Ilana B. Witten

Last updated
Ilana B. Witten
Born
Princeton, New Jersey, U.S.
Alma mater Princeton University
Stanford University
Known forOptogenetics and role of cholinergic interneurons in addiction
AwardsDaniel X Freedman Prize
NYSCF-Robertson Neuroscience Investigator Award
McKnight Scholars Award in Neuroscience
NIH Director’s New Innovator Award
Scientific career
FieldsNeuroscience
InstitutionsPrinceton University

Ilana B. Witten is an American neuroscientist and professor of psychology and neuroscience at Princeton University. Witten studies the mesolimbic pathway, with a focus on the striatal neural circuit mechanisms driving reward learning and decision making.

Contents

Early life and education

Witten grew up in Princeton, New Jersey, where her parents were both professors at Princeton University. [1] Her father, Edward Witten, is a theoretical physicist and professor of mathematics at Princeton University, and her mother, Chiara Nappi is a professor of physics. [1] Witten attended Princeton High School in her hometown and then stayed close to home attending Princeton University for her undergraduate education. [1] Witten's sister, Daniela Witten, pursued an undergraduate degree in mathematics and biology at Stanford University. [2]

At Princeton, Witten majored in physics, but it was during her undergraduate degree that she became fascinated by biology, specifically neuroscience. [1] During her first year at Princeton, Witten worked as a research assistant in the lab of Lee Merrill Silver, studying molecular biology and genetics. [3] Later in her undergraduate degree, Witten joined the lab of Michael J. Berry, where she conducted research towards her undergraduate thesis in computational neuroscience. [4] Her undergraduate honors thesis was titled “Testing for Metabolic Efficiency in the Neural Code of the Retina” and was awarded by the Department of Physics. [4] Witten graduated with an A.B. in physics in 2002 at Princeton. [1]

Inspired by her undergraduate research experiences, Witten pursued her graduate education in neuroscience at Stanford University in 2003. [5] Under the mentorship of Eric Knudsen, Witten explored the neurobiological mechanisms of attention and strategies of information processing in the central nervous system of owls. [6]

Sensory Information Processing in Barn Owls

Prediction is a fundamental neural computation performed by the brain to mediate appropriate behavioral responses to changing and uncertain environments. [7] In Witten's early graduate work, she explored how a specific neural circuit in the barn owl predicts the location of motion auditory stimuli. [7] The optical tectum is an area of the barn owl brain that helps to orient an owls gaze towards an auditory stimulus, and this is enabled by neurons encoding information from the auditory system to make a topographic map of auditory space. [7] Witten wanted to understand how this topographic map changes when auditory stimuli are moving. [7] She found that auditory receptive fields both sharpen and shift with stimulus position, showing that auditory fields make predictive shifts to track the location of auditory stimuli. [7]

Witten then became interested in exploring how the brain detects a singular object when it must integrate a variety of sensory stimuli and information from various channels. [8] Using a Hebbian Plasticity model, Witten proposed that the synaptic plasticity underlying object detection and representation in the brain results from the difference in spatial representations of one type of input relative to that of another. [8] She found that the amount of plasticity for each channel of sensory input depended on the strength and the width of the receptive field for that channel. [8] With stronger inputs guiding plasticity, this could account for the development and maintenance of aligned sensory representations in the brain. [8]

Using Optogenetics to Dissect Reward Circuits

After defending her PhD in 2008, Witten stayed at Stanford to conduct her postdoctoral studies in the lab of Karl Deisseroth. [1] Under Deisseroth's mentorship, Witten learned how to use optogenetic technologies to dissect genetically defined cell types within neural circuits, and Witten's particular interest was cholinergic neurons in the brain's reward circuitry. [9]  In a first author paper in Science, published in 2010, Witten dissected the role of cholinergic neurons in the nucleus accumbens which, although they make up only 1% of the local neurons, play significant roles in modulating circuitry and driving behavior. [9] She further found that these cholinergic interneurons were activated by cocaine administration, yet silencing them lead to increased medium spiny neuron activity in the NaC and prevented cocaine conditioning in mice. [9] Witten's finding highlighted the critical role such a small population of neurons can play in mediating behavioral outcomes. [8]

Since inhibition of cholinergic interneurons in the striatum ameliorated drug-induced conditioning, Witten and Deisseroth filed a patent for the use of optogenetic technologies in cholinergic interneurons in the NAc or striatum. [10] They proposed to first use the technology to better understand reward behaviors and addiction in rodent models, and later to target specific neural circuits in the treatment of addiction disorders in humans through the administration of opsin encoding polynucleotides into the striatum. [10] Through optical or electrical stimulation, this technology would enable temporally-precise treatment strategies for those suffering from addiction. [10]

Witten then wanted to apply optogenetics to rat models to explore neural reward circuitry, so she created Th::Cre and Chat::Cre driver lines in rats. [11] With these novel driver lines, Witten injected viruses to express Cre-dependent opsins in the rat brain to clarify the causal relationship between dopamine neuron firing and positive reinforcement in her novel rate driver lines. [11] Witten did confirm that stimulating Ventral Tegmental Area Dopamine neurons in Th::Cre rats did produce intracranial self-stimulation which highlighted the power of her tool for dissecting specific neural circuits in rats using optogenetics, which was previously not possible. [11]

Witten continued to explore cholinergic circuits in the striatum and the role of dopamine neurons in driving reward behaviors throughout her time in the Deisseroth Lab and became co-author on many papers during her four-year tenure in the lab. [12]

Career and research

Following postdoctoral work in the Deisseroth Lab, Witten was recruited to Princeton University in 2012 to become an assistant professor of psychology and neuroscience within the Princeton Neuroscience Institute and Department of Psychology. [1] Witten started her lab at Princeton and was dedicated to exploring the neural circuits driving reward learning and decision making in rodent models. [5] Through the use of techniques like optogenetics, rodent behavior, electrophysiology, imaging, and computational modeling, Witten and her team are able to discover novel mechanisms by which striatal and other reward circuitry drive behaviors. [5] In 2018, Ilana was promoted to associate professor and granted tenure at Princeton University. [13]

In addition to her role as a principal investigator, Witten is a member of the committee for PNI graduate student admissions, a member of committee to select URMs for PNI summer program, a member of the committee for redesigning the graduate student curriculum, as well as many other committee roles to support her Princeton neuroscience community. [5]   Witten also teaches many classes at Princeton and is a member of BRAIN CoGS (Circuits of Cognitive Systems), a 7-lab NIH funded project to understand how working memory function underlies decision making. [14]

Dissecting Reward Circuitry

In 2016, Witten and her team at Princeton published a paper looking at the distinct functions of different populations of midbrain dopamine neurons defined by their striatal target region. [15] They found that dopamine neurons that project to the ventral striatum have stronger responses to reward consumption and reward predicting cues where as the dopamine neurons that project to the dorsomedial striatum respond robustly to contralateral choices. [15]  Though both subpopulations displayed reward-prediction error, Witten's findings show that distinct dopamine terminal input locations support specialization of function in the striatum. [15]

Continuing to study striatal neurons implicated in reward learning, Witten returned to findings from her postdoctoral work on cholinergic striatal interneurons to probe the connection between their activity profiles, synaptic plasticity, and reward learning. [16] Witten and her team found that activity of cholinergic neurons regulates extinction learned cocaine-context associations. [16] Further, cholinergic neurons mediate a sustained reduction in presynaptic glutamatergic input into the medium spiny neurons of the striatum. [16] This work highlighted, for the first time, the modulatory role of cholinergic interneurons in the striatum. [16]

Circuits Encoding Social and Spatial Information

Since social interaction is intrinsically rewarding, Witten became interested in shaping part of her research program around understanding social information processing within the dopaminergic reward system. In 2017, Witten and her team explored a unique subset of prelimbic (PL) cortical neurons implicated in social behavior that project to the nucleus accumbens (NAc), amygdala, and ventral tegmental area. [17]  Interestingly, activation of the PL-NAc projection lead to decreased social preference, so Witten and her team sought to understand what information this projection was conveying. [17] They found that it conveyed both spatial and social information that allowed the formation of social-spatial associations to guide social behavior. [17]

Diverse Dopamine Neuron Encoding

Witten and her colleagues then examined the dopaminergic neurons in the VTA more rigorously. [18] Though these neurons are canonically associated with reward circuitry, they have been implicated in various other behavioral variables, so Witten was interested in looking at their ability to encode reward, reward predicting cues, reward history, spatial position, kinematics, and behavioral choice. [18] Through in vivo calcium imaging, Witten and her team found functional clusters of VTA DA neurons associated with both reward associated and non-reward associated variables, and these neurons were also spatially clustered within the VTA. [18]

Awards and honors

Select publications

Related Research Articles

<span class="mw-page-title-main">Striatum</span> Nucleus in the basal ganglia of the brain

The striatum or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamatergic and dopaminergic inputs from different sources; and serves as the primary input to the rest of the basal ganglia.

<span class="mw-page-title-main">Basal ganglia</span> Group of subcortical nuclei involved in the motor and reward systems

The basal ganglia (BG) or basal nuclei are a group of subcortical nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into external and internal regions, and in the division of the striatum. Positioned at the base of the forebrain and the top of the midbrain, they have strong connections with the cerebral cortex, thalamus, brainstem and other brain areas. The basal ganglia are associated with a variety of functions, including regulating voluntary motor movements, procedural learning, habit formation, conditional learning, eye movements, cognition, and emotion.

The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">Nigrostriatal pathway</span> Bilateral pathway in the brain

The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.

<span class="mw-page-title-main">Ventral tegmental area</span> Group of neurons on the floor of the midbrain

The ventral tegmental area (VTA), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and other dopamine pathways; it is widely implicated in the drug and natural reward circuitry of the brain. The VTA plays an important role in a number of processes, including reward cognition and orgasm, among others, as well as several psychiatric disorders. Neurons in the VTA project to numerous areas of the brain, ranging from the prefrontal cortex to the caudal brainstem and several regions in between.

<span class="mw-page-title-main">Interneuron</span> Neurons that are not motor or sensory

Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, enabling communication between sensory or motor neurons and the central nervous system. They play vital roles in reflexes, neuronal oscillations, and neurogenesis in the adult mammalian brain.

<span class="mw-page-title-main">Primate basal ganglia</span>

The basal ganglia form a major brain system in all vertebrates, but in primates there are special differentiating features. The basal ganglia include the striatum, globus pallidus, substantia nigra and subthalamic nucleus. In primates the pallidus is divided into an external and internal globus pallidus, the external globus pallidus is present in other mammals but not the internal globus pallidus. Also in primates, the dorsal striatum is divided by a large nerve tract called the internal capsule into two masses named the caudate nucleus and the putamen. These differences contribute to a complex circuitry of connections between the striatum and cortex that is specific to primates, reflecting different functions in primate cortical areas.

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of inhibitory GABAergic neuron representing approximately 90% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.The reward system motivates animals to approach stimuli or engage in behaviour that increases fitness. Survival for most animal species depends upon maximizing contact with beneficial stimuli and minimizing contact with harmful stimuli. Reward cognition serves to increase the likelihood of survival and reproduction by causing associative learning, eliciting approach and consummatory behavior, and triggering positively-valenced emotions. Thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals. In drug addiction, certain substances over-activate the reward circuit, leading to compulsive substance-seeking behavior resulting from synaptic plasticity in the circuit.

Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by expression of light-sensitive ion channels, pumps or enzymes specifically in the target cells. On the level of individual cells, light-activated enzymes and transcription factors allow precise control of biochemical signaling pathways. In systems neuroscience, the ability to control the activity of a genetically defined set of neurons has been used to understand their contribution to decision making, learning, fear memory, mating, addiction, feeding, and locomotion. In a first medical application of optogenetic technology, vision was partially restored in a blind patient with Retinitis pigmentosa.

Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

<span class="mw-page-title-main">Patricia Janak</span> American neuroscientist (born 1965)

Patricia Janak is a Bloomberg Distinguished Professor at Johns Hopkins University who studies the biological basis of behavior through associative learning. Janak applies this research to pathological behaviors, such as addiction and posttraumatic stress disorder, to improve understanding of how stimuli affect relapse and responses.

D. James "Jim" Surmeier, an American neuroscientist and physiologist of note, is the Nathan Smith Davis Professor and Chair in the Department of Neuroscience at Northwestern University Feinberg School of Medicine. His research is focused on the cellular physiology and circuit properties of the basal ganglia in health and disease, primarily Parkinson's and Huntington's disease as well as pain.

Lisa Gunaydin is an American neuroscientist and assistant professor at the Weill Institute for Neurosciences at the University of California San Francisco. Gunaydin helped discover optogenetics in the lab of Karl Deisseroth and now uses this technique in combination with neural and behavioral recordings to probe the neural circuits underlying emotional behaviors.

<span class="mw-page-title-main">Meaghan Creed</span> Canadian Neuroscientist

Meaghan Creed is a Canadian neuroscientist and associate professor of anesthesiology at Washington University in St. Louis. Creed has conducted research on understanding and optimizing deep brain stimulation in the basal ganglia for the treatment of neurological and psychiatric disorders. Her work has been recognized at the national and international level by Pfizer, the American Association for the Advancement of Science (AAAS), the Whitehall Foundation, Brain and Behavior Research Foundation and the Rita Allen Foundation.

Camilla Bellone is an Italian neuroscientist and assistant professor in the Department of Basic Neuroscience at the University of Geneva, in Switzerland. Bellone's laboratory explores the molecular mechanisms and neural circuits underlying social behavior and probes how defects at the molecular and circuit level give rise to psychiatric disease states such as Autism Spectrum Disorders.

Jessica Cardin is an American neuroscientist who is an associate professor of neuroscience at Yale University School of Medicine. Cardin's lab studies local circuits within the primary visual cortex to understand how cellular and synaptic interactions flexibly adapt to different behavioral states and contexts to give rise to visual perceptions and drive motivated behaviors. Cardin's lab applies their knowledge of adaptive cortical circuit regulation to probe how circuit dysfunction manifests in disease models.

Stephanie J. Cragg is a British physiologist who is Professor of Neuroscience at the University of Oxford. She holds a joint appointment as Professor in the University Department of Physiology, Anatomy and Genetics and as a Fellow, Director of Studies and Tutor for Medicine at the college Christ Church, Oxford.

References

  1. 1 2 3 4 5 6 7 "Illuminating the brain: Neuroscientist Ilana Witten". Princeton University. Retrieved 2020-04-24.
  2. ↑ "Full Bio". Daniela Witten. Retrieved 2020-04-24.
  3. ↑ "Neurotree - Ilana B. Witten". neurotree.org. Retrieved 2020-04-24.
  4. 1 2 Witten, Ilana B. (2002). "Testing for Metabolic Efficiency in the Neural Code of the Retina".{{cite journal}}: Cite journal requires |journal= (help)
  5. 1 2 3 4 "Ilana Witten | Neuroscience". pni.princeton.edu. Retrieved 2020-04-24.
  6. ↑ "Eric I. Knudsen's Profile | Stanford Profiles". profiles.stanford.edu. Retrieved 2020-04-24.
  7. 1 2 3 4 5 Witten, Ilana B.; Bergan, Joseph F.; Knudsen, Eric I. (November 2006). "Dynamic shifts in the owl's auditory space map predict moving sound location". Nature Neuroscience. 9 (11): 1439–1445. doi:10.1038/nn1781. ISSN   1546-1726. PMID   17013379. S2CID   7581888.
  8. 1 2 3 4 5 Witten, Ilana B.; Knudsen, Eric I.; Sompolinsky, Haim (August 2008). "A Hebbian learning rule mediates asymmetric plasticity in aligning sensory representations". Journal of Neurophysiology. 100 (2): 1067–1079. doi:10.1152/jn.00013.2008. ISSN   0022-3077. PMC   2525701 . PMID   18525023.
  9. 1 2 3 Witten, Ilana B.; Lin, Shih-Chun; Brodsky, Matthew; Prakash, Rohit; Diester, Ilka; Anikeeva, Polina; Gradinaru, Viviana; Ramakrishnan, Charu; Deisseroth, Karl (2010-12-17). "Cholinergic interneurons control local circuit activity and cocaine conditioning". Science. 330 (6011): 1677–1681. Bibcode:2010Sci...330.1677W. doi:10.1126/science.1193771. ISSN   1095-9203. PMC   3142356 . PMID   21164015.
  10. 1 2 3 "US Patent for Optogenetic control of reward-related behaviors Patent (Patent # 9,992,981 issued June 12, 2018) - Justia Patents Search". patents.justia.com. Retrieved 2020-04-24.
  11. 1 2 3 Witten, Ilana B.; Steinberg, Elizabeth E.; Lee, Soo Yeun; Davidson, Thomas J.; Zalocusky, Kelly A.; Brodsky, Matthew; Yizhar, Ofer; Cho, Saemi L.; Gong, Shiaoching; Ramakrishnan, Charu; Stuber, Garret D. (2011-12-08). "Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement". Neuron. 72 (5): 721–733. doi:10.1016/j.neuron.2011.10.028. ISSN   1097-4199. PMC   3282061 . PMID   22153370.
  12. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Ilana B. Witten - Publications". neurotree.org. Retrieved 2020-04-24.
  13. ↑ "News". Witten Lab. 2016-05-03. Retrieved 2020-04-24.
  14. ↑ "BRAIN CoGS". BRAIN CoGS. Retrieved 2020-04-24.
  15. 1 2 3 Parker, Nathan F.; Cameron, Courtney M.; Taliaferro, Joshua P.; Lee, Junuk; Choi, Jung Yoon; Davidson, Thomas J.; Daw, Nathaniel D.; Witten, Ilana B. (June 2016). "Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target". Nature Neuroscience. 19 (6): 845–854. doi:10.1038/nn.4287. ISSN   1546-1726. PMC   4882228 . PMID   27110917.
  16. 1 2 3 4 Lee, Junuk; Finkelstein, Joel; Choi, Jung Yoon; Witten, Ilana B. (2016-06-01). "Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association". Neuron. 90 (5): 1071–1085. doi: 10.1016/j.neuron.2016.05.001 . ISSN   0896-6273. PMC   4893317 . PMID   27210555.
  17. 1 2 3 Murugan, M.; Park, M.; Taliaferro, J.; Jang, H. J.; Cox, J.; Parker, N. F.; Bhave, V.; Nectow, A.; Pillow, J. W.; Witten, I. B. (2017-06-26). "Combined social and spatial coding in a descending projection from the prefrontal cortex". bioRxiv: 155929. doi: 10.1101/155929 . PMC   5889923 .
  18. 1 2 3 Engelhard, Ben; Finkelstein, Joel; Cox, Julia; Fleming, Weston; Jang, Hee Jae; Ornelas, Sharon; Koay, Sue Ann; Thiberge, Stephan Y.; Daw, Nathaniel D.; Tank, David W.; Witten, Ilana B. (June 2019). "Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons". Nature. 570 (7762): 509–513. Bibcode:2019Natur.570..509E. doi:10.1038/s41586-019-1261-9. ISSN   1476-4687. PMC   7147811 . PMID   31142844.
  19. ↑ "Brain & Behavior Research Foundation's Klerman & Freedman Awards Dinner Celebrates 30 Years of Scientific Grants, and Honors Foundation's Scientific Council". Brain & Behavior Research Foundation. 2017-07-27. Retrieved 2020-04-24.
  20. ↑ "The New York Stem Cell Foundation announces 2017 class of NYSCF - Robertson investigators". EurekAlert!. Retrieved 2020-04-24.
  21. ↑ "Ilana Witten". Simons Foundation. 2017-08-22. Retrieved 2020-04-24.
  22. ↑ "UPDATE: Nine Princeton researchers receive NIH BRAIN Initiative awards". Princeton University. Retrieved 2020-04-24.
  23. 1 2 "Grantome: Search". Grantome. Retrieved 2020-04-24.
  24. ↑ "Awardees". McKnight Foundation. Retrieved 2020-04-24.
  25. ↑ Foundation, Brain & Behavior Research. "Brain & Behavior Research Foundation's Klerman & Freedman Awards Dinner Celebrates 30 Years of Scientific Grants, and Honors Foundation's Scientific Council". www.prnewswire.com. Retrieved 2020-04-24.
  26. 1 2 3 4 5 6 7 8 9 10 11 12 "Department of Psychology". psych.princeton.edu. Retrieved 2020-04-24.
  27. ↑ "Ilana Witten receives a Pew Scholarship and a Sloan Foundation Fellowship | Neuroscience". pni.princeton.edu. Retrieved 2020-04-24.
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