Sacha Nelson, M.D., Ph.D.
Professor of Biology
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
Contact Information
lab website

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:

Cell-type-specific repression by Mecp2 is biased toward long genes. Sugino K., Hempel C.M., Okaty, B. W., Arnson H.A., Kato, S., Dani V.S.and Nelson S.B. (2014) J. Neurosci. In Press

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

Convergence of corollary discharge and proprioceptive streams onto multimodal cerebellar granule cells. Huang C.C., Sugino K., Shima Y., Guo C., Bai S., Mensh B.D., Nelson S.B., and Hantman A.W. (2013) eLife. 2:e00400. PMC3582988

A Critical and Cell-Autonomous Role for MeCP2 in Synaptic Scaling Up. Blackman M.P., Djukic B., Nelson S.B., and Turrigiano G.G. (2012) J. Neurosci. 32:13529-13536. PMC3483036

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

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

A quantitative comparison of cell-type-specific microarray gene expression profiling methods in the mouse brain.Okaty BW, Sugino K, Nelson SB. PLoS One. 2011 Jan 27;6(1):e16493.

Activity-dependent changes in the firing properties of neocortical fast-spiking interneurons in the absence of large changes in gene expression. Miller MN, Okaty BW, Kato S, Nelson SB. Dev Neurobiol. 2011 Jan 1;71(1):62-70. doi: 10.1002/dneu.20811.

Ten years of Nature Reviews Neuroscience: insights from the highly cited. Luo L, Rodriguez E, Jerbi K, Lachaux JP, Martinerie J, Corbetta M, Shulman GL, Piomelli D, Turrigiano GG, Nelson SB, Joëls M, de Kloet ER, Holsboer F, Amodio DM, Frith CD, Block ML, Zecca L, Hong JS, Dantzer R, Kelley KW, Craig AD. Nat Rev Neurosci. 2010 Oct;11(10):718-26.

Dissecting differential gene expression within the circadian neuronal circuit of Drosophila. Nagoshi E, Sugino K, Kula E, Okazaki E, Tachibana T, Nelson S, Rosbash M. Nat Neurosci. 2010 Jan;13(1):60-8.

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

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

A role for microRNAs in the Drosophila circadian clock. Kadener S, Menet JS, Sugino K, Horwich MD, Weissbein U, Nawathean P, Vagin VV, Zamore PD, Nelson SB, Rosbash M. Genes Dev. 2009 Sep 15;23(18):2179-91.

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

Genome-wide identification of targets of the drosha-pasha/DGCR8 complex. Kadener S, Rodriguez J, Abruzzi KC, Khodor YL, Sugino K, Marr MT 2nd, Nelson S, Rosbash M. RNA. 2009 Apr;15(4):537-45.

Region-specific spike-frequency acceleration in layer 5 pyramidal neurons mediated by Kv1 subunits. Miller MN, Okaty BW, Nelson SB. J Neurosci. 2008 Dec 17;28(51):13716-26.

Strength through diversity. Nelson SB, Turrigiano GG. Neuron. 2008 Nov 6;60(3):477-82. Review.

The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Chen B, Wang SS, Hattox AM, Rayburn H, Nelson SB, McConnell SK. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11382-7.

A manual method for the purification of fluorescently labeled neurons from the mammalian brain. Hempel CM, Sugino K, Nelson SB. Nat Protoc. 2007;2(11):2924-9.

Layer V neurons in mouse cortex projecting to different targets have distinct physiological properties. Hattox AM, Nelson SB. J Neurophysiol. 2007 Dec;98(6):3330-40.

Multiple forms of long-term plasticity at unitary neocortical layer 5 synapses. Sjöström PJ, Turrigiano GG, Nelson SB. (2007) Neuropharmacology. 2007 Jan;52(1):176-84.

Probing the transcriptome of neuronal cell types. Nelson SB, Hempel C, Sugino K. (2006) Curr Opin Neurobiol. 2006 Oct;16(5):571-6. Review.

Potentiation of cortical inhibition by visual deprivation. Maffei A, Nataraj K, Nelson SB, Turrigiano GG. (2006) Nature. 2006 Sep 7;443(7107):81-4.

The problem of neuronal cell types: a physiological genomics approach. Nelson SB, Sugino K, Hempel CM. (2006) Trends Neurosci. 2006 Jun;29(6):339-45. Review.

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

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

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

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

Selective reconfiguration of layer 4 visual cortical circuitry by visual deprivation. Maffei A, Nelson SB, Turrigiano GG. (2004) Nat Neurosci. 2004 Dec;7(12):1353-9.

Endocannabinoid-dependent neocortical layer-5 LTD in the absence of postsynaptic spiking.Sjöström PJ, Turrigiano GG and Nelson SB. (2004) J Neurophysiol. 2004 Dec;92(6):3338-43.

A proportional but slower NMDA potentiation follows AMPA potentiation in LTP. Watt AJ, Sjöström PJ, Hausser M, Nelson SB, Turrigiano GG. (2004) Nat Neurosci. 2004 May;7(5):518-24.

Homeostatic plasticity in the developing nervous system. Turrigiano GG, Nelson SB. (2004) Nat Rev Neurosci. 5:97-107.

Activity dependent remodeling of presynaptic inputs by postsynaptic expression of activated CaMKII. Pratt KG. Watt A.J, Griffith LC. Nelson SB, and Turrigiano GG (2003) Neuron 39:269-281.

The NMDA to AMPA ratio at synapses onto layer 2/3 pyramidal neurons is conserved across prefrontal and visual cortices. Myme C, Sugino K, Turrigiano GG and Nelson SB (2003) J. Neurophysiol. 90:771-779.

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

Cortical circuits: diverse or canonical? Nelson SB (2002) Neuron 36: 19-27.

Critical periods for experience-dependent synaptic scaling in visual cortex.Desai NS, Cudmore RH, Nelson SB, Turrigiano GG. (2002) Nat Neurosci. 2002 Aug;5(8):783-9.

Spike timing, calcium signals and synaptic plasticity.Sjöström PJ, Nelson SB. (2002) Curr Opin Neurobiol. 2002 Jun;12(3):305-14.

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

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

Synaptic plasticity: taming the beast. Abbott LF, Nelson SB. (2000) Nat Neurosci. 3 Suppl:1178-83.

Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Watt AJ, van Rossum MC, MacLeod KM, Nelson SB, Turrigiano GG. (2000) Neuron. 26(3):659-70.

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

Synaptic depression and cortical gain control. Abbott L.F., Sen K., Varela J.A., and Nelson S.B. (1997) Science  275: 220.  

Last update: August 15, 2014.

View Complete Publication List on PubMed: Sacha Nelson


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