Research Article: New Research | Sensory and Motor Systems Movement and VIP interneuron activation differentially modulate encoding in mouse auditory cortex https://doi.org/10.1523/ENEURO.0164-19.2019 Cite as: eNeuro 2019; 10.1523/ENEURO.0164-19.2019 Received: 3 May 2019 Revised: 2 August 2019 Accepted: 14 August 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 Bigelow 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. Running head: MOVEMENT AND VIP ACTIVATION IN AUDITORY CORTEX 1 1 1. Manuscript Title: Movement and VIP interneuron activation differentially modulate encoding in 2 mouse auditory cortex 3 4 2. Abbreviated Title: Movement and VIP activation in auditory cortex 5 6 3. Author Names and Affiliations 7 James Bigelow1,3, Ryan J. Morrill1,2,3, Jefferson Dekloe1,3, Andrea R. Hasenstaub1,2,3 8 1Coleman Memorial Laboratory 9 2Neuroscience Graduate Program 10 3Department of Otolaryngology–Head and Neck Surgery, University of California, San 11 Francisco, 94143 12 13 4. Correspondence should be addressed to: 14 Dr. Andrea R. Hasenstaub 15 Sandler Neurosciences Center 16 Department of Otolaryngology–Head and Neck Surgery 17 675 Nelson Rising Lane 18 Box 0444 19 University of California, San Francisco 20 San Francisco, CA 94143 21 [email protected] 22 23 6. Number of Figures: 6 24 25 7. Number of Tables: 0 26 27 8. Number of Multimedia: 0 28 29 9. Number of words for Abstract: 217 30 31 10. Number of words for Significance Statement: 120 32 33 11. Number of words for Introduction: 673 34 35 12. Number of words for Discussion: 1658 36 37 13. Acknowledgements: The authors thank Dr. Michael Stryker for helpful suggestions and 38 feedback on the manuscript. 39 40 14. Conflict of Interest: ‘Authors report no conflict of interest’ 41 42 15. Funding sources: 43 44 This work was supported by to National Institutes of Health fellowship F32DC016846 to J.B., the 45 National Science Foundation GRFP to R.J.M., National Institutes of Health Grant 46 R01DC014101 to A.R.H., the Klingenstein Foundation to A.R.H., Hearing Research Inc. to 47 A.R.H., and the Coleman Memorial Fund to A.R.H. MOVEMENT AND VIP ACTIVATION IN AUDITORY CORTEX 2 48 Abstract 49 50 Information processing in sensory cortex is highly sensitive to non-sensory variables such 51 as anesthetic state, arousal, and task engagement. Recent work in mouse visual cortex (VCtx) 52 suggests that evoked firing rates, stimulus-response mutual information, and encoding 53 efficiency increase when animals are engaged in movement. A disinhibitory circuit appears 54 central this change: inhibitory neurons expressing vasoactive intestinal peptide (VIP) are 55 activated during movement, and disinhibit pyramidal cells by suppressing other inhibitory 56 interneurons. Paradoxically, although movement activates a similar disinhibitory circuit in 57 auditory cortex (ACtx), most ACtx studies report reduced spiking during movement. It is unclear 58 whether the resulting changes in spike rates result in corresponding changes in stimulus- 59 response mutual information. We examined ACtx responses evoked by tone cloud stimuli, in 60 awake mice of both sexes, during spontaneous movement and still conditions. VIP+ cells were 61 optogenetically activated on half of trials, permitting independent analysis of the consequences 62 of movement and VIP activation, as well as their intersection. Movement decreased stimulus- 63 related spike rates as well as mutual information and encoding efficiency. VIP interneuron 64 activation tended to increase stimulus-evoked spike rates but not stimulus-response mutual 65 information, thus reducing encoding efficiency. The intersection of movement and VIP activation 66 was largely consistent with a linear combination of these main effects: VIP activation recovered 67 movement-induced reduction in spike rates, but not information transfer. 68 69 Significance Statement 70 The ability of the brain to represent information about the sensory environment is heavily 71 influenced by the behavioral state of the animal. In visual cortex, it is well known that locomotor 72 activity enhances visual stimulus processing. By contrast, the present study found that sound 2 MOVEMENT AND VIP ACTIVATION IN AUDITORY CORTEX 3 73 processing in auditory cortex is degraded during locomotor activity. Whereas enhanced stimulus 74 processing in visual cortex is thought to depend on VIP+ interneuron activation, optogenetic 75 activation of VIP+ interneurons in auditory cortex failed to improve stimulus processing. These 76 findings imply that circuitry activated during movement has opposite influences on stimulus 77 processing in visual and auditory cortices. Such differences could reflect a resource allocation 78 shift during movement favoring spatial perception in service of the animal’s navigational needs. 3 MOVEMENT AND VIP ACTIVATION IN AUDITORY CORTEX 4 79 Introduction 80 81 It is now widely accepted that information processing in sensory cortex is highly sensitive to 82 behavioral state (Busse et al., 2017). Numerous studies have documented that visual cortex 83 (VCtx) neurons’ ability to represent visual stimuli is enhanced during movement, as reflected by 84 elevated stimulus-evoked spiking, increased stimulus-response mutual information, increased 85 encoding efficiency, and decreased noise correlations among neuron pairs (Dadarlat and 86 Stryker, 2017). In parallel with these changes in firing patterns, movement is associated with 87 improved visual stimulus detection at the behavioral level (Bennett et al., 2013), as well as 88 instantiation of several forms of lasting adult cortical plasticity (Kaneko et al., 2017). A specific 89 disinhibitory circuit activated by subcortical motor signals appears to be responsible for this 90 movement-related enhancement of encoding (Lee et al., 2013): ascending projections from the 91 midbrain locomotor region activate basal forebrain cholinergic neurons, which in turn activate 92 inhibitory interneurons in VCtx expressing vasoactive intestinal peptide (VIP+). VIP+ neurons 93 are key constituents of a disinhibitory circuit in which they preferentially suppress other inhibitory 94 interneurons, especially those expressing somatostatin (Sst+), thus elevating pyramidal cell 95 firing rates (Pi et al., 2013). Importantly, optogenetic activation and genetic blockade 96 experiments have found that VIP+ interneuron activity is both necessary and sufficient to 97 account for the effects of movement in VCtx studied thus far, including augmented visually- 98 evoked responses (Fu et al., 2014) and instantiation of adult cortical plasticity (Fu et al., 2015). 99 Disinhibition of pyramidal neurons by VIP-Sst circuit activation has been observed 100 elsewhere in the brain, including the auditory cortex (ACtx) (Pi et al., 2013). As in VCtx, VIP+ 101 interneurons in ACtx are activated during movement (Fu et al., 2014). Paradoxically, however, 102 studies of ACtx generally find that most neurons exhibit diminished stimulus-evoked firing rates 103 during movement (Schneider et al., 2014, Zhou et al., 2014). These outcomes imply that, in 4 MOVEMENT AND VIP ACTIVATION IN AUDITORY CORTEX 5 104 contrast to VCtx, VIP+ activation does not fully reproduce the effects of movement in ACtx. It is 105 possible that VIP+-mediated disinhibition of evoked responses in ACtx resulting from movement 106 may be overwhelmed by other sources of inhibition, such as elevated inhibitory interneuron 107 activity initiated by projections from motor cortex (Nelson et al., 2013, Schneider et al., 2014). If 108 so, strengthening the influence of VIP+ interneurons through optogenetic activation could 109 recover or reverse the loss in stimulus-evoked spike rates associated with movement. 110 Nevertheless, it is not presently understood whether the differential changes in firing rate 111 resulting from movement and VIP+ activation produce corresponding changes in information 112 transfer. As numerous studies have documented, cell- or population-level differences in overall 113 firing rates between conditions may not coincide with differences in information representation, 114 let alone in the same direction. For instance, optogenetic activation of interneurons expressing 115 parvalbumin and somatostatin in ACtx reduced spike rates without changing stimulus-response 116 mutual information, suggesting increased encoding efficiency (Phillips and Hasenstaub, 2016). 117 It follows that stimulus information in ACtx could be preserved despite reduced stimulus-evoked 118 spike rates during movement, reflecting increased encoding efficiency. Consistent with this 119 possibility, ACtx neurons in cats performing a spatial auditory task exhibited significant 120 increases in spatial sensitivity despite a reduction in overall firing rates (Lee and Middlebrooks, 121 2011; see also Christensen and Pillow, 2017). Alternatively, recent behavioral experiments 122 observed reduced sound detection accuracy during movement (McGinley et al., 2015), 123 suggesting