Emily received her bachelor's degree in biology from the University of Illinois at Urbana- Champaign. She completed her Ph.D. in neuroscience from the University of California, San Diego in 2011 in the lab of Anirvan Ghosh, studying the role of adhesion molecules in determining the electrophysiological properties of hippocampal interneurons, and identified the role of the LRR-containing protein Elfn1 in establishing target cell specificity. She continued working on the molecular control of synapse function at F. Hoffmann-La Roche in Basel, Switzerland before joining the Deisseroth Lab at Stanford in 2014. As a postdoc, she has developed methods for labeling RNA in intact, transparent tissues, and is working to apply this multiplexed transcriptional analysis to understand the role of habenular cell types in motivated behavior.
Honors & Awards
Ruth L Kirschstein NRSA Postdoctoral Fellowship, NIMH (2016-2018)
Cortical Interneurons in Health and Disease Conference, Best Poster Award, EMBO (2012)
Neuroplasticy of Aging Training Grant, UCSD-NIH (2008)
National Science Foundation, Graduate Research Fellowship, Honorable Mention, NSF (2007)
Best Senior Thesis, Dept. of Molecular and Cellular Biology, University of Illinois, Urbana-Champaign (2006)
Chancellors's Scholars Summer Research Grant, Campus Honors Program, UIUC (2005)
Education & Certifications
Postdoctoral Fellow, F. Hoffmann-La Roche / University of Basel (2013)
Ph.D., University of California, San Diego, Neuroscience (2011)
B.S., University of Illinois, Urbana-Champaign, Biology (2006)
Dr. Sylwestrak has developed protocols for labeling RNA in intact, transparent tissues, in order to merge molecular information with three dimensional structural information. Her more recent work focuses on understanding how heterogenous, molecularly-defined neuronal populations work together to drive behavior. She uses cell-type specific activity monitoring and behavioral analysis to tackle this question in the habenula. This thalamic structure shows a rich transcriptional diversity, and has been associated with several neuropsychiatric disorders, but we lack a detailed understanding of how different cell types map onto behavior in healthy and pathological states. Her current work reveals that different habenular cell types encode predictive or resultant aspects of motivated behavior and can adapt their activity to different reward contexts, suggesting that habenular dysfunction may contribute to altered reward processing and behavioral flexibility in neuropsychiatric disorders.
Three-dimensional intact-tissue sequencing of single-cell transcriptional states.
Science (New York, N.Y.)
Retrieving high-content gene-expression information while retaining 3D positional anatomy at cellular resolution has been difficult, limiting integrative understanding of structure and function in complex biological tissues. Here we develop and apply a technology for 3D intact-tissue RNA sequencing, termed STARmap (Spatially-resolved Transcript Amplicon Readout Mapping), which integrates hydrogel-tissue chemistry, targeted signal amplification, and in situ sequencing. The capabilities of STARmap were tested by mapping 160 to 1,020 genes simultaneously in sections of mouse brain at single-cell resolution with high efficiency, accuracy and reproducibility. Moving to thick tissue blocks, we observed a molecularly-defined gradient distribution of excitatory-neuron subtypes across cubic millimeter-scale volumes (>30,000 cells), and discovered a short-range 3D self-clustering in many inhibitory-neuron subtypes that could be identified and described with 3D STARmap.
View details for DOI 10.1126/science.aat5691
View details for PubMedID 29930089
Multiplexed Intact-Tissue Transcriptional Analysis at Cellular Resolution
2016; 164 (4): 792-804
In recently developed approaches for high-resolution imaging within intact tissue, molecular characterization over large volumes has been largely restricted to labeling of proteins. But volumetric nucleic acid labeling may represent a far greater scientific and clinical opportunity, enabling detection of not only diverse coding RNA variants but also non-coding RNAs. Moreover, scaling immunohistochemical detection to large tissue volumes has limitations due to high cost, limited renewability/availability, and restricted multiplexing capability of antibody labels. With the goal of versatile, high-content, and scalable molecular phenotyping of intact tissues, we developed a method using carbodiimide-based chemistry to stably retain RNAs in clarified tissue, coupled with amplification tools for multiplexed detection. The resulting technology enables robust measurement of activity-dependent transcriptional signatures, cell-identity markers, and diverse non-coding RNAs in rodent and human tissue volumes. The growing set of validated probes is deposited in an online resource for nucleating related developments from across the scientific community.
View details for DOI 10.1016/j.cell.2016.01.038
View details for Web of Science ID 000369998300023
View details for PubMedID 26871636
- NEUROSCIENCE Sculpting neuronal connectivity NATURE 2013; 503 (7474): 42-43
Elfn1 Regulates Target-Specific Release Probability at CA1-Interneuron Synapses
2012; 338 (6106): 536-540
Although synaptic transmission may be unidirectional, the establishment of synaptic connections with specific properties can involve bidirectional signaling. Pyramidal neurons in the hippocampus form functionally distinct synapses onto two types of interneurons. Excitatory synapses onto oriens-lacunosum moleculare (O-LM) interneurons are facilitating and have a low release probability, whereas synapses onto parvalbumin interneurons are depressing and have a high release probability. Here, we show that the extracellular leucine-rich repeat fibronectin containing 1 (Elfn1) protein is selectively expressed by O-LM interneurons and regulates presynaptic release probability to direct the formation of highly facilitating pyramidal-O-LM synapses. Thus, postsynaptic expression of Elfn1 in O-LM interneurons regulates presynaptic release probability, which confers target-specific synaptic properties to pyramidal cell axons.
View details for DOI 10.1126/science.1222482
View details for Web of Science ID 000310195800060
View details for PubMedID 23042292
The Rett Syndrome Protein MeCP2 Regulates Synaptic Scaling
JOURNAL OF NEUROSCIENCE
2012; 32 (3): 989-994
Synaptic scaling is a form of homeostatic synaptic plasticity characterized by cell-wide changes in synaptic strength in response to changes in overall levels of neuronal activity. Here we report that bicuculline-induced increase in neuronal activity leads to a decrease in mEPSC amplitude and a decrease in expression of the AMPA receptor subunit GluR2 in rat hippocampal cultures. Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. Downregulation of MeCP2 by shRNA expression or genetic deletion blocks the bicuculline-induced decrease in GluR2 expression and mEPSC amplitude. These observations indicate that MeCP2 mediates activity-dependent synaptic scaling, and suggest that the pathophysiology of Rett syndrome, which is caused by mutations in MeCP2, may involve defects in activity-dependent regulation of synaptic currents.
View details for DOI 10.1523/JNEUROSCI.0175-11.2012
View details for Web of Science ID 000299324900024
View details for PubMedID 22262897
LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation
2009; 64 (6): 799-806
We identify the leucine-rich repeat transmembrane protein LRRTM2 as a key regulator of excitatory synapse development and function. LRRTM2 localizes to excitatory synapses in transfected hippocampal neurons, and shRNA-mediated knockdown of LRRTM2 leads to a decrease in excitatory synapses without affecting inhibitory synapses. LRRTM2 interacts with PSD-95 and regulates surface expression of AMPA receptors, and lentivirus-mediated knockdown of LRRTM2 in vivo decreases the strength of evoked excitatory synaptic currents. Structure-function studies indicate that LRRTM2 induces presynaptic differentiation via the extracellular LRR domain. We identify Neurexin1 as a receptor for LRRTM2 based on affinity chromatography. LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. These observations indicate that an LRRTM2-Neurexin1 interaction plays a critical role in regulating excitatory synapse development.
View details for DOI 10.1016/j.neuron.2009.12.019
View details for Web of Science ID 000273425800008
View details for PubMedID 20064388
Endocannabinoid Signaling Is Required for Development and Critical Period Plasticity of the Whisker Map in Somatosensory Cortex
2009; 64 (4): 537-549
Type 1 cannabinoid (CB1) receptors mediate widespread synaptic plasticity, but how this contributes to systems-level plasticity and development in vivo is unclear. We tested whether CB1 signaling is required for development and plasticity of the whisker map in rat somatosensory cortex. Treatment with the CB1 antagonist AM251 during an early critical period for layer (L) 2/3 development (beginning postnatal day [P] 12-16) disrupted whisker map development, leading to inappropriate whisker tuning in L2/3 column edges and a blurred map. Early AM251 treatment also prevented experience-dependent plasticity in L2/3, including deprivation-induced synapse weakening and weakening of deprived whisker responses. CB1 blockade after P25 did not disrupt map development or plasticity. AM251 had no acute effect on sensory-evoked spiking and only modestly affected field potentials, suggesting that plasticity effects were not secondary to gross activity changes. These findings implicate CB1-dependent plasticity in systems-level development and early postnatal plasticity of the whisker map.
View details for DOI 10.1016/j.neuron.2009.10.005
View details for Web of Science ID 000272378900011
View details for PubMedID 19945395
View details for PubMedCentralID PMC2796273
TWO DISTINCT POPULATIONS OF PROJECTION NEURONS IN THE RAT LATERAL PARAFASCICULAR THALAMIC NUCLEUS AND THEIR CHOLINERGIC RESPONSIVENESS
2009; 162 (1): 155-173
The lateral parafascicular nucleus (lPf) is a member of the intralaminar thalamic nuclei, a collection of nuclei that characteristically provides widespread projections to the neocortex and basal ganglia and is associated with arousal, sensory, and motor functions. Recently, lPf neurons have been shown to possess different characteristics than other cortical-projecting thalamic relay neurons. We performed whole cell recordings from lPf neurons using an in vitro rat slice preparation and found two distinct neuronal subtypes that were differentiated by distinct morphological and physiological characteristics: diffuse and bushy. Diffuse neurons, which had been previously described, were the predominant neuronal subtype (66%). These neurons had few, poorly-branching, extended dendrites, and rarely displayed burst-like action potential discharge, a ubiquitous feature of thalamocortical relay neurons. Interestingly, we discovered a smaller population of bushy neurons (34%) that shared similar morphological and physiological characteristics with thalamocortical relay neurons of primary sensory thalamic nuclei. In contrast to other thalamocortical relay neurons, activation of muscarinic cholinergic receptors produced a membrane hyperpolarization via activation of M(2) receptors in most lPf neurons (60%). In a minority of lPf neurons (33%), muscarinic agonists produced a membrane depolarization via activation of predominantly M(3) receptors. The muscarinic receptor-mediated actions were independent of lPf neuronal subtype (i.e. diffuse or bushy neurons); however the cholinergic actions were correlated with lPf neurons with different efferent targets. Retrogradely-labeled lPf neurons from frontal cortical fluorescent bead injections primarily consisted of bushy type lPf neurons (78%), but more importantly, all of these neurons were depolarized by muscarinic agonists. On the other hand, lPf neurons labeled by striatal injections were predominantly hyperpolarized by muscarinic agonists (63%). Our results indicate two distinct subpopulations of lPf projection neurons, and interestingly lPf neurons respond differentially to muscarinic receptor activation based on their axonal target.
View details for DOI 10.1016/j.neuroscience.2009.04.043
View details for Web of Science ID 000267200300016
View details for PubMedID 19393292