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Original Paper Brain Behav Evol 2009;73:43–58 DOI: 10.1159/000204962 Received: January 29, 2008 Returned for revision: February 27, 2008 Accepted after second revision: November 3, 2008 Published online: February 27, 2009 © Free Author Copy – for personal use only Brain-Derived Neurotrophic Factor mRNA Expression in the Brain of the Teleost Fish, Anguilla anguilla, the European Eel ANY DISTRIBUTION OF THIS ARTICLE WITHOUT WRITTEN CONSENT FROM S. KARGER AG, BASEL IS A VIOLATION OF THE COPYRIGHT. Written permission to distriba the PDF will granted a, b Victoria S. Suzanne M. Paula Murphy uteBarry L. beRoberts against payment of a pera mission fee, which based and Department of Zoology, Trinity College, University of Dublin, Dublin, Ireland; b Department of isCellular the numberIll.of, accesses Molecular Pharmacology, Chicago Medical School at Rosalind Franklin University,onChicago, USA required. Please contact [email protected] Dalton a Borich a Key Words Brain-derived neurotrophic factor ⴢ Neurotrophins ⴢ Brain ⴢ Teleost fish ⴢ Regeneration Abstract The spatial expression pattern of Brain-Derived Neurotrophic Factor (BDNF) mRNA in the brain of the European eel (Anguilla anguilla) was determined using non-radioactive in situ hybridization, and mapped and compared to that of other vertebrates. Riboprobes were prepared based on a partial cDNA coding sequence for A. anguilla BDNF that was amplified using degenerate primers, cloned and sequenced. As in other animal groups, in the eel, BDNF mRNA expression was seen in the telencephalon, hypothalamus, tectum, many primary and secondary sensory centers, and cranial motor nuclei. However, in contrast to mammals, BDNF mRNA expression was observed in some brain stem nuclei, such as the reticular formation, that contain cell bodies of neurons that project down the spinal cord. We suggest that these differences might relate to the continual growth of teleost fish. Copyright © 2009 S. Karger AG, Basel Introduction The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) plays crucial roles in both the developing and mature mammalian nervous system. It is important dur© 2009 S. Karger AG, Basel 0006–8977/09/0731–0043$26.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Accessible online at: www.karger.com/bbe ing development in regulating neuronal survival, promoting axonal pathfinding and elongation towards targets, and in supporting synaptic plasticity [McAllister et al., 1999; Huang and Reichardt, 2001; Gillespie, 2003; Cohen-Cory and Lom, 2004] and is involved in neuronal © Free Author Copy – for personal use only plasticity and survival in the adult nervous system [ConDISTRIBUTION 1998; OF THIS ARTICLE WITHOUT WRITTEN FROM S. KARGER AG, BASEL I nor and ANY Dragunow, McAllister et al., CONSENT 1999; SchinWritten permission to distribute the PDF will be granted against payment of a permission fee, wh der and Poo, 2000]. Because these are functions that are likely to be required by neurons recovering from injury, neurotrophins have also been implicated in regeneration, and an insufficiency of such growth-enhancing molecules in the injured mammalian nervous system has been thought to contribute to its limited regeneration ability [reviewed in Schwab and Bartholdi, 1996]. The overall expression pattern of BDNF mRNA has been described from in situ hybridization studies of the rat and pig brain [Wetmore et al., 1990; Castrén et al. 1995; Conner et al., 1997] and immunohistochemical studies have revealed the distribution of BDNF protein in the rat [Conner et al., 1997; Yan et al., 1997; Friedman et al., 1998; Furukawa et al., 1998] and human [Murer et al., 1999], but to date comprehensive descriptions of BDNF mRNA and protein expression patterns have not been published for the avian brain or for the brain of any anamniote. The presence of BDNF mRNA in specific brain regions has been noted though: for example, BDNF mRNA is expressed in the mesencephalic tectum of chick [Herzog and von Bartheld, 1998] and frog [Duprey-Díaz et al., 2002] and BDNF protein expression has been reported in pigeon Victoria S. Dalton Radiopharmaceuticals Research Institute ANSTO, PMB 1 Menai, Sydney, NSW 2234 (Australia) Tel. +61 2 9717 9879, Fax +61 2 9717 9262 E-Mail: [email protected] or [email protected] Abbreviations used in this paper A AP Cb CbSg CbSm cc CP Dc Dd Dl Dlp Dm DO DP dV E EC flt GL GS HAd HAv HC HL HV IC IRF LC LL LLp LV LVII LX M MLF MLFd MO MRF nCC ndil anterior thalamic nucleus area postrema cerebellum granular layer of cerebellum molecular layer of cerebellum cerebellar crest nucleus pretectalis centralis central zone of the area dorsalis dorsal zone of the area dorsalis lateral zone of the area dorsalis posterior portion of lateral zone of the area dorsalis medial zone of the area dorsalis descending octavolateralis nucleus dorsal posterior thalamic nucleus descending tract of trigeminal nerve entopeduncular nucleus external cell layer telencephalic lateral longitudinal fasciculus glomerulus (olfactory bulb) secondary gustatory nucleus dorsal habenular nucleus ventral habenular nucleus caudal zone of periventricular hypothalamus inferior lobe of hypothalamus ventral zone of periventricular nucleus hypothalamus internal cell layer inferior reticular formation locus coeruleus lateral lemniscus posterior lateral line nerve nucleus lateralis valvulae facial lobe vagal lobe Mauthner-like cell medial longitudinal fasciculus dorsal subdivision of medial longitudinal fasciculus magnocellular octavolateralis nucleus medial reticular formation commissural nucleus of Cajal diffuse nucleus of inferior lobe [Theiss and Güntürkün, 2001] and frog [Duprey-Díaz et al., 2002] tectum and in the hypothalamo-hypophyseal system of Xenopus [Wang et al., 2005]. With regard to teleost fish, BDNF expression has been confirmed in the brain of the southern platyfish [Götz et al., 1992], in the developing zebrafish brain and retina [Hashimoto and Heinrich, 1997; Lum et al., 2001], and in the tench retina [Caminos et al., 1999]. Five neurotrophin receptors have been described in zebrafish [Martin et al., 1995], two of which have been reported to be isoforms of the Trk B receptor and their mRNA is widely distributed throughout the brain and spinal cord of larval zebrafish [Martin et al., 1995]. Hannestad et al. [2000] observed immunoreactivity for Trk B in the adenohypophysis, striatum and retina during development of Dicentrarchus. 44 Brain Behav Evol 2009;73:43–58 nI nIV nIXm nMLF nTL nVIIm nVm nVs nXm OEN ON PPd PGm PMg PMm PMp PPp PT PVO Rinf SC SCO sgt SO SPV SRF sv T TO TP TPp TS VCb Vd Vl VL VM Vp VST Vv nucleus isthmi trochlear nucleus glossopharyngeal motor nucleus nucleus of medial longitudinal fasciculus nucleus lateralis tuberis facial motor nucleus trigeminal motor nucleus trigeminal sensory nucleus vagal motor nucleus octavolateralis efferent nucleus optic nerve nucleus pretectalis periventricularis, pars dorsalis preglomerular nuclear complex nucleus preopticus magnocellularis, pars gigantocellularis nucleus preopticus magnocellularis, pars magnocellularis nucleus preopticus magnocellularis, pars parvocellularis nucleus preopticus parvocellularis posterior posterior thalamic nucleus paraventricular organ inferior raphe nucleus suprachiasmatic nucleus subcommissural organ secondary gustatory tract superior olive stratum periventriculare superior reticular formation saccus vasculosus tectum tangential octavolateralis nucleus nucleus posterior tuberis periventricular nucleus of posterior tuberculum torus semicircularis valvula cerebelli dorsal nucleus of the area ventralis lateral nucleus of the area ventralis ventrolateral nucleus of the thalamus ventromedial nucleus of the thalamus posterior nucleus of the area ventralis vestibulospinal tract ventral nucleus of the area ventralis The present study is based on the European eel, Anguilla anguilla, a teleost fish whose rapid morphological and functional regeneration after a complete spinal cord transection has now been studied by us in some detail [Doyle et al., 2001; Dervan and Roberts 2003a, b; Doyle and Roberts, 2004 a, b, 2006]. Here we aimed to: (1) isolate and characterize a cDNA fragment complementary to the mRNA sequence which encodes the mature form of eel BDNF protein molecule and (2) examine BDNF mRNA expression throughout the eel brain using in situ hybridization analysis. This report provides the background to a subsequent study on the eel in which we shall examine how BDNF mRNA expression in the eel central nervous system might be affected by spinal cord transection and its subsequent repair. Dalton /Borich /Murphy /Roberts Materials and Methods For the present study, comprehensive sets of eel brain sections were hybridized so that the pattern of BDNF expression throughout the whole brain could be charted. Animals and Tissue Preparation The brains were obtained from European eels, A. anguilla L. (n = 30), of unknown sex in a non-migratory, immature stage of the life cycle caught in the wild in Counties Mayo and Westmeath, Ireland. The eels ranged in length from 300 to 500 mm and were kept in aquaria with recirculating water at 25 ° C. The procedures were approved by a local committee and were carried out in accordance with the European Communities Council Directive (86/609/EEC). All chemicals were from Sigma, UK, unless stated. For tissue extraction, eels were sedated by immersion in tricaine methane sulfonate (MS 222, 0.4 g/l H2O, pH 7.4) and then injected subcutaneously with alphaxalone anaesthetic (0.4 ml ‘Saffan’, Schering-Plough Animal Health, IE). For RNA extraction, fresh brain tissue was dissected, snap frozen in liquid nitrogen and stored at –80 ° C. For histology, each anaesthetized eel was perfused through the heart with phosphate-buffered saline solution (PBS; 0.1 M, pH 7.4) containing procaine (1 g/l) followed by a fixative solution of 4% paraformaldehyde (PFA) in PBS. The brain was removed and postfixed in 4% PFA/PBS for 24 h. After postfixation, the brains for in situ hybridization were mounted in 5% agar/PBS and completely sectioned (100 m) serially in the horizontal or transverse planes with a vibrating microtome (VT1000S, Leica Microsystems, Germany). The sections were then dehydrated through a series of methanol/PBT (PBT = 0.1% Triton X-100 in PBS; 25, 50, 75%; 1 ! 5 min) washes, followed by 2 ! 5 min 100% methanol washes and stored at –20 ° C. Two additional perfused brains were equilibrated in 30% sucrose/ PBS solution overnight at 4 ° C and frozen in optimal cutting temperature compound (BDH, UK) before being cut on a cryostat (OTF, Bright, Huntingdon, UK). These sections (30 m) were then stained with cresyl violet (0.5%) to provide reference series for cytoarchitectural study. lows: 95 ° C for 1 min followed by 35 cycles of 95 ° C for 30 s, 62 ° C for 40 s, 72 ° C for 1 min. PCR products were cloned into the pCR쏐II vector using the TA Cloning Dual Promoter Kit (Invitrogen, UK) and the insert sequenced on both DNA strands. The corresponding amino acid sequence was predicted using MacVector TM software (Accelrys, San Diego, Calif., USA). In order to confirm the identity of the cloned putative eel BDNF sequence, BLASTN searches [Altschul et al., 1997] of the NCBI database were carried out. ClustalW alignments [Higgins, 1994] with the eel BDNF cDNA and predicted amino acid sequences were also carried out with neurotrophin sequences retrieved from the NCBI GenBank and GenPept databases. where S = C and G, R = G and A, Y = C and T. PCR was carried out using 1% of the sscDNA template, 0.6 M of each BDNF primer, 2 units Taq DNA polymerase (New England Biolabs, UK) and 0.2 mM dNTPs (Invitrogen, UK). Cycling conditions were as fol- Probe Synthesis and in situ Hybridization Plasmid DNA, containing the BDNF insert, was linearized with appropriate restriction enzymes (i.e., EcoRV and BamHI, New England Biolabs, UK). Antisense and sense RNA probes were generated by in vitro transcription with SP6 and T7 RNA polymerases (Roche, Germany), respectively in the presence of digoxigenin-labeled ribonucleotides (Roche, Germany) from 1 g of linearized plasmid. For in situ hybridization, free-floating sections were rehydrated through a series of methanol/PBT (75, 50, 25%; each 1 ! 5 min) washes at 4 ° C. After 2 ! 10 min washes in PBT, they were treated with proteinase K (10 g/ml in 50 mM Tris-HCl pH 7.5, 5 mM EDTA) for 5 min at room temperature, washed twice in PBT and fixed for 20 min in 0.2% glutaraldehyde/4% PFA in PBT. Fixation was followed by washes in PBT at room temperature (3 ! 5 min) and 1 ! 30 min at 55 ° C. The sections were prehybridized at 55 ° C for 15 min in a hybridization solution containing 2% blocking reagent (Roche, Germany), 50% formamide, 5! SSC, 0.5% 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 500 g/ml Heparin, 1 g/ml yeast tRNA, 0.1% Tween 20 and 5 mM EDTA and left to prehybridize overnight at 55 ° C in fresh solution. Probes were denatured at 80 ° C for 3 min and sections were then incubated at 55 ° C overnight in hybridization solution containing either antisense or sense BDNF probe at a concentration of 2 ng/l. RNase free conditions were maintained throughout all prehybridization and hybridization steps as advised in Rattray and Michael [1998]. Post-hybridization washes were carried out at 60 ° C as follows: 2 ! 10 min in 2! SSC; 3 ! 20 min in 2! SSC/0.1% CHAPS; 3 ! 20 min in 0.2! SSC/0.1% CHAPS. The sections were then washed for 2 ! 10 min in TNT (TNT = 100 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% Tween 20) at room temperature and blocked in blocking buffer (0.1 M maleic acid, 0.15 M NaCl, 3% blocking reagent (Roche, Germany)) for 3 h at 4 ° C. Sections were incubated overnight in fresh blocking buffer containing a 1:1000 dilution of anti-digoxigenin Fab fragments conjugated with alkaline phosphatase (Roche, Germany) at 4 ° C. The sections were washed (5 ! 1 h) at room temperature in TNT and rocked in TNT overnight at 4 ° C. On the day the signal was developed, sections were washed in 3 changes of NMT (NMT = 100 mM Tris-HCl, pH 9.5, 100 mM NaCl, 50 mM MgCl2) for 15 min each. The chromogenic reaction was carried out in NMT containing 175 g/ml 4-nitro blue tetrazolium chloride (NBT; Roche, Germany) and 62.5 g/ml 5-bromo-4-chloro-3-indolyl-phophate (BCIP; Roche, Germany). Sections were developed in the dark at room temperature and then fixed in 4% PFA/ PBS before mounting on slides. BDNF in Eel Brain Brain Behav Evol 2009;73:43–58 Cloning of an Anguilla anguilla BDNF cDNA Fragment Total RNA was extracted from the brain of one animal using Tri reagent (MRC, Cincinnati, Ohio, USA) and single-stranded complementary DNA (sscDNA) was synthesized from 1 g of DNase treated total RNA in the presence of oligo (dT)12–18 primers (Invitrogen, UK), using PowerScriptTM Reverse Transcriptase (BD Biosciences, UK) according to the manufacturer’s instructions. Degenerate PCR primers were designed using MacVectorD software (Accelrys, San Diego, Calif., USA), based on conserved coding regions of available BDNF cDNA sequences from four teleost species: carp, platyfish, zebrafish and flounder (GenBank accession numbers L27171, X59942, NM_131595 and AY074888, respectively). The resulting degenerate primer sequences were as follows: forward: 5ⴕ- CTCRCGGGTGATGATCAGCAACCA-3ⴕ and reverse: 5ⴕ-TSCCYCTY TTAATGGTCAATGTGCATA-3ⴕ, 45 Fig. 1. Partial 467 bp cDNA sequence for Anguilla anguilla BDNF (GenBank accession number AY762996) with predicted amino acid sequence (GenPept accession number AAV31512). The binding positions of the forward and reverse degenerate primers are located in the boxed regions. Positions of degenerate bases are marked by the closed arrowheads. Degenerate nucleotide choices are included at the relevant positions. The open arrowheads indicate the position of a consensus sequence for an N-glycosylation site. The arrow marks the site at which the precursor is cleaved to form mature BDNF. Microscopic Examination, Data Analysis Light microscopic images were collected using a microscope (Nikon E600) and a digital camera (Optronics, Goleta, Calif.). The locations of the labeled cell profiles were charted at 40! magnification using a camera lucida. Cells were included when the label was clearly visible above background but absent from sense controls. In order to designate the labeled cells, correlations were made between the cresyl violet-stained and hybridized sections. Standard nomenclature, as used in previous studies on A. anguilla [Meredith et al., 1987; Meredith and Roberts, 1987; Roberts et al., 1989; Molist et al., 1993; Kapsimali et al., 2000; Bosch and Roberts, 2001] was followed whenever possible, otherwise the brain atlas for A. japonica [Mukuda and Ando, 2003], a closely related species [Minegishi et al., 2005], was utilized. Results Molecular Characterization of BDNF cDNA A 467 bp partial cDNA fragment was amplified, cloned and sequenced (fig. 1), that was deemed to encode A. anguilla BDNF. This conclusion was based on the results of 46 Brain Behav Evol 2009;73:43–58 pairwise alignments, which revealed a high level of nucleotide (87–88% with other teleost fish) and protein (ranging from 79 to 97% for all species examined) identity between the cloned sequence and other BDNF sequences from various species but lower identity level (^58%) with other neurotrophin amino acid sequences. In a multiple alignment between the predicted and other neurotrophin amino acid sequences, it was observed that the cloned fragment encompasses the five variable regions that exist between the mature forms of the peptide sequences for the different neurotrophin family members (fig. 2). Furthermore, all results retrieved by a BLASTN search of the NCBI GenBank database with the 467 bp cDNA sequence were BDNF sequences from other species. The best sequence match, with an Expect Value of 2e–142, was found to be the BDNF cDNA sequence for the flounder, Paralichthys olivaceus (GenBank accession number AY074888), which shared 89% identity over 459 bases with the 467 bp cloned fragment from A. anguilla. On submission to the NCBI GenBank database, the partial eel BDNF cDNA sequence was assigned the accession Dalton /Borich /Murphy /Roberts Fig. 2. Multiple alignment of the predicted amino acid sequence for Anguilla anguilla BDNF (GenPept accession number AAV31512) with amino acid sequences for BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) from other species. NT-6/7 refers to neurotrophin-6 or neurotrophin-7 as they appear to be orthologues of the same gene in different species [Dethleffsen et al., 2003]. The amino and the carboxyl termini are indicated by the boxes labeled N-term and Cterm, respectively. The variable regions between neurotrophins defined by Dethleffsen et al. [2003] are boxed and marked by the roman numerals I–V. For the purposes of diagrammatic clarity regions of amino acid sequences only relevant to the eel BDNF sequence are included and, therefore, portions of prepro- and propeptide regions from some species have been excluded. GenPept accession numbers and percentage identity with the eel BDNF sequence (AAV31512) were as follows: BDNF: platyfish (PLA): CAA42567, 97%; zebrafish (ZEB): NP_571670, 95%; rat: AAH87634, 91%; NGF: zebrafish: AAO31814, 43%; rat: P25427, 46%; NT-3: zebrafish: AAH92731, 46%; rat: NP_112335, 49%; NT6/7: zebrafish: AAO31821, 46%; platyfish: AA61923, 47%; NT-4/5: rat: AAA41728, 53%. The sequence for Tetraodon (TET) NT-4/5 was taken from Dethleffsen et al. [2003] and shared 43% identity with the eel BDNF sequence. * = Identical amino acids; R = conservative substitutions. BDNF in Eel Brain Brain Behav Evol 2009;73:43–58 47 A B D C 48 E Brain Behav Evol 2009;73:43–58 Dalton /Borich /Murphy /Roberts number AY762996. The predicted amino acid sequence was given the GenPept accession number AAV31512. Fig. 3. BDNF mRNA transcript location in transverse sections of the rostral and middle regions of the eel brain. A Caudal portion of the central zone of the area dorsalis (Dc in fig. 5C). B Rostral portion of the lateral nucleus of the area ventralis. Regions containing labeled cells are indicated by the arrows in A and B. C The stratum periventriculare of the tectum (SPV in fig. 6A–D) is denoted by arrowheads. Labeling in the torus semicircularis (TS in fig. 6B–D) is indicated by arrows. D Labeled cells are depicted in the anterior (arrowheads; A in fig. 5F) and ventrolateral (VL) nuclei of the thalamus, in the nucleus preopticus magnocellularis, pars gigantocellularis (PMg), nucleus preopticus parvocellularis posterior (PPp) and suprachiasmatic nucleus (arrows; SC in fig. 5F). Labeling was not seen in the rostral portion of the ventromedial nucleus of the thalamus (VM in fig. 5F), the region marked by *. E nucleus preopticus magnocellularis, pars parvocellularis (PMp in fig. 5C). Scale bars = 200 m for A , C and D and 100 m for B and E . packed cells in the ventral nucleus of the area ventralis (Vv) was also apparent at this level, although the lateral (Vl) and dorsal (Vd) nuclei of the area ventralis were not labeled (fig. 5B). More caudally, densely packed cells in the posterior area of lateral zone of the area dorsalis (Dlp) were moderately labeled (fig. 5C). The medial region of lateral zone of the area dorsalis (Dl) was not labeled although more laterally located cells did show a moderate signal. Most of the cells in the medial (Dm) and central (Dc; fig. 3A) zone of the area dorsalis were moderately labeled. A few scattered cells lining the ventricle in the posterior nucleus of the area ventralis (Vp) were lightly labeled. In the most caudal sections of the telencephalon (fig. 5D), the majority of cells in the area dorsalis were moderately labeled. A few scattered cells were lightly labeled in the entopeduncular nucleus (E) and the posterior nucleus of the area ventralis (Vp). The BDNF mRNA expression pattern for the diencephalon is indicated in table 1 and figures 3, 5 and 6. In the rostral portion of the nucleus preopticus parvocellularis posterior (PPp), strong labeling of small densely packed cells was observed (fig. 5D) and more caudally, densely packed cells were moderately labeled in this nucleus (fig. 3D, 5E, F). Strong to moderate labeling was also obvious in the magnocellular nuclei of the preoptic area (PMp: fig. 3E, 5C; PMm: fig. 5D; PMg: fig. 3D, 5F). BDNF mRNA expression was also evident in the suprachiasmatic nucleus (SC), the cells of which were heavily labeled in the rostral region of this nucleus (fig. 5D) and moderately labeled more caudally (fig. 3D, 5E, F). In the epithalamus, most of the cells of the dorsal and ventral habenular nuclei (HAd and HAv; fig. 5E, F) were moderately labeled. Moderate to light labeling of cells was seen in various thalamic nuclei (fig. 3D, 5E, F, 6A, B), except in the rostral portion of the ventromedial nucleus where no labeling was seen (fig. 3D, 5F, 6A). Strong labeling was apparent in densely packed hypothalamic cells with a periventricular location such as the nucleus of the lateralis tuberis (nTL; fig. 6A, B), the caudal (HC) and ventral (HV) zones of the periventricular hypothalamus (fig. 6B–D). Moderate labeling was also observed in the majority of the cells in the diffuse nucleus of the inferior lobe (ndil; fig. 6C, D). Light labeling was seen in the subcommissural organ (SCO; fig. 6A) in occasional cells. Moderate labeling was seen in the majority of cells in the nucleus pretectalis periventricularis, pars dorsalis (PPd; fig. 6A) and light labeling of some scattered cells was observed in the nucleus pretectalis centralis (CP; fig. 6A). BDNF in Eel Brain Brain Behav Evol 2009;73:43–58 Spatial Distribution of BDNF mRNA Expression in the Eel Brain and Rostral Spinal Cord Expression of BDNF mRNA was detected using antisense RNA probe and was found in localized positions throughout the brain, most robustly in parts of the diencephalon and mesencephalon. It was also notable that several cell groups in the rhombencephalon expressed BDNF. Throughout, the signal was restricted to cells that had neuronal morphology and was not observed in equivalent sections hybridized to the BDNF sense control probe (fig. 4). Charts showing the distribution of the cells within the brain of one animal, with BDNF transcripts represented by black dots, are provided in figures 5–8. Illustrative photomicrographs are provided in figures 3 and 4. In addition, the BDNF mRNA expression patterns, as seen in all the hybridized brains, are summarized in table 1 in a semiquantitative manner as described in the table legend in correspondence with Conner et al. [1997]. The cell groupings of the telencephalon are listed in table 1. Weak labeling of scattered cells was observed in all layers of the olfactory bulb (fig. 5A). In the most rostral telencephalic hemispheres, moderate labeling was seen mainly in the dorsal, medial and lateral zones of the area dorsalis and the lateral nucleus of the area ventralis (fig. 3B). More caudally in the telencephalon (fig. 5B), moderate labeling was still apparent in the area dorsalis; however, labeling was absent in the central zone of the area dorsalis (Dc). Moderate labeling of small densely 49 A 50 B C D E F Brain Behav Evol 2009;73:43–58 Dalton /Borich /Murphy /Roberts Nuclei of the posterior tuberculum that showed light labeling were the preglomerular nuclear complex in scattered cells (PGm; fig. 6A–C) and the periventricular nucleus of the posterior tuberculum in the majority of cells (TPp; fig. 6A). Moderate labeling of most of the cells was seen in the paraventricular organ (PVO; fig. 6A) and strong labeling of densely packed cells in the nucleus posterior tuberis (TP; fig. 6C) was observed. The expression pattern for BDNF mRNA in the mesencephalon is indicated in table 1 and figure 3 and 6. The numerous small, densely packed neurons of the stratum periventriculare, the deepest and only tectal layer to show BDNF expression, labeled intensely (SPV; fig. 3C, 6A–D). Densely packed cells in the torus semicircularis were moderately labeled (TS; fig. 3C, 6B–D). The signal was strong in neurons in the nucleus lateralis valvulae (LV; fig. 6D), otherwise cells in other regions of the mesencephalic tegmentum mostly showed moderate expression. Some cell masses in the mesencephalic tegmentum that were not labeled included the red, superior raphe, lateral mesencephalic profundus, and interpeduncular nuclei, as well as the tegmental lateral group. The expression pattern of BDNF mRNA in the rhombencephalon is summarized in table 1. Most cell groups showed BDNF expression, although none was particularly robust (fig. 4, 7, 8). Little labeling was seen in the cerebellum although a few scattered cells in the Purkinje cell layer were lightly labeled (fig. 7B). Large cells in the superior (SRF; fig. 7A), medial (MRF; fig. 4C, E, 7B–D) and inferior (IRF; fig. 8A–C) divisions of the reticular formation, including ‘identifiable’ neurons such as the Mauthner-like cell, were moderately labeled (M; fig. 4F, 7B). This large cell is similar to the Mauthner neuron of other teleosts in many respects, including a close relationship with the octavus system [Meredith et al., 1987]. In the octavolateral system, moderate labeling of scattered cells was seen in the magnocellular nucleus (MO; fig. 7B-D) and octavolateral efferent nucleus (OEN; fig. 8A), and of most cells in the tangential nucleus (TO; fig. 7D), but only light labeling of occasional cells was observed in the descending nucleus (DO; fig. 8B). The majority of cells in the motor nuclei of certain cranial nerves (trochlear, facial, glosso-pharyngeal and vagal, nIV, nVIIm, nIXm, nXm; fig. 4A, 6D, 8A–C), and a few, scattered cells of the trigeminal motor nucleus (nVm; fig. 7A) were moderately labeled. But labeling (moderate) was only seen in sensory regions of the trigeminal nerve (nVs; fig. 7A), the rostral portion of the vagal lobe (LX; fig. 8B) and occasionally (light) in the facial lobe (LVII; fig. 7C, D). The commissural nucleus of Cajal was not labeled (nCC; fig. 8C). In the rostral spinal cord, large cells were labeled throughout the ventral horn whilst smaller cells showed BDNF mRNA expression in the dorsal horn. Discussion Our survey of BDNF mRNA expression in the eel reveals a pattern similar to that reported for the mammalian [Wetmore et al., 1990; Conner et al., 1997], avian [Herzog and von Bartheld, 1998] and amphibian brain [Duprey-Díaz et al., 2002; Wang et al., 2005]. As in these species, eel expression was seen in portions of all brain regions. The labeling was particularly strong in the preoptic area, the hypothalamus, the periventricular nucleus of the posterior tuberis and the nucleus lateralis valvulae. However, in contrast to what has been reported for mammals, BDNF mRNA expression in the eel was also evident in the reticular formation and other brain stem nuclei, some of which project down the spinal cord and are involved in the control of movement. showing groups of labeled cells (indicated by the arrows) in the facial motor nucleus. B Adjacent section to that in A hybridized to the sense probe. C Transverse section at the level of the medial reticular formation. Arrows indicate examples of regions containing groups of labeled cells. D Corresponding sense control for C . E Horizontal section showing labeled cells (examples indicated by arrows) in the medial reticular formation. F Mauthner-like cell (M in fig. 7B). Scale bars = 200 m for A–E , 100 m for F. Anguilla anguilla BDNF cDNA A. anguilla, an elopomorph, is, to date, the most basic teleost for which BDNF has been sequenced. In pairwise alignments, the amino acid sequence for eel BDNF displayed only 33% identity with the sequence of the lamprey neurotrophin, lf-nt [Hallböök et al., 1998]. On the other hand, it showed 79% identity with the BDNF sequence for the ray [Hallböök et al., 1991], a cartilaginous fish, and 86–97% identity with BDNF sequences from other teleost fish, Xenopus, chicken, rat, pig and human. This result might be reflective of the second of two gene duplication events thought to be responsible for the evolution of the neurotrophin family from a single ancestral gene in invertebrates [Bothwell, 2006], which occurred BDNF in Eel Brain Brain Behav Evol 2009;73:43–58 Fig. 4. Photomicrographs showing sections of the rhombencephalon hybridized to antisense (A , C , E and F) and sense (B and D) BDNF probes. A Transverse section of the rhombencephalon 51 A Fig. 5. BDNF expression in rostral regions of the eel brain. The profiles are merged camera lucida tracings of two to five successive transverse sections, the approximate level of which is indicated by the vertical lines in the sagittal view of the brain at the top right. Neuronal groups, the names for which are given in full in the Abbreviations list, are outlined on the right side of each profile; the dots on the left side represent the distribution of neuronal cell bodies expressing BDNF. For clarity they are shown as being of the same size although they are not, and as having equivalent expression levels. An indication of the differences in expression level is provided in table 1. A scale bar, which represents 500 m, is provided in figure 5 and also applies to figures 6, 7 and 8. B E C D F A C B Fig. 6. BDNF expression in middle regions of the eel brain. See the legend for figure 5 for further explanation. 52 Brain Behav Evol 2009;73:43–58 D Dalton /Borich /Murphy /Roberts Table 1. Semi-quantitative Assessment of BDNF mRNA Expression Telencephalon Olfactory bulb Internal cell layer External cell layer Glomerulus Telencephalic hemispheres Area dorsalis Medial zone Lateral zone Lateral zone, posterior area Dorsal zone Central zone (rostral) Central zone (caudal) Area ventralis Lateral nucleus (rostral) Lateral nucleus (middle) Lateral nucleus (caudal) Dorsal nucleus (rostral) Dorsal nucleus (caudal) Ventral nucleus (rostral) Ventral nucleus (caudal) Posterior nucleus Entopeduncular nucleus Diencephalon Nucleus preopticus Magnocellularis, pars parvocellulis Magnocellularis, pars magnocellularis (rostral) Magnocellularis, pars magnocellularis (caudal) Parvocellularis posterior (rostral) Parvocellularis posterior (caudal) Magnocellularis, pars gigantocellularis Suprachiasmatic nucleus (rostral) Suprachiasmatic nucleus (caudal) Dorsal habenular nucleus Ventral habenular nucleus Thalamus Anterior nucleus Ventrolateral nucleus Ventromedial nucleus (rostral) Ventromedial nucleus (caudal) Dorsal posterior nucleus Posterior nucleus Nucleus lateralis tuberis Diffuse nucleus of inferior lobe Caudal zone of periventricular hypothalamus Ventral zone of periventricular hypothalamus Subcommissural organ Nucleus pretectalis periventricularis, pars dorsalis Nucleus pretectalis centralis Preglomerular nuclear complex Periventricular nucleus of posterior tuberculum Paraventricular organ Nucleus posterior tuberis BDNF in Eel Brain +/2 +/2 +/2 ++/2-3 ++/2-3 ++/3 ++/3 – ++/3 ++/3 – +/2 – +/3 – ++/3 +/2 +/2 +++/3 +++/3 ++/2 +++/3 ++/3 ++/3 +++/3 ++/3 ++/3 ++/3 ++/2 ++/3 – +/3 ++/2 +/3 +++/3 ++/3 +++/3 +++/3 +/1 ++/3 +/2 +/2 +/3 ++/3 +++/3 Mesencephalon Torus semicircularis Stratum periventriculare of tectum Nucleus of the medial longitudinal fasciculus Red nucleus Oculomotor nucleus Trochlear nucleus Nucleus lateralis valvulae Secondary gustatory nucleus Nucleus isthmi Superior reticular nucleus ++/3 +++/3 ++/2 – ++/3 ++/3 +++/3 ++/3 ++/3 ++/3 Rhombencephalon Cerebellum-Purkinje cell layer Locus coeruleus Superior olive Inferior raphe nucleus Area postrema Superior reticular formation Mauthner-like cell Medial reticular formation Inferior reticular formation Magnocellular octavolateral nucleus Tangential octavolateral nucleus Octavolateral efferent nucleus Descending octavolateral nucleus Sensory nucleus of the trigeminal nerve Facial lobe Trigeminal motor nucleus Facial motor nucleus Glossopharyngeal motor nucleus Vagal lobe (rostral) Vagal lobe (caudal) Vagal motor nucleus Commissural nucleus of Cajal +/2 +/2 ++/3 ++/2 +/2 ++/2 ++ ++/2 ++/3 ++/2 ++/3 ++/2 +/1 ++/3 +/2 ++/2 ++/3 ++/3 ++/3 – ++/3 – Rostral spinal cord Dorsal horn Ventral horn ++/2 ++/2 Expression level: – = none + = weak ++ = moderate +++ = strong; cells labeled: 1 = very few cells, 2 = some scattered cells, 3 = most cells. Nuclei have been divided into rostral, caudal and/ or middle when labeling differed between levels. Brain Behav Evol 2009;73:43–58 53 A C B Fig. 7. BDNF expression in more caudal re- gions of the eel brain. See the legend for figure 5 for further explanation. after the emergence of agnathan fish but before the emergence of cartilaginous fish [Hallböök, 1999; Hallböök et al., 2006]. BDNF mRNA Expression in the Eel Brain The ventral region of the lateral zone of the area dorsalis of the telencephalon, where moderate labeling of some cells was seen throughout, has been suggested as the teleostean equivalent of the mammalian hippocampus [Wullimann and Rink, 2002; Yamamoto et al., 2007]. In the rodent, strong BDNF expression is seen in the hippocampus [Conner et al., 1997] and BDNF has been implicated in hippocampal synaptic plasticity [Patterson et al., 1996; Kang et al., 1997], and might serve this role in teleost fishes as well. In the eel brain, labeling was seen in regions of the medial zone of the area dorsalis and in the entopeduncular nucleus, regions that have been homolo54 Brain Behav Evol 2009;73:43–58 D gized with the mammalian amygdala [Braford and Northcutt, 1974; Reiner and Northcutt, 1992; Wullimann and Rink, 2002], where BDNF mRNA expression has been observed [Conner et al., 1997]. More medially in the diencephalon, clusters of neurons expressed BDNF strongly, including the nucleus posterior tuberis. This zone contains dopaminergic cells [Roberts et al., 1989; Rink and Wullimann, 2001] and connects reciprocally with the dorsal and ventral telencephalon [Folgueira et al., 2004a, b; Rink and Wullimann, 2004]. Accordingly, it has been proposed as the source of the ascending dopaminergic system of the teleostean brain [Rink and Wullimann, 2001; Wullimann and Rink, 2002]. The equivalent ascending system in other vertebrates originates in the mesencephalic tegmentum, where in teleosts there are no dopaminergic neurons, an observation that leads to questions about the Dalton /Borich /Murphy /Roberts A C Fig. 8. BDNF expression in the most cau- dal regions of the eel brain. See the legend for figure 5 for further explanation. B striatal/basal ganglia organization [Meek, 1994]. In this context, it is perhaps interesting to note that mammalian mesencephalic dopaminergic neurons do synthesize BDNF [Seroogy et al., 1994; Conner et al., 1997]. In the eel, as in mammals [Conner et al., 1997], BDNF expression was observed in sensory regions, and in sensory integrating structures. For example, BDNF mRNA expression in the eel was seen in nuclei of the lateral line and octaval systems. Strong BDNF mRNA expression was observed in the torus semicircularis, which receives multimodal input from the lateral line and octavus systems and the tectum, and is considered to be a homologue of the mammalian inferior colliculus [Schellart, 1990]. Multimodal relay centers of the diencephalon, such as the thalamus and the preglomerular complex, which may be homologous to the dorsal thalamus in mammals [Yamamoto and Ito, 2005; Ishikawa et al., 2007], also expressed BDNF mRNA. BDNF mRNA expression has been described in many of the thalamic nuclei of the rat [Conner et al., 1997]. Strong BDNF mRNA expression was also seen in the eel in the nucleus lateralis valvulae, a relay station of indirect cerebellar pathways that appears to be concerned with visual and non-visual sensory information in fish [Meek, 1990; Schellart, 1990; Wullimann et al., 1996; Yang et al., 2004, 2007]. The nucleus lateralis valvulae has been compared to the pontine nuclei of the mammalian brain stem [Yang et al., 2004] in which BDNF mRNA expression has been described in the rat [Conner et al., 1997]. A few scattered cells were labeled in the Purkinje cell layer of the cerebellum, which lies at the border of the outer molecular layers (CbSm) and the granular layer (CbSg). Neurogenesis persists in the adult fish brain and the main site of proliferative activity is the cerebellum, but 5-bromo-2-deoxyuridine labeled cells have also been found in regions such as the telencephalon, diencephalon, mesencephalon and rhombencephalon [Zupanc and Horschke, 1995; Zupanc, 1999, 2001; Zikopoulos et al., 2000]. BDNF appears to be important in neurogenesis in the mammalian brain [Rossi et al., 2006; Chen et al., 2007; Tonchev et al., 2007; Bath et al., 2008] and it may be the case therefore that BDNF supports neurogenesis in the cerebellum and other regions of the eel brain mentioned above. Moderate BDNF mRNA expression was observed in the eel throughout the motor column (cranial nerves III– X), the neurons of which contribute to eye, jaw and gill movements. BDNF mRNA expression in equivalent cell groups in the mammalian brain is more varied. For example, none has been seen in the dorsal motor nucleus or nucleus ambiguus of the vagus nerve [Wetmore et al., 1990; Conner et al., 1997] nor in the trochlear nucleus, whereas BDNF mRNA is expressed by oculomotor neurons [Conner et al., 1997]. BDNF in Eel Brain Brain Behav Evol 2009;73:43–58 55 Many other tegmental motor systems in the eel contribute to locomotory control by providing supraspinal input to spinal neurons; the eel, as other teleosts, has no direct input equivalent to the mammalian corticospinal pathway [Bosch and Roberts, 2001]. There was no BDNF mRNA expression in the red nucleus but moderate labeling for BDNF mRNA was seen in other spinally projecting nuclei such as the inferior raphe nucleus, the Mauthner-like cell, the superior, medial and inferior divisions of the reticular formation, the nucleus of the medial longitudinal fasciculus, the ventromedial nucleus of the thalamus and some octavolateral nuclei. Little BDNF expression is seen in homologous adult mammalian brain stem nuclei although in the rat, cells immunoreactive for BDNF have been reported in the spinal vestibular, dorsal raphe and gigantocellular reticular nuclei [Conner et al., 1997; Furukawa et al., 1998; Murer et al., 1999]. However, these, and other cell groups of the reticular formation, lack BDNF mRNA expression [Ceccatelli et al., 1991; Friedman et al., 1991; Conner et al., 1997] although BDNF mRNA is expressed transiently in these regions during development [Friedman et al., 1991]. It is tempting to think that the basal BDNF expression of some of the eel descending neurons might be a factor that aids in their regeneration after cordotomy. However, the correlation between BDNF expression and axon regrowth is not precise, as BDNF mRNA expression was seen in both rapidly [e.g., inferior reticular nucleus; Becker et al., 1997, 1998; Roberts et al., unpublished observations] and slowly (e.g., Mauthner cell) regenerating systems. More likely perhaps, the difference in BDNF expression might lie in the different growth patterns of fish and mammals. Eels, as other teleost fish, continue to grow throughout life and BDNF levels might need to be sustained as this continual growth impacts on the nervous system. The growth of the body involves an increase in the size and number of muscle fibers [Willemse and van den Berg, 1978], the innervating motoneurons of which progressively grow [Smit et al., 1991]. 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