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The Habenular Nuclei: a Conserved Asymmetric Relay Station in the Vertebrate Brain

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The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Bianco, Isaac H. and Stephen W. Wilson. 2009. The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philosophical Transactions of the Royal Society B: Biological Sciences 364(1519): 1005-1020. Published Version doi://10.1098/rstb.2008.0213 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10886852 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Phil. Trans. R. Soc. B (2009) 364, 1005–1020 doi:10.1098/rstb.2008.0213 Published online 4 December 2008 Review The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain Isaac H. Bianco1,2,* and Stephen W. Wilson1,* 1Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK 2Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA 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. Keywords: habenula; asymmetry; interpeduncular nucleus; zebrafish; dorsal diencephalic conduction system 1. ANATOMY AND CONNECTIVITY the posterior commissure and the habenular commis- The dorsal diencephalic conduction (DDC) system sure runs between them (Nieuwenhuys et al. 1998; is one of two major pathways that interconnect the Butler & Hodos 2005). limbic forebrain and sites in the mid- and hindbrain, In mammals, the habenular complex comprises two the other pathway being the medial forebrain bundle separate nuclei on each side: the ‘medial’ (MHb) and (MFB; Sutherland 1982). These two pathways appear ‘lateral’ (LHb) habenulae. The LHb is further to represent parallel neural circuits—they share sources subdivided into principal medial and lateral subdivi- of afferent inputs as well as efferent targets and there is sions. Despite sharing some sources of afferent inputs an overlap in their physiology and function. and efferent targets, the medial and lateral habenulae The DDC comprises three core components: the appear to represent largely distinct subcircuits within habenular nuclei; the stria medullaris (SM), which is the the DDC (Herkenham & Nauta 1977, 1979; Kim & main fibre tract through which inputs from the forebrain Chang 2005). In outlining the anatomy of this arrive at the habenulae; and the fasciculus retroflexus circuit, we shall focus primarily on the patterns of (FR), a prominent fibre tract that predominantly carries connectivity in the rat, which have been well studied efferent axons from the habenula towards the targets in (figure 1). Some species differences will also be the midbrain/hindbrain. In this review, we will focus on mentioned, where relevant, but we will not attempt a the anatomy and connectivity of the habenulae and the description of the comparative neuroanatomy of the interpeduncular nucleus (IPN). The latter is a major DDC in any detail. target of habenular efferent connectivity in all vertebrates and consequently plays a pivotal role in the modulation of (i) Medial habenula nuclei downstream of the DDC. In §3, we will review the MHb circuitry is highly conserved (Sutherland 1982). various classes of neural asymmetry that have been The MHb primarily receives inputs from the septum described in the DDC, especially of anamniotes, and in and projects to the IPN of the ventral midbrain. This §4, we will discuss work in zebrafish that has addressed efferent connection comprises the ‘core’ of the FR and the developmental mechanisms by which DDC circuit appears to be conserved in all vertebrate species that asymmetries emerge. have been examined. (a) Habenula Afferent connectivity The bilaterally paired habenular nuclei (Hb) are The major source of afferent innervation of the MHb positioned adjacent to the third ventricle, rostral to derives from the supracommissural septum, with axons coursing in the SM (Herkenham & Nauta 1977). * Authors and addresses for correspondence: Department of Septal sites themselves receive inputs from the Molecular and Cellular Biology, Harvard University, Cambridge, hippocampus and subiculum. Axons from the two MA 02138, USA ([email protected]); Department of Cell and Developmental Biology, University College London WC1E 6BT, most significant septal nuclei also terminate in different UK ([email protected]). subdomains of the MHb—the septofimbrial nucleus One contribution of 14 to a Theme Issue ‘Mechanisms and functions innervates the rostral MHb while the nucleus triangu- of brain and behavioural asymmetries’. laris innervates the caudal MHb. In the rat, almost 1005 This journal is q 2008 The Royal Society This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1006 I. H. Bianco & S. W. Wilson Review. The habenular nuclei HippoF P septum Dors. Teg. sf tr MHb IPN region DTN, VTN, NI DBB Acb Thal FrCx SC Circad. raphe SCN retina nuclei LH LC LPO LHb VTA EP SNc CPu Figure 1. Connectivity of the DDC. This schematic shows the principal connections of the medial and lateral habenulae and interpeduncular nucleus as described in mammals, in particular the rat. Thick arrows highlight the septum–MHb–IPN axis and the convergence of limbic and striatal inputs into the lateral habenula. Notably, there are very limited data regarding the relative functional importance of the various connections shown here. Acb, nucleus accumbens; Circad., potential sources of circadian information; CPu, caudate/putamen; Dors. Teg. region, dorsal tegmental region; DBB, nucleus of diagonal band; DTN, ventral tegmental nucleus of Gu¨dden; EP, entopeduncular nucleus; FrCx, frontal cortex; HippoF, hippocampal formation; IPN, interpeduncular nucleus; LC, locus coeruleus; LH, lateral hypothalamic area; LHb, lateral habenula; LPO, lateral preoptic area; MHb, medial habenula; NI, nucleus incerta; P, pineal; SC, superior colliculus; SCN, suprachiasmatic nucleus; SNc, substantia nigra pars compacta; sf, septofimbrial nucleus; Thal, thalamic nuclei; tr, nucleus triangularis; VTA, ventral tegmental area; VTN, ventral tegmental nucleus of Gu¨dden. every neuron in these two septal nuclei is likely to MHb innervate the ventral IPN and lateral MHb project to the MHb. More minor inputs derive from the neurons project to the dorsal IPN (Herkenham & nucleus of the diagonal band (DBB). Nauta 1979; Contestabile & Flumerfelt 1981). The MHb also receives ascending inputs, principally After making lesions in the MHb, Ronnekleiv & derived from monoaminergic nuclei, which are also the Moller (1979) observed degenerating terminals in the targets of both medial and lateral habenular efferent pineal organ, suggesting that it may also be an MHb axons. Dopaminergic inputs derive from the inter- efferent target. fascicular nucleus of the ventral tegmental area (VTA; Although little is known about the intrinsic habe- Phillipson & Pycock 1982) and noradrenergic inputs nular circuitry and the extent to which communication from the locus coeruleus (Gottesfeld 1983). These exists between the MHb and LHb, two observations latter axons reach the MHb by coursing anteriorly in provide evidence for a medial-to-lateral connection. the MFB and then joining the SM. A subset of MHb axons project through the LHb and in so doing display en passant boutons that might Efferent connectivity represent presynaptic terminals (Kim & Chang The main target of MHb axons is the IPN (Herkenham & 2005), and sectioning of the MHb efferent axons has Nauta 1979). The MHb contains both cholinergic been reported to reduce substance P levels in the LHb neurons (in its ventral two-thirds) and dorsally located (see Sutherland 1982). substance P-containing neurons (Contestabile et al. 1987). Both types are contacted by the major afferent (ii) Lateral habenula axons from the septofimbrial nucleus and nucleus When compared with the MHb, the LHb shows triangularis, and both project down the core of the FR broader and less evolutionarily conserved connectivity. to innervate the IPN. MHb axons terminate in a It is thought to be involved in the motor–limbic topographic manner, wherein the neurons of the dorsal interface because it receives significant pallidal inputs MHb innervate the lateral IPN, those of the medial as well as afferent connections from numerous Phil. Trans. R. Soc. B (2009) Review. The habenular nuclei I. H. Bianco & S. W. Wilson 1007 components of the limbic system. The LHb projects to 2007). For example, the LHb projects to the limbic a wide range of targets, especially
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