Daily exposure of awake mice to a phase-reversing visual grating stimulus leads to enhancement of the visual-evoked potential (VEP) in layer 4 of the primary visual cortex (V1). This stimulus-selective response potentiation (SRP) resembles and shares mechanistic requirements with canonical long-term synaptic potentiation (LTP). However, it remains to be determined how this augmentation of a population response translates into altered neuronal activity of individual V1 neurons. To address this question, we performed longitudinal calcium imaging of layer 4 excitatory neurons in V1 and tracked changes associated with the induction and expression of SRP. We found no evidence for a net change in the fraction of visually responsive neurons as the stimulus became familiar. However, endoscopic calcium imaging of layer 4 principal neurons revealed that somatic calcium transients in response to phase-reversals of the familiar visual stimulus are reduced and undergo strong within-session adaptation. Conversely, neuropil calcium responses and VEPs are enhanced during familiar stimulus viewing, and the VEPs show reduced within-session adaptation. Consistent with the exquisite selectivity of SRP, the plasticity of cellular responses to phase-reversing gratings did not translate into altered orientation selectivity to drifting gratings. Our findings suggest a model in which augmentation of fast, short-latency synaptic (dendritic) responses, manifested as enhanced layer 4 VEPs, recruits inhibition to suppress cellular activity. Reduced cellular activity to the familiar stimulus may account for the behavioral correlate of SRP, orientation-selective long-term habituation.

Stimulus-selective response plasticity (SRP) is a robust and lasting modification of primary visual cortex (V1) that occurs in response to exposure to novel visual stimuli. It is readily observed as a pronounced increase in the magnitude of visual evoked potentials (VEPs) recorded in response to phase-reversing grating stimuli in neocortical layer 4. The expression of SRP at the individual neuron level is equally robust, but the qualities vary depending on the neuronal type and how activity is measured. This form of plasticity is highly selective for stimulus features such as stimulus orientation, spatial frequency, and contrast. Several key insights into the significance and underlying mechanisms of SRP have recently been made. First, it occurs concomitantly and shares core mechanisms with behavioral habituation, indicating that SRP reflects the formation of long-term familiarity that can support recognition of innocuous stimuli. Second, SRP does not manifest within a recording session but only emerges after an off-line period of several hours that includes sleep. Third, SRP requires not only canonical molecular mechanisms of Hebbian synaptic plasticity within V1, but also the opposing engagement of two key subclasses of cortical inhibitory neuron: the parvalbumin- and somatostatin-expressing GABAergic interneurons. Fourth, pronounced shifts in the power of cortical oscillations from high frequency (gamma) to low frequency (alpha/beta) oscillations provide respective readouts of the engagement of these inhibitory neuronal subtypes following familiarization. In this article we will discuss the implications of these findings and the outstanding questions that remain to gain a deeper understanding of this striking form of experience-dependent plasticity.

Recognizing familiar but innocuous stimuli and suppressing behavioral response to those stimuli are critical steps in dedicating cognitive resources to significant elements of the environment. Recent work in the visual system has uncovered key neocortical mechanisms of this familiarity that emerges over days. Specifically, exposure to phase-reversing gratings of a specific orientation causes long-lasting stimulus-selective response potentiation (SRP) in layer 4 of mouse primary visual cortex (V1) as the animal’s behavioral responses are reduced through habituation. This plasticity and concomitant learning require the NMDA receptor and the activity of parvalbumin-expressing (PV+) inhibitory neurons. Changes over the course of seconds and minutes have been less well studied in this paradigm, so we have here characterized cortical plasticity occurring over seconds and minutes, as well as days, to identify separable forms of plasticity accompanying familiarity. In addition, we show evidence of interactions between plasticity over these different timescales and reveal key mechanistic differences. Layer 4 visual-evoked potentials (VEPs) are potentiated over days, and they are depressed over minutes, even though both forms of plasticity coincide with significant reductions in behavioral response. Adaptation, classically described as a progressive reduction in synaptic or neural activity, also occurs over the course of seconds, but appears mechanistically separable over a second as compared to tens of seconds. Interestingly, these short-term forms of adaptation are modulated by long-term familiarity, such that they occur for novel but not highly familiar stimuli. Genetic knock-down of NMDA receptors within V1 prevents all forms of plasticity while, importantly, the modulation of short-term adaptation by long-term familiarity is gated by PV+ interneurons. Our findings demonstrate that different timescales of adaptation/habituation have divergent but overlapping mechanisms, providing new insight into how the brain is modified by experience to encode familiarity.