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8 Publications

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    06/02/21 | The anterior cingulate cortex directs exploration of alternative strategies.
    Tervo DG, Kuleshova E, Manakov M, Proskurin M, Karlsson M, Lustig A, Behnam R, Karpova AY
    Neuron. 2021 Jun 2;109(11):1876-87. doi: 10.1016/j.neuron.2021.03.028

    The ability to adjust one's behavioral strategy in complex environments is at the core of cognition. Doing so efficiently requires monitoring the reliability of the ongoing strategy and, when appropriate, switching away from it to evaluate alternatives. Studies in humans and non-human primates have uncovered signals in the anterior cingulate cortex (ACC) that reflect the pressure to switch away from the ongoing strategy, whereas other ACC signals relate to the pursuit of alternatives. However, whether these signals underlie computations that actually underpin strategy switching or merely reflect tracking of related variables remains unclear. Here we provide causal evidence that the rodent ACC actively arbitrates between persisting with the ongoing behavioral strategy and temporarily switching away to re-evaluate alternatives. Furthermore, by individually perturbing distinct output pathways, we establish that the two associated computations-determining whether to switch strategy and committing to the pursuit of a specific alternative-are segregated in the ACC microcircuitry.

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    10/22/18 | Imaging cortical dynamics in GCaMP transgenic rats with a head-mounted widefield macroscope.
    Scott BB, Thiberge SY, Guo C, Tervo DG, Brody CD, Karpova AY, Tank DW
    Neuron. 2018 Oct 22:. doi: 10.1016/j.neuron.2018.09.050

    Widefield imaging of calcium dynamics is an emerging method for mapping regional neural activity but is currently limited to restrained animals. Here we describe cScope, a head-mounted widefield macroscope developed to image large-scale cortical dynamics in rats during natural behavior. cScope provides a 7.8 × 4 mm field of view and dual illumination paths for both fluorescence and hemodynamic correction and can be fabricated at low cost using readily attainable components. We also report the development of Thy-1 transgenic rat strains with widespread neuronal expression of the calcium indicator GCaMP6f. We combined these two technologies to image large-scale calcium dynamics in the dorsal neocortex during a visual evidence accumulation task. Quantitative analysis of task-related dynamics revealed multiple regions having neural signals that encode behavioral choice and sensory evidence. Our results provide a new transgenic resource for calcium imaging in rats and extend the domain of head-mounted microscopes to larger-scale cortical dynamics.

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    10/16/18 | Expanding the optogenetics toolkit by topological inversion of rhodopsins.
    Brown J, Behnam R, Coddington L, Tervo DG, Martin K, Proskurin M, Kuleshova E, Park J, Phillips J, Bergs AC, Gottschalk A, Dudman JT, Karpova AY
    Cell. 2018 Oct 16;175(4):1131-40. doi: 10.1016/j.cell.2018.09.026

    Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.

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    10/19/16 | A designer AAV variant permits efficient retrograde access to projection neurons.
    Tervo DG, Hwang B, Viswanathan S, Gaj T, Lavzin M, Ritola KD, Lindo S, Michael S, Kuleshova E, Ojala D, Huang C, Gerfen CR, Schiller J, Dudman JT, Hantman AW, Looger LL, Schaffer DV, Karpova AY
    Neuron. 2016 Oct 19;92(2):372-82. doi: 10.1016/j.neuron.2016.09.021

    Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations. VIDEO ABSTRACT.

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    02/11/16 | Toward the neural implementation of structure learning.
    Tervo DG, Tenenbaum JB, Gershman SJ
    Current Opinion in Neurobiology. 2016 Feb 11;37:99-105. doi: 10.1016/j.conb.2016.01.014

    Despite significant advances in neuroscience, the neural bases of intelligence remain poorly understood. Arguably the most elusive aspect of intelligence is the ability to make robust inferences that go far beyond one's experience. Animals categorize objects, learn to vocalize and may even estimate causal relationships - all in the face of data that is often ambiguous and sparse. Such inductive leaps are thought to result from the brain's ability to infer latent structure that governs the environment. However, we know little about the neural computations that underlie this ability. Recent advances in developing computational frameworks that can support efficient structure learning and inductive inference may provide insight into the underlying component processes and help pave the path for uncovering their neural implementation.

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    09/25/14 | Behavioral variability through stochastic choice and its gating by anterior cingulate cortex.
    Tervo DG, Proskurin M, Manakov M, Kabra M, Vollmer A, Branson K, Karpova AY
    Cell. 2014 Sep 25;159(1):21-32. doi: 10.1016/j.cell.2014.08.037

    Behavioral choices that ignore prior experience promote exploration and unpredictability but are seemingly at odds with the brain's tendency to use experience to optimize behavioral choice. Indeed, when faced with virtual competitors, primates resort to strategic counterprediction rather than to stochastic choice. Here, we show that rats also use history- and model-based strategies when faced with similar competitors but can switch to a "stochastic" mode when challenged with a competitor that they cannot defeat by counterprediction. In this mode, outcomes associated with an animal's actions are ignored, and normal engagement of anterior cingulate cortex (ACC) is suppressed. Using circuit perturbations in transgenic rats, we demonstrate that switching between strategic and stochastic behavioral modes is controlled by locus coeruleus input into ACC. Our findings suggest that, under conditions of uncertainty about environmental rules, changes in noradrenergic input alter ACC output and prevent erroneous beliefs from guiding decisions, thus enabling behavioral variation.

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    10/05/12 | Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty.
    Karlsson MP, Tervo DG, Karpova AY
    Science. 2012 Oct 5;338:135-9. doi: 10.1126/science.1226518

    Regions within the prefrontal cortex are thought to process beliefs about the world, but little is known about the circuit dynamics underlying the formation and modification of these beliefs. Using a task that permits dissociation between the activity encoding an animal’s internal state and that encoding aspects of behavior, we found that transient increases in the volatility of activity in the rat medial prefrontal cortex accompany periods when an animal’s belief is modified after an environmental change. Activity across the majority of sampled neurons underwent marked, abrupt, and coordinated changes when prior belief was abandoned in favor of exploration of alternative strategies. These dynamics reflect network switches to a state of instability, which diminishes over the period of exploration as new stable representations are formed.

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    10/01/07 | Rapidly inducible, genetically targeted inactivation of neural and synaptic activity in vivo.
    Tervo D, Karpova AY
    Current Opinion in Neurobiology. 2007 Oct;17(5):581-6. doi: 10.1016/j.conb.2007.10.002

    Inducible and reversible perturbation of the activity of selected neurons in vivo is critical to understanding the dynamics of brain circuits. Several genetically encoded systems for rapid inducible neuronal silencing have been developed in the past few years offering an arsenal of tools for in vivo experiments. Some systems are based on ion-channels or pumps, others on G protein coupled receptors, and yet others on modified presynaptic proteins. Inducers range from light to small molecules to peptides. This diversity results in differences in the various parameters that may determine the applicability of each tool to a particular biological question. Although further development would be beneficial, the current silencing tool kit already provides the ability to make specific perturbations of circuit function in behaving animals.

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