Elizabeth Steinberg is a postdoctoral fellow in Dr. Robert Malenka’s lab in the Department of Psychiatry at Stanford University. Her research is focused on understanding how neural circuits for emotion, motivation and movement work together to control behavior in health and disease. At present, she is investigating the function and organization of connections between the amygdala and midbrain dopamine neurons. Elizabeth obtained her Ph.D. in Neuroscience in 2013 from the University of California at San Francisco, where she trained with Dr. Patricia Janak. Her doctoral research focused on identifying causal roles for dopamine neurons in reinforcement learning. Prior to her graduate training, Elizabeth studied Neuroscience and Philosophy at Columbia University.
Honors & Awards
National Institutes of Health Pathway to Independence Award (K99/R00), NIMH (2018-2023)
Postdoctoral Research Fellowship, A.P. Giannini Foundation (2015-2018)
Poster Prize, Gordon Research Conference: Amygdala Function in Emotion, Cognition and Disease (2017)
Trainee Professional Development Award, Society for Neuroscience (2017)
Allison Doupe Travel Fellowship, McKnight Foundation (2016)
Helena Anna Henzl-Gabor Postdoctoral Travel Grant, Stanford University (2015)
Dean’s Postdoctoral Fellowship, Stanford University (2014)
Graduate Research Award, UCSF (2012)
Earle C. Anthony Travel Award, UCSF (2011)
Poster Prize, FENS-IBRO School “Causal Neuroscience: Interacting with Neural Circuits” (2011)
Graduate Research Fellowship, National Science Foundation (2007-2010)
Summa Cum Laude, Columbia University (2004)
Honors in Biological Science, Columbia University (2004)
Dean's List, Columbia University (2000-2004)
Bachelor of Arts, Columbia University (2004)
Doctor of Philosophy, University of California San Francisco (2013)
Robert Malenka, Postdoctoral Faculty Sponsor
Learning what to approach.
2018; 16 (10): e3000043
Most decisions share a common goal: maximize reward and minimize punishment. Achieving this goal requires learning which choices are likely to lead to favorable outcomes. Dopamine is essential for this process, enabling learning by signaling the difference between what we expect to get and what we actually get. Although all animals appear to use this dopamine prediction error circuit, some do so more than others, and this neural heterogeneity correlates with individual variability in behavior. In this issue of PLOS Biology, Lee and colleagues show that manipulating a simple task parameter can bias the animals' behavioral strategy and modulate dopamine release, implying that how we learn is just as flexible as what we learn.
View details for DOI 10.1371/journal.pbio.3000043
View details for PubMedID 30307969
Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (4): 822-829
The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼ 15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure-function relationships of the light-gated pore.
View details for DOI 10.1073/pnas.1523341113
View details for Web of Science ID 000368617900023
View details for PubMedCentralID PMC4743797
- Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping CELL 2015; 162 (3): 622-634
Illuminating circuitry relevant to psychiatric disorders with optogenetics
CURRENT OPINION IN NEUROBIOLOGY
2015; 30: 9-16
The brain's remarkable capacity to generate cognition and behavior is mediated by an extraordinarily complex set of neural interactions that remain largely mysterious. This complexity poses a significant challenge in developing therapeutic interventions to ameliorate psychiatric disease. Accordingly, few new classes of drugs have been made available for patients with mental illness since the 1950s. Optogenetics offers the ability to selectively manipulate individual neural circuit elements that underlie disease-relevant behaviors and is currently accelerating the pace of preclinical research into neurobiological mechanisms of disease. In this review, we highlight recent findings from studies that employ optogenetic approaches to gain insight into normal and aberrant brain function relevant to mental illness. Emerging data from these efforts offers an exquisitely detailed picture of disease-relevant neural circuits in action, and hints at the potential of optogenetics to open up entirely new avenues in the treatment of psychiatric disorders.
View details for DOI 10.1016/j.conb.2014.08.004
View details for Web of Science ID 000348337600002
View details for PubMedID 25215625
Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons.
2015; 85 (2): 429-438
Ventral tegmental area (VTA) dopamine (DA) neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders. Optogenetic approaches involving transgenic Cre-driver mouse lines provide powerful tools for dissecting DA-specific functions. However, the emerging complexity of VTA circuits requires Cre-driver mouse lines that restrict transgene expression to a precisely defined cell population. Because of recent work reporting that VTA DA neurons projecting to the lateral habenula release GABA, but not DA, we performed an extensive anatomical, molecular, and functional characterization of prominent DA transgenic mouse driver lines. We find that transgenes under control of the tyrosine hydroxylase, but not the dopamine transporter, promoter exhibit dramatic non-DA cell-specific expression patterns within and around VTA nuclei. Our results demonstrate how Cre expression in unintentionally targeted cells in transgenic mouse lines can confound the interpretation of supposedly cell-type-specific experiments. This Matters Arising paper is in response to Stamatakis et al. (2013), published in Neuron. See also the Matters Arising Response paper by Stuber et al. (2015), published concurrently with this Matters Arising in Neuron.
View details for DOI 10.1016/j.neuron.2014.12.036
View details for PubMedID 25611513
- Positive Reinforcement Mediated by Midbrain Dopamine Neurons Requires D1 and D2 Receptor Activation in the Nucleus Accumbens PLOS ONE 2014; 9 (4)
A causal link between prediction errors, dopamine neurons and learning
2013; 16 (7): 966-U248
Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.
View details for DOI 10.1038/nn.3413
View details for Web of Science ID 000321180900032
View details for PubMedID 23708143
View details for PubMedCentralID PMC3705924
Establishing causality for dopamine in neural function and behavior with optogenetics
2013; 1511: 46-64
Dopamine (DA) is known to play essential roles in neural function and behavior. Accordingly, DA neurons have been the focus of intense experimental investigation that has led to many important advances in our understanding of how DA influences these processes. However, it is becoming increasingly appreciated that delineating the precise contributions of DA neurons to cellular, circuit, and systems-level phenomena will require more sophisticated control over their patterns of activity than conventional techniques can provide. Specifically, the roles played by DA neurons are likely to depend on their afferent and efferent connectivity, the timing and length of their neural activation, and the nature of the behavior under investigation. Recently developed optogenetic tools hold great promise for disentangling these complex issues. Here we discuss the use of light-sensitive microbial opsins in the context of outstanding questions in DA research. A major technical advance offered by these proteins is the ability to bidirectionally modulate DA neuron activity in in vitro and in vivo preparations on a time scale that more closely approximates those of neural, perceptual and behavioral events. In addition, continued advances in rodent genetics and viral-mediated gene delivery have contributed to the ability to selectively target DA neurons or their individual afferent and efferent connections. Further, these tools are suitable for use in experimental subjects engaged in complex behaviors. After reviewing the strengths and limitations of optogenetic methodologies, we conclude by describing early efforts in the application of this valuable new approach that demonstrate its potential to improve our understanding of the neural and behavioral functions of DA. This article is part of a Special Issue entitled Optogenetics (7th BRES).
View details for DOI 10.1016/j.brainres.2012.09.036
View details for Web of Science ID 000320087000005
View details for PubMedID 23031636
Recombinase-Driver Rat Lines: Tools, Techniques, and Optogenetic Application to Dopamine-Mediated Reinforcement
2011; 72 (5): 721-733
Currently there is no general approach for achieving specific optogenetic control of genetically defined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically restricted recombinase-driver rat lines suitable for driving gene expression in specific cell types, expressing Cre recombinase under the control of large genomic regulatory regions (200-300 kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell types. We additionally developed methods for utilizing optogenetic tools in freely moving rats and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). These studies complement existing targeting approaches by extending the generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.
View details for DOI 10.1016/j.neuron.2011.10.028
View details for Web of Science ID 000297971100008
View details for PubMedID 22153370
View details for PubMedCentralID PMC3282061
Perceptual learning directs auditory cortical map reorganization through top-down influences
JOURNAL OF NEUROSCIENCE
2006; 26 (18): 4970-4982
The primary sensory cortex is positioned at a confluence of bottom-up dedicated sensory inputs and top-down inputs related to higher-order sensory features, attentional state, and behavioral reinforcement. We tested whether topographic map plasticity in the adult primary auditory cortex and a secondary auditory area, the suprarhinal auditory field, was controlled by the statistics of bottom-up sensory inputs or by top-down task-dependent influences. Rats were trained to attend to independent parameters, either frequency or intensity, within an identical set of auditory stimuli, allowing us to vary task demands while holding the bottom-up sensory inputs constant. We observed a clear double-dissociation in map plasticity in both cortical fields. Rats trained to attend to frequency cues exhibited an expanded representation of the target frequency range within the tonotopic map but no change in sound intensity encoding compared with controls. Rats trained to attend to intensity cues expressed an increased proportion of nonmonotonic intensity response profiles preferentially tuned to the target intensity range but no change in tonotopic map organization relative to controls. The degree of topographic map plasticity within the task-relevant stimulus dimension was correlated with the degree of perceptual learning for rats in both tasks. These data suggest that enduring receptive field plasticity in the adult auditory cortex may be shaped by task-specific top-down inputs that interact with bottom-up sensory inputs and reinforcement-based neuromodulator release. Top-down inputs might confer the selectivity necessary to modify a single feature representation without affecting other spatially organized feature representations embedded within the same neural circuitry.
View details for DOI 10.1523/JNEUROSCI.3771-05.2006
View details for Web of Science ID 000237271700030
View details for PubMedID 16672673