiation of dorsal Habenular neurons and, through localized chemokine signaling, directs the posterior outgrowth of their newly emerging axons towards their postsynaptic target, the midbrain interpeduncular nucleus.

  • Distinct requirements for Wntless in Habenular development.
    Developmental biology, 2015
    Co-Authors: Yung Shu Kuan, Joshua T Gamse, Sara Roberson, Courtney M. Akitake, Lea Fortuno, Cecilia B. Moens, Marnie E Halpern
    Abstract:

    Secreted Wnt proteins play pivotal roles in development, including regulation of cell proliferation, differentiation, progenitor maintenance and tissue patterning. The transmembrane protein Wntless (Wls) is necessary for secretion of most Wnts and essential for effective Wnt signaling. During a mutagenesis screen to identify genes important for development of the Habenular Nuclei in the dorsal forebrain, we isolated a mutation in the sole wls gene of zebrafish and confirmed its identity with a second, independent allele. Early embryonic development appears normal in homozygous wls mutants, but they later lack the ventral Habenular Nuclei, form smaller dorsal habenulae and otic vesicles, have truncated jaw and fin cartilages and lack swim bladders. Activation of a reporter for β-catenin-dependent transcription is decreased in wls mutants, indicative of impaired signaling by the canonical Wnt pathway, and expression of Wnt-responsive genes is reduced in the dorsal diencephalon. Wnt signaling was previously implicated in patterning of the zebrafish brain and in the generation of left–right (L–R) differences between the bilaterally paired dorsal Habenular Nuclei. Outside of the epithalamic region, development of the brain is largely normal in wls mutants and, despite their reduced size, the dorsal habenulae retain L–R asymmetry. We find that homozygous wls mutants show a reduction in two cell populations that contribute to the presumptive dorsal habenulae. The results support distinct temporal requirements for Wls in Habenular development and reveal a new role for Wnt signaling in the regulation of dorsal Habenular progenitors.

Su Youne Chang - One of the best experts on this subject based on the ideXlab platform.

  • dendritic morphology local circuitry and intrinsic electrophysiology of neurons in the rat medial and lateral Habenular Nuclei of the epithalamus
    The Journal of Comparative Neurology, 2005
    Co-Authors: Su Youne Chang
    Abstract:

    The Habenular complex of the epithalamus in the mammalian brain receives input from the limbic forebrain and pallidum and, in turn, projects to numerous midbrain structures. Traditionally, the Habenular complex is divided into the medial nucleus and two divisions of the lateral nucleus. Based on their distinct input and output pathways, the habenula is considered to constitute three, partially overlapping channels that regulate information flow from the limbic forebrain and pallidum to the midbrain. As a step to improve our understanding of how information delivered from the limbic forebrain and pallidum is processed in the habenula, we examined the electrical property and morphology of medial and lateral Habenular cells. For this study, we generated live brain slices from rat habenula and performed whole cell recording. During recording, we filled Habenular cells with biocytin. Medial Habenular cells generate tonic trains of action potentials, whereas lateral Habenular cells are capable of producing action potentials in burst mode. Lateral Habenular cells produce dendrites that are much longer than those of medial Habenular cells. Two distinct intrinsic circuits exist in the medial Habenular nucleus, whereas in the lateral Habenular nucleus, intrinsic axons travel largely from medial to lateral direction. The connection between the two Habenular Nuclei is asymmetrical in that only the medial habenula sends projection to the lateral habenula. The differences in the electrical and morphological properties of medial and lateral Habenular cells indicate that the two Nuclei process and integrate information in distinct fashions that is delivered from the limbic forebrain and pallidum. J. Comp. Neurol. 483:236–250, 2005. © 2005 Wiley-Liss, Inc.

  • Dendritic morphology, local circuitry, and intrinsic electrophysiology of neurons in the rat medial and lateral Habenular Nuclei of the epithalamus
    The Journal of comparative neurology, 2005
    Co-Authors: Uhnoh Kim, Su Youne Chang
    Abstract:

    The Habenular complex of the epithalamus in the mammalian brain receives input from the limbic forebrain and pallidum and, in turn, projects to numerous midbrain structures. Traditionally, the Habenular complex is divided into the medial nucleus and two divisions of the lateral nucleus. Based on their distinct input and output pathways, the habenula is considered to constitute three, partially overlapping channels that regulate information flow from the limbic forebrain and pallidum to the midbrain. As a step to improve our understanding of how information delivered from the limbic forebrain and pallidum is processed in the habenula, we examined the electrical property and morphology of medial and lateral Habenular cells. For this study, we generated live brain slices from rat habenula and performed whole cell recording. During recording, we filled Habenular cells with biocytin. Medial Habenular cells generate tonic trains of action potentials, whereas lateral Habenular cells are capable of producing action potentials in burst mode. Lateral Habenular cells produce dendrites that are much longer than those of medial Habenular cells. Two distinct intrinsic circuits exist in the medial Habenular nucleus, whereas in the lateral Habenular nucleus, intrinsic axons travel largely from medial to lateral direction. The connection between the two Habenular Nuclei is asymmetrical in that only the medial habenula sends projection to the lateral habenula. The differences in the electrical and morphological properties of medial and lateral Habenular cells indicate that the two Nuclei process and integrate information in distinct fashions that is delivered from the limbic forebrain and pallidum.