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      Automated task training and longitudinal monitoring of mouse mesoscale cortical circuits using home cages

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          Abstract

          We report improved automated open-source methodology for head-fixed mesoscale cortical imaging and/or behavioral training of home cage mice using Raspberry Pi-based hardware. Staged partial and probabilistic restraint allows mice to adjust to self-initiated headfixation over 3 weeks’ time with ~50% participation rate. We support a cue-based behavioral licking task monitored by a capacitive touch-sensor water spout. While automatically head-fixed, we acquire spontaneous, movement-triggered, or licking task-evoked GCaMP6 cortical signals. An analysis pipeline marked both behavioral events, as well as analyzed brain fluorescence signals as they relate to spontaneous and/or task-evoked behavioral activity. Mice were trained to suppress licking and wait for cues that marked the delivery of water. Correct rewarded go-trials were associated with widespread activation of midline and lateral barrel cortex areas following a vibration cue and delayed frontal and lateral motor cortex activation. Cortical GCaMP signals predicted trial success and correlated strongly with trial-outcome dependent body movements.

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          Most cited references49

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          A mesoscale connectome of the mouse brain.

          Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
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            Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance.

            An increasingly powerful approach for studying brain circuits relies on targeting genetically encoded sensors and effectors to specific cell types. However, current approaches for this are still limited in functionality and specificity. Here we utilize several intersectional strategies to generate multiple transgenic mouse lines expressing high levels of novel genetic tools with high specificity. We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. High functionality was shown in example mouse lines for GCaMP6, YCX2.60, VSFP Butterfly 1.2, and Jaws. These novel transgenic lines greatly expand the ability to monitor and manipulate neuronal activities with increased specificity.
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              Olfactory exposure to males, including men, causes stress and related analgesia in rodents.

              We found that exposure of mice and rats to male but not female experimenters produces pain inhibition. Male-related stimuli induced a robust physiological stress response that results in stress-induced analgesia. This effect could be replicated with T-shirts worn by men, bedding material from gonadally intact and unfamiliar male mammals, and presentation of compounds secreted from the human axilla. Experimenter sex can thus affect apparent baseline responses in behavioral testing.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                15 May 2020
                2020
                : 9
                : e55964
                Affiliations
                [1 ]Department of Psychiatry, Kinsmen Laboratory of Neurological Research VancouverCanada
                [2 ]Djavad Mowafaghian Centre for Brain Health, University of British Columbia VancouverCanada
                University of California, San Diego United States
                University of California, Berkeley United States
                University of California, San Diego United States
                Author notes
                [†]

                University of Montreal, Montreal, Canada.

                Author information
                https://orcid.org/0000-0002-0093-4490
                Article
                55964
                10.7554/eLife.55964
                7332290
                32412409
                b9a14a7b-38b9-4a17-befa-24afe46d624c
                © 2020, Murphy et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 12 February 2020
                : 07 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: FDN-143209
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001674, Fondation Leducq;
                Award Recipient :
                Funded by: Canadian Neurophotonics Platform;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000245, Michael Smith Foundation for Health Research;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R21
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Tools and Resources
                Neuroscience
                Custom metadata
                A new methodology and protocol use automated brain imaging and task training technology to probe links between behavior and mouse cortical circuits.

                Life sciences
                cortex,homecage,automation,mesoscale,imaging,mouse
                Life sciences
                cortex, homecage, automation, mesoscale, imaging, mouse

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