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4 Janelia Publications

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    01/18/23 | Mesolimbic dopamine adapts the rate of learning from action.
    Coddington LT, Lindo SE, Dudman JT
    Nature. 2023 Jan 18:. doi: 10.1038/s41586-022-05614-z

    Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions. Policy learning and value learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction; however, so far there has been little consideration of how direct policy learning might inform our understanding. Here we used a comprehensive dataset of orofacial and body movements to understand how behavioural policies evolved as naive, head-restrained mice learned a trace conditioning paradigm. Individual differences in initial dopaminergic reward responses correlated with the emergence of learned behavioural policy, but not the emergence of putative value encoding for a predictive cue. Likewise, physiologically calibrated manipulations of mesolimbic dopamine produced several effects inconsistent with value learning but predicted by a neural-network-based model that used dopamine signals to set an adaptive rate, not an error signal, for behavioural policy learning. This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies, expanding the explanatory power of reinforcement learning models for animal learning.

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    12/31/17 | A topographic axis of transcriptional identity in thalamus.
    Phillips JW, Schulman A, Hara E, Liu C, Shields BC, Korff W, Lemire A, Dudman JT, Nelson SB, Hantman AW
    bioRxiv. 2017 Dec 31:241315. doi: 10.1101/241315

    A fundamental goal in neuroscience is to uncover common principles by which different modalities of information are processed. In the mammalian brain, thalamus acts as the essential hub for forebrain circuits handling inputs from sensory, motor, limbic, and cognitive pathways. Whether thalamus imposes common transformations on each of these modalities is unknown. Molecular characterization offers a principled approach to revealing the organization of thalamus. Using near-comprehensive and projection-specific transcriptomic sequencing, we found that almost all thalamic nuclei fit into one of three profiles. These profiles lie on a single axis of genetic variance which is aligned with the mediolateral spatial axis of thalamus. Genes defining this axis of variance include receptors and ion channels, providing a systematic diversification of input/output transformations across the topography of thalamus. Single cell transcriptional profiling revealed graded heterogeneity within individual thalamic nuclei, demonstrating that a spectrum of cell types and potentially diverse input/output transforms exist within a given thalamic nucleus. Together, our data argue for an archetypal organization of pathways serving diverse input modalities, and provides a comprehensive organizational scheme for thalamus.

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    04/07/17 | Deconstructing behavioral neuropharmacology with cellular specificity.
    Shields BC, Kahuno E, Kim C, Apostolides PF, Brown J, Lindo S, Mensh BD, Dudman JT, Lavis LD, Tadross MR
    Science (New York, N.Y.). 2017 Apr 07;356(6333):. doi: 10.1126/science.aaj2161

    Behavior has molecular, cellular, and circuit determinants. However, because many proteins are broadly expressed, their acute manipulation within defined cells has been difficult. Here, we combined the speed and molecular specificity of pharmacology with the cell type specificity of genetic tools. DART (drugs acutely restricted by tethering) is a technique that rapidly localizes drugs to the surface of defined cells, without prior modification of the native target. We first developed an AMPAR antagonist DART, with validation in cultured neuronal assays, in slices of mouse dorsal striatum, and in behaving mice. In parkinsonian animals, motor deficits were causally attributed to AMPARs in indirect spiny projection neurons (iSPNs) and to excess phasic firing of tonically active interneurons (TANs). Together, iSPNs and TANs (i.e., D2 cells) drove akinesia, whereas movement execution deficits reflected the ratio of AMPARs in D2 versus D1 cells. Finally, we designed a muscarinic antagonist DART in one iteration, demonstrating applicability of the method to diverse targets.

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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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