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Brain Asymmetry: Switching from Left to Right

2005; Elsevier BV; Volume: 15; Issue: 9 Linguagem: Inglês

10.1016/j.cub.2005.04.026

1879-0445

Shin-Yi Lin, Rebecca D. Burdine,

Child and Animal Learning Development

The relationship between structural and functional asymmetries in the brain remains unclear. A recent report describes a zebrafish mutant that provides us with some enticing clues about this relationship. The relationship between structural and functional asymmetries in the brain remains unclear. A recent report describes a zebrafish mutant that provides us with some enticing clues about this relationship. The vertebrate brain contains a number of striking left–right asymmetries [1Bisazza A. Rogers L.J. Vallortigara G. The origins of cerebral asymmetry: a review of evidence of behavioural and brain lateralization in fishes, reptiles and amphibians.Neurosci. Biobehav. Rev. 1998; 22: 411-426Crossref PubMed Scopus (337) Google Scholar, 2Toga A.W. Thompson P.M. Mapping brain asymmetry.Nat. Rev. Neurosci. 2003; 4: 37-48Crossref PubMed Scopus (931) Google Scholar]. For example, in humans language is processed predominantly in the left hemisphere — an observation that has become a classic example of brain lateralization [2Toga A.W. Thompson P.M. Mapping brain asymmetry.Nat. Rev. Neurosci. 2003; 4: 37-48Crossref PubMed Scopus (931) Google Scholar]. However, some individuals have been found who process language with either their right or both hemispheres, and they have language skills similar to those with typical left-sided processing [3Knecht S. Drager B. Floel A. Lohmann H. Breitenstein C. Deppe M. Henningsen H. Ringelstein E.B. Behavioural relevance of atypical language lateralization in healthy subjects.Brain. 2001; 124: 1657-1665Crossref PubMed Scopus (93) Google Scholar]. It is not clear, therefore, to what degree lateralized processing influences our language abilities. We also do not understand how this and other functional asymmetries are initiated or maintained in the brain during development. One possibility is that asymmetries in the structure of the brain may influence the subsequent function of the organ. Yet individuals with anatomical reversals in brain structure, due to a condition called situs inversus totalis, still retain left-sided language processing [4Kennedy D.N. O’Craven K.M. Ticho B.S. Goldstein A.M. Makris N. Henson J.W. Structural and functional brain asymmetries in human situs inversus totalis.Neurology. 1999; 53: 1260-1265Crossref PubMed Google Scholar]. These results suggest that, for some cognitive tasks, function may not follow structure. Experiments reported in this issue of Current Biology [5Barth K.A. Miklosi A. Watkins J. Bianco I.H. Wilson S.W. Andrew R.J. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy and a subset of behavioral responses.Curr. Biol. 2005; 15 (this issue): 000-000Abstract Full Text Full Text PDF Scopus (141) Google Scholar] challenge us to re-examine the relationship between structural and functional asymmetries in the brain, and prompt further investigation of the connection between left–right patterning in the brain and the rest of the body. The zebrafish is known to have both behavioral and neuroanatomical asymmetries. They show biased turning direction and preferential eye use when encountering familiar versus novel stimuli [6Miklosi A. Andrew R.J. Savage H. Behavioural lateralisation of the tetrapod type in the zebrafish (Brachydanio rerio).Physiol. Behav. 1997; 63: 127-135Crossref PubMed Scopus (80) Google Scholar]. For example, they predominantly use their left eye to view known objects and their right eye to view unfamiliar objects. The zebrafish forebrain displays neuroanatomical asymmetries in both the pineal complex and the habenular nuclei within the dorsal diencephalon [7Concha M.L. Burdine R.D. Russell C. Schier A.F. Wilson S.W. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.Neuron. 2000; 28: 399-409Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 8Liang J.O. Etheridge A. Hantsoo L. Rubinstein A.L. Nowak S.J. Izpisua Belmonte J.C. Halpern M.E. Asymmetric nodal signaling in the zebrafish diencephalon positions the pineal organ.Development. 2000; 127: 5101-5112PubMed Google Scholar, 9Concha M.L. Russell C. Regan J.C. Tawk M. Sidi S. Gilmour D.T. Kapsimali M. Sumoy L. Goldstone K. Amaya E. et al.Local tissue interactions across the dorsal midline of the forebrain establish CNS laterality.Neuron. 2003; 39: 423-438Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 10Gamse J.T. Thisse C. Thisse B. Halpern M.E. The parapineal mediates left-right asymmetry in the zebrafish diencephalon.Development. 2003; 130: 1059-1068Crossref PubMed Scopus (146) Google Scholar, 11Aizawa H. Bianco I.H. Hamaoka T. Miyashita T. Uemura O. Concha M.L. Russell C. Wilson S.W. Okamoto H. Laterotopic representation of left-right information onto the dorso-ventral axis of a zebrafish midbrain target nucleus.Curr. Biol. 2005; 15: 238-243Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. The pineal complex consists of a centrally located pineal organ whose stalk is displaced from the midline and a laterally placed parapineal organ. The paired dorsal habenular nuclei show asymmetries in gene expression, structural organization and axonal projections. These asymmetries are generally concordant, with left-sided parapineal placement accompanied by a denser left habenular nucleus, while right-sided parapineal placement accompanies a denser right habenular nucleus [7Concha M.L. Burdine R.D. Russell C. Schier A.F. Wilson S.W. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.Neuron. 2000; 28: 399-409Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 9Concha M.L. Russell C. Regan J.C. Tawk M. Sidi S. Gilmour D.T. Kapsimali M. Sumoy L. Goldstone K. Amaya E. et al.Local tissue interactions across the dorsal midline of the forebrain establish CNS laterality.Neuron. 2003; 39: 423-438Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 10Gamse J.T. Thisse C. Thisse B. Halpern M.E. The parapineal mediates left-right asymmetry in the zebrafish diencephalon.Development. 2003; 130: 1059-1068Crossref PubMed Scopus (146) Google Scholar]. Interestingly, the specific sidedness of these asymmetries is preserved on a population level: Most wild-type fish have left-sided placement of the parapineal and a denser left habenular nucleus [7Concha M.L. Burdine R.D. Russell C. Schier A.F. Wilson S.W. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.Neuron. 2000; 28: 399-409Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 10Gamse J.T. Thisse C. Thisse B. Halpern M.E. The parapineal mediates left-right asymmetry in the zebrafish diencephalon.Development. 2003; 130: 1059-1068Crossref PubMed Scopus (146) Google Scholar]. The coordination of their neuroanatomical placement raises the possibility that these structures regulate behaviors that manifest themselves on a population level [1Bisazza A. Rogers L.J. Vallortigara G. The origins of cerebral asymmetry: a review of evidence of behavioural and brain lateralization in fishes, reptiles and amphibians.Neurosci. Biobehav. Rev. 1998; 22: 411-426Crossref PubMed Scopus (337) Google Scholar]. Previous studies have revealed that the pineal complex and the habenular nuclei are subject to laterality signals during development. Genes encoding components of the Nodal pathway show left-sided gene expression in the developing forebrain, and alterations of this left-sided gene expression are associated with subsequent randomization of asymmetries in the pineal complex and habenular nuclei [7Concha M.L. Burdine R.D. Russell C. Schier A.F. Wilson S.W. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.Neuron. 2000; 28: 399-409Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 8Liang J.O. Etheridge A. Hantsoo L. Rubinstein A.L. Nowak S.J. Izpisua Belmonte J.C. Halpern M.E. Asymmetric nodal signaling in the zebrafish diencephalon positions the pineal organ.Development. 2000; 127: 5101-5112PubMed Google Scholar]. Left-sided expression of Nodal pathway genes plays a similar role in directing the asymmetries of visceral organs, suggesting a shared mechanism for generating asymmetries in the viscera and the brain (for example, see [12Yan Y.T. Gritsman K. Ding J. Burdine R.D. Corrales J.D. Price S.M. Talbot W.S. Schier A.F. Shen M.M. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation.Genes Dev. 1999; 13: 2527-2537Crossref PubMed Scopus (206) Google Scholar, 13Ahmad N. Long S. Rebagliati M. A southpaw joins the roster: the role of the zebrafish nodal-related gene southpaw in cardiac LR asymmetry.Trends Cardiovasc. Med. 2004; 14: 43-49Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 14Long S. Ahmad N. Rebagliati M. The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry.Development. 2003; 130: 2303-2316Crossref PubMed Scopus (286) Google Scholar]). Barth and colleagues [5Barth K.A. Miklosi A. Watkins J. Bianco I.H. Wilson S.W. Andrew R.J. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy and a subset of behavioral responses.Curr. Biol. 2005; 15 (this issue): 000-000Abstract Full Text Full Text PDF Scopus (141) Google Scholar] have now advanced our understanding of asymmetric structures and functions a step further with their characterization of the frequent situs inversus (fsi) mutant. Zebrafish fsi mutants show a variably penetrant phenotype of reversed laterality in the brain. This abnormal right-sided placement of forebrain structures is predictably preceded by right-sided Nodal expression in the developing forebrain. The group then linked these structural asymmetries to perturbations in functional asymmetries, focusing on left-right lateralized behaviors. By comparing the behavior of fsi fish that displayed right-sided structural asymmetries with those that displayed wild-type left-sided asymmetries, Barth et al. [5Barth K.A. Miklosi A. Watkins J. Bianco I.H. Wilson S.W. Andrew R.J. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy and a subset of behavioral responses.Curr. Biol. 2005; 15 (this issue): 000-000Abstract Full Text Full Text PDF Scopus (141) Google Scholar] discovered three functional consequences of the structural reversal. Some lateralized behaviors showed reversals that accompanied the structural asymmetry, suggesting that these behaviors are influenced by the asymmetric pineal/habenular system. A separate behavior showed similar laterality, regardless of the sidedness of the structural asymmetry. The identification of unaffected lateralities demonstrates that not all functional asymmetries of the brain are regulated by the specific structural asymmetries in the forebrain. Future research should clarify whether these behaviors are regulated by structural asymmetries in other areas of the brain. Finally, a completely novel behavior manifested in larvae with reversed forebrain structures. This last class may help us understand how complex behaviors are influenced or even created by structural asymmetries. Importantly, these experiments correlate asymmetric gene expression, asymmetric brain structure and lateralized behaviors for the first time. The fsi mutant fish also show reversal of left-right asymmetry in the viscera. This is as expected, because Nodal signaling is required for left-right patterning in the zebrafish viscera [12Yan Y.T. Gritsman K. Ding J. Burdine R.D. Corrales J.D. Price S.M. Talbot W.S. Schier A.F. Shen M.M. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation.Genes Dev. 1999; 13: 2527-2537Crossref PubMed Scopus (206) Google Scholar, 13Ahmad N. Long S. Rebagliati M. A southpaw joins the roster: the role of the zebrafish nodal-related gene southpaw in cardiac LR asymmetry.Trends Cardiovasc. Med. 2004; 14: 43-49Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 14Long S. Ahmad N. Rebagliati M. The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry.Development. 2003; 130: 2303-2316Crossref PubMed Scopus (286) Google Scholar]. From the behavioral data reported by Barth et al. [5Barth K.A. Miklosi A. Watkins J. Bianco I.H. Wilson S.W. Andrew R.J. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy and a subset of behavioral responses.Curr. Biol. 2005; 15 (this issue): 000-000Abstract Full Text Full Text PDF Scopus (141) Google Scholar], Nodal signaling seems to be responsible for only a subset of the asymmetries in the brain. Presumably, a separate set of unknown genes establishes these other functional asymmetries. So while there is evidence for a single genetic pathway regulating asymmetries in the viscera, these studies argue for the existence of multiple, parallel pathways directing brain asymmetries — at least on a functional level. The experiments of Barth et al. [5Barth K.A. Miklosi A. Watkins J. Bianco I.H. Wilson S.W. Andrew R.J. fsi zebrafish show concordant reversal of laterality of viscera, neuroanatomy and a subset of behavioral responses.Curr. Biol. 2005; 15 (this issue): 000-000Abstract Full Text Full Text PDF Scopus (141) Google Scholar] encourage a re-examination of functional asymmetries in situs inversus totalis individuals. Investigation of a greater variety of cognitive processes may uncover a subset of lateralized functions that are reversed in situs inversus totalis individuals, who display reversals of both neural and visceral anatomy. The current study can also serve as a foundation for the identification of genes underlying the Nodal-independent brain asymmetries. A lingering question remains regarding these newly correlated structural and functional asymmetries in the zebrafish: does asymmetry in the brain really matter? A handful of studies maintain that it does: chickens with bilateral visual perception show reduced efficiency at some tasks relative to their lateralized counterparts [15Rogers L.J. Evolution of hemispheric specialization: advantages and disadvantages.Brain Lang. 2000; 73: 236-253Crossref PubMed Scopus (263) Google Scholar]; maintenance of asymmetry between specific odor-perception neurons in worms is important for odor discrimination [16Wes P.D. Bargmann C.I. C. elegans odour discrimination requires asymmetric diversity in olfactory neurons.Nature. 2001; 410: 698-701Crossref PubMed Scopus (161) Google Scholar]; and loss of asymmetry in parts of the fly brain diminish long-term memory [17Pascual A. Huang K.L. Neveu J. Preat T. Neuroanatomy: brain asymmetry and long-term memory.Nature. 2004; 427: 605-606Crossref PubMed Scopus (127) Google Scholar]. To take the question further: Why is coordinated asymmetry in a population important? How do the behaviors regulated by the pineal complex and the habenular nuclei benefit from population-level coordination of laterality? For example, it would be interesting if right-sided fsi mutants show a quantifiable defect in social interactions when introduced into a population of left-sided fish. Perhaps stereotypical turning direction is important for predator response or mating behavior. Intriguingly, a few fish with altered asymmetry in the brain and viscera can be found in most laboratory wild-type stocks. Is it possible that these individuals serve some important role in the population in the wild? Or are they at a disadvantage compared to their left-brained counterparts and only survive in the relative safety of the lab? These and other studies will bring us closer to understanding how and why our brains show so many asymmetries.