Brain Region-specific Gain Modulation of Place Cells by VIP Neurons

Brain Region-specific Gain Modulation of Place Cells by VIP Neurons | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Brain Region-specific Gain Modulation of Place Cells by VIP Neurons Koen Vervaeke, Nora Lenkey, Anna Christina Garvert, Mate Neubrandt This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4320313/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Gain modulation allows neurons to dynamically adjust their responsiveness to sensory inputs without changing selectivity. While this process is well-characterized in sensory areas, its role in higher-order brain regions, like those governing spatial navigation and memory, is unclear. Here, we used all-optical methods in mice performing a spatial task to demonstrate that vasoactive-intestinal peptide (VIP)-expressing neurons selectively control the gain of place fields in the retrosplenial cortex (RSC) through disinhibition. Optogenetic manipulation revealed that this disinhibition selectively amplifies in-field activity, improving spatial coding accuracy. In contrast, VIP neurons in the hippocampus have minimal impact on place field gain. Notably, simulations indicate that the benefit of gain modulation for RSC place cells is exceptionally large compared to hippocampal place cells due to their much higher out-of-field activity and, therefore, lower signal-to-noise ratio. These findings reveal an area-specific specialization of VIP-mediated gain control, enhancing spatial coding and, potentially, the formation of new spatial memories. Biological sciences/Neuroscience/Neural circuits Biological sciences/Neuroscience/Cellular neuroscience Gain modulation retrosplenial cortex hippocampus inhibitory interneurons VIP neurons place cells disinhibition two-photon microscopy optogenetics ArchT ChrimsonR GCaMP6. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files FigureS1.pdf Supp. Figure S1. In vitro validation of ArchT effect on VIP cells in RSC L2/3 and CA1. A-I) Effect of ArchT stimulation of VIP cells in RSC. Opsin labelled VIP cells were patch-clamped in RSC brain slices and optogenetic stimulation was performed using a 638 nm diode laser (0.15-3.3 mW/mm2, 12 Cells, 3 animals). A) Schematic of the experiment. B) Coronal section (40 μm thick) showing ArchT-TdTomato labeling in RSC VIP cells. C) Example VIP cell firing with the fluorescent image of the cell (ArchT-TdTomato, overlaid with the oblique illumination image). D) Example of light stimulation on the membrane potential of VIP cells. Red trace shows the optical stimulation pattern (2 mW/mm2 for 15 s). E) Mean change in the membrane potential during ArchT stimulation. Paired t-test; membrane potential Before- vs. During stimulation p = 0.0013, During vs. After stimulation p = 0.00004, Before vs After stimulation p = 0.24. F) The hyperpolarizing effect was stable over 15 seconds. Membrane potential was sampled for 1 second at the beginning (#1), the middle (#2), and the end (#3) during the long stimulation (see example in panel D). Paired t-test; membrane potential First vs. Middle p = 0.07, Middle vs. Last p = 0.52, First vs. Last p = 0.17. G) ArchT stimulation decreases the firing frequency in VIP cells. Firing is induced by injection of a current pulse. H) Mean change in action potential (AP) frequency of VIP cells during opto stimulation. Paired t-test; firing frequency Before vs. During p = 0.015, During vs. After p = 0.014, Before vs. After p = 0.48. I) The effect on the firing frequency was stable over 15 seconds. Paired t-test; firing frequency during the stimulation First vs. Middle p = 0.6, Middle vs. Last p = 0.56, First vs. Last p = 0.45. J-M) CA1 data: same as on panel E-F and H-I (8 Cells, 2 animals). Statistics for panel: K) paired t-test; membrane potential Before vs. During p = 0.0012, During vs. After p = 0.0011, Before vs. After p = 0.0081. L) paired t-test; membrane potential during the stimulation First vs. Middle p = 0.00014, Middle vs. Last p = 0.000042, First vs. Last p = 0.32. M) paired t-test, firing frequency Before vs. During p = 0.0012, During vs. After p = 0.0011, Before vs. After p = 0.0081. N) paired t-test; firing frequency during the stimulation First vs. Middle p = 0.00993, Middle vs Last p = 0.7, First vs Last p = 0.0033. For statistical analysis on panels E, F, H, I, and J-M, data with different light intensities were pooled together. FigureS2.pdf Supp. Figure S2. In vitro validation of ChrimsonR effect on RSC L2/3 and CA1 VIP cells. A-F) Effect of ChrimsonR stimulation in RSC VIP cells. Opsin-labeled VIP cells were patch-clamped in vitro brain slices; optogenetic stimulation was carried out with a 625 nm LED (4-22 mW/mm2, 15 cells, 3 animals). A) Schematic of the experiment. B) Coronal section (40 μm thick) showing ChrimsonR-TdTomato labeling in RSC VIP cells. C) Example VIP cell firing with the fluorescent image of the patched cell (ChrimsonRTdTomato). D) Example of the ChrimsonR effect on VIP cell firing in the RSC. The top row, red, shows the optical stimulation pattern (red, 20 Hz sinusoid stimulation for 9 s). Bottom: the VIP cell's membrane potential during stimulation (black). The cell fires at least one action potential during each sinus cycle. Doublets are marked with red stars. E) The recording on panel D) is enlarged at three time points: at the beginning, middle, and end of Opto-stimulation. Note that at least one action potential was evoked by each stimulation, even at the end of the stimulus. F) Mean change in the number of action potentials (AP) during a sinus cycle in VIP cells during opto stimulation. The mean AP number per cycle was calculated by taking 1 second at the beginning, the middle, and the end of the 9-second opto stimulation. (Paired t-test: firing frequency during the stimulation 9 mW/mm2 First vs. Middle p = 0.18, Middle vs. Last p = 0.7, First vs. Last p = 0.29; firing frequency during the stimulation 18-22 mW/mm2 First vs. Middle p = 0.1, Middle vs. Last p = 0.89, First vs. Last p = 0.11). G-I) Same experiments were done in area CA1 (9 cells, 3 animals). Paired t-test for panel I: firing frequency during the stimulation 9 mW/mm2; First vs. Middle p = 0.25, Middle vs. Last p = 0.21, First vs. Last p = 0.07; firing frequency during the stimulation 18 mW/mm2 First vs. Middle p = 0.01, Middle vs. Last p = 0.09, First vs. Last p = 0.007. Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4320313","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":296693619,"identity":"124891d8-0a37-4833-9975-0a506e7eb8b8","order_by":0,"name":"Koen Vervaeke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBACCTBZAcSHGRgOACkeIrWcIVkLYxsDRD1RQLK9+dhj3nnb5PiOsz88XMBwWIafgffgA3xapHmOpRvzbrttLHmYx+DwDIbDPJINfMkG+LTISeSYSc7cdjtxw2EeBjAyOMBjJoFfS/43yZlzbtdvOMz+gDgt0hI5bBIfG24nGBxmMCBOi2TPMTOJD8duG84E+YXHIJ1HspnHGK9fJI43P5NIqLktz3f++OPPPBXW9vzsPYYP8GlBAyDjmUlQPwpGwSgYBaMAOwAA3JZDneMiUg0AAAAASUVORK5CYII=","orcid":"","institution":"University of Oslo","correspondingAuthor":true,"prefix":"","firstName":"Koen","middleName":"","lastName":"Vervaeke","suffix":""},{"id":296693620,"identity":"775f8a99-8b3c-464b-861f-667afcb0bb33","order_by":1,"name":"Nora Lenkey","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Nora","middleName":"","lastName":"Lenkey","suffix":""},{"id":296693621,"identity":"eb23ece7-e53a-4609-94ed-ef849ed9070d","order_by":2,"name":"Anna Christina Garvert","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Christina","lastName":"Garvert","suffix":""},{"id":296693622,"identity":"62006dc2-d6ac-4c11-b148-7a767cc195cb","order_by":3,"name":"Mate Neubrandt","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Mate","middleName":"","lastName":"Neubrandt","suffix":""}],"badges":[],"createdAt":"2024-04-24 21:15:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4320313/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4320313/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-60679-4","type":"published","date":"2025-07-01T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56133987,"identity":"5bc4c882-13ef-48b7-bf5a-0e380835c7ea","added_by":"auto","created_at":"2024-05-09 02:30:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":224647,"visible":true,"origin":"","legend":"\u003cp\u003eMost VIP neurons in RSC are positively modulated by locomotion. A) Head-fixed mouse running laps in darkness on a Styrofoam wheel enriched with tactile cues searching for a hidden water reward (tactile cues are 2 sandpaper strips and 2 rows of hot glue spikes). B) Mean running speed (top) and lick rate (bottom) of well-trained mice (mean ± SEM across 18 sessions, 4 mice). C) Top: Cartoon of coronal brain section illustrating the location of the chronic window implant. Bottom: Example chronic window implanted above RSC (window diameter is 2.5 mm centered at -2.2 posterior from bregma). The black square shows a typical field of view (FOV) next to the central sinus. D) Two-photon fluorescence image showing a typical FOV of VIP cells expressing GCamp6s in L2/3 of RSC (147 μm below the pia). VIP-Cre mice were injected with an AAV to deliver Cre-dependent GCaMP6s. E) Example fluorescence traces (fractional change in fluorescence, DF/F) of 5 VIP cells during 8 laps. Bottom traces show the mouse's position on the track, speed, and lick rate. Grey-shaded areas indicate periods when the mouse velocity falls below 10 cm/s (indicated by a blue line in the speed plot). F) Distribution of Pearson correlation coefficients between VIP neuronal activity and running speed (837 VIP cells in total, 18 sessions, 4 mice). Blue, negatively modulated VIP cells having correlation values \u0026lt; 95 percentile of shuffled random distribution; Red, positively modulated VIP cells having correlation values \u0026gt; 95 percentile of the shuffled random distribution; Grey, non-modulated VIP cells. G) Average activity profile of neurons classified in F (mean ± SEM). H) Percentage of VIP cells classified in (F); Averaged across sessions. Positively modulated, 395 / 837 cells; Negatively modulated, 177 / 837 cells; Unmodulated, 265 / 837 cells. I) Top: Average running speed aligned to start and stop events (mean ± SEM, 18 sessions, 4 mice). Stop and start events around the reward location were discarded from the dataset. Bottom: Activity of VIP neurons positively correlated with locomotion (classified in (F)) aligned to running start and stop events (note that some mice did not show any start or stop events in some sessions). J) Activity of VIP neurons that were negatively correlated with locomotion aligned to running start and stop events (18 sessions, 4 mice).\u003c/p\u003e","description":"","filename":"Binder11.png","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/fd338fc01cc6e052dce898f0.png"},{"id":56133944,"identity":"ef14148c-14cd-4038-9b84-bb564d5cc658","added_by":"auto","created_at":"2024-05-09 02:30:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":501437,"visible":true,"origin":"","legend":"\u003cp\u003eVIP cells disinhibit place-tuned neurons in RSC. A) Two-photon fluorescence image showing a typical FOV of principal cells expressing GCaMP6s in L2/3 of RSC (143 μm from the pia, Thy1-GCaMP6s (GP4.3) mice). B) Example fluorescence traces of 5 place-tuned cells during 5 laps. The bottom traces show the mouse's position on the track, speed, and lick rate. C) Examples of 8 place-tuned neurons during a session of 68 trials. D) Session-averaged responses of place-tuned neurons sorted according to the position of peak response (665 cells, 12 sessions, 5 mice). E) Left: Diagram illustrating simultaneous two-photon imaging of principal neurons and optogenetic inhibition of VIP cells using ArchT. An AAV was injected in RSC to deliver a Cre-dependent and red-shifted ArchT opsin to VIP cells (5 mice). Left bottom panel: two-photon fluorescence image showing an example of VIP neurons expressing ArchT (120 μm from the pia). Middle panel: In 25 % of randomly chosen trials, red light (638 nm, intensity 3 mW/mm2) was applied through the objective during the trial (between 10-157 cm along the track). Responses of an example place cell are shown throughout 54 laps. Stimulated trials are labeled with a red arrow. Right: Trials sorted by “optooff” trials, “opto-on” trials, and “after-opto” trials (trials right after an opto-on trial). F) Average responses of example place cells during opto-off trials, opto-on trials, and after-opto trials. The top left panel is the cell shown in (E). G) Scatter plot showing peak DF/F amplitude in the place field during opto-off and opto-on trials (each dot is a cell). The regression line is shown with red (R2 = 0.51). The pie chart shows the percentage of significantly modulated place cells (1167 cells, 15 sessions, 5 mice). H) Left: Effect of inhibiting VIP cells on DF/F peak amplitude in the place field across all sessions (mean ± SEM, 1167 cells, 15 sessions, 5 animals, Wilcoxon signed-rank test, p = 0.00012 for opto-off vs. opto-on, p = 0.00043 for opto-on vs. opto-after, p = 0.104 for opto-off vs. opto-after). Each data point is the median amplitude of all place cells in a session. Right: Percentage change in DF/F normalized to peak amplitude in opto-off condition: (DF/FON - DF/FOFF) / (DF/FOFF), in ArchT-expressing mice. I-L) Same as (E-H), but with VIP cells expressing the excitatory opsin ChrimsonR (20 Hz sinusoidal modulated 638 nm light, peak intensity 10 mW/mm2, 467 cells, 11 sessions, 6 mice). (K) R2 = 0.68 for the regression line. (L) Left: Summary of the effect of photo-stimulation of ChrimsonR in VIP cells on DF/F peak amplitude across all sessions Wilcoxon signed-rank test, p = 0.0039 for opto-off vs. opto-on, p = 0.00098 for opto-on vs. opto-after, p = 0.0068 for opto-off vs. opto-after.\u003c/p\u003e","description":"","filename":"Binder12.png","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/911289fb865df43a60fad442.png"},{"id":56133967,"identity":"b815173b-158b-4517-9b2b-03edf1c8d400","added_by":"auto","created_at":"2024-05-09 02:30:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58275,"visible":true,"origin":"","legend":"\u003cp\u003eVIP neurons control the gain of place fields in RSC. A) Schematic of possible arithmetic transformations of tuning curves. First panel: Cartoon of place cell tuning curve. Modulation can change the in-field (grey shading) and/or out-of-field firing rates. Second panel: Linear transform of a tuning curve by plotting DF/FOPTO-ON versus DF/FOPTO-OFF for each spatial bin. This enables quantifying the change in gain (m) and the offset (b) between the opto-modulated and control tuning curve. Third panel: Example of pure gain modulation (m) changes, causing a multiplicative/divisive effect without offset change. Fourth panel: Example of pure offset (b) changes, causing an additive/subtractive effect without a change in gain (m). B) Examples of linearly transformed tuning curves when inhibiting (ArchT) or enhancing (ChrimsonR) VIP neuron activity. Each plot shows 80 data points of a single place cell (80 spatial bins of ~2 cm representing the entire track), showing DF/FOPTOON versus DF/FOPTO-OFF. Insets show place-tuning curves (blue: control, red: modulated). The parameters of the linear fit (y = m*x + b) are indicated (red). C) Each linear fit is based on the average gain (m) and offset (b) of all place cells in a session of mice that expressed ArchT (15 sessions, 5 mice) or opsin-free control mice (9 sessions, 12 mice). D) Distribution of the gain (left) and offset (right) values of all place cells’ linear transforms in ArchT mice (1167 place cells) compared to opsin-free mice (648 place cells). The gain significantly decreased during VIP inhibition, while the offset did not change (Kolmogorov-Smirnov test; gain: p = 1.24 x 10-116, offset: p = 0.43.) Insets: The 90% confidence intervals were calculated from the control (No opsin) distributions. Pie charts show the fraction of cells with significantly different gain (20.8 % decreased, 2.8 % increased) or offset (6.6 % decreased, 5.7 % increased) compared to the control distribution. E) Contribution of the changes in gain and offset to the change in place field DF/F peak (median, 25th, 75th percentiles are shown with the grey box, minimum and maximum values of the distribution are shown with error bars, calculated only for the significantly modulated cells). The effect of gain modulation is significantly larger during VIP cell inhibition. Mann-Whitney test, p = 1.3 x 10-180 for ArchT. (F-H) Same as C-E but when enhancing VIP cells with ChrimsonR (ChrimsonR expressing mice: 467 cells, 11 sessions, 6 mice; opsin-free control mice: 690 cells, 11 sessions, 10 mice, Kolmogorov-Smirnov test; gain: p = 2.5 x 10-6, offset: p = 1.61 x 10- 5). Pie chart gain: 4.7 % decreased, 25.3 % increased. Pie chart offset: 8.8 % decreased, 20.1 % increased. The effect of gain modulation is significantly larger during VIP cell excitation compared to offset modulation. Mann-Whitney test, p = 5.1 * 10-9 for ChrimsonR.\u003c/p\u003e","description":"","filename":"Binder13.png","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/a3dd381d065b78ec59ea2ccf.png"},{"id":56133934,"identity":"caa8f647-9542-4d76-b457-251585aff7b8","added_by":"auto","created_at":"2024-05-09 02:30:05","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":359901,"visible":true,"origin":"","legend":"\u003cp\u003eVIP neuronal activity has little effect on hippocampal place fields. A) Two-photon fluorescence image showing a typical FOV of principal cells expressing GCaMP6s in stratum pyramidale of hippocampal area CA1 (Thy1-GCaMP6s mice). B) Example fluorescence traces of 5 place-tuned cells during 5 laps. Bottom traces show the mouse's position on the track, speed, and lick rate. C) Examples of 8 place-tuned neurons during a session for 25 trials. D) Session-averaged responses of place-tuned neurons sorted according to the position of peak response (1079 cells, 9 sessions, 7 mice). E) Left: Diagram illustrating simultaneous two-photon imaging of principal neurons and optogenetic inhibition of VIP cells using ArchT. An AAV was injected in area CA1 to deliver a Cre-dependent and red-shifted ArchT opsin to VIP cells (7 mice). Left bottom panel: two-photon fluorescence image showing an example of VIP neurons expressing ArchT (100 μm from the top of the hippocampus). Middle panel: In 33 % of randomly chosen trials, red light (638 nm, intensity 6 mW/mm2) was applied through the objective during the trial (between 10-157 cm along the track). Responses of an example place cell are shown throughout 48 laps. Stimulated trials are labeled with a red arrow. Right: Trials sorted by “opto-off” trials, “opto-on” trials, and “after-opto” trials (trials right after an opto-on trial). F) Average responses of example place cells during opto-off trials, opto-on trials, and after-opto trials. The top left panel is the cell shown in (E). G) Scatter plot showing peak DF/F amplitude in the place field during opto-off and opto-on trials (each dot is a cell). Pie chart shows the percentage of significantly modulated place cells (1644 place cells, 17 sessions, 7 mice). H) Left: Effect of inhibiting VIP cells on DF/F peak amplitude in the place field across all sessions (mean ± SEM, 17 sessions, 7 animals, Wilcoxon signed-rank test, p = 0.38 for opto-off vs. opto-on, p = 0.72 for opto-on vs. opto-after, p = 0.72 for opto-off vs. opto-after). Each data point is the median peak amplitude of all place cells in a session. Right: Percentage change in DF/F normalized to peak amplitude in opto-off condition: (DF/FON - DF/FOFF) / (DF/FOFF), in ArchT-expressing mice. I-L) Same as (E-H) but expressing the excitatory opsin ChrimsonR in VIP cells (20 Hz sinusoidal modulated 638 nm light, peak intensity 10 mW/mm2, 1287 cells, 12 sessions, 6 animals). (L) Left: Summary of the effect of photo-stimulation of ChrimsonR in VIP cells on DF/F peak amplitude across all sessions (12 sessions, 6 animals, Wilcoxon signed-rank test, p = 0.002 for opto-off vs opto-on, p = 0.00049 for opto-on vs opto-after, p = 0.027 for opto-off vs opto-after). Right: Percentage change in DF/F normalized to peak amplitude in opto-off condition: (DF/FON - DF/FOFF) / (DF/FOFF), in ChrimsonR-expressing mice.\u003c/p\u003e","description":"","filename":"Binder14.png","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/a03df1dd05b872604a0ee112.png"},{"id":56133970,"identity":"d365d4f3-e5c1-461a-9fd0-569a144d5c75","added_by":"auto","created_at":"2024-05-09 02:30:24","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":219274,"visible":true,"origin":"","legend":"\u003cp\u003eVIP-mediated gain modulation of place cells enhances spatial coding in RSC but not in the hippocampus. A) Cartoon of coronal brain section illustrating the location of the chronic window implant to record neuronal activity in RSC. B) Example of actual (black) and predicted (blue) mouse position obtained by Bayesian decoding using the activity of recorded RSC cells. All cells in a FOV were used for decoding. C) Left: Cartoon illustrating the experimental design for inhibiting VIP cells with ArchT while measuring place cell activity in RSC. Middle: decoding error (mean ± SEM across sessions, 5 mice, 11 sessions, Wilcoxon signed rank test, opto-on vs. opto-off p = 0.001, opto-on vs. after-opto = 0.0093, after-opto vs. opto-off p= 0.0186) Right: decoding error as a function of position along the track (mean ± SEM across sessions) D) Spatial information content (mean ± SEM across sessions). Each data point is the median of a session (Wilcoxon signed rank test, opto-on vs. opto-off p = 0.0337, optoon vs. after-opto p = 0.5845, after-opto vs. opto-off p = 0.2061). E-F) The Same as (C-D), but for optogenetic experiments enhancing VIP neurons' activity using ChrimsonR (6 mice, 7 sessions, Decoding error: Wilcoxon signed rank test, opto-on vs. opto-off p = 0.0078, opto-on vs. after-opto = 0.0195, after-opto vs. opto-off p = 0.6406, Spatial information content: Wilcoxon signed rank test, opto-on vs. opto-off p = 0.0117, opto-on vs. after-opto p = 0.4219, after-opto vs. opto-off p = 0.6406). G-L) Same as (A-F) but for hippocampal CA1 cells. Decoding error in ArchT experiments: 7 mice, 15 sessions, Wilcoxon signed rank test, opto-on vs. opto-off p = 0.8616 opto-on vs. after-opto = 0.1262, after-opto vs. opto-off p= 0.0946; Spatial information content ArchT experiments: Wilcoxon signed rank test, opto-on vs. optooff p = 0.1947, opto-on vs. after-opto p = 0.6606, after-opto vs. opto-off p = 0.0946; Decoding error in ChrimsonR experiments: 6 mice, 12 sessions, Wilcoxon signed rank test, opto-on vs. opto-off p = 0.311 opto-on vs. after-opto = 0.6045, after-opto vs. optooff p= 0.2661; Spatial information content in ChrimsonR experiments: Wilcoxon signed rank test, opto-on vs. opto-off p = 0.0061, opto-on vs. after-opto p = 0.0461, after-opto vs. opto-off p = 0.0024. M) Data showing the in-field and out-of-field firing rates of place cells in RSC and hippocampal area CA1 (RSC, 299 cells, CA1, 141 cells. Extracellular recording data obtained from Alexander et al. 18). N) Example firing rates of 5 simulated place cells as a function of position along the track. We simulated ensembles of 30 such place cells with Poisson-distributed firing rates and empirically restrained place field widths that tile a linear track with the same length as our experiments. For each ensemble, we varied the in-field and out-of-field firing rates and decoded the position decoding error (plotted in (O)). O) Top: the relationship between decoding performance, in-field firing rate, and outof- field firing rate calculated from simulated data. Superimposed data points are the experimentally observed in-field and out-of-field firing rates in RSC and area CA1 as shown in (M). Bottom: Example of an RSC (red) and hippocampal (blue) place tuning curve, illustrating the high out-of-field firing rate in RSC but not in area CA1.\u003c/p\u003e","description":"","filename":"Binder15.png","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/5821b9d2d3b203e459819ff1.png"},{"id":85832440,"identity":"639fba94-a967-4efc-985b-c845f6e25c14","added_by":"auto","created_at":"2025-07-02 07:55:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1668251,"visible":true,"origin":"","legend":"","description":"","filename":"Lenkeyetalmanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1_covered_7a4f849d-9769-4383-a55a-65e7c1070dec.pdf"},{"id":56133979,"identity":"51818123-f100-4600-b760-0ec866904aa9","added_by":"auto","created_at":"2024-05-09 02:30:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":845457,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Figure S1. In vitro validation of ArchT effect on VIP cells in RSC L2/3 and CA1. A-I) Effect of ArchT stimulation of VIP cells in RSC. Opsin labelled VIP cells were patch-clamped in RSC brain slices and optogenetic stimulation was performed using a 638 nm diode laser (0.15-3.3 mW/mm2, 12 Cells, 3 animals). A) Schematic of the experiment. B) Coronal section (40 μm thick) showing ArchT-TdTomato labeling in RSC VIP cells. C) Example VIP cell firing with the fluorescent image of the cell (ArchT-TdTomato, overlaid with the oblique illumination image). D) Example of light stimulation on the membrane potential of VIP cells. Red trace shows the optical stimulation pattern (2 mW/mm2 for 15 s). E) Mean change in the membrane potential during ArchT stimulation. Paired t-test; membrane potential Before- vs. During stimulation p = 0.0013, During vs. After stimulation p = 0.00004, Before vs After stimulation p = 0.24. F) The hyperpolarizing effect was stable over 15 seconds. Membrane potential was sampled for 1 second at the beginning (#1), the middle (#2), and the end (#3) during the long stimulation (see example in panel D). Paired t-test; membrane potential First vs. Middle p = 0.07, Middle vs. Last p = 0.52, First vs. Last p = 0.17. G) ArchT stimulation decreases the firing frequency in VIP cells. Firing is induced by injection of a current pulse. H) Mean change in action potential (AP) frequency of VIP cells during opto stimulation. Paired t-test; firing frequency Before vs. During p = 0.015, During vs. After p = 0.014, Before vs. After p = 0.48. I) The effect on the firing frequency was stable over 15 seconds. Paired t-test; firing frequency during the stimulation First vs. Middle p = 0.6, Middle vs. Last p = 0.56, First vs. Last p = 0.45. J-M) CA1 data: same as on panel E-F and H-I (8 Cells, 2 animals). Statistics for panel: K) paired t-test; membrane potential Before vs. During p = 0.0012, During vs. After p = 0.0011, Before vs. After p = 0.0081. L) paired t-test; membrane potential during the stimulation First vs. Middle p = 0.00014, Middle vs. Last p = 0.000042, First vs. Last p = 0.32. M) paired t-test, firing frequency Before vs. During p = 0.0012, During vs. After p = 0.0011, Before vs. After p = 0.0081. N) paired t-test; firing frequency during the stimulation First vs. Middle p = 0.00993, Middle vs Last p = 0.7, First vs Last p = 0.0033. For statistical analysis on panels E, F, H, I, and J-M, data with different light intensities were pooled together.\u003c/p\u003e","description":"","filename":"FigureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/c9816a74854e28922a34568d.pdf"},{"id":56133990,"identity":"6d2de5d6-6a07-4093-b52c-3856f77dc770","added_by":"auto","created_at":"2024-05-09 02:30:36","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1086750,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Figure S2. In vitro validation of ChrimsonR effect on RSC L2/3 and CA1 VIP cells. A-F) Effect of ChrimsonR stimulation in RSC VIP cells. Opsin-labeled VIP cells were patch-clamped in vitro brain slices; optogenetic stimulation was carried out with a 625 nm LED (4-22 mW/mm2, 15 cells, 3 animals). A) Schematic of the experiment. B) Coronal section (40 μm thick) showing ChrimsonR-TdTomato labeling in RSC VIP cells. C) Example VIP cell firing with the fluorescent image of the patched cell (ChrimsonRTdTomato). D) Example of the ChrimsonR effect on VIP cell firing in the RSC. The top row, red, shows the optical stimulation pattern (red, 20 Hz sinusoid stimulation for 9 s). Bottom: the VIP cell's membrane potential during stimulation (black). The cell fires at least one action potential during each sinus cycle. Doublets are marked with red stars. E) The recording on panel D) is enlarged at three time points: at the beginning, middle, and end of Opto-stimulation. Note that at least one action potential was evoked by each stimulation, even at the end of the stimulus. F) Mean change in the number of action potentials (AP) during a sinus cycle in VIP cells during opto stimulation. The mean AP number per cycle was calculated by taking 1 second at the beginning, the middle, and the end of the 9-second opto stimulation. (Paired t-test: firing frequency during the stimulation 9 mW/mm2 First vs. Middle p = 0.18, Middle vs. Last p = 0.7, First vs. Last p = 0.29; firing frequency during the stimulation 18-22 mW/mm2 First vs. Middle p = 0.1, Middle vs. Last p = 0.89, First vs. Last p = 0.11). G-I) Same experiments were done in area CA1 (9 cells, 3 animals). Paired t-test for panel I: firing frequency during the stimulation 9 mW/mm2; First vs. Middle p = 0.25, Middle vs. Last p = 0.21, First vs. Last p = 0.07; firing frequency during the stimulation 18 mW/mm2 First vs. Middle p = 0.01, Middle vs. Last p = 0.09, First vs. Last p = 0.007.\u003c/p\u003e","description":"","filename":"FigureS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4320313/v1/270035b830f4dd8ef510b531.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Brain Region-specific Gain Modulation of Place Cells by VIP Neurons","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Gain modulation, retrosplenial cortex, hippocampus, inhibitory interneurons, VIP neurons, place cells, disinhibition, two-photon microscopy, optogenetics, ArchT, ChrimsonR, GCaMP6.","lastPublishedDoi":"10.21203/rs.3.rs-4320313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4320313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Gain modulation allows neurons to dynamically adjust their responsiveness to sensory inputs without changing selectivity. While this process is well-characterized in sensory areas, its role in higher-order brain regions, like those governing spatial navigation and memory, is unclear. Here, we used all-optical methods in mice performing a spatial task to demonstrate that vasoactive-intestinal peptide (VIP)-expressing neurons selectively control the gain of place fields in the retrosplenial cortex (RSC) through disinhibition. Optogenetic manipulation revealed that this disinhibition selectively amplifies in-field activity, improving spatial coding accuracy. In contrast, VIP neurons in the hippocampus have minimal impact on place field gain. Notably, simulations indicate that the benefit of gain modulation for RSC place cells is exceptionally large compared to hippocampal place cells due to their much higher out-of-field activity and, therefore, lower signal-to-noise ratio. These findings reveal an area-specific specialization of VIP-mediated gain control, enhancing spatial coding and, potentially, the formation of new spatial memories.","manuscriptTitle":"Brain Region-specific Gain Modulation of Place Cells by VIP Neurons","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 02:29:33","doi":"10.21203/rs.3.rs-4320313/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f86aee00-ffe7-4618-a6ca-d740b19978e6","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31291487,"name":"Biological sciences/Neuroscience/Neural circuits"},{"id":31291488,"name":"Biological sciences/Neuroscience/Cellular neuroscience"}],"tags":[],"updatedAt":"2025-07-02T07:55:37+00:00","versionOfRecord":{"articleIdentity":"rs-4320313","link":"https://doi.org/10.1038/s41467-025-60679-4","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-07-01 04:00:00","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2024-05-09 02:29:33","video":"","vorDoi":"10.1038/s41467-025-60679-4","vorDoiUrl":"https://doi.org/10.1038/s41467-025-60679-4","workflowStages":[]},"version":"v1","identity":"rs-4320313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4320313","identity":"rs-4320313","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}