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      Contrast gain control occurs independently of both parvalbumin-positive interneuron activity and shunting inhibition in auditory cortex

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          Abstract

          Contrast gain control is the systematic adjustment of neuronal gain in response to the contrast of sensory input. It is widely observed in sensory cortical areas and has been proposed to be a canonical neuronal computation. Here, we investigated whether shunting inhibition from parvalbumin-positive interneurons—a mechanism involved in gain control in visual cortex—also underlies contrast gain control in auditory cortex. First, we performed extracellular recordings in the auditory cortex of anesthetized male mice and optogenetically manipulated the activity of parvalbumin-positive interneurons while varying the contrast of the sensory input. We found that both activation and suppression of parvalbumin interneuron activity altered the overall gain of cortical neurons. However, despite these changes in overall gain, we found that manipulating parvalbumin interneuron activity did not alter the strength of contrast gain control in auditory cortex. Furthermore, parvalbumin-positive interneurons did not show increases in activity in response to high-contrast stimulation, which would be expected if they drive contrast gain control. Finally, we performed in vivo whole-cell recordings in auditory cortical neurons during high- and low-contrast stimulation and found that no increase in membrane conductance was observed during high-contrast stimulation. Taken together, these findings indicate that while parvalbumin-positive interneuron activity modulates the overall gain of auditory cortical responses, other mechanisms are primarily responsible for contrast gain control in this cortical area.

          NEW & NOTEWORTHY We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

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          Normalization as a canonical neural computation.

          There is increasing evidence that the brain relies on a set of canonical neural computations, repeating them across brain regions and modalities to apply similar operations to different problems. A promising candidate for such a computation is normalization, in which the responses of neurons are divided by a common factor that typically includes the summed activity of a pool of neurons. Normalization was developed to explain responses in the primary visual cortex and is now thought to operate throughout the visual system, and in many other sensory modalities and brain regions. Normalization may underlie operations such as the representation of odours, the modulatory effects of visual attention, the encoding of value and the integration of multisensory information. Its presence in such a diversity of neural systems in multiple species, from invertebrates to mammals, suggests that it serves as a canonical neural computation.
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            Cortical interneurons that specialize in disinhibitory control

            In the mammalian cerebral cortex, the diversity of interneuronal subtypes underlies a division of labor subserving distinct modes of inhibitory control 1–7 . A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation 8,9 . Although several interneuron populations are known to target other interneurons to varying degrees 10–15 , little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively 3,6,16,17 . During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell-type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.
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              High-Performance Genetically Targetable Optical Neural Silencing via Light-Driven Proton Pumps

              The ability to silence the activity of genetically specified neurons in a temporally precise fashion would open up the ability to investigate the causal role of specific cell classes in neural computations, behaviors, and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate very powerful, safe, multiple-color silencing of neural activity. The gene archaerhodopsin-31 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. In addition, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally-relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins2,3 or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue-green light-drivable proton pump from the fungus Leptosphaeria maculans 4 (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue vs. red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of “optogenetic” voltage and ion modulator, which will broadly empower new neuroscientific, biological, neurological, and psychiatric investigations.
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                Author and article information

                Journal
                J Neurophysiol
                J. Neurophysiol
                jn
                J Neurophysiol
                JN
                Journal of Neurophysiology
                American Physiological Society (Bethesda, MD )
                0022-3077
                1522-1598
                1 April 2020
                18 March 2020
                18 March 2020
                : 123
                : 4
                : 1536-1551
                Affiliations
                [1] 1Department of Physiology, Anatomy and Genetics, University of Oxford , Oxford, United Kingdom
                [2] 2University College London , London, United Kingdom
                [3] 3Department of Biomedical Sciences, City University of Hong Kong , Hong Kong
                Author notes
                [*]

                J. W. H. Schnupp and B. D. B. Willmore are joint last authors.

                Address for correspondence: J. Cooke, Institute of Behavioural Neuroscience, Department of Experimental Psychology, University College London, 26 Bedford Way, London WC1H 0AP, United Kingdom (e-mail: james.cooke@ 123456ucl.ac.uk ).
                Author information
                https://orcid.org/0000-0002-2468-7148
                Article
                JN-00587-2019 JN-00587-2019
                10.1152/jn.00587.2019
                7191518
                32186432
                1edf1ba2-e842-4703-a40d-0da5bece6104
                Licensed under Creative Commons Attribution CC-BY 4.0: © the American Physiological Society. ISSN 0022-3077.

                Licensed under Creative Commons Attribution CC-BY 4.0: © the American Physiological Society.

                History
                : 12 September 2019
                : 16 March 2020
                : 18 March 2020
                Funding
                Funded by: Wellcome Trust (Wellcome) 10.13039/100004440
                Award ID: WT076508AIA
                Award ID: WT108369/Z/2015/Z
                Award ID: 096588/Z/11/Z
                Categories
                Research Article
                Neural Circuits

                Neurology
                auditory cortex,circuit mechanisms,contrast gain control,parvalbumin-positive interneurons,shunting inhibition

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