Mechanisms underlying gain modulation in the cortex

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 link phenomenological observations of gain modulation to underlying cellular and circuit-level mechanisms. Finally, we place these cellular and circuit interactions in the larger context of their impact on perception and cognition.

Fig. 1 |. Cellular and network-level mechanisms of gain modulation.

GABAergic inhibition is a key mediator of gain modulation at both the cellular and network levels. a | Changes in external and internal influences converge to modulate neural gain at the single-cell level via a common set of mechanisms. The mechanisms include changes in the relative positions and amplitudes of active excitatory and inhibitory synaptic inputs to the dendrites, shunting inhibition at the soma and the overall conductance and depolarization state of the neuron^,,–,,,. Gain is also affected by the statistics of synaptic input, including short-term synaptic dynamics and the relative timing of inhibitory and excitatory inputs that give rise to synaptically driven fluctuations in the membrane potential (V_m)^,,,. b | Cellular mechanisms converge to produce multiplicative gain modulation. As highlighted by computational models^, and experimental data^–, divisive gain modulation of pyramidal neuron (PYR) responses can arise from a combination of increased shunting conductance and increased synaptically driven V_m fluctuations, both of which are driven by GABAergic inhibition. c | GABAergic inhibition can regulate gain at the network level flexibly over time, as different sources of synaptic inhibition are recruited into circuit activity^,. Over time, or over repeated sensory stimulation, some GABAergic populations maintain or increase their responses (darker shading signifies more activity), whereas others show adaptation (that is, reduce their responses to repeated stimulation), altering the relative amount of inhibition from each population onto postsynaptic PYRs. d | Schematic of hypothetical Ca⁺ fluorescence traces from somatostatin-positive (SST⁺) interneurons (blue) and parvalbumin-positive (PV⁺) interneurons (orange) in the primary visual cortex in response to repeated visual stimulation. e | Gain modulation of different neural populations may change independently over time. Schematic shows one possible trajectory of the relative visual response gain of a PV⁺ interneuron–SST⁺ interneuron pair (upper panel) or a vasoactive intestinal peptide-expressing (VIP⁺) interneuron–PYR pair (lower panel) over time.

Fig. 2 |. Multiple modes of state-dependent cortical gain modulation.

Different behavioural states during wakefulness are associated with discrete modes of gain modulation. Arousal and locomotion increase the gain of visually evoked responses in the rodent primary visual cortex through different mechanisms. a | During quiescence, arousal is low, as denoted by a constricted pupil, and cortical neurons typically show moderate spontaneous firing and moderate firing in response to a visual stimulus. b | During periods of locomotion, arousal increases, as denoted by pupil dilation. In association with locomotion cortical neurons depolarize and exhibit enhanced spontaneous and visually evoked firing^,,,. c | By contrast, during periods of high arousal without motor activity, spontaneous firing decreases whereas sensory-evoked responses increase.