How left and right brain hemispheres acquire neuroanatomical and cognitive specializations remains a mystery. The zebrafish is a powerful genetic model to explore the developmental basis of laterality in the vertebrate brain. The larval dorsal diencephalon consists of an asymmetric pineal complex and adjacent paired nuclei, the medial habenulae (Ha), which exhibit left-right differences in size, organization, neuropil density, and patterns of gene expression. In all vertebrates, axons from the medial habenulae project within a prominent fiber bundle to a shared midbrain target, the interpeduncular nucleus (IPN), serving as an important relay between the basal forebrain and brainstem nuclei. In zebrafish, habenular projections from the left and right sides of the brain innervate the target differently, in part due to a molecular asymmetry in an axon guidance cue. Analysis of the zebrafish Ha-IPN conduction system has led to a model whereby a slight anatomical asymmetry in one part of the brain, the pineal complex, can influence an adjacent region and its connections, triggering a cascade of differences throughout the brain. This model has implications for the study of many developmental neurological disorders, including schizophrenia, which had been previously linked to abnormalities in brain laterality. The overall goal of the proposed study is to characterize the zebrafish Ha-IPN system in greater detail using a unique set of asymmetrically expressed and region specific molecular markers. Subnuclear regions of the habenular nuclei will be carefully defined and new transgenic tools applied to trace their distinct afferent and efferent projections. A mutation recently identified as mapping to the zebrafish wntless gene, that affects development of the Ha-IPN system, will be analyzed to test the hypotheses that Wnt signaling influences the proliferation of habenular precursor cells and the establishment of brain asymmetry. An ongoing mutagenesis screen will identify new mutations that perturb the development and asymmetry of the dorsal diencephalon, or are essential for the formation of Ha-IPN connectivity. These fundamental studies in a vertebrate genetic model will provide much needed insight into poorly understand yet evolutionarily conserved brain regions, which mediate diverse behaviors and have been implicated in neurodevelopmental disorders.

Public Health Relevance

Specialization of the left and right hemispheres is essential for normal brain function and abnormalities in brain laterality have been linked to a number of developmental neurological conditions, including schizophrenia. The proposed experiments using a genetic model system, the zebrafish, will increase our knowledge of how left-right differences arise in the developing brain by characterizing asymmetry in a highly conserved yet poorly understood forebrain to midbrain neural conduction pathway.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Neurogenesis and Cell Fate Study Section (NCF)
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Henken, Deborah B
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Carnegie Institution of Washington, D.C.
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Roberson, Sara; Halpern, Marnie E (2018) Development and connectivity of the habenular nuclei. Semin Cell Dev Biol 78:107-115
Duboué, Erik R; Hong, Elim; Eldred, Kiara C et al. (2017) Left Habenular Activity Attenuates Fear Responses in Larval Zebrafish. Curr Biol 27:2154-2162.e3
Roberson, Sara; Halpern, Marnie E (2017) Convergence of signaling pathways underlying habenular formation and axonal outgrowth in zebrafish. Development 144:2652-2662
Facchin, Lucilla; Duboué, Erik R; Halpern, Marnie E (2015) Disruption of Epithalamic Left-Right Asymmetry Increases Anxiety in Zebrafish. J Neurosci 35:15847-59
Dong, Fei; Liu, Chia-Yang; Yuan, Yong et al. (2015) Perturbed meibomian gland and tarsal plate morphogenesis by excess TGF? in eyelid stroma. Dev Biol 406:147-57
Kuan, Yung-Shu; Roberson, Sara; Akitake, Courtney M et al. (2015) Distinct requirements for Wntless in habenular development. Dev Biol 406:117-128
deCarvalho, Tagide N; Subedi, Abhignya; Rock, Jason et al. (2014) Neurotransmitter map of the asymmetric dorsal habenular nuclei of zebrafish. Genesis 52:636-55
Wu, Shu-Yu; de Borsetti, Nancy Hernandez; Bain, Emily J et al. (2014) Mediator subunit 12 coordinates intrinsic and extrinsic control of epithalamic development. Dev Biol 385:13-22
Hong, Elim; Santhakumar, Kirankumar; Akitake, Courtney A et al. (2013) Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway. Proc Natl Acad Sci U S A 110:21171-6
Reed, Andrea; Snyder, James; Staats, Sarah et al. (2013) Duration and mutual entrainment of changes in parenting practices engendered by behavioral parent training targeting recently separated mothers. J Fam Psychol 27:343-54

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