ABSTRACT Cortical gain regulation allows neurons to respond adaptively to changing inputs. Neural gain is modulated by internal and external influences, including attentional and arousal

states, motor activity and neuromodulatory input. These influences converge to a common set of mechanisms for gain modulation, including GABAergic inhibition, synaptically driven

fluctuations in membrane potential, changes in cellular conductance and changes in other biophysical neural properties. Recent work has identified GABAergic interneurons as targets of

neuromodulatory input and mediators of state-dependent gain modulation. Here, we review the engagement and effects of gain modulation in the cortex. We highlight key recent findings that

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support SIMILAR CONTENT BEING VIEWED BY OTHERS ENDOGENOUS ACTIVITY MODULATES STIMULUS AND CIRCUIT-SPECIFIC NEURAL TUNING AND PREDICTS PERCEPTUAL BEHAVIOR Article Open access 11 August 2020

FREQUENCY MODULATION OF CORTICAL RHYTHMICITY GOVERNS BEHAVIORAL VARIABILITY, EXCITABILITY AND SYNCHRONY OF NEURONS IN THE VISUAL CORTEX Article Open access 03 December 2022 OPPOSITE FORMS OF

ADAPTATION IN MOUSE VISUAL CORTEX ARE CONTROLLED BY DISTINCT INHIBITORY MICROCIRCUITS Article Open access 24 February 2022 REFERENCES * Reynolds, J. H. & Heeger, D. J. The normalization

model of attention. _Neuron_ 61, 168–185 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, S. H. et al. Activation of specific interneurons improves V1 feature

selectivity and visual perception. _Nature_ 488, 379–383 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ohshiro, T., Angelaki, D. E. & DeAngelis, G. C. A normalization

model of multisensory integration. _Nat. Neurosci._ 14, 775–782 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Carandini, M. & Heeger, D. J. Summation and division by

neurons in primate visual cortex. _Science_ 264, 1333–1336 (1994). Article  CAS  PubMed  Google Scholar  * Carandini, M. & Heeger, D. J. Normalization as a canonical neural computation.

_Nat. Rev. Neurosci._ 13, 51–62 (2011). Article  PubMed  PubMed Central  CAS  Google Scholar  * Salinas, E. & Thier, P. Gain modulation: a major computational principle of the central

nervous system. _Neuron_ 27, 15–21 (2000). Article  CAS  PubMed  Google Scholar  * Andersen, R. A., Snyder, L. H., Bradley, D. C. & Xing, J. Multimodal representation of space in the

posterior parietal cortex and its use in planning movements. _Annu. Rev. Neurosci._ 20, 303–330 (1997). Article  CAS  PubMed  Google Scholar  * Pouget, A. & Snyder, L. H. Computational

approaches to sensorimotor transformations. _Nat. Neurosci._ 3, 1192–1198 (2000). Article  CAS  PubMed  Google Scholar  * Salinas, E. & Sejnowski, T. J. Impact of correlated synaptic

input on output firing rate and variability in simple neuronal models. _J. Neurosci._ 20, 6193–6209 (2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Finn, I. M., Priebe, N. J.

& Ferster, D. The emergence of contrast-invariant orientation tuning in simple cells of cat visual cortex. _Neuron_ 54, 137–152 (2007). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Sclar, G. & Freeman, R. D. Orientation selectivity in the cat’s striate cortex is invariant with stimulus contrast. _Exp. Brain Res._ 46, 457–461 (1982). Article  CAS  PubMed

  Google Scholar  * Skottun, B. C., Bradley, A., Sclar, G., Ohzawa, I. & Freeman, R. D. The effects of contrast on visual orientation and spatial frequency discrimination: a comparison

of single cells and behavior. _J. Neurophysiol._ 57, 773–786 (1987). Article  CAS  PubMed  Google Scholar  * Anderson, J. S., Lampl, I., Gillespie, D. C. & Ferster, D. The contribution

of noise to contrast invariance of orientation tuning in cat visual cortex. _Science_ 290, 1968–1972 (2000). Article  CAS  PubMed  Google Scholar  * McAdams, C. J. & Maunsell, J. H.

Effects of attention on the reliability of individual neurons in monkey visual cortex. _Neuron_ 23, 765–773 (1999). Article  CAS  PubMed  Google Scholar  * Somers, D. C., Nelson, S. B. &

Sur, M. An emergent model of orientation selectivity in cat visual cortical simple cells. _J. Neurosci._ 15, 5448–5465 (1995). Article  CAS  PubMed  PubMed Central  Google Scholar  * Treue,

S. & Martinez Trujillo, J. C. Feature-based attention influences motion processing gain in macaque visual cortex. _Nature_ 399, 575–579 (1999). Article  CAS  PubMed  Google Scholar  *

Baccus, S. A. & Meister, M. Fast and slow contrast adaptation in retinal circuitry. _Neuron_ 36, 909–919 (2002). Article  CAS  PubMed  Google Scholar  * Ruff, D. A., Ni, A. M. &

Cohen, M. R. Cognition as a window into neuronal population space. _Annu. Rev. Neurosci._ 41, 77–97 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shadlen, M. N., Britten,

K. H., Newsome, W. T. & Movshon, J. A. A computational analysis of the relationship between neuronal and behavioral responses to visual motion. _J. Neurosci._ 16, 1486–1510 (1996).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Barlow, H. B., Kaushal, T. P., Hawken, M. & Parker, A. J. Human contrast discrimination and the threshold of cortical neurons. _J.

Opt. Soc. Am. A_ 4, 2366–2371 (1987). Article  CAS  PubMed  Google Scholar  * Boynton, G. M., Demb, J. B., Glover, G. H. & Heeger, D. J. Neuronal basis of contrast discrimination. _Vis.

Res._ 39, 257–269 (1999). Article  CAS  PubMed  Google Scholar  * Clatworthy, P. L., Chirimuuta, M., Lauritzen, J. S. & Tolhurst, D. J. Coding of the contrasts in natural images by

populations of neurons in primary visual cortex (V1). _Vis. Res._ 43, 1983–2001 (2003). Article  CAS  PubMed  Google Scholar  * Parker, A. & Hawken, M. Capabilities of monkey cortical

cells in spatial-resolution tasks. _J. Opt. Soc. Am. A_ 2, 1101–1114 (1985). Article  CAS  PubMed  Google Scholar  * Watson, A. B. Gain, noise, and contrast sensitivity of linear visual

neurons. _Vis. Neurosci._ 4, 147–157 (1990). Article  CAS  PubMed  Google Scholar  * Eldar, E., Cohen, J. D. & Niv, Y. Amplified selectivity in cognitive processing implements the neural

gain model of norepinephrine function. _Behav. Brain Sci._ 39, e206 (2016). Article  PubMed  Google Scholar  * Natan, R. G., Carruthers, I. M., Mwilambwe-Tshilobo, L. & Geffen, M. N.

Gain control in the auditory cortex evoked by changing temporal correlation of sounds. _Cereb. Cortex_ 27, 2385–2402 (2017). PubMed  Google Scholar  * Mineault, P. J., Tring, E.,

Trachtenberg, J. T. & Ringach, D. L. Enhanced spatial resolution during locomotion and heightened attention in mouse primary visual cortex. _J. Neurosci._ 36, 6382–6392 (2016). THIS

PAPER DEMONSTRATES THAT THE RELATIVE GAIN OF VISUAL RESPONSES BETWEEN QUIESCENCE AND LOCOMOTION IS HETEROGENEOUS ACROSS CELLS AND DEPENDS ON THE (SPATIAL-FREQUENCY) TUNING PROPERTIES OF THE

CELL. Article  CAS  PubMed  PubMed Central  Google Scholar  * Reimer, J. et al. Pupil fluctuations track fast switching of cortical states during quiet wakefulness. _Neuron_ 84, 355–362

(2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bennett, C., Arroyo, S. & Hestrin, S. Subthreshold mechanisms underlying state-dependent modulation of visual responses.

_Neuron_ 80, 350–357 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ohshiro, T., Angelaki, D. E. & DeAngelis, G. C. A neural signature of divisive normalization at the

level of multisensory integration in primate cortex. _Neuron_ 95, 399–411.e8 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ratan Murty, N. A. & Arun, S. P.

Multiplicative mixing of object identity and image attributes in single inferior temporal neurons. _Proc. Natl Acad. Sci. USA_ 115, E3276–E3285 (2018). Article  PubMed  CAS  PubMed Central 

Google Scholar  * Niell, C. M. & Stryker, M. P. Modulation of visual responses by behavioral state in mouse visual cortex. _Neuron_ 65, 472–479 (2010). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Vinck, M., Batista-Brito, R., Knoblich, U. & Cardin, J. A. Arousal and locomotion make distinct contributions to cortical activity patterns and visual

encoding. _Neuron_ 86, 740–754 (2015). THIS PAPER SHOWS THAT AROUSAL AND LOCOMOTION DIFFERENTIALLY REGULATE NEURAL ACTIVITY AND SENSORY RESPONSE GAIN IN MOUSE V1. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Destexhe, A., Contreras, D. & Steriade, M. Spatiotemporal analysis of local field potentials and unit discharges in cat cerebral cortex during natural

wake and sleep states. _J. Neurosci._ 19, 4595–4608 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Livingstone, M. S. & Hubel, D. H. Effects of sleep and arousal on the

processing of visual information in the cat. _Nature_ 291, 554–561 (1981). Article  CAS  PubMed  Google Scholar  * Pakan, J. M. et al. Behavioral-state modulation of inhibition is

context-dependent and cell type specific in mouse visual cortex. _eLife_ 5, e14985 (2016). THIS PAPER SHOWS THAT LOCOMOTION-INDUCED GAIN MODULATION OF NEURONAL ACTIVITY IS CONTEXT DEPENDENT,

AND VARIES ACROSS LIGHT AND DARK CONDITIONS AND ACROSS DISTINCT CELL POPULATIONS. Article  PubMed  PubMed Central  CAS  Google Scholar  * Dadarlat, M. C. & Stryker, M. P. Locomotion

enhances neural encoding of visual stimuli in mouse V1 _J. Neurosci._ 37, 3764–3775 (2017). THIS PAPER DEMONSTRATES THAT LOCOMOTION ENHANCES NEURAL ENCODING OF VISUAL STIMULI THROUGH

INCREASED FIRING RATES AND DECREASED NOISE CORRELATIONS ACROSS THE POPULATION. Article  CAS  PubMed  PubMed Central  Google Scholar  * Schneider, D. M., Nelson, A. & Mooney, R. A

synaptic and circuit basis for corollary discharge in the auditory cortex. _Nature_ 513, 189–194 (2014). THIS ARTICLE SHOWS THAT LOCOMOTION DECREASES THE RESPONSE GAIN IN THE MOUSE PRIMARY

AUDITORY CORTEX VIA INHIBITORY INTERNEURON ACTIONS IN THE LOCAL CORTICAL CIRCUIT. Article  CAS  PubMed  PubMed Central  Google Scholar  * Schneider, D. M., Sundararajan, J. & Mooney, R.

A cortical filter that learns to suppress the acoustic consequences of movement. _Nature_ 561, 391–395 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Munoz, W., Tremblay,

R., Levenstein, D. & Rudy, B. Layer-specific modulation of neocortical dendritic inhibition during active wakefulness. _Science_ 355, 954–959 (2017). THIS PAPER SHOWS THAT DISTINCT SST +

INTERNEURON POPULATIONS DEMONSTRATE LAMINA-DEPENDENT AND STATE-DEPENDENT DIFFERENCES IN GAIN MODULATION IN S1. Article  CAS  PubMed  Google Scholar  * Maunsell, J. H. R. Neuronal mechanisms

of visual attention. _Annu. Rev. Vis. Sci._ 1, 373–391 (2015). Article  PubMed  PubMed Central  Google Scholar  * McAdams, C. J. & Reid, R. C. Attention modulates the responses of

simple cells in monkey primary visual cortex. _J. Neurosci._ 25, 11023–11033 (2005). Article  CAS  PubMed  PubMed Central  Google Scholar  * Reynolds, J. H., Pasternak, T. & Desimone, R.

Attention increases sensitivity of V4 neurons. _Neuron_ 26, 703–714 (2000). Article  CAS  PubMed  Google Scholar  * Connor, C. E., Gallant, J. L., Preddie, D. C. & Van Essen, D. C.

Responses in area V4 depend on the spatial relationship between stimulus and attention. _J. Neurophysiol._ 75, 1306–1308 (1996). Article  CAS  PubMed  Google Scholar  * Connor, C. E.,

Preddie, D. C., Gallant, J. L. & Van Essen, D. C. Spatial attention effects in macaque area V4. _J. Neurosci._ 17, 3201–3214 (1997). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Lee, J. & Maunsell, J. H. A normalization model of attentional modulation of single unit responses. _PLOS ONE_ 4, e4651 (2009). Article  PubMed  PubMed Central  CAS  Google Scholar 

* Martinez-Trujillo, J. C. & Treue, S. Feature-based attention increases the selectivity of population responses in primate visual cortex. _Curr. Biol._ 14, 744–751 (2004). Article  CAS

  PubMed  Google Scholar  * Williford, T. & Maunsell, J. H. Effects of spatial attention on contrast response functions in macaque area V4. _J. Neurophysiol._ 96, 40–54 (2006). Article 

PubMed  Google Scholar  * Reynolds, J. H., Chelazzi, L. & Desimone, R. Competitive mechanisms subserve attention in macaque areas V2 and V4. _J. Neurosci._ 19, 1736–1753 (1999). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Ecker, A. S., Denfield, G. H., Bethge, M. & Tolias, A. S. On the structure of neuronal population activity under fluctuations in

attentional state. _J. Neurosci._ 36, 1775–1789 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rabinowitz, N. C., Goris, R. L., Cohen, M. & Simoncelli, E. P. Attention

stabilizes the shared gain of V4 populations. _eLife_ 4, e08998 (2015). Article  PubMed  PubMed Central  Google Scholar  * Tiesinga, P. H. & Sejnowski, T. J. Rapid temporal modulation of

synchrony by competition in cortical interneuron networks. _Neural Comput._ 16, 251–275 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Reynolds, J. H. & Chelazzi, L.

Attentional modulation of visual processing. _Annu. Rev. Neurosci._ 27, 611–647 (2004). Article  CAS  PubMed  Google Scholar  * Schoups, A., Vogels, R., Qian, N. & Orban, G. Practising

orientation identification improves orientation coding in V1 neurons. _Nature_ 412, 549–553 (2001). Article  CAS  PubMed  Google Scholar  * Jurjut, O., Georgieva, P., Busse, L. &

Katzner, S. Learning enhances sensory processing in mouse V1 before improving behavior. _J. Neurosci._ 37, 6460–6474 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kaneko,

M. & Stryker, M. P. Sensory experience during locomotion promotes recovery of function in adult visual cortex. _eLife_ 3, e02798 (2014). Article  PubMed  PubMed Central  Google Scholar 

* Chance, F. S., Abbott, L. F. & Reyes, A. D. Gain modulation from background synaptic input. _Neuron_ 35, 773–782 (2002). Article  CAS  PubMed  Google Scholar  * Ho, N. & Destexhe,

A. Synaptic background activity enhances the responsiveness of neocortical pyramidal neurons. _J. Neurophysiol._ 84, 1488–1496 (2000). Article  CAS  PubMed  Google Scholar  * Prescott, S. A.

& De Koninck, Y. Gain control of firing rate by shunting inhibition: roles of synaptic noise and dendritic saturation. _Proc. Natl Acad. Sci. USA_ 100, 2076–2081 (2003). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Shu, Y., Hasenstaub, A., Badoual, M., Bal, T. & McCormick, D. A. Barrages of synaptic activity control the gain and sensitivity of cortical

neurons. _J. Neurosci._ 23, 10388–10401 (2003). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cardin, J. A., Palmer, L. A. & Contreras, D. Cellular mechanisms underlying

stimulus-dependent gain modulation in primary visual cortex neurons in vivo. _Neuron_ 59, 150–160 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ly, C. & Doiron, B.

Divisive gain modulation with dynamic stimuli in integrate-and-fire neurons. _PLOS Comput. Biol._ 5, e1000365 (2009). Article  PubMed  PubMed Central  CAS  Google Scholar  * Miller, K. D.

& Troyer, T. W. Neural noise can explain expansive, power-law nonlinearities in neural response functions. _J. Neurophysiol._ 87, 653–659 (2002). Article  PubMed  Google Scholar  *

Hansel, D. & van Vreeswijk, C. How noise contributes to contrast invariance of orientation tuning in cat visual cortex. _J. Neurosci._ 22, 5118–5128 (2002). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Bulsara, A., Jacobs, E. W., Zhou, T., Moss, F. & Kiss, L. Stochastic resonance in a single neuron model: theory and analog simulation. _J. Theor. Biol._ 152,

531–555 (1991). Article  CAS  PubMed  Google Scholar  * Wiesenfeld, K. & Moss, F. Stochastic resonance and the benefits of noise: from ice ages to crayfish and SQUIDs. _Nature_ 373,

33–36 (1995). Article  CAS  PubMed  Google Scholar  * Khubieh, A., Ratte, S., Lankarany, M. & Prescott, S. A. Regulation of cortical dynamic range by background synaptic noise and

feedforward inhibition. _Cereb. Cortex_ 26, 3357–3369 (2016). Article  PubMed  PubMed Central  Google Scholar  * Atallah, B. V., Bruns, W., Carandini, M. & Scanziani, M.

Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. _Neuron_ 73, 159–170 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Katzner, S.,

Busse, L. & Carandini, M. GABAA inhibition controls response gain in visual cortex. _J. Neurosci._ 31, 5931–5941 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * de la

Rocha, J., Doiron, B., Shea-Brown, E., Josic, K. & Reyes, A. Correlation between neural spike trains increases with firing rate. _Nature_ 448, 802–806 (2007). Article  PubMed  CAS 

Google Scholar  * Gentet, L. J., Avermann, M., Matyas, F., Staiger, J. F. & Petersen, C. C. Membrane potential dynamics of GABAergic neurons in the barrel cortex of behaving mice.

_Neuron_ 65, 422–435 (2010). Article  CAS  PubMed  Google Scholar  * Pala, A. & Petersen, C. C. State-dependent cell-type-specific membrane potential dynamics and unitary synaptic inputs

in awake mice. _eLife_ 7, e35869 (2018). Article  PubMed  PubMed Central  Google Scholar  * Polack, P. O., Friedman, J. & Golshani, P. Cellular mechanisms of brain state-dependent gain

modulation in visual cortex. _Nat. Neurosci._ 16, 1331–1339 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Poulet, J. F. & Petersen, C. C. Internal brain state regulates

membrane potential synchrony in barrel cortex of behaving mice. _Nature_ 454, 881–885 (2008). Article  CAS  PubMed  Google Scholar  * Chen, N., Sugihara, H. & Sur, M. An

acetylcholine-activated microcircuit drives temporal dynamics of cortical activity. _Nat. Neurosci._ 18, 892–902 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Carvalho, T.

P. & Buonomano, D. V. Differential effects of excitatory and inhibitory plasticity on synaptically driven neuronal input–output functions. _Neuron_ 61, 774–785 (2009). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Mitchell, S. J. & Silver, R. A. Shunting inhibition modulates neuronal gain during synaptic excitation. _Neuron_ 38, 433–445 (2003). Article 

CAS  PubMed  Google Scholar  * Murphy, B. K. & Miller, K. D. Multiplicative gain changes are induced by excitation or inhibition alone. _J. Neurosci._ 23, 10040–10051 (2003). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Abbott, L. F. & Chance, F. S. Drivers and modulators from push–pull and balanced synaptic input. _Prog. Brain Res._ 149, 147–155 (2005).

Article  CAS  PubMed  Google Scholar  * Ayaz, A. & Chance, F. S. Gain modulation of neuronal responses by subtractive and divisive mechanisms of inhibition. _J. Neurophysiol._ 101,

958–968 (2009). Article  PubMed  Google Scholar  * Brozovic, M., Abbott, L. F. & Andersen, R. A. Mechanism of gain modulation at single neuron and network levels. _J. Comput. Neurosci._

25, 158–168 (2008). Article  CAS  PubMed  Google Scholar  * Vogels, T. P. & Abbott, L. F. Gating multiple signals through detailed balance of excitation and inhibition in spiking

networks. _Nat. Neurosci._ 12, 483–491 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fellous, J. M., Rudolph, M., Destexhe, A. & Sejnowski, T. J. Synaptic background

noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity. _Neuroscience_ 122, 811–829 (2003). Article  CAS  PubMed  Google Scholar  * Holt, G.

R. & Koch, C. Shunting inhibition does not have a divisive effect on firing rates. _Neural Comput._ 9, 1001–1013 (1997). Article  CAS  PubMed  Google Scholar  * Litwin-Kumar, A.,

Oswald, A. M., Urban, N. N. & Doiron, B. Balanced synaptic input shapes the correlation between neural spike trains. _PLOS Comput. Biol._ 7, e1002305 (2011). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Rosenbaum, R. & Josic, K. Membrane potential and spike train statistics depend distinctly on input statistics. _Phys. Rev. E Stat. Nonlin. Soft Matter Phys._

84, 051902 (2011). Article  PubMed  CAS  Google Scholar  * Shea-Brown, E., Josic, K., de la Rocha, J. & Doiron, B. Correlation and synchrony transfer in integrate-and-fire neurons: basic

properties and consequences for coding. _Phys. Rev. Lett._ 100, 108102 (2008). Article  PubMed  CAS  Google Scholar  * Tchumatchenko, T. & Wolf, F. Representation of dynamical stimuli

in populations of threshold neurons. _PLOS Comput. Biol._ 7, e1002239 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Arsiero, M., Luscher, H. R., Lundstrom, B. N. &

Giugliano, M. The impact of input fluctuations on the frequency–current relationships of layer 5 pyramidal neurons in the rat medial prefrontal cortex. _J. Neurosci._ 27, 3274–3284 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Higgs, M. H., Slee, S. J. & Spain, W. J. Diversity of gain modulation by noise in neocortical neurons: regulation by the slow

afterhyperpolarization conductance. _J. Neurosci._ 26, 8787–8799 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hong, S., Ratte, S., Prescott, S. A. & De Schutter, E.

Single neuron firing properties impact correlation-based population coding. _J. Neurosci._ 32, 1413–1428 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lundstrom, B. N.,

Famulare, M., Sorensen, L. B., Spain, W. J. & Fairhall, A. L. Sensitivity of firing rate to input fluctuations depends on time scale separation between fast and slow variables in single

neurons. _J. Comput. Neurosci._ 27, 277–290 (2009). Article  PubMed  Google Scholar  * Rauch, A., La Camera, G., Luscher, H. R., Senn, W. & Fusi, S. Neocortical pyramidal cells respond

as integrate-and-fire neurons to in vivo-like input currents. _J. Neurophysiol._ 90, 1598–1612 (2003). Article  PubMed  Google Scholar  * Larkum, M. E., Senn, W. & Luscher, H. R.

Top-down dendritic input increases the gain of layer 5 pyramidal neurons. _Cereb. Cortex_ 14, 1059–1070 (2004). Article  PubMed  Google Scholar  * Mehaffey, W. H., Doiron, B., Maler, L.

& Turner, R. W. Deterministic multiplicative gain control with active dendrites. _J. Neurosci._ 25, 9968–9977 (2005). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jarvis, S.,

Nikolic, K. & Schultz, S. R. Neuronal gain modulability is determined by dendritic morphology: a computational optogenetic study. _PLOS Comput. Biol._ 14, e1006027 (2018). Article 

PubMed  PubMed Central  CAS  Google Scholar  * Quiquempoix, M. et al. Layer 2/3 pyramidal neurons control the gain of cortical output. _Cell Rep._ 24, 2799–2807.e4 (2018). Article  CAS 

PubMed  Google Scholar  * Sato, T. K., Haider, B., Hausser, M. & Carandini, M. An excitatory basis for divisive normalization in visual cortex. _Nat. Neurosci._ 19, 568–570 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Haider, B. & McCormick, D. A. Rapid neocortical dynamics: cellular and network mechanisms. _Neuron_ 62, 171–189 (2009). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Silver, R. A. Neuronal arithmetic. _Nat. Rev. Neurosci._ 11, 474–489 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Nelson,

S., Toth, L., Sheth, B. & Sur, M. Orientation selectivity of cortical neurons during intracellular blockade of inhibition. _Science_ 265, 774–777 (1994). Article  CAS  PubMed  Google

Scholar  * Atallah, B. V., Scanziani, M. & Carandini, M. Atallah et al. reply. _Nature_ 508, E3 (2014). Article  CAS  PubMed  Google Scholar  * El-Boustani, S., Wilson, N. R., Runyan, C.

A. & Sur, M. El-Boustani et al. reply. _Nature_ 508, E3–E4 (2014). Article  CAS  PubMed  Google Scholar  * Wilson, N. R., Runyan, C. A., Wang, F. L. & Sur, M. Division and

subtraction by distinct cortical inhibitory networks in vivo. _Nature_ 488, 343–348 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Natan, R. G., Rao, W. & Geffen, M. N.

Cortical interneurons differentially shape frequency tuning following adaptation. _Cell Rep._ 21, 878–890 (2017). THIS PAPER SHOWS THAT DISTINCT CORTICAL INTERNEURON POPULATIONS DIFFERENTLY

MODULATE THE GAIN OF FREQUENCY-TUNED EXCITATORY RESPONSES DURING ADAPTATION. Article  CAS  PubMed  PubMed Central  Google Scholar  * Phillips, E. A. & Hasenstaub, A. R. Asymmetric

effects of activating and inactivating cortical interneurons. _eLife_ 5, e18383 (2016). THIS PAPER SHOWS THAT OPTOGENETIC ACTIVATION OF GABAERGIC INTERNEURONS IN THE CORTEX DOES NOT FULLY

CAPTURE THE IMPACT OF INHIBITION ON EXCITATORY NEURON RESPONSE GAIN. Article  PubMed  PubMed Central  CAS  Google Scholar  * Seybold, B. A., Phillips, E. A. K., Schreiner, C. E. &

Hasenstaub, A. R. Inhibitory actions unified by network integration. _Neuron_ 87, 1181–1192 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fishell, G. & Rudy, B.

Mechanisms of inhibition within the telencephalon: ‘‘where the wild things are’’. _Annu. Rev. Neurosci._ 34, 535–567 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Markram,

H. et al. Interneurons of the neocortical inhibitory system. _Nat. Rev. Neurosci._ 5, 793–807 (2004). Article  CAS  PubMed  Google Scholar  * El-Boustani, S. & Sur, M. Response-dependent

dynamics of cell-specific inhibition in cortical networks in vivo. _Nat. Commun._ 5, 5689 (2014). Article  CAS  PubMed  Google Scholar  * Lee, A. M. et al. Identification of a brainstem

circuit regulating visual cortical state in parallel with locomotion. _Neuron_ 83, 455–466 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cardin, J. A. Inhibitory

interneurons regulate temporal precision and correlations in cortical circuits. _Trends Neurosci._ 41, 689–700 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cone, J. J.,

Scantlen, M. D., Histed, M. H. & Maunsell, J. H. R. Different inhibitory interneuron cell classes make distinct contributions to visual contrast perception. _eNeuro_

https://doi.org/10.1523/ENEURO.0337-18.2019 (2019). Article  PubMed  PubMed Central  Google Scholar  * Ayzenshtat, I., Karnani, M. M., Jackson, J. & Yuste, R. Cortical control of spatial

resolution by VIP+ interneurons. _J. Neurosci._ 36, 11498–11509 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hong, Y. K., Lacefield, C. O., Rodgers, C. C. & Bruno, R.

M. Sensation, movement and learning in the absence of barrel cortex. _Nature_ 561, 542–546 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Otchy, T. M. et al. Acute

off-target effects of neural circuit manipulations. _Nature_ 528, 358–363 (2015). Article  CAS  PubMed  Google Scholar  * Wolff, S. B. & Olveczky, B. P. The promise and perils of causal

circuit manipulations. _Curr. Opin. Neurobiol._ 49, 84–94 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Phillips, E. A. K., Schreiner, C. E. & Hasenstaub, A. R.

Cortical interneurons differentially regulate the effects of acoustic context. _Cell Rep._ 20, 771–778 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fu, Y. et al. A

cortical circuit for gain control by behavioral state. _Cell_ 156, 1139–1152 (2014). THIS PAPER PROVIDES EVIDENCE THAT VIP + INTERNEURONS ARE ACTIVATED BY LOCOMOTION AND MAY CONTRIBUTE TO

STATE-DEPENDENT VISUAL RESPONSE GAIN MODULATION IN MOUSE V1. Article  CAS  PubMed  PubMed Central  Google Scholar  * Karnani, M. M. et al. Opening holes in the blanket of inhibition:

localized lateral disinhibition by VIP interneurons. _J. Neurosci._ 36, 3471–3480 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Karnani, M. M. et al. Cooperative

subnetworks of molecularly similar interneurons in mouse neocortex. _Neuron_ 90, 86–100 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, S., Kruglikov, I., Huang, Z. J.,

Fishell, G. & Rudy, B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. _Nat. Neurosci._ 16, 1662–1670 (2013). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Pi, H. J. et al. Cortical interneurons that specialize in disinhibitory control. _Nature_ 503, 521–524 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Batista-Brito, R. et al. Developmental dysfunction of VIP interneurons impairs cortical circuits. _Neuron_ 95, 884–895.e9 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Dipoppa, M. et al. Vision and locomotion shape the interactions between neuron types in mouse visual cortex. _Neuron_ 98, 602–615.e8 (2018). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Ozeki, H., Finn, I. M., Schaffer, E. S., Miller, K. D. & Ferster, D. Inhibitory stabilization of the cortical network underlies visual surround suppression. _Neuron_ 62,

578–592 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tsodyks, M. V., Skaggs, W. E., Sejnowski, T. J. & McNaughton, B. L. Paradoxical effects of external modulation of

inhibitory interneurons. _J. Neurosci._ 17, 4382–4388 (1997). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kato, H. K., Asinof, S. K. & Isaacson, J. S. Network-level control

of frequency tuning in auditory cortex. _Neuron_ 95, 412–423.e4 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Garcia Del Molino, L. C., Yang, G. R., Mejias, J. F. &

Wang, X. J. Paradoxical response reversal of top-down modulation in cortical circuits with three interneuron types. _eLife_ 6, e29742 (2017). Article  PubMed  PubMed Central  Google Scholar

  * Litwin-Kumar, A., Rosenbaum, R. & Doiron, B. Inhibitory stabilization and visual coding in cortical circuits with multiple interneuron subtypes. _J. Neurophysiol._ 115, 1399–1409

(2016). Article  PubMed  PubMed Central  Google Scholar  * Zhou, M. et al. Scaling down of balanced excitation and inhibition by active behavioral states in auditory cortex. _Nat. Neurosci._

17, 841–850 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Boly, M. et al. Baseline brain activity fluctuations predict somatosensory perception in humans. _Proc. Natl

Acad. Sci. USA_ 104, 12187–12192 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fox, M. D., Snyder, A. Z., Vincent, J. L. & Raichle, M. E. Intrinsic fluctuations within

cortical systems account for intertrial variability in human behavior. _Neuron_ 56, 171–184 (2007). Article  CAS  PubMed  Google Scholar  * Hesselmann, G., Kell, C. A., Eger, E. &

Kleinschmidt, A. Spontaneous local variations in ongoing neural activity bias perceptual decisions. _Proc. Natl Acad. Sci. USA_ 105, 10984–10989 (2008). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Hesselmann, G., Kell, C. A. & Kleinschmidt, A. Ongoing activity fluctuations in hMT+ bias the perception of coherent visual motion. _J. Neurosci._ 28, 14481–14485

(2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Palva, J. M. & Palva, S. Roles of multiscale brain activity fluctuations in shaping the variability and dynamics of

psychophysical performance. _Prog. Brain Res._ 193, 335–350 (2011). Article  PubMed  Google Scholar  * Diamond, D. M., Campbell, A. M., Park, C. R., Halonen, J. & Zoladz, P. R. The

temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes–Dodson law.

_Neural. Plast._ 2007, 60803 (2007). Article  PubMed  PubMed Central  Google Scholar  * Yerkes, R. M. & Dodson, J. D. The relation of strength of stimulus to rapidity of habit-formation.

_J. Comp. Neurol. Psychol._ 18, 459–482 (1908). Article  Google Scholar  * He, B. J. Spontaneous and task-evoked brain activity negatively interact. _J. Neurosci._ 33, 4672–4682 (2013).

Article  PubMed  PubMed Central  CAS  Google Scholar  * Bullock, T., Elliott, J. C., Serences, J. T. & Giesbrecht, B. Acute exercise modulates feature-selective responses in human

cortex. _J. Cognit. Neurosci._ 29, 605–618 (2017). Article  Google Scholar  * He, B. J. & Zempel, J. M. Average is optimal: an inverted-U relationship between trial-to-trial brain

activity and behavioral performance. _PLOS Comput. Biol._ 9, e1003348 (2013). Article  PubMed  PubMed Central  CAS  Google Scholar  * Murphy, P. R., Vandekerckhove, J. & Nieuwenhuis, S.

Pupil-linked arousal determines variability in perceptual decision making. _PLOS Comput. Biol._ 10, e1003854 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * Aston-Jones, G.

& Cohen, J. D. An integrative theory of locus coeruleus–norepinephrine function: adaptive gain and optimal performance. _Annu. Rev. Neurosci._ 28, 403–450 (2005). Article  CAS  PubMed 

Google Scholar  * Murphy, P. R., O’Connell, R. G., O’Sullivan, M., Robertson, I. H. & Balsters, J. H. Pupil diameter covaries with BOLD activity in human locus coeruleus. _Hum. Brain

Mapp._ 35, 4140–4154 (2014). Article  PubMed  PubMed Central  Google Scholar  * Joshi, S., Li, Y., Kalwani, R. M. & Gold, J. I. Relationships between pupil diameter and neuronal activity

in the locus coeruleus, colliculi, and cingulate cortex. _Neuron_ 89, 221–234 (2016). Article  CAS  PubMed  Google Scholar  * Reimer, J. et al. Pupil fluctuations track rapid changes in

adrenergic and cholinergic activity in cortex. _Nat. Commun._ 7, 13289 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Erisken, S. et al. Effects of locomotion extend

throughout the mouse early visual system. _Curr. Biol._ 24, 2899–2907 (2014). Article  CAS  PubMed  Google Scholar  * Tang, L. & Higley, M. J. Layer 5 circuits in V1 differentially

control visuomotor behavior. _bioRxiv_ https://doi.org/10.1101/540807 (2019). * Saleem, A. B., Ayaz, A., Jeffery, K. J., Harris, K. D. & Carandini, M. Integration of visual motion and

locomotion in mouse visual cortex. _Nat. Neurosci._ 16, 1864–1869 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Neske, G. T., Nestvogel, D., Steffan, P. J. & McCormick,

D. A. Distinct waking states for strong evoked responses in primary visual cortex and optimal visual detection performance. _J. Neurosci_. 39, 10044–10059 (2019). Article  PubMed  PubMed

Central  Google Scholar  * Bullock, T., Cecotti, H. & Giesbrecht, B. Multiple stages of information processing are modulated during acute bouts of exercise. _Neuroscience_ 307, 138–150

(2015). Article  CAS  PubMed  Google Scholar  * Benjamin, A. V., Wailes-Newson, K., Ma-Wyatt, A., Baker, D. H. & Wade, A. R. The effect of locomotion on early visual contrast processing

in humans. _J. Neurosci._ 38, 3050–3059 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * McGinley, M. J., David, S. V. & McCormick, D. A. Cortical membrane potential

signature of optimal states for sensory signal detection. _Neuron_ 87, 179–192 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Barson, D. et al. Simultaneous mesoscopic and

two-photon imaging of neuronal activity in cortical circuits. _Nat. Methods_ https://doi.org/10.1038/s41592-019-0625-2 (2019). Article  PubMed  CAS  PubMed Central  Google Scholar  * Clancy,

K. B., Orsolic, I. & Mrsic-Flogel, T. D. Locomotion-dependent remapping of distributed cortical networks. _Nat. Neurosci._ 22, 778–786 (2019). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Shimaoka, D., Harris, K. D. & Carandini, M. Effects of arousal on mouse sensory cortex depend on modality. _Cell Rep._ 22, 3160–3167 (2018). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Musall, S., Kaufman, M. T., Juavinett, A. L., Gluf, S. & Churchland, A. K. Single-trial neural dynamics are dominated by richly varied movements. _Nat.

Neurosci._ 22, 1677–1686 (2019). THIS STUDY REPORTS THAT ANIMAL MOVEMENTS CAPTURE THE MAJORITY OF NEURAL VARIABILITY ACROSS THE CORTEX, AND THOSE THAT ARE TASK-ALIGNED ACCOUNT FOR FEATURES

COMMONLY ATTRIBUTED TO COGNITIVE TASK DEMANDS. Article  CAS  PubMed  PubMed Central  Google Scholar  * Disney, A. A., Alasady, H. A. & Reynolds, J. H. Muscarinic acetylcholine receptors

are expressed by most parvalbumin-immunoreactive neurons in area MT of the macaque. _Brain Behav._ 4, 431–445 (2014). Article  PubMed  PubMed Central  Google Scholar  * Disney, A. A. &

Aoki, C. Muscarinic acetylcholine receptors in macaque V1 are most frequently expressed by parvalbumin-immunoreactive neurons. _J. Comp. Neurol._ 507, 1748–1762 (2008). Article  PubMed 

PubMed Central  Google Scholar  * Disney, A. A., Domakonda, K. V. & Aoki, C. Differential expression of muscarinic acetylcholine receptors across excitatory and inhibitory cells in

visual cortical areas V1 and V2 of the macaque monkey. _J. Comp. Neurol._ 499, 49–63 (2006). Article  CAS  PubMed  Google Scholar  * Disney, A. A. & Reynolds, J. H. Expression of m1-type

muscarinic acetylcholine receptors by parvalbumin-immunoreactive neurons in the primary visual cortex: a comparative study of rat, guinea pig, ferret, macaque, and human. _J. Comp. Neurol._

522, 986–1003 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Letzkus, J. J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex.

_Nature_ 480, 331–335 (2011). Article  CAS  PubMed  Google Scholar  * Porter, J. T. et al. Selective excitation of subtypes of neocortical interneurons by nicotinic receptors. _J. Neurosci._

19, 5228–5235 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Urban-Ciecko, J., Jouhanneau, J. S., Myal, S. E., Poulet, J. F. A. & Barth, A. L. Precisely timed nicotinic

activation drives SST inhibition in neocortical circuits. _Neuron_ 97, 611–625.e5 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Disney, A. A., Aoki, C. & Hawken, M. J.

Gain modulation by nicotine in macaque V1. _Neuron_ 56, 701–713 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gil, Z., Connors, B. W. & Amitai, Y. Differential

regulation of neocortical synapses by neuromodulators and activity. _Neuron_ 19, 679–686 (1997). Article  CAS  PubMed  Google Scholar  * Hasselmo, M. E. & Bower, J. M. Cholinergic

suppression specific to intrinsic not afferent fiber synapses in rat piriform (olfactory) cortex. _J. Neurophysiol._ 67, 1222–1229 (1992). Article  CAS  PubMed  Google Scholar  * Kimura, F.

Cholinergic modulation of cortical function: a hypothetical role in shifting the dynamics in cortical network. _Neurosci. Res._ 38, 19–26 (2000). Article  CAS  PubMed  Google Scholar  *

Kimura, F., Fukuda, M. & Tsumoto, T. Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording: possible differential effect depending on the

source of input. _Eur. J. Neurosci._ 11, 3597–3609 (1999). Article  CAS  PubMed  Google Scholar  * Disney, A. A., Aoki, C. & Hawken, M. J. Cholinergic suppression of visual responses in

primate V1 is mediated by GABAergic inhibition. _J. Neurophysiol._ 108, 1907–1923 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Soma, S., Shimegi, S., Osaki, H. & Sato,

H. Cholinergic modulation of response gain in the primary visual cortex of the macaque. _J. Neurophysiol._ 107, 283–291 (2012). Article  CAS  PubMed  Google Scholar  * Herrero, J. L.,

Gieselmann, M. A. & Thiele, A. Muscarinic and nicotinic contribution to contrast sensitivity of macaque area V1 neurons. _Front. Neural Circuits_ 11, 106 (2017). Article  PubMed  PubMed

Central  Google Scholar  * Askew, C., Intskirveli, I. & Metherate, R. Systemic nicotine increases gain and narrows receptive fields in A1 via integrated cortical and subcortical actions.

_eNeuro_ https://doi.org/10.1523/ENEURO.0192-17.2017 (2017). Article  PubMed  PubMed Central  Google Scholar  * Herrero, J. L. et al. Acetylcholine contributes through muscarinic receptors

to attentional modulation in V1. _Nature_ 454, 1110–1114 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Pinto, L. et al. Fast modulation of visual perception by basal

forebrain cholinergic neurons. _Nat. Neurosci._ 16, 1857–1863 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Stewart, A. E., Yan, Z., Surmeier, D. J. & Foehring, R. C.

Muscarine modulates Ca2+ channel currents in rat sensorimotor pyramidal cells via two distinct pathways. _J. Neurophysiol._ 81, 72–84 (1999). Article  CAS  PubMed  Google Scholar  *

Lorenzon, N. M. & Foehring, R. C. Relationship between repetitive firing and afterhyperpolarizations in human neocortical neurons. _J. Neurophysiol._ 67, 350–363 (1992). Article  CAS 

PubMed  Google Scholar  * McCormick, D. A. & Prince, D. A. Mechanisms of action of acetylcholine in the guinea-pig cerebral cortex in vitro. _J. Physiol._ 375, 169–194 (1986). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Schwindt, P. C., Spain, W. J. & Crill, W. E. Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat

sensorimotor cortex in vitro. _J. Neurophysiol._ 59, 468–481 (1988). Article  CAS  PubMed  Google Scholar  * Wang, Z. & McCormick, D. A. Control of firing mode of corticotectal and

corticopontine layer V burst-generating neurons by norepinephrine, acetylcholine, and 1S,3R-ACPD. _J. Neurosci._ 13, 2199–2216 (1993). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Eggermann, E. & Feldmeyer, D. Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4. _Proc. Natl Acad. Sci. USA_ 106, 11753–11758 (2009). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Gulledge, A. T., Park, S. B., Kawaguchi, Y. & Stuart, G. J. Heterogeneity of phasic cholinergic signaling in neocortical neurons. _J.

Neurophysiol._ 97, 2215–2229 (2007). Article  CAS  PubMed  Google Scholar  * Gulledge, A. T. & Stuart, G. J. Cholinergic inhibition of neocortical pyramidal neurons. _J. Neurosci._ 25,

10308–10320 (2005). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dasgupta, R., Seibt, F. & Beierlein, M. Synaptic release of acetylcholine rapidly suppresses cortical activity

by recruiting muscarinic receptors in layer 4. _J. Neurosci._ 38, 5338–5350 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Higley, M. J., Soler-Llavina, G. J. &

Sabatini, B. L. Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration. _Nat. Neurosci._ 12, 1121–1128 (2009). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Giessel, A. J. & Sabatini, B. L. M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK

channels. _Neuron_ 68, 936–947 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Foehring, R. C., Schwindt, P. C. & Crill, W. E. Norepinephrine selectively reduces slow

Ca2+- and Na+-mediated K+ currents in cat neocortical neurons. _J. Neurophysiol._ 61, 245–256 (1989). Article  CAS  PubMed  Google Scholar  * Madison, D. V. & Nicoll, R. A. Actions of

noradrenaline recorded intracellularly in rat hippocampal CA1 pyramidal neurones, in vitro. _J. Physiol._ 372, 221–244 (1986). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Mueller, D., Porter, J. T. & Quirk, G. J. Noradrenergic signaling in infralimbic cortex increases cell excitability and strengthens memory for fear extinction. _J. Neurosci._ 28, 369–375

(2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dodt, H. U., Pawelzik, H. & Zieglgansberger, W. Actions of noradrenaline on neocortical neurons in vitro. _Brain Res._

545, 307–311 (1991). Article  CAS  PubMed  Google Scholar  * Mynlieff, M. & Dunwiddie, T. V. Noradrenergic depression of synaptic responses in hippocampus of rat: evidence for mediation

by α1-receptors. _Neuropharmacology_ 27, 391–398 (1988). Article  CAS  PubMed  Google Scholar  * Guan, D., Armstrong, W. E. & Foehring, R. C. Electrophysiological properties of

genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine. _J. Neurophysiol._ 113, 2014–2032 (2015). Article 

PubMed  PubMed Central  Google Scholar  * Waterhouse, B. D., Mouradian, R., Sessler, F. M. & Lin, R. C. Differential modulatory effects of norepinephrine on synaptically driven responses

of layer V barrel field cortical neurons. _Brain Res._ 868, 39–47 (2000). Article  CAS  PubMed  Google Scholar  * Armstrong-James, M. & Fox, K. Effects of ionophoresed noradrenaline on

the spontaneous activity of neurones in rat primary somatosensory cortex. _J. Physiol._ 335, 427–447 (1983). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bassant, M. H., Ennouri,

K. & Lamour, Y. Effects of iontophoretically applied monoamines on somatosensory cortical neurons of unanesthetized rats. _Neuroscience_ 39, 431–439 (1990). Article  CAS  PubMed  Google

Scholar  * Foote, S. L., Freedman, R. & Oliver, A. P. Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. _Brain Res._ 86, 229–242 (1975). Article  CAS

  PubMed  Google Scholar  * Waterhouse, B. D., Moises, H. C. & Woodward, D. J. Noradrenergic modulation of somatosensory cortical neuronal responses to iontophoretically applied putative

neurotransmitters. _Exp. Neurol._ 69, 30–49 (1980). Article  CAS  PubMed  Google Scholar  * Waterhouse, B. D., Moises, H. C. & Woodward, D. J. Alpha-receptor-mediated facilitation of

somatosensory cortical neuronal responses to excitatory synaptic inputs and iontophoretically applied acetylcholine. _Neuropharmacology_ 20, 907–920 (1981). Article  CAS  PubMed  Google

Scholar  * Ego-Stengel, V., Bringuier, V. & Shulz, D. E. Noradrenergic modulation of functional selectivity in the cat visual cortex: an in vivo extracellular and intracellular study.

_Neuroscience_ 111, 275–289 (2002). Article  CAS  PubMed  Google Scholar  * Seillier, L. et al. Serotonin decreases the gain of visual responses in awake macaque V1. _J. Neurosci._ 37,

11390–11405 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Watakabe, A. et al. Enriched expression of serotonin 1B and 2A receptor genes in macaque visual cortex and their

bidirectional modulatory effects on neuronal responses. _Cereb. Cortex_ 19, 1915–1928 (2009). Article  PubMed  Google Scholar  * Dugue, G. P. et al. Optogenetic recruitment of dorsal raphe

serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice. _PLOS ONE_ 9, e105941 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * Davis, M.,

Strachan, D. I. & Kass, E. Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle. _Science_ 209, 521–523 (1980). Article  CAS  PubMed 

Google Scholar  * Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V. & Arnsten, A. F. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory.

_Nat. Neurosci._ 10, 376–384 (2007). Article  CAS  PubMed  Google Scholar  * Williams, G. V. & Goldman-Rakic, P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal

cortex. _Nature_ 376, 572–575 (1995). Article  CAS  PubMed  Google Scholar  * Noudoost, B. & Moore, T. Control of visual cortical signals by prefrontal dopamine. _Nature_ 474, 372–375

(2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lur, G. & Higley, M. J. Glutamate receptor modulation is restricted to synaptic microdomains. _Cell Rep._ 12, 326–334

(2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Athilingam, J. C., Ben-Shalom, R., Keeshen, C. M., Sohal, V. S. & Bender, K. J. Serotonin enhances excitability and gamma

frequency temporal integration in mouse prefrontal fast-spiking interneurons. _eLife_ 6, e31991 (2017). Article  PubMed  PubMed Central  Google Scholar  * Kawaguchi, Y. & Shindou, T.

Noradrenergic excitation and inhibition of GABAergic cell types in rat frontal cortex. _J. Neurosci._ 18, 6963–6976 (1998). Article  CAS  PubMed  PubMed Central  Google Scholar  * Demb, J.

B. Multiple mechanisms for contrast adaptation in the retina. _Neuron_ 36, 781–783 (2002). Article  CAS  PubMed  Google Scholar  * Farley, B. J., Quirk, M. C., Doherty, J. J. &

Christian, E. P. Stimulus-specific adaptation in auditory cortex is an NMDA-independent process distinct from the sensory novelty encoded by the mismatch negativity. _J. Neurosci._ 30,

16475–16484 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fishman, Y. I. & Steinschneider, M. Searching for the mismatch negativity in primary auditory cortex of the

awake monkey: deviance detection or stimulus specific adaptation? _J. Neurosci._ 32, 15747–15758 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kohn, A. & Movshon, J. A.

Neuronal adaptation to visual motion in area MT of the macaque. _Neuron_ 39, 681–691 (2003). Article  CAS  PubMed  Google Scholar  * Szymanski, F. D., Garcia-Lazaro, J. A. & Schnupp, J.

W. Current source density profiles of stimulus-specific adaptation in rat auditory cortex. _J. Neurophysiol._ 102, 1483–1490 (2009). Article  PubMed  Google Scholar  * Ulanovsky, N., Las,

L. & Nelken, I. Processing of low-probability sounds by cortical neurons. _Nat. Neurosci._ 6, 391–398 (2003). Article  CAS  PubMed  Google Scholar  * Dean, I., Robinson, B. L., Harper,

N. S. & McAlpine, D. Rapid neural adaptation to sound level statistics. _J. Neurosci._ 28, 6430–6438 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Barlow, H. in

_Sensory Communication_ (MIT Press, 1961). * Niyogi, R. K. & Wong-Lin, K. Dynamic excitatory and inhibitory gain modulation can produce flexible, robust and optimal decision-making.

_PLOS Comput. Biol._ 9, e1003099 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Busse, L., Wade, A. R. & Carandini, M. Representation of concurrent stimuli by population

activity in visual cortex. _Neuron_ 64, 931–942 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hahnloser, R. H., Douglas, R. J. & Hepp, K. Attentional recruitment of

inter-areal recurrent networks for selective gain control. _Neural Comput._ 14, 1669–1689 (2002). Article  PubMed  Google Scholar  * Thiele, A. & Bellgrove, M. A. Neuromodulation of

attention. _Neuron_ 97, 769–785 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schwartz, O. & Simoncelli, E. P. Natural signal statistics and sensory gain control. _Nat.

Neurosci._ 4, 819–825 (2001). Article  CAS  PubMed  Google Scholar  * Willmore, B. D., Bulstrode, H. & Tolhurst, D. J. Contrast normalization contributes to a biologically-plausible

model of receptive-field development in primary visual cortex (V1). _Vis. Res._ 54, 49–60 (2012). Article  PubMed  Google Scholar  * Ni, A. M., Ruff, D. A., Alberts, J. J., Symmonds, J.

& Cohen, M. R. Learning and attention reveal a general relationship between population activity and behavior. _Science_ 359, 463–465 (2018). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Lee, S., Park, J. & Smirnakis, S. M. Internal gain modulations, but not changes in stimulus contrast, preserve the neural code. _J. Neurosci._ 39, 1671–1687 (2019). CAS 

PubMed  PubMed Central  Google Scholar  * McGinley, M. J. et al. Waking state: rapid variations modulate neural and behavioral responses. _Neuron_ 87, 1143–1161 (2015). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Rose, D. & Blakemore, C. Effects of bicuculline on functions of inhibition in visual cortex. _Nature_ 249, 375–377 (1974). Article  CAS  PubMed 

Google Scholar  * Carandini, M. & Ferster, D. Membrane potential and firing rate in cat primary visual cortex. _J. Neurosci._ 20, 470–484 (2000). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Isaacson, J. S. & Scanziani, M. How inhibition shapes cortical activity. _Neuron_ 72, 231–243 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang, Y.

P. & Oertner, T. G. Optical induction of synaptic plasticity using a light-sensitive channel. _Nat. Methods_ 4, 139–141 (2007). Article  CAS  PubMed  Google Scholar  * Allen, B. D.,

Singer, A. C. & Boyden, E. S. Principles of designing interpretable optogenetic behavior experiments. _Learn. Mem._ 22, 232–238 (2015). Article  PubMed  PubMed Central  Google Scholar  *

Cottam, J. C., Smith, S. L. & Hausser, M. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing. _J. Neurosci._ 33, 19567–19578 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Pfeffer, C. K., Xue, M., He, M., Huang, Z. J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections

between molecularly distinct interneurons. _Nat. Neurosci._ 16, 1068–1076 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was

supported by US National Institutes of Health (NIH) R01 MH102365, NIH R01 EY022951, NIH R01 MH113852, a Simons Foundation Autism Research Initiative (SFARI) Research Grant, a Smith Family

Award for Excellence in Biomedical Research, a Klingenstein Fellowship Award, an Alfred P. Sloan Fellowship, a US National Alliance for Research on Schizophrenia & Depression (NARSAD)

Young Investigator Award, a McKnight Fellowship and a grant from the Ludwig Family Foundation to J.A.C.; and a Brown-Coxe fellowship and a NARSAD Young Investigator Award to K.A.F. The

authors thank M. J. Higley and members of the Cardin and Higley laboratories for insightful discussions, and Q. Perrenoud for help with illustration. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Neuroscience, Yale University, New Haven, CT, USA Katie A. Ferguson & Jessica A. Cardin * Kavli Institute for Neuroscience, Yale University, New Haven, CT,

USA Jessica A. Cardin Authors * Katie A. Ferguson View author publications You can also search for this author inPubMed Google Scholar * Jessica A. Cardin View author publications You can

also search for this author inPubMed Google Scholar CONTRIBUTIONS Both authors researched data for article, made substantial contributions to discussions of the content, wrote the manuscript

and reviewed or edited the manuscript before submission. CORRESPONDING AUTHOR Correspondence to Jessica A. Cardin. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

interests. ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Reviews Neuroscience_ thanks C. Angeloni, M. Geffen, J. Reynolds and the other, anonymous, reviewer(s) for their

contribution to the peer review of this work. PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. GLOSSARY

* Gain modulation A phenomenon whereby the gain or sensitivity of a neuron to inputs, such as visual stimuli, is altered without changing selectivity. * Input–output (I/O) relationship The

relationship between the inputs a neuron receives (such as synaptic inputs, direct currents or sensory stimulation) and the firing rate responses of that neuron. * Synaptic summation The

summation of synaptic inputs to a neuron either spatially (when nearby synapses are coactive on a dendritic branch) or temporally (when synaptic inputs occur within a short time window

mediated by the membrane time constant, τ). * Iceberg effect An effect whereby, if subthreshold responses to a stimulus are less selective than the neuron’s firing, a linear increase or

decrease in activity may alter the neuron’s selectivity by raising or lowering the tuning curve of the neuron across the threshold. * Monocular deprivation An experimental paradigm in which

an animal is deprived of vision from one eye during a critical developmental period. The mature binocular visual cortex then responds predominantly to inputs from the non-deprived eye. *

Stochastic resonance A phenomenon in which the addition of noise non-linearly enhances the information content of a signal, by boosting resonant frequencies over a sensor’s detection

threshold (such as a cell’s spike threshold). * Shunting inhibition A GABAergic synaptic input that minimally affects the membrane potential of a cell that is near the inhibitory synaptic

reversal potential, but that leads to a reduction of nearby excitatory postsynaptic potential amplitudes. * Pairwise correlations A normalized measure of covariation between pairs of neurons

that can give insight into their tuning similarity (signal correlations) or shared trial-to-trial variability (noise correlations). * Dendritic saturation A phenomenon in which an already

depolarized dendritic branch shows reduced excitatory responses to temporally correlated excitatory inputs due to reduced driving force. * Synaptic efficacy The influence that a presynaptic

input has on a postsynaptic cell’s probability of firing an action potential. * Adaptation A decrease in sensitivity to constant or repeated stimuli, leading to reduced stimulus-evoked

neural responses over time. * Forward suppression A rapid form of sensory adaptation whereby the response to a stimulus is reduced when preceded by a stimulus with similar features. *

Feedback inhibition A type of inhibition delivered through recurrent connections: that is, local inhibitory cells target the same population of excitatory cells that drive local inhibitory

activity. * Brain states Spatiotemporal patterns of neural-network activity across the brain that are dynamically regulated by behaviour, the environment and the internal state. * Pupil

diameter The diameter of the pupil of the eye. The diameter is tightly coupled to various emotional and cognitive factors, including global arousal and attention, even when controlling for

changes in luminance and depth accommodation. * Attractor dynamics Temporal patterns that evolve towards a stable state from a large range of starting conditions. Attractor network

characterization facilitates the identification of key network properties. * Winner-take-all mechanism A computational principle in which non-linearities in a recurrent neural network create

strong competition between neurons. Only neurons (or sets thereof) with the strongest responses remain active, providing a mechanism for input selection or segregation. * Dimensionality

reduction Reduction of the number of random variables of a system to a smaller set of principal variables to aid analysis. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Ferguson, K.A., Cardin, J.A. Mechanisms underlying gain modulation in the cortex. _Nat Rev Neurosci_ 21, 80–92 (2020). https://doi.org/10.1038/s41583-019-0253-y Download

citation * Accepted: 25 November 2019 * Published: 07 January 2020 * Issue Date: February 2020 * DOI: https://doi.org/10.1038/s41583-019-0253-y SHARE THIS ARTICLE Anyone you share the

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