Sacha Nelson, M.D., Ph.D.
Gyula and Katica Tauber Professor of Life Sciences
Physiological genomics of the mammalian neocortex

B.A., B.S., Brown University
M.D., University of California, San Diego
Ph.D., University of California, San Diego

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The mammalian neocortex is our most complex organ and plays an indispensable role in many human behaviors. Impaired function of cortical circuits are central to a diverse set of neurological and psychiatric diseases including autism spectrum disorders, epilepsy, schizophrenia and Alzheimer’s disease.  Despite their functional and clinical importance, the cell types that comprise the neocortex and the molecular mechanisms that specify their properties and connectivity are only partly understood. We study the development and function of the neocortex in the laboratory mouse using a combination of genetic, genomic and electrophysiological approaches. Question that we focus on include: “What genetic and epigenetic mechanisms allow different cell types to develop different patterns of connectivity?” “How does activity regulate the cell tyoe-specific expression of neuronal ion channels and synaptic molecules” and “How do genetic lesions that produce disease in mice and humans alter cellular physiology and gene expression?” To answer these questions we use new driver strains developed here and by our collaborators to genetically or virally deliver mutant alleles to specific neuronal cell types. We monitor effects on physiology and connectivity using patch clamp recording and high resolution anatomy. To evaluate changes in gene expression we developed methods for manually sorting fluorescent neurons and performing genome-wide expression profiling. Using these approaches we have discovered some of the ion channels that mediate specific firing properties of cortical neurons and have identified physiological and molecular mechanisms that cause cortical impairment in the autism spectrum disorder Rett Syndrome. Current projects are focused on the role of cell adhesion molecules in regulating connectivity, the importance of DNA methylation for maintaining neuronal cell identity, and the molecular mechanisms of circuit homeostasis.  

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Selected Publications:

Moreno-Juan V, Filipchuk A, Antón-Bolaños N, Mezzera C, Gezelius H, Andrés B, Rodríguez-Malmierca L, Susín R, Schaad O, Iwasato T, Schüle R, Rutlin M, Nelson S, Ducret S, Valdeolmillos M, Rijli FM, López-Bendito G (2017). "Prenatal thalamic waves regulate cortical area size prior to sensory processing." Nat Commun. 2017 Feb 3;8:14172.

Abraira VE, Kuehn ED, Chirila AM, Springel MW, Toliver AA, Zimmerman AL, Orefice LL, Boyle KA, Bai L, Song BJ, Bashista KA, O'Neill TG, Zhuo J, Tsan C, Hoynoski J, Rutlin M, Kus L, Niederkofler V, Watanabe M, Dymecki SM, Nelson SB, Heintz N, Hughes DI, and Ginty DD (2017). "The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn." Cell 168(1-2): 295-310 e219.

Crittenden JR, Tillberg PW, Riad MH, Shima Y, Gerfen CR, Curry J, Housman DE, Nelson SB, Boyden ES and Graybiel AM (2016). "Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons." Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11318-11323.

O'Toole SM, Ferrer MM, Mekonnen J, Zhang H, Shima Y, Ladle DR and Nelson SB (2016). "Dicer maintains the identity and function of proprioceptive sensory neurons." J Neurophysiol: jn 00763 02016.

Steinmetz, CC, Tatavarty V, Sugino K, Shima Y, Joseph A, Lin H, Rutlin M, Lambo M, Hempel CM, Okaty BW, Paradis S, Nelson SB and Turrigiano GG (2016). "Upregulation of mu3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway." Cell Rep 16(10): 2711-2722.

Shima Y, Sugino K, Hempel C, Shima M, Taneja P, Bullis JB, Mehta S, Lois C, and Nelson SB (2016). "A mammalian enhancer trap resource for discovering and manipulating neuronal cell types." Elife. 2016 Mar 21;5. pii: e13503.

Choy JM, Suzuki N, Shima Y, Budisantoso T, Nelson SB, and Bekkers JM (2015). "Optogenetic Mapping of Intracortical Circuits Originating from Semilunar Cells in the Piriform Cortex." Cereb Cortex. 2015 Oct 26. pii: bhv258.

Clark EA and Nelson SB (2015). "Synapse and genome: An elusive tete-a-tete. Sci Signal 8(396): pe2.

Nelson SB and Valakh V (2015). "Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders." Neuron 87(4): 684-698.

Sugino K, Hempel CM, Okaty BW, Arnson HA, Kato S, Dani VS and Nelson SB (2014) "Cell-type-specific repression by Mecp2 is biased toward long genes." J Neurosci 34(38): 12877-12883.

Grange P, Bohland JW, Okaty BW, Sugino K, Bokil H, Nelson SB, Ng L, Hawrylycz M, and Mitra PP (2014) "Cell-type based model explaining co-expression patterns of genes in the brain." Proc Natl Acad Sci U S A. 111(14):5397-402. PMC3986204.

Huang CC, Sugino K, Shima Y, Guo C, Bai S, Mensh BD, Nelson SB, and Hantman AW (2013) "Convergence of corollary discharge and proprioceptive streams onto multimodal cerebellar granule cells." eLife. 2:e00400. PMC3582988

Blackman MP, Djukic B, Nelson SB, and Turrigiano GG (2012) "A Critical and Cell-Autonomous Role for MeCP2 in Synaptic Scaling Up." J. Neurosci. 32:13529-13536. PMC3483036

Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsani D, Fu Y, Lin Y, Lu J, Nelson SB, Huang ZJ (2011). "A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex." Neuron 71(6):995-1013.

Okaty BW, Sugino K, Nelson SB (2011). "Cell type-specific transcriptomics in the brain." J Neurosci. 2011 May 11;31(19):6939-43.

Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB (2009). "Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome." J Neurosci. 2009 Sep 30;29(39):12187-95.

Dani VS, Nelson SB (2009). "Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome." J Neurosci. 2009 Sep 9;29(36):11263-70.

Okaty BW, Miller MN, Sugino K, Hempel CM, Nelson SB (2009). "Transcriptional and electrophysiological maturation of neocortical fast-spiking GABAergic interneurons."J Neurosci. 2009 May 27;29(21):7040-52.

Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. (2006). "The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression." Neuron. 2006 Feb 2;49(3):341-8.

Sugino K, Hempel CM, Miller MN, Hattox AM, Shapiro P, Wu C, Huang ZJ, Nelson SB. "Molecular taxonomy of major neuronal classes in the adult mouse forebrain." (2006) Nat Neurosci. 2006 Jan;9(1):99-107. Erratum in: Nat Neurosci. 2006 Feb;9(2):292.

Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB. (2005) "Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome." Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12560-5.

Song S, Sjöström PJ, Reigl M, Nelson S, Chklovskii DB. "Highly nonrandom features of synaptic connectivity in local cortical circuits" (2005). PLoS Biol. 2005 Mar;3(3):e68. Epub 2005 Mar 1. Erratum in: PLoS Biol. 2005 Oct;3(10):e350.

Sjöström PJ, Turrigiano GG, and Nelson SB (2003). "Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors." Neuron 39:641-654 (see also Preview 579-581).

Chung S, Li X, Nelson SB. (2002). "Short-term depression at thalamocortical synapses contributes to rapid adaptation of cortical sensory responses in vivo." Neuron. 34(3):437-46.

Sjöström PJ, Turrigiano GG, Nelson SB. (2001). "Rate, timing, and cooperativity jointly determine cortical synaptic plasticity." Neuron. Dec 20;32:1149-64.

Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998). "Activity-dependent scaling of quantal amplitude in neocortical pyramidal neurons." Nature 391: 892-895.

Abbott LF, Sen K, Varela JA, and Nelson SB (1997). "Synaptic depression and cortical gain control." Science  275: 220.  

Last update: April 7, 2017.

View Complete Publication List on PubMed: Sacha Nelson


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