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

doi:10.21203/rs.3.rs-4320313/v1

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

https://doi.org/10.21203/rs.3.rs-4320313/v1

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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.

There is NO Competing Interest.

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.

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

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