Blocking c-Fos Expression Reveals the Role of Auditory Cortex Plasticity in Sound Frequency Discrimination Learning

Abstract

The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.

Familiarity with social sounds alters c-Fos expression in auditory cortex and interacts with estradiol in locus coeruleus

“…Since our pup experienced animals had five-days of experience with vocalizing pups by the time we exposed them to call playback, these subjects may have already experienced substantial cortical plasticity to optimize pup-call recognition. Since c-Fos expression not only reflects neural activation but also active cellular mechanisms for learning (de Hoz et al, 2017; Mayer et al, 2010), c-Fos-IR would then be low in response to the already familiar auditory cues. Diminished production of a plasticity associated protein in response to a familiar stimuli, that previously gained meaning through social experience, might be reflected in a reduced subset of neurons constituting the most behaviorally useful circuit (Kilgard, 2012) and preserving established sensorineural representation of those sounds.…”

“…Here we asked whether E2 availability, manipulated systemically with subcutaneous implants, modulates how the noradrenergic LC responds when virgin ovariectomized females hear pup ultrasonic isolation vocalizations, either for the first time as adults (novel) or after social experience raising pups so that the call category is familiar. We measured the expression of the plasticity-associated immediate early gene (IEG) c-fos (Dragunow and Faull, 1989; Sagar et al, 1988; Montag-Sallaz et al, 1999) in the LC as well as the AC (de Hoz et al, 2017).…”

Tafa-2 plays an essential role in neuronal survival and neurobiological function in mice

“…Mice lacking c-Fos in the CNS have impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity [ 41 ]. And a recent report demonstrated a role of c-Fos in experience-dependent plasticity and learning [ 42 ]. NF1 is found within the mammalian postsynapse, where it is known to bind to NMDA receptor complex [ 43 ].…”

c-Fos-MMP-9 pathway in central amygdala mediates approach motivation but not reward consumption

“…Mice with local blockade of c-fos expression in the CeA with lentivector carrying shRNA (14) and control animals (Fig 1a,b) were subjected to discrimination training in Intel-liCages (11). This protocol allows for balancing appetitive and aversive conditions and measurement of different components of reward-driven as well as aversively motivated behaviors.…”

“…c-Fos, as a component of AP-1 transcription factor regulates gene expression of MMP-9, an enzyme involved in synaptic remodeling (12), necessary for, among others, reward-related learning (13). In the current study, we used RNAi-based approach to locally block c-Fos expression via lentiviral vector (14) and nanoparticles releasing a specific inhibitor to block MMP-9 activity in CeA (11) in order to elucidate the role of c-Fos-MMP-9 pathway in CeA in different subcomponents of reward-driven and aversively motivated behaviors. To confirm MMP-9 specificity of the manipulation we used a lentiviral vector inducing local, CeAspecific, overexpression of MMP-9.…”