Brain Structure and Function

, Volume 223, Issue 4, pp 1897–1907 | Cite as

A postmortem stereological study of the amygdala in Williams syndrome

  • Caroline H. Lew
  • Kimberly M. Groeniger
  • Ursula Bellugi
  • Lisa Stefanacci
  • Cynthia M. Schumann
  • Katerina Semendeferi
Original Article
  • 118 Downloads

Abstract

Perturbations to the amygdala have been observed in neurological disorders characterized by abnormalities in social behavior, such as autism and schizophrenia. Here, we quantitatively examined the amygdala in the postmortem human brains of male and female individuals diagnosed with Williams Syndrome (WS), a neurodevelopmental disorder caused by a well-defined deletion of ~ 26 genes, and accompanied by a consistent behavioral profile that includes profound hypersociability. Using unbiased stereological sampling, we estimated nucleus volume, number of neurons, neuron density, and neuron soma area in four major amygdaloid nuclei- the lateral nucleus, basal nucleus, accessory basal nucleus, and central nucleus- in a sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. Boundaries of the four nuclei examined were drawn on Nissl-stained coronal sections as four separate regions of interest for data collection. We found that the lateral nucleus contains significantly more neurons in WS compared to TD. WS and TD do not demonstrate significant differences in neuron number in the basal, accessory basal, or central nuclei, and there are no significant differences between WS and TD in nuclei volume, neuron density, and neuron soma area in any of the four nuclei. A similarly designed study reported a decrease in lateral nucleus neuron number in autism, mirroring the opposing extremes of the two disorders in the social domain. These results suggest that the number of neurons in the lateral nucleus may contribute to pathological disturbances in amygdala function and sociobehavioral phenotype.

Keywords

Williams syndrome Neuropathology Neuroanatomy Neuron number Amygdala 

Notes

Acknowledgements

This research was supported by the National Institutes of Health P01 NICHD033113, 5R03MH103697 and R56MH109587. We wish to thank the tissue donors and their families whose gift to science made this study possible, and especially Terry Monkaba and the Williams Syndrome Association. WS human tissue was obtained under the Ursula Bellugi WS Brain Collection, curated by KS at UC San Diego. Typically, developing human tissue was obtained from the University of Maryland Brain and Tissue Bank, which is a Brain and Tissue Repository of NIH NeuroBioBank. We thank Chelsea Brown, Valerie Judd, Hailee Orfant and Deion Cuevas for tissue processing assistance, and Kari Hanson, Branka Hrvoj, and Linnea Wilder for feedback.

Compliance with ethical standards

Ethical statement

The authors declare they have no conflict of interest. This article does not contain any studies with human participants or authors performed by any of the authors. For this type of study formal consent is not required.

References

  1. Adolphs R (2001) The neurobiology of social cognition. Curr Opin Neurobiol 11:231–239CrossRefPubMedGoogle Scholar
  2. Adolphs R, Tranel D, Damasio H, Damasio A (1994) Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372:669–672CrossRefPubMedGoogle Scholar
  3. Adolphs R, Tranel D, Hamann S, Young a W, Calder a J, Phelps E, Lee A, Damasio a GP R (1999) Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37:1111–1117CrossRefPubMedGoogle Scholar
  4. Aggleton JP, Burton MJ, Passingham RE (1980) Cortical and subcortical afferents to the amygdala of the rhesus monkey (Macaca mulatta). Brain Res 190:347–368CrossRefPubMedGoogle Scholar
  5. Ashwin C, Baron-Cohen S, Wheelwright S, O’Riordan M, Bullmore ET (2007) Differential activation of the amygdala and the “social brain” during fearful face-processing in Asperger Syndrome. Neuropsychologia 45:2–14CrossRefPubMedGoogle Scholar
  6. Barbas H (1995) Anatomic basis of cognitive-emotional interactions in the primate prefrontal cortex. Neurosci Biobehav Rev 19:499–510CrossRefPubMedGoogle Scholar
  7. Barbas H, Pandya DN (1989) Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol 286:353–375CrossRefPubMedGoogle Scholar
  8. Barger N, Stefanacci L, Semendeferi K (2007) A comparative volumetric analysis of the amygdaloid complex and basolateral division in the human and ape brain. Am J Phys Anthropol 403:392–403CrossRefGoogle Scholar
  9. Barger N, Stefanacci L, Schumann CM, Sherwood CC, Annese J, Allman JM, Buckwalter JA, Hof PR, Semendeferi K (2012) Neuronal populations in the basolateral nuclei of the amygdala are differentially increased in humans compared with apes: a stereological study. J Comp Neurol 520:3035–3054CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bauman MD, Toscano JE, Mason W, Lavenex P, Amaral DG (2006) The expression of social dominance following neonatal lesions of the amygdala or hippocampus in rhesus monkeys (Macaca mulatta). Behav Neurosci 120:749–760CrossRefPubMedGoogle Scholar
  11. Bernier PJ, Bedard A, Vinet J, Levesque M, Parent A (2002) Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc Natl Acad Sci USA 99:11464–11469CrossRefPubMedPubMedCentralGoogle Scholar
  12. Berretta S, Pantazopoulos H, Lange N (2007) Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia. Biol Psychiatry 62:884–893CrossRefPubMedGoogle Scholar
  13. Brierley B, Shaw P, David AS (2002) The human amygdala: a systematic review and meta-analysis of volumetric magnetic resonance imaging. Brain Res Brain Res Rev 39:84–105CrossRefPubMedGoogle Scholar
  14. Carmichael ST, Price JL (1995) Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. J Comp Neurol 363:615–641CrossRefPubMedGoogle Scholar
  15. Chailangkarn T et al (2016) A human neurodevelopmental model for Williams syndrome. Nature 536(7616):338–343CrossRefPubMedPubMedCentralGoogle Scholar
  16. Chareyron LJ, Lavenex PB, Amaral DG, Lavenex P (2012) Postnatal development of the amygdala: a stereological study in macaque monkeys. J Comp Neurol 520:1965–1984CrossRefPubMedPubMedCentralGoogle Scholar
  17. Courchesne E, Carper R, Akshoomoff N (2003) Evidence of brain overgrowth in the first year of life in autism. JAMA 290:337–344CrossRefPubMedGoogle Scholar
  18. de Luis O, Valero MC, Pérez Jurado LA (2000) WBSCR14, a putative transcription factor gene deleted in Williams–Beuren syndrome: complete characterisation of the human gene and the mouse ortholog. Eur J Hum Genet 8:215–222CrossRefPubMedGoogle Scholar
  19. Edelmann L, Prosnitz A, Pardo S, Bhatt J, Cohen N, Lauriat T, Ouchanov L, Gonza-lez PJ, Manghi ER, Bondy P, Esquivel M, Monge S, Fallas M, Splendore A, Francke U, Burton BK, McInnes LA (2007) An atypical deletion of the Williams syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet 44:136–143CrossRefPubMedGoogle Scholar
  20. Emery NJ, Capitanio JP, Mason WA, Machado CJ, Mendoza SP, Amaral DG (2001) The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta). Behav Neurosci 115:515–544CrossRefPubMedGoogle Scholar
  21. Feyder M et al (2010) Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams’ syndrome. Am J Psychiatry 167:1508–1517CrossRefPubMedPubMedCentralGoogle Scholar
  22. Galaburda a M, Bellugi U (2000) V. Multi-level analysis of cortical neuroanatomy in Williams syndrome. J Cogn Neurosci 12:74–88CrossRefPubMedGoogle Scholar
  23. Gallagher M, Holland PC (1994) The amygdala complex: multiple roles in associative learning and attention. Proc Natl Acad Sci USA 91:11771–11776CrossRefPubMedPubMedCentralGoogle Scholar
  24. García-Fiñana M, Cruz-Orive LM, Mackay CE, Pakkenberg B, Roberts N (2003) Comparison of MR imaging against physical sectioning to estimate the volume of human cerebral compartments. Neuroimage 18:505–516CrossRefPubMedGoogle Scholar
  25. Gittins RA, Harrison PJ (2011) A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord 133:328–332CrossRefPubMedGoogle Scholar
  26. Goossens L, Kukolja J, Onur OA, Fink GR, Maier W, Griez E, Schruers K, Hurlemann R (2009) Selective processing of social stimuli in the superficial amygdala. Hum Brain Mapp 30:3332–3338CrossRefPubMedGoogle Scholar
  27. Gunderson HJG, Jensen EB (1987) The efficiency of systematic of systematic smapling in stereology and its prediction. Microscopy 147:229–263CrossRefGoogle Scholar
  28. Haas BW, Hoeft F, Searcy YM, Mills D, Bellugi U, Reiss A (2009) Individual differences in social behavior predict amygdala response to fearful facial expressions in Williams syndrome. Neuropsychologia 48:1283–1288CrossRefPubMedPubMedCentralGoogle Scholar
  29. Haas BW, Hoeft F, Searcy YM, Mills D, Bellugi U, Reiss A (2010) Individual differences in social behavior predict amygdala response to fearful facial expressions in Williams syndrome. Neuropsychologia 48:1283–1288CrossRefPubMedGoogle Scholar
  30. Haas BW, Sheau K, Kelley RG, Thompson PM, Reiss AL (2014) Regionally specific increased volume of the amygdala in Williams syndrome: evidence from surface-based modeling. Hum Brain Mapp 35:866–874CrossRefPubMedGoogle Scholar
  31. Hrvoj-Mihic B, Hanson KL, Lew CH, Stefanacci L, Jacobs B, Bellugi U, Semendeferi K (2017) Basal dendritic morphology of cortical pyramidal neurons in Williams syndrome: prefrontal cortex and beyond. Front Neurosci 11:1–13CrossRefGoogle Scholar
  32. Janak PH, Tye KM (2015) From circuits to behaviour in the amygdala. Nature 517:284–292CrossRefPubMedPubMedCentralGoogle Scholar
  33. Järvinen A, Korenberg JR, Bellugi U (2013) The social phenotype of Williams syndrome. Curr Opin Neurobiol 23:414–422CrossRefPubMedPubMedCentralGoogle Scholar
  34. Järvinen-Pasley A, Adolphs R, Yam A, Hill KJ, Grichanik M, Reilly J, Mills D, Reiss AL, Korenberg JR, Bellugi U (2010) Affiliative behavior in Williams syndrome: social perception and real-life social behavior. Neuropsychologia 48:2110–2119CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kordower JH, Piecinski P, Rakic P (1992) Neurogenesis of the amygdaloid nuclear complex in the Rhesus monkey. Dev Brain Res 68:9–15CrossRefGoogle Scholar
  36. Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, Schmidt-Kastner R, Korr H, Steinbusch HWM, Hof PR, Schmitz C (2007) Volume, neuron density and total neuron number in five subcortical regions in schizophrenia. Brain 130:678–692CrossRefPubMedGoogle Scholar
  37. LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM (1990) The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci 10:1062–1069CrossRefPubMedGoogle Scholar
  38. Leichnetz GR, Astruc J (1976) The efferent projections of the medial prefrontal cortex in the squirrel monkey (Saimiri sciureus). Brain Res 109:455–472CrossRefPubMedGoogle Scholar
  39. Leichnetz GR, Astruc J (1977) The course of some prefrontal corticofugals to the pallidum, substantia innominata, and amygdaloid complex in monkeys. Exp Neurol 54:104–109CrossRefPubMedGoogle Scholar
  40. Leichnetz GR, Povlishock JT, Astruc J (1976) A prefronto-amygdaloid projection in the monkey: Light and electron microscopic evidence. Neurosci Lett 2:261–265CrossRefPubMedGoogle Scholar
  41. Lew CH, Brown C, Bellugi U, Semendeferi K (2017) Neuron density is decreased in the prefrontal cortex in Williams syndrome. Autism Res 10:99–112CrossRefPubMedGoogle Scholar
  42. Martens M, Wilson SJ, Dudgeon P, Reutens DC (2009) Approachability and the amygdala: Insights from Williams syndrome. Neuropsychologia 47:2446–2453CrossRefPubMedGoogle Scholar
  43. Meda SA, Pryweller JR, Thornton-Wells TA (2012) Regional brain differences in cortical thickness, surface area and subcortical volume in individuals with Williams syndrome. PLoS One 7Google Scholar
  44. Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, Morris CA, Keating MT (1998) Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes. Hum Genet 103:590–599CrossRefPubMedGoogle Scholar
  45. Merla G, Brunetti-Pierri N, Micale L, Fusco C (2010) Copy number variants at Williams–Beuren syndrome 7q11.23 region. Hum Genet 128:3–26CrossRefPubMedGoogle Scholar
  46. Meunier M, Bachevalier J, Murray E, Málková L, Mishkin M (1999) Effects of aspiration versus neurotoxic lesions of the amygdala on emotional responses in monkeys. Eur J Neurosci 11:4403–4418CrossRefPubMedGoogle Scholar
  47. Meyer-Lindenberg A, Hariri AR, Munoz KE, Mervis CB, Mattay VS, Morris CA, Berman KF (2005) Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci 8:991–993CrossRefPubMedGoogle Scholar
  48. Mosconi M (2009) Longitudinal study of amygdala volume and joint attention in 2-to 4-year-old children with autism. Arch Gen Psychiatry 66:509–516CrossRefPubMedPubMedCentralGoogle Scholar
  49. Müller F, O’Rahilly R (2006) The amygdaloid complex and the medial and lateral ventricular eminences in staged human embryos. J Anat 208:547–564CrossRefPubMedPubMedCentralGoogle Scholar
  50. Muñoz KE, Meyer-Lindenberg A, Hariri AR, Mervis CB, Mattay VS, Morris CA, Berman KF (2010) Abnormalities in neural processing of emotional stimuli in Williams syndrome vary according to social vs. non-social content. Neuroimage 50:340–346CrossRefPubMedGoogle Scholar
  51. Murray EA (2007) The amygdala, reward and emotion. Trends Cogn Sci 11:489–497CrossRefPubMedGoogle Scholar
  52. Nikolić I, Kostović I (1986) Development of the lateral amygdaloid nucleus in the human fetus: transient presence of discrete cytoarchitectonic units. Anat Embryol (Berl) 174:355–360CrossRefGoogle Scholar
  53. Reiss AL, Eckert M, Rose FE, Karchemskiy A, Kesler S, Chang M, Reynolds MF, Kwon H, Galaburda A (2004) An experiment of nature: brain anatomy parallels cognition and behavior in Williams syndrome. J Neurosci 24:5009–5015CrossRefPubMedPubMedCentralGoogle Scholar
  54. Rubinow MJ, Mahajan G, May W, Overholser JC, Jurjus GJ, Dieter L, Herbst N, Steffens DC, Miguel-Hidalgo JJ, Rajkowska G, Stockmeier CA (2016) Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study. Brain Struct Funct 221(1):171–184CrossRefPubMedGoogle Scholar
  55. Saddoris MP, Gallagher M, Schoenbaum G (2005) Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex. Neuron 46:321–331CrossRefPubMedGoogle Scholar
  56. Sakurai T, Dorr NP, Takahashi N, McInnes LA, Elder GA, Buxbaum JD (2011) Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions. Autism Res 4:28–39CrossRefPubMedGoogle Scholar
  57. Schumann CM, Amaral DG (2005) Stereological estimation of the number of neurons in the human amygdaloid complex. J Comp Neurol 491:320–329CrossRefPubMedPubMedCentralGoogle Scholar
  58. Schumann CM, Amaral DG (2006) Stereological analysis of amygdala neuron number in autism. J Neurosci 26:7674–7679CrossRefPubMedGoogle Scholar
  59. Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Lammers CR, Reiss AL, Amaral DG (2004) The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 24:6392–6401CrossRefPubMedGoogle Scholar
  60. Schumann CM, Bauman MD, Amaral DG (2011) Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders. Neuropsychologia 49:745–759CrossRefPubMedGoogle Scholar
  61. Seymour B, Dolan R (2008) Emotion, decision making, and the amygdala. Neuron 58:662–671CrossRefPubMedGoogle Scholar
  62. Sorvari H, Soininen H, Paljarvi L, Karkola K, Pitkanen A (1995) Distribution of parvalbumin-immunoreactive cells and fibers in the human amygdaloid complex. J Comp Neurol 360:185–212CrossRefPubMedGoogle Scholar
  63. Stefanacci L, Amaral DG (2000) Topographic organization of cortical inputs to the lateral nucleus of the macaque monkey amygdala: a retrograde tracing study. J Comp Neurol 421:52–79CrossRefPubMedGoogle Scholar
  64. Stefanacci L, Amaral DG (2002) Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study. J Comp Neurol 451:301–323CrossRefPubMedGoogle Scholar
  65. Strømme P, Bjørnstad PG, Ramstad K (2002) Prevalence Estimation of Williams Syndrome. J Child Neurol 17:269–271CrossRefPubMedGoogle Scholar
  66. Vivanti G, Hocking DR, Fanning P, Dissanayake C (2017) The social nature of overimitation: insights from Autism and Williams syndrome. Cognition 161:10–18CrossRefPubMedGoogle Scholar
  67. West MJ, Gundersen HJ (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J Comp Neurol 296:1–22CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Caroline H. Lew
    • 1
  • Kimberly M. Groeniger
    • 1
  • Ursula Bellugi
    • 2
  • Lisa Stefanacci
    • 1
  • Cynthia M. Schumann
    • 3
  • Katerina Semendeferi
    • 1
    • 4
  1. 1.Department of Anthropology, Social Sciences Building Rm. 210University of California, San DiegoLa JollaUSA
  2. 2.Laboratory for Cognitive NeuroscienceSalk Institute for Biological StudiesLa JollaUSA
  3. 3.Department of Psychiatry and Behavioral Sciences, MIND InstituteUniversity of California, DavisSacramentoUSA
  4. 4.Kavli Institute for Brain and MindUniversity of CaliforniaLa JollaUSA

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