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Research

Decades-old material now available for de novo research
Today, nearly half a century after the first brains were processed in the Rakic/Goldman-Rakic laboratories, these materials are still being used to generate data for publication. Notably, investigators from outside Yale, including researchers from the University of Illinois, University of California, and as far away as the University of Sydney, have come to visit the Department of Neuroscience at Yale and, using materials in collection 1, analyze neurogenesis in different brain structures not previously examined by the Rakic laboratory.

At the establishment of MacBrainResource in early 2017, we started populating collections 1 to 5 and making them easily and widely accessible to researchers around the world. To celebrate the 5th anniversary of MacBrainResouce in 2021, we are adding collections 6 and 7. At its introduction, collection 6 is already an impressive set of serially stained sections for different neuronal and non-neuronal markers. This collection includes several brains in which coronal series of sections ~1 mm apart are stained for: calbindin (CB), choline acetyltransferase (ChAT), calretinin (CR), ionized calcium binding adaptor molecule 1 (Iba1), Myelin basic protein (MBP), neuronal nuclear protein (NeuN), Nissl, neuropeptide Y (NPY), oligodendrocyte transcription factor 2 (Olig-2), parvalbumin (PV), neurofilament protein (SMI-32), somatostatin (SOM), tyrosine hydroxylase (TH) and other. Collection 7 consists of brain tissue blocks, most of them frozen and already tested for immunohistochemical viability. The hope is that these new collections grow over the years to include male and female specimens within different developmental age groups.

In the past, to test the viability of collection 1, Dr. Duque used [3H]-thymidine injections from decades ago to compare neuron labeling to BrdU injected more recently. He found substantial differences in the number and distribution of labeled cells, indicating that the random incorporation of BrdU into the genes of dividing cells makes the fate of postmitotic neurons more prone to unpredictable errors than the incorporation of the more natural DNA constituent nucleotide. Because the results of his work have wide implications for studies that use BrdU in cell- migration, placement, connectivity and survival they were highlighted by several journals and gave rise to an invited chapter in a technical book series. In addition, Dr. Duque’s work on the development of the subplate utilized more than 40 cases from Collection 1 and illustrated how novel and noteworthy studies can be conducted using MacBrainResource, without having to sacrifice a single additional animal. These studies, and those previous ones in the laboratory of Dr. Pasko Rakic, were pivotal for the creation of MacBrainResource. Newer studies include development of cortical convolutions and gliogenesis in the outer subventricular zone as well as neurogenesis in the thalamus.

The potential of Collections 2-5 has been highlighted in recent original studies and publications by Drs. Selemon, Morozov and colleagues. Before the creation of MacBrainResource, Collection 4 was extensively used by Dr. Selemon to investigate the effects of x-irradiation in development. Most recently it has been used to corroborate findings from a new automated tract tracing method applied to diffusion tensor imaging (DTI) data and to study the effects of fetal x-irradiation on the numbers of dopaminergic cells of the substantia nigra and ventral tegmental areas. Collection 5 is being used to investigate cannabinoid receptors in cerebral neural stem cells. Currently all collections are being used in de novo investigations and for the collection of preliminary data essential for new grant applications. These collections hold a wealth of unmined data for normative primate brain structure that has yet to be tapped, as well as data regarding the morphologic consequences of lesions including prenatal irradiation. (See publications).

Publications (supported by MH113257)

Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, Xu C,Li Q, Morozov YM, Andrijevic D, Vrselja Z, Spajic, A, Santpere G, Li M, Zhang S, Liu Y, Spurrier J, Zhang L, Gudelj I, Rapan L, Takahashi H, Huttner A, Fan R, Strittmatter SM, Sousa AMM, Rakic P, Sestan N, Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells, Neuron (2021), DOI: 10.1016/j.neuron.2021.10.036.

Leslie SN, Kanyo J, Datta D, Wilson RS, Zeiss C, Duque A, Lam TT, Arnsten AFT, Nairn AC, Simple, Single-Shot Phosphoproteomic Analysis of Heat-Stable Tau Identifies Age-Related Changes in pS235- and pS396-Tau Levels in Non-human Primates, Frontiers in Aging Neuroscience (2021), DOI: 10.3389/fnagi.2021.767322.

Duque A, Arellano JI, Rakic P. An assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases. Molecular Psychiatry. 19 October 2021. DOI: 10.1038/s41380-021-01314-8.

Rockland, K. Cytochrome oxidase “blobs”: a call for more anatomy. Brain Struct Funct. 12 August 2021. DOI: 10.1007/s00429-021-02360-2.

Galvin VC, Yang S, Lowet AS, Datta D, Duque A, Arnsten AFT, Wang M. M1 receptors interacting with NMDAR enhance delay-related neuronal firing and improve working memory performance. Current Research in Neurobiology. Volume 2, 2021, 100016. 2021 Jul 9; DOI: 10.1016/j.crneur.2021.100016.

Arellano JI, Morozov YM, Micali N, Rakic P. Radial Glial Cells: New Views on Old Questions Neurochemical Research. Neurochem Res. 2021 March 16; DOI: 10.1007/s11064-021-03296-z.

Datta D, Leslie SN, Wang M, Morozov YM, Mentone SA, Zeiss C, Duque A, Rakic P, Yang S, Horvath TL, van Dyck CH, Nairn AC. Arnsten, AFT. Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates Alzheimer’s Dement. 2021; 1–13. 2021 February 11; DOI: 10.1002/alz.12325.

Morozov YM, Mackie K, Rakic P. Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration. Int. J. Molec. Sci. 21, 8657. 2020 October 16; DOI:10.3390/ijms21228657.

Kaur N, Han W, Li Z, Madrigal MP, Shim S, Pochareddy S, Gulden FO, Li M, Xu X, Xing X, Takeo Y, Li Z, Lu K, Imamura Kawasawa Y, Ballester-Lurbe B, Moreno-Bravo JA, Chédotal A, Terrado J, Pérez-Roger I, Koleske AJ, Sestan N. Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold. Neuron. 2020 September 23;107(6):1197-1211.e9. PubMed PMID: 32707082; PubMed Central PMCID: PMC7529949; DOI: 10.1016/j.neuron.2020.06.035.

Micali N, Kim SK, Diaz-Bustamante M, Stein-O'Brien G, Seo S, Shin JH, Rash BG, Ma S, Wang Y, Olivares NA, Arellano JI, Maynard KR, Fertig EJ, Cross AJ, Bürli RW, Brandon NJ, Weinberger DR, Chenoweth JG, Hoeppner DJ, Sestan N, Rakic P, Colantuoni C, McKay RD. Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates. Cell reports. 2020 May 5;31(5):107599. PubMed PMID: 32375049; PubMed Central PMCID: PMC7357345; DOI: 10.1016/j.celrep.2020.107599.

Selemon LD, Begovic A. Reduced Midbrain Dopamine Neuron Number in the Adult Non-human Primate Brain after Fetal Radiation Exposure. Neuroscience 2020 August 21; 442:193-201. PubMed PMID: 32659340; PubMed Central PMCID: PMC7438262; DOI: 10.1016/j.neuroscience.2020.07.005.

Falcone C, Penna E, Hong T, Tarantal AF, Hof PR, Hopkins WD, Sherwood CC, Noctor SC, Martínez-Cerdeño V. Cortical Interlaminar Astrocytes Are Generated Prenatally, Mature Postnatally, and Express Unique Markers in Human and Nonhuman Primates. Cerebral cortex (New York, NY 1991). 2020 September 15. PubMed PMID: 32930323; DOI: 10.1093/cercor/bhaa231.

Franjic D, Choi J, Skarica M, Xu C, Li Q, Ma S, Tebbenkamp AT, Santpere G, Arellano JI, Gudelj I, Jankovic-Rapan L, Sousa AM, Rakic P, Sestan N. Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells. bioRxiv: the preprint server for biology. 2020 January 02. DOI: 10.1101/2019.12.31.889139.

Shibata M, Pattabiraman K, Lorente-Galdos B, Andrijevic D, Sousa AM, Santpere G, Sestan N. Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid. bioRxiv: the preprint server for biology. 2019 December 31. DOI: 10.1101/2019.12.31.891036.

Shibata M, Pattabiraman K, Muchnik SK, Sestan N. Hominini-Specific Regulation of CBLN2 Increases Prefrontal Synaptogenesis. bioRxiv : the preprint server for biology. 2019 December 31. DOI: 10.1101/2019.12.31.891069.

Haldipur P, Aldinger KA, Bernardo S, Deng M, Timms AE, Overman LM, Winter C, Lisgo SN, Razavi F, Silvestri E, Manganaro L, Adle-Biassette H, Guimiot F, Russo R, Kidron D, Hof PR, Gerrelli D, Lindsay SJ, Dobyns WB, Glass IA, Alexandre P, Millen KJ. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum. Science (New York, N.Y.). 2019 October 25;366(6464):454-460. PubMed PMID: 31624095; PubMed Central PMCID: PMC6897295; DOI: 10.1126/science.aax7526.

Rash BG, Duque A, Morozov YM, Arellano JI, Micali N, Rakic P. Gliogenesis in the outer subventricular zone promotes enlargement and gyrification of the primate cerebrum. Proceedings of the National Academy of Sciences of the United States of America. 2019 April 2;116(14):7089-7094. PubMed PMID: 30894491; PubMed Central PMCID: PMC6452694; DOI: 10.1073/pnas.1822169116.

Duque A, Spector R. A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders. Brain structure & function. 2019 September;224(7):2281-2295. PubMed PMID: 31278571; PubMed Central PMCID: PMC6852840; DOI: 10.1007/s00429-019-01917-6.

Vrselja Z, Daniele SG, Silbereis J, Talpo F, Morozov YM, Sousa AMM, Tanaka BS, Skarica M, Pletikos M, Kaur N, Zhuang ZW, Liu Z, Alkawadri R, Sinusas AJ, Latham SR, Waxman SG, Sestan N. Restoration of brain circulation and cellular functions hours post-mortem. Nature. 2019 April;568(7752):336-343. PubMed PMID: 30996318; PubMed Central PMCID: PMC6844189; DOI: 10.1038/s41586-019-1099-1.

Selemon L, Duque A. MacBrainResource: Virtual access to decades-old primate brains. Research Outreach Magazine - Health & Medicine. 2019 March; 2517-701X(106):94-97; DOI: 10.32907/RO-106-9497.

Zhu Y, Sousa AMM, Gao T, Skarica M, Li M, Santpere G, Esteller-Cucala P, Juan D, Ferrández-Peral L, Gulden FO, Yang M, Miller DJ, Marques-Bonet T, Imamura Kawasawa Y, Zhao H, Sestan N. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science (New York, N.Y.). 2018 December 14;362(6420). PubMed PMID: 30545855; PubMed Central PMCID: PMC6900982; DOI: 10.1126/science.aat8077.

Duque A, Selemon L. MacBrainResource: sharing primate specimens around the world. (2018). Research Features Magazine. Health and Medicine. May 1st, 2018 Issue. England. https://researchfeatures.com/2018/05/01/macbrainresource-sharing-primate-specimens/.

Legacy Publications (selected examples)