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2432 Janelia Publications

Showing 131-140 of 2432 results
08/19/23 | A competitive disinhibitory network for robust optic flow processing in Drosophila
Mert Erginkaya , Tomás Cruz , Margarida Brotas , Kathrin Steck , Aljoscha Nern , Filipa Torrão , Nélia Varela , Davi Bock , Michael Reiser , M Eugenia Chiappe
bioRxiv. 2023 Aug 19:. doi: 10.1101/2023.08.06.552150

Many animals rely on optic flow for navigation, using differences in eye image velocity to detect deviations from their intended direction of travel. However, asymmetries in image velocity between the eyes are often overshadowed by strong, symmetric translational optic flow during navigation. Yet, the brain efficiently extracts these asymmetries for course control. While optic flow sensitive-neurons have been found in many animal species, far less is known about the postsynaptic circuits that support such robust optic flow processing. In the fly Drosophila melanogaster, a group of neurons called the horizontal system (HS) are involved in course control during high-speed translation. To understand how HS cells facilitate robust optic flow processing, we identified central networks that connect to HS cells using full brain electron microscopy datasets. These networks comprise three layers: convergent inputs from different, optic flow-sensitive cells, a middle layer with reciprocal, and lateral inhibitory interactions among different interneuron classes, and divergent output projecting to both the ventral nerve cord (equivalent to the vertebrate spinal cord), and to deeper regions of the fly brain. By combining two-photon optical imaging to monitor free calcium dynamics, manipulating GABA receptors and modeling, we found that lateral disinhibition between brain hemispheres enhance the selectivity to rotational visual flow at the output layer of the network. Moreover, asymmetric manipulations of interneurons and their descending outputs induce drifts during high-speed walking, confirming their contribution to steering control. Together, these findings highlight the importance of competitive disinhibition as a critical circuit mechanism for robust processing of optic flow, which likely influences course control and heading perception, both critical functions supporting navigation.

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08/14/23 | Cell-type-specific plasticity shapes neocortical dynamics for motor learning
Shouvik Majumder , Koichi Hirokawa , Zidan Yang , Ronald Paletzki , Charles R. Gerfen , Lorenzo Fontolan , Sandro Romani , Anant Jain , Ryohei Yasuda , Hidehiko K. Inagaki
bioRxiv. 2023 Aug 14:. doi: 10.1101/2023.08.09.552699

Neocortical spiking dynamics control aspects of behavior, yet how these dynamics emerge during motor learning remains elusive. Activity-dependent synaptic plasticity is likely a key mechanism, as it reconfigures network architectures that govern neural dynamics. Here, we examined how the mouse premotor cortex acquires its well-characterized neural dynamics that control movement timing, specifically lick timing. To probe the role of synaptic plasticity, we have genetically manipulated proteins essential for major forms of synaptic plasticity, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Cofilin, in a region and cell-type-specific manner. Transient inactivation of CaMKII in the premotor cortex blocked learning of new lick timing without affecting the execution of learned action or ongoing spiking activity. Furthermore, among the major glutamatergic neurons in the premotor cortex, CaMKII and Cofilin activity in pyramidal tract (PT) neurons, but not intratelencephalic (IT) neurons, is necessary for learning. High-density electrophysiology in the premotor cortex uncovered that neural dynamics anticipating licks are progressively shaped during learning, which explains the change in lick timing. Such reconfiguration in behaviorally relevant dynamics is impeded by CaMKII manipulation in PT neurons. Altogether, the activity of plasticity-related proteins in PT neurons plays a central role in sculpting neocortical dynamics to learn new behavior.

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08/09/23 | Dynamics of cortical contrast adaptation predict perception of signals in noise.
Angeloni CF, Młynarski W, Piasini E, Williams AM, Wood KC, Garami L, Hermundstad AM, Geffen MN
Nature Communications. 2023 Aug 09;14(1):4817. doi: 10.1038/s41467-023-40477-6

Neurons throughout the sensory pathway adapt their responses depending on the statistical structure of the sensory environment. Contrast gain control is a form of adaptation in the auditory cortex, but it is unclear whether the dynamics of gain control reflect efficient adaptation, and whether they shape behavioral perception. Here, we trained mice to detect a target presented in background noise shortly after a change in the contrast of the background. The observed changes in cortical gain and behavioral detection followed the dynamics of a normative model of efficient contrast gain control; specifically, target detection and sensitivity improved slowly in low contrast, but degraded rapidly in high contrast. Auditory cortex was required for this task, and cortical responses were not only similarly affected by contrast but predicted variability in behavioral performance. Combined, our results demonstrate that dynamic gain adaptation supports efficient coding in auditory cortex and predicts the perception of sounds in noise.

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08/08/23 | Stimulus edges induce orientation tuning in superior colliculus.
Liang Y, Lu R, Borges K, Ji N
Nature Communications. 2023 Aug 08;14(1):4756. doi: 10.1038/s41467-023-40444-1

Orientation columns exist in the primary visual cortex (V1) of cat and primates but not mouse. Intriguingly, some recent studies reported the presence of orientation and direction columns in the mouse superficial superior colliculus (sSC), while others reported a lack of columnar organization therein. Using in vivo calcium imaging of sSC in the awake mouse brain, we found that the presence of columns is highly stimulus dependent. Specifically, we observed orientation and direction columns formed by sSC neurons retinotopically mapped to the edge of grating stimuli. For both excitatory and inhibitory neurons in sSC, orientation selectivity can be induced by the edge with their preferred orientation perpendicular to the edge orientation. Furthermore, we found that this edge-induced orientation selectivity is associated with saliency encoding. These findings indicate that the tuning properties of sSC neurons are not fixed by circuit architecture but rather dependent on the spatiotemporal properties of the stimulus.

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08/07/23 | Learning produces a hippocampal cognitive map in the form of an orthogonalized state machine.
Weinan Sun , Johan Winnubst , Maanasa Natrajan , Chongxi Lai , Koichiro Kajikawa , Michalis Michaelos , Rachel Gattoni , Carsen Stringer , Daniel Flickinger , James E. Fitzgerald , Nelson Spruston
bioRxiv. 2023 Aug 07:. doi: 10.1101/2023.08.03.551900

Cognitive maps confer animals with flexible intelligence by representing spatial, temporal, and abstract relationships that can be used to shape thought, planning, and behavior. Cognitive maps have been observed in the hippocampus, but their algorithmic form and the processes by which they are learned remain obscure. Here, we employed large-scale, longitudinal two-photon calcium imaging to record activity from thousands of neurons in the CA1 region of the hippocampus while mice learned to efficiently collect rewards from two subtly different versions of linear tracks in virtual reality. The results provide a detailed view of the formation of a cognitive map in the hippocampus. Throughout learning, both the animal behavior and hippocampal neural activity progressed through multiple intermediate stages, gradually revealing improved task understanding and behavioral efficiency. The learning process led to progressive decorrelations in initially similar hippocampal neural activity within and across tracks, ultimately resulting in orthogonalized representations resembling a state machine capturing the inherent structure of the task. We show that a Hidden Markov Model (HMM) and a biologically plausible recurrent neural network trained using Hebbian learning can both capture core aspects of the learning dynamics and the orthogonalized representational structure in neural activity. In contrast, we show that gradient-based learning of sequence models such as Long Short-Term Memory networks (LSTMs) and Transformers do not naturally produce such representations. We further demonstrate that mice exhibited adaptive behavior in novel task settings, with neural activity reflecting flexible deployment of the state machine. These findings shed light on the mathematical form of cognitive maps, the learning rules that sculpt them, and the algorithms that promote adaptive behavior in animals. The work thus charts a course toward a deeper understanding of biological intelligence and offers insights toward developing more robust learning algorithms in artificial intelligence.

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08/06/23 | Multi-day Neuron Tracking in High Density Electrophysiology Recordings using EMD
Augustine Xiaoran Yuan , Jennifer Colonell , Anna Lebedeva , Adam Charles , Timothy Harris
bioRxiv. 2023 Aug 06:. doi: 10.1101/2023.08.03.551724

Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. New advances in high density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here we propose a neuron tracking method that can identify the same cells independent of firing statistics, which are used by most existing methods. Our method is based on between-day non-rigid alignment of spike sorted clusters. We verified the same cell identify using measured visual receptive fields. This method succeeds on datasets separated from one to 47 days, with an 86% average recovery rate.

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08/04/23 | Biomechanical origins of proprioceptor feature selectivity and topographic maps in the Drosophila leg.
Mamiya A, Sustar A, Siwanowicz I, Qi Y, Lu T, Gurung P, Chen C, Phelps JS, Kuan AT, Pacureanu A, Lee WA, Li H, Mhatre N, Tuthill JC
Neuron. 2023 Aug 04:. doi: 10.1016/j.neuron.2023.07.009

Our ability to sense and move our bodies relies on proprioceptors, sensory neurons that detect mechanical forces within the body. Different subtypes of proprioceptors detect different kinematic features, such as joint position, movement, and vibration, but the mechanisms that underlie proprioceptor feature selectivity remain poorly understood. Using single-nucleus RNA sequencing (RNA-seq), we found that proprioceptor subtypes in the Drosophila leg lack differential expression of mechanosensitive ion channels. However, anatomical reconstruction of the proprioceptors and connected tendons revealed major biomechanical differences between subtypes. We built a model of the proprioceptors and tendons that identified a biomechanical mechanism for joint angle selectivity and predicted the existence of a topographic map of joint angle, which we confirmed using calcium imaging. Our findings suggest that biomechanical specialization is a key determinant of proprioceptor feature selectivity in Drosophila. More broadly, the discovery of proprioceptive maps reveals common organizational principles between proprioception and other topographically organized sensory systems.

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08/03/23 | Lysosomal release of amino acids at ER three-way junctions regulates transmembrane and secretory protein mRNA translation.
Choi H, Liao Y, Yoon YJ, Grimm J, Lavis LD, Singer RH, Lippincott-Schwartz J
bioRxiv. 2023 Aug 03:. doi: 10.1101/2023.08.01.551382

One-third of the mammalian proteome is comprised of transmembrane and secretory proteins that are synthesized on endoplasmic reticulum (ER). Here, we investigate the spatial distribution and regulation of mRNAs encoding these membrane and secretory proteins (termed "secretome" mRNAs) through live cell, single molecule tracking to directly monitor the position and translation states of secretome mRNAs on ER and their relationship to other organelles. Notably, translation of secretome mRNAs occurred preferentially near lysosomes on ER marked by the ER junction-associated protein, Lunapark. Knockdown of Lunapark reduced the extent of secretome mRNA translation without affecting translation of other mRNAs. Less secretome mRNA translation also occurred when lysosome function was perturbed by raising lysosomal pH or inhibiting lysosomal proteases. Secretome mRNA translation near lysosomes was enhanced during amino acid deprivation. Addition of the integrated stress response inhibitor, ISRIB, reversed the translation inhibition seen in Lunapark knockdown cells, implying an eIF2 dependency. Altogether, these findings uncover a novel coordination between ER and lysosomes, in which local release of amino acids and other factors from ER-associated lysosomes patterns and regulates translation of mRNAs encoding secretory and membrane proteins.

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08/02/23 | Investigating the composition and recruitment of the mycobacterial ImuA'-ImuB-DnaE2 mutasome.
Gessner S, Martin ZA, Reiche MA, Santos JA, Dinkele R, Ramudzuli A, Dhar N, de Wet TJ, Anoosheh S, Lang DM, Aaron J, Chew T, Herrmann J, Müller R, McKinney JD, Woodgate R, Mizrahi V, Venclovas Č, Lamers MH, Warner DF
eLife. 2023 Aug 02;12:. doi: 10.7554/eLife.75628

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial mutasome' - minimally comprising DnaE2 polymerase and ImuA' and ImuB accessory proteins - remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III β subunit (β clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an mutant containing a disrupted β clamp-binding motif abolishes ImuB-β clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this β clamp-binding antibiotic collapses pre-formed ImuB-β clamp complexes. These observations establish the essentiality of the ImuB-β clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.

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08/01/23 | Organizing memories for generalization in complementary learning systems.
Weinan Sun , Madhu Advani , Nelson Spruston , Andrew Saxe , James E. Fitzgerald
Nature Neuroscience. 2023 Aug 01;26(8):1438-1448. doi: 10.1038/s41593-023-01382-9

Our ability to remember the past is essential for guiding our future behavior. Psychological and neurobiological features of declarative memories are known to transform over time in a process known as systems consolidation. While many theories have sought to explain the time-varying role of hippocampal and neocortical brain areas, the computational principles that govern these transformations remain unclear. Here we propose a theory of systems consolidation in which hippocampal-cortical interactions serve to optimize generalizations that guide future adaptive behavior. We use mathematical analysis of neural network models to characterize fundamental performance tradeoffs in systems consolidation, revealing that memory components should be organized according to their predictability. The theory shows that multiple interacting memory systems can outperform just one, normatively unifying diverse experimental observations and making novel experimental predictions. Our results suggest that the psychological taxonomy and neurobiological organization of declarative memories reflect a system optimized for behaving well in an uncertain future.

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