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:

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.

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

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

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 (2010). "Ten years of Nature Reviews Neuroscience: insights from the highly cited." Nat Rev Neurosci 2010 Oct;11(10):718-26.

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

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.

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

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.

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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).

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

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

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

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.

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

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

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: June 1, 2016.

View Complete Publication List on PubMed: Sacha Nelson

 

 
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