Cholinergic Modulation is Necessary for Upward Firing Rate Homeostasis in Rodent Visual Cortex
Bidirectional homeostatic plasticity allows neurons and circuits to maintain stable firing in the face of developmental or learning-induced perturbations. In primary visual cortex (V1), upward firing rate homeostasis (FRH) only occurs during active wake (AW) and downward during sleep, but how this behavioral state-dependent gating is accomplished is unknown. Here we focus on how AW enables upward FRH in V1 of juvenile Long Evans rats. A major difference between quiet wake (QW) when upward FRH is absent, and AW when it is present, is increased cholinergic (ACh) tone; we therefore chemogenetically inhibited V1-projecting basal forebrain cholinergic (BF ACh) neurons while inducing upward FRH using visual deprivation, and found that upward FRH was completely abolished. Next, we examined the impact on synaptic scaling and intrinsic excitability, two important cellular targets of homeostatic regulation. BF ACh inhibition impaired synaptic scaling up, and dramatically decreased the intrinsic excitability of activity-deprived V1 pyramidal neurons, consistent with the block of upward FRH. Interestingly, knock down of the highly abundant M1 ACh receptor in V1 failed to phenocopy the effects of decreased BF ACh activity on intrinsic excitability, suggesting either that BF ACh activity acts through a different receptor within V1, or acts indirectly via other brain regions or cell types. Together, our results show that BF ACh modulation is a key enabler of upward homeostatic plasticity, and more broadly suggest that neuromodulatory tone is a critical factor that segregates upward and downward homeostatic plasticity into distinct behavioral states. SIGNIFICANCE STATEMENTHebbian, positive feedback-based and homeostatic, negative feedback-based plasticity mechanisms are necessary to maintain the functionality of flexible yet stable complex neuronal circuits. Growing evidence suggests a role for behavioral state in temporally segregating these opposing plasticity mechanisms, but how behavioral states enact this gating remains unknown. Here, we tested the role of acetylcholine (ACh), a widespread neuromodulator largely released during active wake, in the regulation of upward homeostatic plasticity. We found that ACh modulation is indeed necessary for the expression of active wake-gated upward firing rate homeostasis, likely due to its role in maintaining intrinsic excitability of cortical pyramidal neurons. Our results suggest potential mechanisms by which neuromodulatory tone may enable behavioral state gating of homeostatic plasticity.