Publications

Weinreb C, Kannan LT, Newman-Boulle A, Sainburg T, Gillis WF, Plotnikoff A, Makowska S, Pearl JE, Osman MAM, Linderman SW, Datta SR. (2026)

Spontaneous behavior is a succession of self-directed tasks

Neuron. 2026 Jan 28:S0896-6273(25)00894-3. doi: 10.1016/j.neuron.2025.11.021.

Animals achieve high-level goals by sequencing low-level actions. This transformation is best understood in structured tasks that impose a specific mapping between goals and actions. However, it remains unclear whether spontaneous behavior is similarly organized in the service of identifiable goals or how it might be supported by brain regions responsible for goal-oriented behavior, such as the prefrontal cortex (PFC). Here, we show that low-level actions in freely exploring mice are hierarchically organized into seconds-long behavioral states that correspond to task-like programs of behavior. These persistent states structure neural activity in the PFC, which preferentially encodes the identity of states relative to low-level behavioral features and shapes which states are expressed in a given context. These findings argue that spontaneous behavior is organized as a succession of self-directed tasks and identify principles of neural control that are common to structured tasks and spontaneous exploration.

David H Brann, Tatsuya Tsukahara, Cyrus Tau, Dennis Kalloor, Rylin Lubash, Lakshanyaa Thamarai Kannan, Nell Klimpert, Mihaly Kollo, Martín Escamilla-Del-Arenal, Bogdan Bintu, Thomas Bozza, Sandeep R Datta (2025)

A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain

bioRxiv 10.1101/2025.05.02.65173

Although topographical maps organize many peripheral sensory systems, it remains unclear whether olfactory sensory neurons (OSNs) choose which of the ∼1100 odor receptors (ORs) to express based upon their spatial location in the olfactory epithelium (OE) or instead ORs are scattered randomly. Here we reveal that each OR is expressed at a precise mean position along the OE dorsoventral axis, thereby instantiating a receptor map. This patterning reflects the differential use, by precursors and mature OSNs, of a coherent gene expression program controlled by a spatially-varying retinoic acid gradient; this program - which includes key transcription factors and axon guidance genes - translates position into a spatially appropriate distribution of OR choices and aligns the epithelial map of OR identity with the glomerular map present in the olfactory bulb. These results identify a transcriptional code that distinguishes and spatially organizes the vast array of sensory channels that comprise the olfactory system.

Jack W Lindsey, Jeffrey Markowitz, Winthrop F Gillis, Sandeep R Datta, Ashok Litwin-Kumar (2025)

Dynamics of striatal action selection and reinforcement learning

eLife 10.7554/eLife.101747

Spiny projection neurons (SPNs) in dorsal striatum are often proposed as a locus of reinforcement learning in the basal ganglia. Here, we identify and resolve a fundamental inconsistency between striatal reinforcement learning models and known SPN synaptic plasticity rules. Direct-pathway (dSPN) and indirect-pathway (iSPN) neurons, which promote and suppress actions, respectively, exhibit synaptic plasticity that reinforces activity associated with elevated or suppressed dopamine release. We show that iSPN plasticity prevents successful learning, as it reinforces activity patterns associated with negative outcomes. However, this pathological behavior is reversed if functionally opponent dSPNs and iSPNs, which promote and suppress the current behavior, are simultaneously activated by efferent input following action selection. This prediction is supported by striatal recordings and contrasts with prior models of SPN representations. In our model, learning and action selection signals can be multiplexed without interference, enabling learning algorithms beyond those of standard temporal difference models.

Sara Zeppilli, Alonso O Gurrola, Pinar Demetci, David H Brann, Tuan M Pham, Robin Attey, Noga Zilkha, Tali Kimchi, Sandeep R Datta, Ritambhara Singh, Maria A Tosches, Anton Crombach, Alexander Fleischmann (2025)

Single-cell genomics of the mouse olfactory cortex reveals contrasts with neocortex and ancestral signatures of cell type evolution

Nature Neuroscience 28:937-948

Understanding the molecular logic of cortical cell-type diversity can illuminate cortical circuit function and evolution. Here, we performed single-nucleus transcriptome and chromatin accessibility analyses to compare neurons across three- to six-layered cortical areas of adult mice and across tetrapod species. We found that, in contrast to the six-layered neocortex, glutamatergic neurons of the three-layered mouse olfactory (piriform) cortex displayed continuous rather than discrete variation in transcriptomic profiles. Subsets of piriform and neocortical glutamatergic cells with conserved transcriptomic profiles were distinguished by distinct, area-specific epigenetic states. Furthermore, we identified a prominent population of immature neurons in piriform cortex and observed that, in contrast to the neocortex, piriform cortex exhibited divergence between glutamatergic cells in laboratory versus wild-derived mice. Finally, we showed that piriform neurons displayed greater transcriptomic similarity to cortical neurons of turtles, lizards and salamanders than to those of the neocortex. In summary, despite over 200 million years of coevolution alongside the neocortex, olfactory cortex neurons retain molecular signatures of ancestral cortical identity.

Drew Friedmann, Xavier Gonzalez, Ashley Moses, Tanner Watts, Anthony Degleris, Nicole Ticea, Jun H. Song, Sandeep Robert Datta, Scott W. Linderman, Liqun Luo (2024)

Concerted modulation of spontaneous behavior and time-integrated whole-brain neuronal activity by serotonin receptors

bioRxiv 10.1101/2024.08.02.606282

Serotonin neurons from the raphe nuclei project across the entire brain and modulate diverse physiology and behavior by acting on over a dozen receptors. Here, we took a step towards dissecting this complex process by examining the effects of agonists and antagonists of four widely expressed serotonin receptors (2A, 2C, 1A, and 1B) on spontaneous mouse behavior, which we related to time-integrated whole-brain neuronal activity as assessed by the expression of Fos, a canonical immediate-early gene product. Low-dimensional representations of behavioral and Fos map data revealed the dominant factors of variation in each domain, captured predictable differences across drug groups, and enabled predictions of behavioral changes following perturbations in Fos maps and vice versa. Our study provides a rich resource describing the effects of manipulating serotonin receptors on animal behavior and whole-brain integrated neuronal activity. It also establishes an experimental and analysis paradigm for interrogating the relationship between behavior and neuronal activity across different time scales.

Andrea Pierré, Tuan Pham, Jonah Pearl, Sandeep Robert Datta, Jason T. Ritt, Alexander Fleischmann (2024)

A Perspective on Neuroscience Data Standardization with Neurodata Without Borders

Journal of Neuroscience 44:e0381242024.

Neuroscience research has evolved to generate increasingly large and complex experimental data sets, and advanced data science tools are taking on central roles in neuroscience research. Neurodata Without Borders (NWB), a standard language for neurophysiology data, has recently emerged as a powerful solution for data management, analysis, and sharing. We here discuss our labs’ efforts to implement NWB data science pipelines. We describe general principles and specific use cases that illustrate successes, challenges, and non-trivial decisions in software engineering. We hope that our experience can provide guidance for the neuroscience community and help bridge the gap between experimental neuroscience and data science. Key takeaways from this article are that (1) standardization with NWB requires non-trivial design choices; (2) the general practice of standardization in the lab promotes data awareness and literacy, and improves transparency, rigor, and reproducibility in our science; (3) we offer several feature suggestions to ease the extensibility, publishing/sharing, and usability for NWB standard and users of NWB data

Daniel R. Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C. Dubinsky, Hannah C. Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M. Nadaf, Celia C. Beron, Allison E. Girasole, Lynne Chantranupong, Marissa D. Cortopassi, Shannon Prouty, Ludwig Geistlinger, Alexander S. Banks, Thomas S. Scanlan, Sandeep Robert Datta, Michael E. Greenberg, Gabriella L. Boulting, Evan Z. Macosko, Bernardo L. Sabatini (2024)

Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration

Cell 187:5679

Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain.To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone—a regulator of metabolism in many peripheral organs—directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.

Samuel J. Gershman, John A. Assad, Sandeep Robert Datta, Scott W. Linderman, Bernardo L. Sabatini, Naoshige Uchida, Linda Wilbrecht (2024)

Explaining dopamine through prediction errors and beyond

Nature Neuroscience 27:1645

The most influential account of phasic dopamine holds that it reports reward prediction errors (RPEs). The RPE-based interpretation of dopamine signaling is, in its original form, probably too simple and fails to explain all the properties of phasic dopamine observed in behaving animals. This Perspective helps to resolve some of the conflicting interpretations of dopamine that currently exist in the literature. We focus on the following three empirical challenges to the RPE theory of dopamine: why does dopamine (1) ramp up as animals approach rewards, (2) respond to sensory and motor features and (3) influence action selection? We argue that the prediction error concept, once it has been suitably modified and generalized based on an analysis of each computational problem, answers each challenge. Nonetheless, there are a number of additional empirical findings that appear to demand fundamentally different theoretical explanations beyond encoding RPE. Therefore, looking forward, we discuss the prospects for a unifying theory that respects the diversity of dopamine signaling and function as well as the complex circuitry that both underlies and responds to dopaminergic transmission.

Caleb Weinreb, Jonah E. Pearl , Sherry Lin , Mohammed Abdal Monium Osman, Libby Zhang, Sidharth Annapragada, Eli Conlin, Red Hoffmann, Sofia Makowska, Winthrop F. Gillis, Maya Jay, Shaokai Ye, Alexander Mathis, Mackenzie W. Mathis, Talmo Pereira, Scott W. Linderman, Sandeep Robert Datta (2024)

Keypoint-MoSeq: parsing behavior by linking point tracking to pose dynamics

Nature Methods, 21:1329

Keypoint tracking algorithms can flexibly quantify animal movement from videos obtained in a wide variety of settings. However, it remains unclear how to parse continuous keypoint data into discrete actions. This challenge is particularly acute because keypoint data are susceptible to high-frequency jitter that clustering algorithms can mistake for transitions between actions. Here we present keypoint-MoSeq, a machine learning-based platform for identifying behavioral modules (‘syllables’) from keypoint data without human supervision. Keypoint-MoSeq uses a generative model to distinguish keypoint noise from behavior, enabling it to identify syllables whose boundaries correspond to natural sub-second discontinuities in pose dynamics. Keypoint-MoSeq outperforms commonly used alternative clustering methods at identifying these transitions, at capturing correlations between neural activity and behavior and at classifying either solitary or social behaviors in accordance with human annotations. Keypoint-MoSeq also works in multiple species and generalizes beyond the syllable timescale, identifying fast sniff-aligned movements in mice and a spectrum of oscillatory behaviors in fruit flies. Keypoint-MoSeq, therefore, renders accessible the modular structure of behavior through standard video recordings.

Sherry Lin, Winthrop F. Gillis, Caleb Weinreb, Ayman Zeine, Samuel C. Jones, Emma M. Robinson, Jeffrey Markowitz, Sandeep Robert Datta (2024)

Characterizing the structure of mouse behavior using Motion Sequencing

Nature Protocols, 19:3242

Spontaneous mouse behavior is composed from repeatedly used modules of movement (e.g., rearing, running or grooming) that are flexibly placed into sequences whose content evolves over time. By identifying behavioral modules and the order in which they are expressed, researchers can gain insight into the effect of drugs, genes, context, sensory stimuli and neural activity on natural behavior. Here we present a protocol for performing Motion Sequencing (MoSeq), an ethologically inspired method that uses three-dimensional machine vision and unsupervised machine learning to decompose spontaneous mouse behavior into a series of elemental module called ‘syllables’. This protocol is based upon a MoSeq pipeline that includes modules for depth video acquisition, data preprocessing and modeling, as well as a standardized set of visualization tools. Users are provided with instructions and code for building a MoSeq imaging rig and acquiring three-dimensional video of spontaneous mouse behavior for submission to the modeling framework; the outputs of this protocol include syllable labels for each frame of the video data as well as summary plots describing how often each syllable was used and how syllables transitioned from one to the other. In addition, we provide instructions for analyzing and visualizing the outputs of keypoint-MoSeq, a recently developed variant of MoSeq that can identify behavioral motifs from keypoints identified from standard (rather than depth) video. This protocol and the accompanying pipeline significantly lower the bar for users without extensive computational ethology experience to adopt this unsupervised, data-driven approach to characterize mouse behavior.

Kara Fulton, David Zimmerman, Aravi Samuel, Katrin Vogt, Sandeep Robert Datta (2024)

Common principles for odour coding across vertebrates and invertebrates

Nature Reviews Neuroscience 25:453

The olfactory system is an ideal and tractable system for exploring how the brain transforms sensory inputs into behaviour. The basic tasks of any olfactory system include odour detection, discrimination and categorization. The challenge for the olfactory system is to transform the high-dimensional space of olfactory stimuli into the much smaller space of perceived objects and valence that endows odours with meaning. Our current understanding of how neural circuits address this challenge has come primarily from observations of the mechanisms of the brain for processing other sensory modalities, such as vision and hearing, in which optimized deep hierarchical circuits are used to extract sensory features that vary along continuous physical dimensions. The olfactory system, by contrast, contends with an ill-defined, high-dimensional stimulus space and discrete stimuli using a circuit architecture that is shallow and parallelized. Here, we present recent observations in vertebrate and invertebrate systems that relate the statistical structure and state-dependent modulation of olfactory codes to mechanisms of perception and odour-guided behaviour.

Deepanjali Dwivedi, Dimitri Dumontier, Mia Sherer, Sherry Lin, Andrea M. C. Mirow, Yanjie Qiu, Qing Xu, Samuel A. Liebman, Djeckby Joseph, Sandeep R. Datta, Gord Fishell, Gabrielle Pouchelon (2024)

Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development

Nature Comms. 15:5421

During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian “fire together, wire together” precept. However, select connections, essential for circuit development, are transient. They are effectivel connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably,we found that this process impacts the development of normal exploratory behaviors of adult mice.

Brigitta B. Gundersen, William T. O’Brien, Melanie D. Schaffler, Maria N. Schultz, Tatsuya Tsukahara, Sandra Martin Lorenzo, Valerie Nalesso, Alice H. Luo Clayton, Ted Abel, Jacqueline N. Crawley, Sandeep Robert Datta, Yann Herault (2023)

Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome

bioRxiv doi: https://doi.org/10.1101/2023.05.01.538987

A microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine learning approach to analyze behavior, one lab found that arbaclofen also rescued differencesin exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.

Zohreh Farsi, Ally Nicolella, Sean K. Simmons, Sameer Aryal, Nate Shepard, Kira Brenner, Sherry Lin, Linnea Herzog, Sean P. Moran, Katherine J. Stalnaker, Wangyong Shin, Vahid Gazestani, Bryan J. Song, Kevin Bonanno, Hasmik Keshishian, Steven A. Carr, Jen Q. Pan, Evan Z. Macosko, Sandeep Robert Datta, Borislav Dejanovic, Eunjoon Kim, Joshua Z. Levin, Morgan Sheng (2023)

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Neuron 111:3378

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF)mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show(1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologicmechanisms, provide support for both the ‘‘hypo-glutamate’’ and‘‘hyperdopamine’’ hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.

Tatsuya Tsukahara, David Brann, Sandeep Robert Datta (2023)

Mechanisms of SARS-CoV-2-associated anosmia

Physiol. Rev. 103:2759.

Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory epithelium, current evidence suggests that neuronal infection is extremely rare in both the olfactory periphery and the brain, prompting the need for mechanistic models that can explain the widespread anosmia in COVID-19 patients. Starting from work identifying the non-neuronal cell types that are infected by SARS-CoV-2 in the olfactory system, we review the effects of infection of these supportive cells in the olfactory epithelium and in the brain and posit the downstream mechanisms through which sense of smell is impaired in COVID-19 patients. We propose that indirect mechanisms contribute to alteredolfactory system function in COVID-19-associated anosmia, as opposed to neuronal infection or neuroinvasion into the brain. Such indirect mechanisms include tissue damage, inflammatory responses through immune cell infiltration or systemic circulation of cytokines, and downregulation of odorant receptor genes in olfactory sensory neurons in response to local and systemic signals. We also highlight key unresolved questions raised by recent findings.

Tilo Gschwind, Ayman Zeine, Ivan Raikov, ..., Lori L. Isom, Sandeep Robert Datta, Ivan Soltesz (2023)

Hidden behavioral fingerprints in epilepsy

Neuron 111, 1–13

Gschwind et al. show that machine learning-assisted behavioral analysis allows an unbiased assessment of epilepsy in animal models. The automated identification of behavioral phenotypes, including anti-epileptic drug responses, during the readily available inter-ictal periods bears great potential to accelerate rigorous, reproducible preclinical research into epilepsies.

Dana Rubi Levy, Nigel Hunter, Sherry Lin, ..., Rockwell Anyoha, Rebecca M. Shansky, Sandeep Robert Datta (2023)

Mouse spontaneous behavior reflects individual variation rather than estrous state

Current Biology 33, 1–7

Levy et al. track open-field behavior of female mice over weeks and find that behavior reflects individual identity far more than estrous state. Open-field exploration patterns in males are much more variable than in females, arguing for the inclusion of both sexes in studies of spontaneous behaviors.

James P. Bohnslav, Mohammed Abdal Monium Osman, Akshay Jaggi, Sofia Soares, Caleb Weinreb, Sandeep Robert Datta, and Christopher D. Harvey (2023)

ArMo: An Articulated Mesh Approach for Mouse 3D Reconstruction

Characterizing animal behavior requires methods to distill 3D movements from video data. Though keypoint tracking has emerged as a widely used solution to this problem, it only provides a limited view of pose, reducing the body of an animal to a sparse set of experimenter-defined points. To more completely capture 3D pose, recent studies have fit 3D mesh models to subjects in image and video data. However, despite the importance of mice as a model organism in neuroscience research, these methods have not been applied to the 3D reconstruction of mouse behavior. Here, we present ArMo, an articulated mesh model of the laboratory mouse, and demonstrate its application to multi-camera recordings of head-fixed mice running on a spherical treadmill. Using an end-to-end gradient based optimization procedure, we fit the shape and pose of a dense 3D mouse model to data-derived keypoint and point cloud observations. The resulting reconstructions capture the shape of the animal’s surface while compactly summarizing its movements as a time series of 3D skeletal joint angles. ArMo therefore provides a novel alternative to the sparse representations of pose more commonly used in neuroscience research.

Jeffrey E. Markowitz, Winthrop F. Gillis, Maya Jay, Jeffrey Wood, Ryley W. Harris, Robert Cieszkowski, Rebecca Scott, David Brann, Dorothy Koveal, Tomasz Kula, Caleb Weinreb, Mohammed Abdal Monium Osman, Sandra Romero Pinto, Naoshige Uchida, Scott W. Linderman, Bernardo L. Sabatini, Sandeep Robert Datta (2023)

Spontaneous behaviour is structured by reinforcement without explicit reward

Nature, 18 January 2023

Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences. However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour.

Loulwah Mukharesh, MD, Marc A. Bouffard, MD, Elizabeth Fortin, MD, David H. Brann, Sandeep Robert Datta, MD, PhD, Sashank Prasad, MD, Bart K. Chwalisz, MD (2023)

Pseudotumor Cerebri Syndrome With COVID-19: A Case Series

Journal of neuro-ophthalmology, Volume 42, Issue 3

Pseudotumorcerebrisyndrome (PCS) either affects mostly overweight women of childbearing age as idiopathic intracranial hypertension (IIH) or can occur secondary to other medical conditions. Symptoms include headaches, transient visual obscurations(TVOs), pulse-synchronous tinnitus (PST), and vision loss. Diagnosis rests on increased intracranial pressure (ICP) without alternative explanation such as intracranial mass, meningitis, or cerebral venous sinus thrombosis (CVST). COVID-19 is a global pandemic caused by infection with the severe acute respiratory syndrome coronavirus2 (SARS-CoV2). We describe an association between PCS and COVID-19 in adult patients. Potential mechanisms include dysregulation of cerebrospinal fluid (CSF) dynamics in the setting of choroid plexus epithelium and meningeal infection, venous clotting, or quarantine-related lifestyle modifications promoting weight gain. In this study, we report 8 patients (See Supplemental Digital Content, Table 1, http://links.lww.com/WNO/A536) who developed new or worsening PCS shortly after acquiring COVID-19 without meningoencephalitis or major CVST and mostly without significant recent weight gain.

John B. Finlay, David H. Brann, Ralph Abi Hachem, David W. Jang, Allison D. Oliva, Tiffany Ko, Rupali Gupta, Sebastian A. Wellford, E. Ashley Moseman, Sophie S. Jang, Carol H. Yan, Hiroaki Matsunami, Tatsuya Tsukahara, Sandeep Robert Datta, Bradley J. Goldstein (2022)

Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium

Sci. Transl. Med. 14, eadd0484

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss.

Zihe Zhang, David P. Roberson, Masakazu Kotoda, Bruno Boivin, James P. Bohnslav, Rafael González-Cano, David A. Yarmolinsky, Bruna Lenfers Turnes, Nivanthika K. Wimalasena, Shay Q. Neufeld, Lee B. Barrett, Nara L.M. Quintaño, Victor Fattori, Daniel G. Taub, Alexander B. Wiltschko, Nick A. Andrews, Christopher D. Harvey, Sandeep Robert Datta, Clifford J. Woolf (2022)

Automated preclinical detection of mechanical pain hypersensitivity and analgesia

Pain, 163 (2022) 2326–2336

The lack of sensitive and robust behavioral assessments of pain in preclinical models has been a major limitation for both pain research and the development of novel analgesics. Here, we demonstrate a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion. The technology records freely behaving mice, in the dark, over extended periods for continuous acquisition of 2 parallel video data streams: (1) near-infrared frustrated total internal reflection for detecting the degree, force, and timing of surface contact and (2) simultaneous ongoing video graphing of whole-body pose. Using machine vision and machine learning, we automatically extract and quantify behavioral features from these data to reveal moment-by-moment changes that capture the internal pain state of rodents in multiple pain models. We show that these voluntary pain-related behaviors are reversible by analgesics and that analgesia can be automatically and objectively differentiated from sedation. Finally, we used this approach to generate a paw luminance ratio measure that is sensitive in capturing dynamic mechanical hypersensitivity over a period and scalable for high- throughput preclinical analgesic efficacy assessment.

Julia C. Costacurta, Lea Duncker, Blue Sheffer, Winthrop Gillis, Caleb Weinreb, Jeffrey Evan Markowitz, Sandeep R. Datta, Alex H. Williams, Scott W. Linderman (2022)

Distinguishing discrete and continuous behavioral variability using warped autoregressive HMMs

36th Conference on Neural Information Processing Systems (NeurIPS 2022)

A core goal in systems neuroscience and neuroethology is to understand how neural circuits generate naturalistic behavior. One foundational idea is that complex naturalistic behavior may be composed of sequences of stereotyped behavioral syllables, which combine to generate rich sequences of actions. To investigate this, a common approach is to use autoregressive hidden Markov models (ARHMMs) to segment video into discrete behavioral syllables. While these approaches have been successful in extracting syllables that are interpretable, they fail to account for other forms of behavioral variability, such as differences in speed, which may be better described as continuous in nature. To overcome these limitations, we introduce a class of warped ARHMMs (WARHMM). As is the case in the ARHMM, behavior is modeled as a mixture of autoregressive dynamics. However, the dynamics under each discrete latent state (i.e. each behavioral syllable) are additionally modulated by a continuous latent “warping variable.” We present two versions of warped ARHMM in which the warping variable affects the dynamics of each syllable either linearly or nonlinearly. Using depth-camera recordings of freely moving mice, we demonstrate that the failure of ARHMMs to account for continuous behavioral variability results in duplicate cluster assignments. WARHMM achieves similar performance to the standard ARHMM while using fewer behavioral syllables. Further analysis of behavioral measurements in mice demonstrates thatWARHMM identifies structure relating to response vigor.

Korleki Akiti, Iku Tsutsui-Kimura, Yudi Xie, ..., Mackenzie Weygandt Mathis, Naoshige Uchida, Mitsuko Watabe-Uchida (2022)

Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction

Neuron 110, 3789–3804

Animals both explore and avoid novel objects in the environment, but the neural mechanisms that underlie these behaviors and their dynamics remain uncharacterized. Here, we used multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq) to characterize the behavior of mice freely interacting with a novel object. Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of the striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability are explained by a reinforcement-learning (RL) model of threat prediction in which behavior arises from a novelty-induced initial threat prediction (akin to ‘‘shaping bonus’’) and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems.

Tsukahara T, Brann DH, Pashkovski SL, Guitchounts G, Bozza T, Datta SR. (2021)

A transcriptional rheostat couples past activity to future sensory responses

Cell 184:6326–6343

Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the  1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernández-Otero M, Cao Y, Zeine A, Sefah A, Zheng K, Xu Q, Khlestova E, Farhi SL, Bonneau R, Datta SR, Stevens B, and Fishell G (2021) (2021)

GABA-receptive microglia selectively sculpt developing inhibitory circuits

Cell 184:4048-4063

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABA_B receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.

Kanwal JK, Coddington E, Frazer R, Limbania D, Turner G, Davila KJ, Givens MA, Williams V, Datta SR, and Wasserman S (2021) (2021)

Internal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time

Integrative and Comparative Biology 61:867–886

Internal state profoundly alters perception and behavior. For example, a starved fly may approach and consume foods that it would otherwise find undesirable. A socially engaged newt may remain engaged in the presence of a predator, whereas a solitary newt would otherwise attempt to escape. Yet, the definition of internal state is fluid and ill-defined. As an interdisciplinary group of scholars spanning five career stages (from undergraduate to full professor) and six academic institutions, we came together in an attempt to provide an operational definition of internal state that could be useful in understanding the behavior and the function of nervous systems, at timescales relevant to the individual. In this perspective, we propose to define internal state through an integrative framework centered on dynamic and interconnected communication loops within and between the body and the brain. This framework is informed by a synthesis of historical and contemporary paradigms used by neurobiologists, ethologists, physiologists, and endocrinologists. We view internal state as composed of both spatially distributed networks (body–brain communication loops), and temporally distributed mechanisms that weave together neural circuits, physiology, and behavior. Given the wide spatial and temporal scales at which internal state operates—and therefore the broad range of scales at which it could be defined—we choose to anchor our definition in the body. Here we focus on studies that highlight body-to-brain signaling; body represented in endocrine signaling, and brain represented in sensory signaling. This integrative framework of internal state potentially unites the disparate paradigms often used by scientists grappling with body–brain interactions. We invite others to join us as we examine approaches and question assumptions to study the underlying mechanisms and temporal dynamics of internal state.

Chen J, Markowitz JE, Lilascharoen V, Taylor S, Sheurpukdi P, Keller JA, Jensen JR, Lim BK, Datta SR, and Stowers L (2021) (2021)

Flexible scaling and persistence of social vocal communication

Nature 593:108–113

Innate vocal sounds such as laughing, screaming or crying convey one’s feelings to others. In many species, including humans, scaling the amplitude and duration of vocalizations is essential for efective social communication. In mice, female scent triggers male mice to emit innate courtship ultrasonic vocalizations (USVs) . However, whether mice fexibly scale their vocalizations and how neural circuits are structured to generate fexibility remain largely unknown. Here we identify mouse neurons from the lateral preoptic area (LPOA) that express oestrogen receptor 1 (LPOAESR1 neurons) and, when activated, elicit the complete repertoire of USV syllables emitted during natural courtship. Neural anatomy and functional data reveal a two-step, di-synaptic circuit motif in which primary long-range inhibitory LPOAESR1 neurons relieve a clamp of local periaqueductal grey (PAG) inhibition, enabling excitatory PAG USV-gating neurons to trigger vocalizations. We fnd that social context shapes a wide range of USV amplitudes and bout durations. This variability is absent when PAG neurons are stimulated directly; PAG-evoked vocalizations are time-locked to neural activity and stereotypically loud. By contrast, increasing the activity of LPOAESR1 neurons scales the amplitude of vocalizations, and delaying the recovery of the inhibition clamp prolongs USV bouts. Thus, the LPOA disinhibition motif contributes to fexible loudness and the duration and persistence of bouts, which are key aspects of efective vocal social communication.

Dennis EJ, El Hady A, Michaiel A, Clemens A, Tervo DRG, Voigts J, and Datta SR (2021)

Systems Neuroscience of Natural Behaviors in Rodents

J. Neurosci. 41:911–919

Rudolph S, Guo C, Pashkovski SL, Osorno T, Gillis WF, Krauss JM, Nyitrai H, Flaquer I, El-Rifai M, Datta SR and Regehr WG. (2020)

Cerebellum-Specific Deletion of the GABAA Receptor d Subunit Leads to Sex-Specific Disruption of Behavior

Cell Reports 2020.108338

Granule cells (GCs) of the cerebellar input layer express high-affinity d GABAA subunit-containing GABAA receptors (dGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of dGABAA (cerebellar [cb] d knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in  turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb d KO mice display deficits in many behaviors, but motor function is normal. Strikingly, dGABAA deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that dGABAARs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias.

Wiltschko AB, Tsukahara T, Zeine A, Anyoha R, Gillis WF, Markowitz JE, Peterson RE, Katon J, Johnson MJ and Datta SR. (2020)

Revealing the structure of pharmacobehavioral space through Motion Sequencing

Nature Neuroscience 23:1433

Understanding how genes, drugs and neural circuits influence behavior requires the ability to effectively organize information about similarities and differences within complex behavioral datasets. Motion Sequencing (MoSeq) is an ethologically-inspired behavioral analysis method that identifies modular components of 3D mouse body language called “syllables.” Here we show that MoSeq effectively parses behavioral differences and captures similarities elicited by a panel of neuro- and psychoactive drugs administered to a cohort of nearly 700 mice. MoSeq identifies syllables that are characteristic of individual drugs; we leverage this finding to reveal specific on- and off-target effects of both established and candidate therapeutics in a mouse model of autism spectrum disorder. These results demonstrate that MoSeq can meaningfully organize large-scale behavioral data, illustrate the power of a fundamentally modular description of behavior, and suggest that behavioral syllables represent a new class of druggable target.

Pashkovski SL, Iurilli G, Brann D, Chicharro D, Drummey K, Franks KM, Panzeri S, and Datta SR (2020)

Structure and flexibility in cortical representations of odor space

Nature 583:253-58

The cortex organizes sensory information to enable discrimination and generalization. As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and orange, into perceptual categories, such as citrus. Here, by combining chemoinformatics and multiphoton imaging in the mouse, we show that both the piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships through correlated patterns of activity. However, cortical odour codes differ from those in the bulb: cortex more strongly clusters together representations for related odours, selectively rewrites pairwise odour relationships, and better matches odour perception. The bulb-to-cortex transformation depends on the associative network originating within the piriform cortex, and can be reshaped by passive odour experience. Thus, cortex actively builds a structured representation of chemical odour space that highlights odour relationships; this representation is similar across individuals but remains plastic, suggesting a means through which the olfactory system can assign related odour cues to common and yet personalized percepts.

Cooper KW, Brann DH, Farruggia MC, Bhutani S, Pellegrino R, Tsukahara T, Weinreb C, Joseph PV, Larson ED, Parma V, Albers MW, Barlow LA, Datta SR, and Di Pizio A (2020)

COVID-19 and the chemical senses: supporting players take center stage

Neuron 107:219-233.

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.

Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, Chance R, Macaulay IC, Chou H, Fletcher RB, Das D, Street K, Roux de Bezieux H, Choi YG, Risso D, Dudoit S, Purdom E, Mill J, Hachem RA, Matsunami H, Logan DW, Goldstein BJ, Grubb MS, Ngai J, and Datta SR (2020)

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Science Adv. 6:eabc5801

Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; CoV-2)—the causal agent in COVID-19—affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.

Brann DH and Datta SR (2020)

Finding the brain in the nose

Ann. Rev. Neurosci. 43:277

Olfaction is fundamentally distinct from other sensory modalities. Natural odor stimuli are complex mixtures of volatile chemicals that interact in the nose with a receptor array that, in rodents, is built from more than 1,000 unique receptors. These interactions dictate a peripheral olfactory code, which in the brain is transformed and reformatted as it is broadcast across a set of highly interconnected olfactory regions. Here we discuss the problems of characterizing peripheral population codes for olfactory stimuli, of inferring the specific functions of different higher olfactory areas given their extensive recurrence, and of ultimately understanding how odor representations are linked to perception and action.We argue that, despite the differences between olfaction and other sensory modalities, addressing these specific questions will reveal general principles underlying brain function.

Bloom ML, Johnston LB, and Datta SR (2020)

Renewal and differentiation of GCD necklace olfactory sensory neurons

Chem Senses 45:333-46

 

Both canonical olfactory sensory neurons (OSNs) and sensory neurons belonging to the guanylate cyclase D (GCD) “necklace” subsystem are housed in the main olfactory epithelium, which is continuously bombarded by toxins, pathogens, and debris from the outside world. Canonical OSNs address this challenge, in part, by undergoing renewal through neurogenesis; however, it is not clear whether GCD OSNs also continuously regenerate and, if so, whether newborn GCD precursors follow a similar developmental trajectory to that taken by canonical OSNs. Here, we demonstrate that GCD OSNs are born throughout adulthood and can persist in the epithelium for several months. Phosphodiesterase 2A is upregulated early in the differentiation process, followed by the sequential downregulation of β-tubulin and the upregulation of CART protein. The GCD and MS4A receptors that confer sensory responses upon GCD neurons are initially expressed midway through this process but become most highly expressed once CART levels are maximal late in GCD OSN development. GCD OSN maturation is accompanied by a horizontal migration of neurons toward the central, curved portions of the cul-de-sac regions where necklace cells are concentrated. These findings demonstrate that—like their canonical counterparts—GCD OSNs undergo continuous renewal and define a GCD-specific developmental trajectory linking neurogenesis, maturation, and migration.

 

Datta SR, Anderson DJ, Branson K, Perona P, Leifer A (2019)

Computational Neuroethology: A Call to Action

Neuron 104:11-24

The brain is worthy of study because it is in charge of behavior. A flurry of recent technical advances in measuring and quantifying naturalistic behaviors provide an important opportunity for advancing brain science. However, the problem of understanding unrestrained behavior in the context of neural recordings and manipulations remains unsolved, and developing approaches to addressing this challenge is critical. Here we discuss considerations in computational neuroethology-the science of quantifying naturalistic behaviors for understanding the brain-and propose strategies to evaluate progress. We point to open questions that require resolution and call upon the broader systems neuroscience community to further develop and leverage measures of naturalistic, unrestrained behavior, which will enable us to more effectively probe the richness and complexity of the brain.

Markowitz JE, and Datta SR (2019)

The striatum specifies the statistics of behavior

Neuropsychopharmacology 45:222-223

Batty E, Whiteway MR, Saxena S, Biderman D, Abe T, Musall S, Gillis W, Markowitz JE, Churchland A, Cunningham J, Datta SR, Linderman SL, Paninski L (2019)

BehaveNet: nonlinear embedding and Bayesian neural decoding of behavioral videos

NeurIPS 2019

A fundamental goal of systems neuroscience is to understand the relationship between neural activity and behavior. Behavior has traditionally been characterized by low-dimensional, task-related variables such as movement speed or response times. More recently, there has been a growing interest in automated analysis of high-dimensional video data collected during experiments. Here we introduce a probabilistic framework for the analysis of behavioral video and neural activity. This framework provides tools for compression, segmentation, generation, and decoding of behavioral videos. Compression is performed using a convolutional autoencoder (CAE), which yields a low-dimensional continuous representation of behavior. We then use an autoregressive hidden Markov model (ARHMM) to segment the CAE representation into discrete “behavioral syllables.” The resulting generative model can be used to simulate behavioral video data. Finally, based on this generative model, we develop a novel Bayesian decoding approach that takes in neural activity and outputs probabilistic estimates of the full-resolution behavioral video. We demonstrate this framework on two different experimental paradigms using distinct behavioral and neural recording technologies.

Datta SR (2019)

Q&A: Understanding the composition of behavior

BMC Biol. 2019 May 29;17(1):44. doi: 10.1186/s12915-019-0663-3.

Understanding the brain requires understanding behavior. New machine vision and learning techniques are poised to revolutionize our ability to analyze behaviors exhibited by animals in the laboratory. Here we describe one such method, Motion Sequencing (MoSeq), which combines 3D imaging with unsupervised machine learning techniques to identify the syllables and grammar that comprise mouse body language. This Q&A situates MoSeq within the array of novel methods currently being developed for behavioral analysis, enumerates its relative strengths and weaknesses, and describes its future trajectory.

Markowitz JE, Gillis WF, Beron CC, Neufeld SQ, Robertson K, Bhagat ND, Peterson RE, Peterson E, Hyun M, Linderman SW, Sabatini BL, and Datta SR. (2018)

The Striatum Organizes 3D Behavior via Moment-to- Moment Action Selection

Cell. 2018 Jun 28;174(1):44-58.e17. doi: 10.1016/j.cell.2018.04.019. Epub 2018 May 17.

Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.

Mao YT, Zhu JX, Hanamura K, Iurilli G, Datta SR, Dalva MB. (2018)

Filopodia Conduct Target Selection in Cortical Neurons Using Differences in Signal Kinetics of a Single Kinase

Neuron. 2018 May 16;98(4):767-782.e8. doi: 10.1016/j.neuron.2018.04.011. Epub 2018 May 3.

Dendritic filopodia select synaptic partner axons by interviewing the cell surface of potential targets, but how filopodia decipher the complex pattern of adhesive and repulsive molecular cues to find appropriate contacts is unknown. Here, we demonstrate in cortical neurons that a single cue is sufficient for dendritic filopodia to reject or select specific axonal contacts for elaboration as synaptic sites. Super-resolution and live-cell imaging reveals that EphB2 is located in the tips of filopodia and at nascent synaptic sites. Surprisingly, a genetically encoded indicator of EphB kinase activity, unbiased classification, and a photoactivatable EphB2 reveal that simple differences in the kinetics of EphB kinase signaling at the tips of filopodia mediate the choice between retraction and synaptogenesis. This may enable individual filopodia to choose targets based on differences in the activation rate of a single tyrosine kinase, greatly simplifying the process of partner selection and suggesting a general principle.

Pisanello F, Mandelbaum G, Pisanello M, Oldenburg IA, Sileo L, Markowitz JE, Peterson RE, Della Patria A, Haynes TM, Emara MS, Spagnolo B, Datta SR, De Vittorio M, Sabatini BL. (2017)

Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber

Nat Neurosci. 2017 Aug;20(8):1180-1188. doi: 10.1038/nn.4591. Epub 2017 Jun 19.

Optogenetics promises precise spatiotemporal control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either spatially restricted or large brain volumes. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant. We use this mode to activate dorsal versus ventral striatum of individual mice and reveal different effects of each manipulation on motor behavior. Conversely, injecting light over the full numerical aperture of the fiber results in light emission from the entire taper surface, achieving broader and more efficient optogenetic activation of neurons, compared to standard flat-faced fiber stimulation. Thus, tapered fibers permit focal or broad illumination that can be precisely and dynamically matched to experimental needs.

Gillis WF, Datta SR. (2017)

Knowing where the nose is

BMC Biol. 2017 May 15;15(1):42. doi: 10.1186/s12915-017-0382-6.

Improvements in imaging technology and the development of powerful machine learning algorithms are revolutionizing the study of animal behavior in the laboratory. These innovations promise to reveal both global and local features of action relevant to understanding how the brain functions. A study in BMC Biology describes one such tool called OptiMouse, which is an open source platform that uses video to capture key features of mouse behavior, including information relevant to olfactory investigation.See research article: 10.1186/s12915-017-0377-3.

Iurilli G, Datta SR. (2017)

Population Coding in an Innately Relevant Olfactory Area

Neuron. 2017 Mar 8;93(5):1180-1197.e7. doi: 10.1016/j.neuron.2017.02.010. Epub 2017 Feb 28.

Different olfactory cortical regions are thought to harbor distinct sensory representations, enabling each area to play a unique role in odor perception and behavior. In the piriform cortex (PCx), spatially dispersed sensory inputs evoke activity in distributed ensembles of neurons that act as substrates for odor learning. In contrast, the posterolateral cortical amygdala (plCoA) receives hardwired inputs that may link specific odor cues to innate olfactory behaviors. Here we show that despite stark differences in the patterning of plCoA and PCx inputs, odor-evoked neural ensembles in both areas are equally capable of discriminating odors, and exhibit similar odor tuning, reliability, and correlation structure. These results demonstrate that brain regions mediating odor-driven innate behaviors can, like brain areas involved in odor learning, represent odor objects using distributive population codes; these findings suggest both alternative mechanisms for the generation of innate odor-driven behaviors and additional roles for the plCoA in odor perception.

Bear D, Lassance HM, Hoekstra HE and Datta SR. (2016)

The evolving neural and genetic architecture of vertebrate olfaction

Curr. Biol 26:1039-49.

Evolution sculpts the olfactory nervous system in response to the unique sensory challenges facing each species. In vertebrates, dramatic and diverse adaptations to the chemical environment are possible because of the hierarchical structure of the olfactory receptor (OR) gene superfamily: expansion or contraction of OR subfamilies accompanies major changes in habitat and lifestyle; independent selection on OR subfamilies can permit local adaptation or conserved chemical communication; and genetic variation in single OR genes can alter odor percepts and behaviors driven by precise chemical cues. However, this genetic flexibility contrasts with the relatively fixed neural architecture of the vertebrate olfactory system, which requires that new olfactory receptors integrate into segregated and functionally distinct neural pathways. This organization allows evolution to couple critical chemical signals with selectively advantageous responses, but also constrains relationships between olfactory receptors and behavior. The coevolution of the OR repertoire and the olfactory system therefore reveals general principles of how the brain solves specific sensory problems and how it adapts to new ones.

Paul L. Greer, Daniel M. Bear, Jean-Marc Lassance, Rory Kirchner, Hopi E. Hoekstra, Sandeep Robert Datta (2016)

A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction

Cell 165, 1734–1748

Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.

Matthew J. Johnson, David Duvenaud, Alexander B. Wiltschko, Sandeep R. Datta, Ryan P. Adams (2015)

Structured VAEs: Composing Probabilistic Graphical Models and Variational Autoencoders

Advances in Neural Information Processing Systems 2016:2946-2954.

We develop a new framework for unsupervisedlearning that composes probabilistic graphical models with deep learning methods and combines their respective strengths. Our method uses graphical models to express structured probability distributions and recent advances from deep learning to learn flexible feature models and bottom-up recognition networks. All components of these models are learned simultaneously using a single objective, and we develop scalable fitting algorithms that can leverage natural gradient stochastic variational inference, graphical model message passing, and backpropagation with the reparameterization trick. We illustrate this framework with a new structured time series model and an application to mouse behavioral phenotyping.

Alexander B. Wiltschko, Matthew J. Johnson, Giuliano Iurilli, Ralph E. Peterson, Jesse M. Katon, Stan L. Pashkovski, Victoria E. Abraira, Ryan P. Adams, and Sandeep Robert Datta (2015)

Mapping Sub-Second Structure in Mouse Behavior.

Neuron 88:1-15

Complex animal behaviors are likely built from simpler modules, but their systematic identification in mammals remains a significant challenge. Here we use depth imaging to show that 3D mouse pose dynamics are structured at the sub-second timescale. Computational modeling of these fast dynamics effectively describes mouse behavior as a series of reused and stereotyped modules with defined transition probabilities. We demonstrate this combined 3D imaging and machine learning method can be used to unmask potential strategies employed by the brain to adapt to the environment, to capture both predicted and previously hidden phenotypes caused by genetic or neural manipulations, and to systematically expose the global structure of behavior within an experiment. This work reveals that mouse body language is built from identifiable components and is organized in a predictable fashion; deciphering this language establishes an objective framework for characterizing the influence of environmental cues, genes and neural activity on behavior.

Laura Persson, Rochelle M. Witt, Meghan Galligan, Paul L. Greer, Adriana Eisner, Maria F. Pazyra-Murphy, Sandeep R. Datta, Rosalind A. Segal (2014)

Shh-Proteoglycan Interactions Regulate Maturation of Olfactory Glomerular Circuitry.

Dev. Neurobiology 74:1255-67.

The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (ShhAla/Ala), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature ShhAla/Ala mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal
circuitry.

Giessel AJ, Datta SR. (2014)

Olfactory maps, circuits, and computations.

Curr. Opin. Neuro. 24: 120-132.

Sensory information in the visual, auditory and somatosensory systems is organized topographically, with key sensory features ordered in space across neural sheets. Despite the existence of a spatially stereotyped map of odor identity within the olfactory bulb, it is unclear whether the higher olfactory cortex uses topography to organize information about smells. Here, we review recent work on the anatomy, microcircuitry and neuromodulation of two higher-order olfactory areas: the piriform cortex and the olfactory tubercle. The piriform is an archicortical region with an extensive local associational network that constructs representations of odor identity. The olfactory tubercle is an extension of the ventral striatum that may use reward-based learning rules to encode odor valence. We argue that in contrast to brain circuits for other sensory modalities, both the piriform and the olfactory tubercle largely discard any topography present in the bulb and instead use distributive afferent connectivity, local learning rules and input from neuromodulatory centers to build behaviorally relevant representations of olfactory stimuli.

Datta SR and Patterson GH. (2011)

Optical highlighter moelcules in neurobiology.

Curr. Opin. Neuro. 22: 1-10.

The development of advanced optical methods has played a key role in propelling progress in neurobiology. Genetically-encoded fluorescent molecules found in nature have enabled labeling of individual neurons to study their physiology and anatomy. Here we discuss the recent use of both native and synthetic optical highlighter proteins to address key problems in neurobiology, including questions relevant to synaptic function, neuroanatomy, and the organization of neural circuits.

Ferrero, DM, Lemon JK, Fluegge D, Pashkovski SL, Korzan WJ, Datta SR, Spehr M, Fendt M and Liberles SD. (2011)

Detection and Avoidance of a Carnivore Odor by Prey.

PNAS 108: 11235-40.

Predator-prey relationships provide a classic paradigm for the study of innate animal behavior. Odors from carnivores elicit stereotyped fear and avoidance responses in rodents, although sensory mechanisms involved are largely unknown. Here, we identified a chemical produced by predators that activates a mouse olfactory receptor and produces an innate behavioral response. We purified this predator cue from bobcat urine and identified it to be a biogenic amine, 2-phenylethylamine. Quantitative HPLC analysis across 38 mammalian species indicates enriched 2-phenylethylamine production by numerous carnivores, with some producing >3,000-fold more than herbivores examined. Calcium imaging of neuronal responses in mouse olfactory tissue slices identified dispersed carnivore odor-selective sensory neurons that also responded to 2-phenylethylamine. Two prey species, rat and mouse, avoid a 2-phenylethylamine odor source, and loss-of-function studies involving enzymatic depletion of 2-phenylethylamine from a carnivore odor indicate it to be required for full avoidance behavior. Thus, rodent olfactory sensory neurons and chemosensory receptors have the capacity for recognizing interspecies odors. One such cue, carnivore-derived 2-phenylethylamine, is a key component of a predator odor blend that triggers hard-wired aversion circuits in the rodent brain. These data show how a single, volatile chemical detected in the environment can drive an elaborate danger-associated behavioral response in mammals.

Sosulski DL, Lissitsyna MV, Cutforth T, Axel R, and Datta SR. (2011)

Distinct Representations of Olfactory Information in Different Cortical Centers.

Nature 472: 213-16.

Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. Here we investigate how this ordered representation is transformed in higher olfactory centres in mice. We have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfactory bulb to the piriform cortex and the cortical amygdala. The spatial order in the bulb is discarded in the piriform cortex; axons from individual glomeruli project diffusely to the piriform without apparent spatial preference. In the cortical amygdala, we observe broad patches of projections that are spatially stereotyped for individual glomeruli. These projections to the amygdala are overlapping and afford the opportunity for spatially localized integration of information from multiple glomeruli. The identification of a distributive pattern of projections to the piriform and stereotyped projections to the amygdala provides an anatomical context for the generation of learned and innate behaviours.

Ruta VR, Datta SR, Vasconcelos ML, Looger L and Axel R. (2010)

A Dimorphic Pheromone Responsive Circuit in Drosophila from Sensory Input to Descending Output.

Nature 486: 686-90.

Drosophila show innate olfactory-driven behaviours that are observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate these behaviours are genetically programmed. Despite the numerical simplicity of the fly nervous system, features of the anatomical organization of the fly brain often confound the delineation of these circuits. Here we identify a neural circuit responsive to cVA, a pheromone that elicits sexually dimorphic behaviours. We have combined neural tracing using an improved photoactivatable green fluorescent protein (PA-GFP) with electrophysiology, optical imaging and laser-mediated microlesioning to map this circuit from the activation of sensory neurons in the antennae to the excitation of descending neurons in the ventral nerve cord. This circuit is concise and minimally comprises four neurons, connected by three synapses. Three of these neurons are overtly dimorphic and identify a male-specific neuropil that integrates inputs from multiple sensory systems and sends outputs to the ventral nerve cord. This neural pathway suggests a means by which a single pheromone can elicit different behaviours in the two sexes.

Datta SR*, Vasconcelos ML*, Ruta V, Luo S, Wong A, Demir E, Flores J, Balonze K, Dickson BJ and Axel R. (2008)

The Drosophila pheromone cVA activates a sexually dimorphic neural circuit.

Nature 452: 473-7.

Courtship is an innate sexually dimorphic behaviour that can be observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate this behaviour are developmentally programmed. In Drosophila, courtship involves a complex yet stereotyped array of dimorphic behaviours that are regulated by Fru(M), a male-specific isoform of the fruitless gene. Fru(M) is expressed in about 2,000 neurons in the fly brain, including three subpopulations of olfactory sensory neurons and projection neurons (PNs). One set of Fru(+) olfactory neurons expresses the odorant receptor Or67d and responds to the male-specific pheromone cis-vaccenyl acetate (cVA). These neurons converge on the DA1 glomerulus in the antennal lobe. In males, activation of Or67d(+) neurons by cVA inhibits courtship of other males, whereas in females their activation promotes receptivity to other males. These observations pose the question of how a single pheromone acting through the same set of sensory neurons can elicit different behaviours in male and female flies. Anatomical or functional dimorphisms in this neural circuit might be responsible for the dimorphic behaviour. We therefore developed a neural tracing procedure that employs two-photon laser scanning microscopy to activate the photoactivatable green fluorescent protein. Here we show, using this technique, that the projections from the DA1 glomerulus to the protocerebrum are sexually dimorphic. We observe a male-specific axonal arbor in the lateral horn whose elaboration requires the expression of the transcription factor Fru(M) in DA1 projection neurons and other Fru(+) cells. The observation that cVA activates a sexually dimorphic circuit in the protocerebrum suggests a mechanism by which a single pheromone can elicit different behaviours in males and in females.

Danial NN, Walensky LD, Zhang CY, Choi CS, Molina A, Datta SR, Pitter K, Wikstrom JD, Deeney JT, Fisher JK, Robertson K, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB and Korsmeyer SJ. (2007)

Dual role of pro-apoptotic BAD in insulin secretion and beta-cell survival.

Nature Med. 14:144-53.

The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

Sastry KS, Smith AJ, Karpova Y, Datta SR, Kulik G. (2006)

Diverse antiapoptotic signaling pathways activated by vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase in prostate cancer cells converge on BAD.

J Biol Chem. 281:20891-901.

It has been demonstrated that vasoactive intestinal polypeptide, epidermal growth factor, and chronic activation of phosphatidylinositol 3-kinase can protect prostate cancer cells from apoptosis; however, the signaling pathways that they use and molecules that they target are unknown. We report that vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase activate independent signaling pathways that phosphorylate the proapoptotic protein BAD. Vasoactive intestinal polypeptide operated via protein kinase A, epidermal growth factor required Ras activity, and effects of phosphatidylinositol 3-kinase were predominantly mediated by Akt. BAD phosphorylation was critical for the antiapoptotic effects of each signaling pathway. None of these survival signals was able to rescue cells that express BAD with mutations in phosphorylation sites, whereas knockdown of BAD expression with small hairpin RNA rendered cells insensitive to apoptosis. Taken together, these results identify BAD as a convergence point of several antiapoptotic signaling pathways in prostate cells.

Danial NN, Gramm CF, Scorrano L, Zhang C-Y, Krauss S, Ranger AM, Datta SR, Greenberg ME, Kickllder LJ, Lowell BB, Gygi SP and Korsmeyer SJ. (2003)

BAD and glucokinase reside in a mitochondrial complex that integrates glycolosis and apoptosis.

Nature 424:952-956.

Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis.

Ranger AM, Zha J, Harada H, Datta SR, Danial N, Gilmore AP, Kutok JL, Le Beau MM, Greenberg ME and Korsmeyer SJ. (2003)

Bad-deficient mice develop diffuse large B cell lymphoma.

PNAS 100:9324-9.

The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.

Datta SR, Ranger A, Lin MZ, Sturgill JF, Ma Y, Dikkes P, Korsmeyer SJ and Greenberg ME. (2002)

Survival-factor mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.

Dev. Cell 3:631-643.

Growth factor suppression of apoptosis correlates with the phosphorylation and inactivation of multiple proapoptotic proteins, including the BCL-2 family member BAD. However, the physiological events required for growth factors to block cell death are not well characterized. To assess the contribution of BAD inactivation to cell survival, we generated mice with point mutations in the BAD gene that abolish BAD phosphorylation at specific sites. We show that BAD phosphorylation protects cells from the deleterious effects of apoptotic stimuli and attenuates death pathway signaling by raising the threshold at which mitochondria release cytochrome c to induce cell death. These findings establish a function for endogenous BAD phosphorylation, and elucidate a mechanism by which survival kinases block apoptosis in vivo.

Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME and Saudou F. (2002)

The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt.

Dev. Cell 2:831-837.

In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.

Tran H, Brunet A, Grenier JM, Datta SR, Fornace AM, DiStefano PS, Chang LW and Greenberg ME. (2002)

The forkhead transcription factor FOXO3a/FKHRL1 induces a stress response by up-regulating GADD45.

Science 296:530-540.

The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span.

Brunet A, Datta SR, and Greenberg ME. (2001)

Transcription-dependent and –independent control of neuronal survival by the PI3K-Akt signaling pathway.

Curr. Opin. Neurobiol. 11:297-305.

The PI3K-Akt signaling pathway plays a critical role in mediating survival signals in a wide range of neuronal cell types. The recent identification of a number of substrates for the serine/threonine kinase Akt suggests that it blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, recent experiments suggest that Akt may also use metabolic pathways to regulate cell survival.

Masters SC, Yang H, Datta SR, Greenberg ME and Fu H. (2001)

14-3-3 inhibits BAD-induced cell death through interaction with serine-136.

Mol Pharm. 60:1325-1331.

14-3-3 proteins are a family of multifunctional phosphoserine binding molecules that can serve as effectors of survival signaling. Understanding the molecular basis for the prosurvival effect of 14-3-3 may lead to the development of agents useful in the treatment of disorders involving dysregulated apoptosis. One target of 14-3-3 is the proapoptotic Bcl-2 family member Bad. Serine phosphorylation of Bad is associated with 14-3-3 binding and inhibition of Bad-induced cell death, but the relative contributions of the three known phosphorylation sites to 14-3-3 binding have not been established. Here we demonstrate that S136 of Bad is vital for 14-3-3 interaction, but S112 seems to be dispensable. 14-3-3/Bad interaction was strictly dependent on the presence of phosphorylated S136 in vitro, in yeast, and in mammalian cells. However, mutation of S112 did not affect 14-3-3 binding. The death caused by wild-type and S112A Bad, but not that caused by S136A Bad, could be almost completely abrogated by 14-3-3. These data support a critical role for 14-3-3 in regulating Bad proapoptotic activity. The effect of 14-3-3 on Bad is controlled largely by phosphorylation of S136, whereas S112 may represent a 14-3-3-independent pathway.

Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB and Greenberg ME. (2000)

14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.

Mol. Cell 6:41-51.

The Bcl-2 homology 3 (BH3) domain of prodeath Bcl-2 family members mediates their interaction with prosurvival Bcl-2 family members and promotes apoptosis. We report that survival factors trigger the phosphorylation of the proapoptotic Bcl-2 family member BAD at a site (Ser-155) within the BAD BH3 domain. When BAD is bound to prosurvival Bcl-2 family members, BAD Ser-155 phosphorylation requires the prior phosphorylation of Ser-136, which recruits 14-3-3 proteins that then function to increase the accessibility of Ser-155 to survival-promoting kinases. Ser-155 phosphorylation disrupts the binding of BAD to prosurvival Bcl-2 proteins and thereby promotes cell survival. These findings define a mechanism by which survival signals inactivate a proapoptotic Bcl-2 family member, and suggest a role for 14-3-3 proteins as cofactors that regulate sequential protein phosphorylation events.

Datta SR, Brunet A and Greenberg ME. (1999)

Cellular survival: a play in three Akts.

Genes & Dev. 13: 2905-2927.

The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 3′-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-κB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

Bonni A, Brunet A, West A, Datta SR, Takasu M and Greenberg ME. (1999)

Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.

Science 286:1358-62.

A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME (1997)

Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery

Cell 91: 231-241

Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt. However, the mechanism by which Akt functions to promote survival is not understood. We show that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. These findings define a mechanism by which growth factors directly inactivate a critical component of the cell-intrinsic death machinery.
 

Datta SR and Greenberg ME. (1997)

B. O’Malley, Ed. (San Diego, California: Academic Press), pp. 257-306.

Kara A. Fulton, David Zimmerman, Aravi Samuel, Katrin Vogt, Sandeep Robert Datta (0204)

Common principles for odour coding across vertebrates and invertebrates

Nat. Rev. Neurosci. 25:453

The olfactory system is an ideal and tractable system for exploring how the brain transforms sensory inputs into behaviour. The basic tasks of any olfactory system include odour detection, discrimination and categorization. The challenge for the olfactory system is to transform the high-dimensional space of olfactory stimuli into the much smaller space of perceived objects and valence that endows odours with meaning. Our current understanding of how neural circuits address this challenge has come primarily from observations of the mechanisms of the brain for processing other sensory modalities, such as vision and hearing, in which optimized deep hierarchical circuits are used to extract sensory features that vary along continuous physical dimensions. The olfactory system, by contrast, contends with an ill-defined, high-dimensional stimulus space and discrete stimuli using a circuit architecture that is shallow and parallelized. Here, we present recent observations in vertebrate and invertebrate systems that relate the statistical structure and state-dependent modulation of olfactory codes to mechanisms of perception and odour-guided behaviour.