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      Automated Behavioral Experiments in Mice Reveal Periodic Cycles of Task Engagement within Circadian Rhythms

      research-article
      , ,
      eNeuro
      Society for Neuroscience
      auditory, circadian, high throughput, home cage, operant conditioning

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          Abstract

          High-throughput automated experiments accelerate discovery in neuroscience research and reduce bias. To enable high-throughput behavioral experiments, we developed a user-friendly and scalable automated system that can simultaneously train hundreds of mice on behavioral tasks, with time-stamped behavioral information recorded continuously for weeks. We trained 12 cages of C57BL/6J mice (24 mice, 2 mice/cage) to perform auditory behavioral tasks. We found that circadian rhythms modulated overall behavioral activity as expected for nocturnal animals. However, auditory detection and discrimination accuracy remained consistently high in both light and dark cycles. We also found a periodic modulation of behavioral response rates only during the discrimination task, suggesting that the mice periodically reduce task engagement (i.e., take “breaks”) when task difficulty increases due to the more complex stimulus–response paradigm for discrimination versus detection. Our results highlight how automated systems for continuous high-throughput behavioral experiments enable both efficient data collection and new observations on animal behavior.

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          Most cited references15

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          Laboratory routines cause animal stress.

          Eighty published studies were appraised to document the potential stress associated with three routine laboratory procedures commonly performed on animals: handling, blood collection, and orogastric gavage. We defined handling as any non-invasive manipulation occurring as part of routine husbandry, including lifting an animal and cleaning or moving an animal's cage. Significant changes in physiologic parameters correlated with stress (e.g., serum or plasma concentrations of corticosterone, glucose, growth hormone or prolactin, heart rate, blood pressure, and behavior) were associated with all three procedures in multiple species in the studies we examined. The results of these studies demonstrated that animals responded with rapid, pronounced, and statistically significant elevations in stress-related responses for each of the procedures, although handling elicited variable alterations in immune system responses. Changes from baseline or control measures typically ranged from 20% to 100% or more and lasted at least 30 min or longer. We interpret these findings to indicate that laboratory routines are associated with stress, and that animals do not readily habituate to them. The data suggest that significant fear, stress, and possibly distress are predictable consequences of routine laboratory procedures, and that these phenomena have substantial scientific and humane implications for the use of animals in laboratory research.
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            Parallel processing by cortical inhibition enables context-dependent behavior

            Physical features of sensory stimuli are fixed, but sensory perception is context-dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones vs. performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed, while some cells became more active during behavior. Whole-cell recordings showed that excitatory inputs were only modestly affected by context, but inhibition was more sensitive, with PV, SOM+, and VIP+ interneurons balancing inhibition/disinhibition within the network. Cholinergic modulation was involved in context-switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.
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              On the ability to inhibit thought and action: general and special theories of an act of control.

              Response inhibition is an important act of control in many domains of psychology and neuroscience. It is often studied in a stop-signal task that requires subjects to inhibit an ongoing action in response to a stop signal. Performance in the stop-signal task is understood as a race between a go process that underlies the action and a stop process that inhibits the action. Responses are inhibited if the stop process finishes before the go process. The finishing time of the stop process is not directly observable; a mathematical model is required to estimate its duration. Logan and Cowan (1984) developed an independent race model that is widely used for this purpose. We present a general race model that extends the independent race model to account for the role of choice in go and stop processes, and a special race model that assumes each runner is a stochastic accumulator governed by a diffusion process. We apply the models to 2 data sets to test assumptions about selective influence of capacity limitations on drift rates and strategies on thresholds, which are largely confirmed. The model provides estimates of distributions of stop-signal response times, which previous models could not estimate. We discuss implications of viewing cognitive control as the result of a repertoire of acts of control tailored to different tasks and situations. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                5 September 2019
                17 September 2019
                Sep-Oct 2019
                : 6
                : 5
                : ENEURO.0121-19.2019
                Affiliations
                [1]Department of Biology, University of Maryland , College Park, Maryland 20742
                Author notes

                Author contributions: N.A.F. and P.O.K. designed research; N.A.F. and K.B. performed research; N.A.F. contributed unpublished reagents/analytic tools; N.A.F. analyzed data; N.A.F. and P.O.K. wrote the paper.

                This research was supported by Department of Health and Human Services (DHHS) | National Institutes of Health (NIH) | National Institute on Deafness and Other Communication Disorders Grant RO1-DC-009607; DHHS | NIH | National Institute of Neurological Disorders and Stroke Grant U01-NS-090569; and DHHS | NIH | National Institute of Neurological Disorders and Stroke Grant U19-NS-107464.

                Correspondence should be addressed to Patrick O. Kanold at Pkanold@ 123456umd.edu .
                Author information
                https://orcid.org/0000-0001-6530-5559
                https://orcid.org/0000-0002-7529-5435
                Article
                eN-MNT-0121-19
                10.1523/ENEURO.0121-19.2019
                6775758
                31488550
                e1873744-8e70-45bd-b586-7ab7c4725a9b
                Copyright © 2019 Francis et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 27 March 2019
                : 21 August 2019
                : 26 August 2019
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 17, Pages: 10, Words: 6796
                Funding
                Funded by: http://doi.org/10.13039/100000055HHS | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)
                Award ID: RO1 DC009607
                Funded by: http://doi.org/10.13039/100000065HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
                Award ID: U01 NS090569
                Categories
                7
                7.2
                Methods/New Tools
                Novel Tools and Methods
                Custom metadata
                September/October 2019

                auditory,circadian,high throughput,home cage,operant conditioning

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