File : Ji & Suga 2012 - 10 - 31 - R 4 1 2 3 Histaminergic Modulation of Nonspecific Plasticity of 4 the Auditory System and Differential Gating 5 6 Running title : Histaminergic modulation of cortical plasticity

28 In the auditory system of the big brown bat (Eptesicusfuscus), paired conditioned 29 tonal (CS) and unconditioned leg (US) stimuli for auditory fear conditioning elicit tone-30 specific plasticity represented by best frequency (BF) shifts which are augmented by 31 acetylcholine, whereas unpaired CS and US for pseudo-conditioning elicit a small BF 32 shift and prominent nonspecific plasticity at the same time. The latter represents the 33 nonspecific augmentations of auditory responses accompanied by the broadening of 34 frequency tuning and decrease in threshold. It is unknown which neuromodulators are 35 important in evoking the nonspecific plasticity. We found that HA and a HA3R agonist 36 (α-methyl-HA) decreased, but an HA3R antagonist (thioperamide) increased cortical 37 auditory responses; that the HA3R agonist applied to the primary auditory cortex prior to 38 pseudo-conditioning abolished the nonspecific augmentation in the cortex without 39 affecting the small cortical BF shift; and that antagonists of acetylcholine, noradrenaline, 40 dopamine and serotonin receptors did not abolish the nonspecific augmentation elicited 41 by pseudo-conditioning. The histaminergic system plays an important role in eliciting the 42 arousal and defensive behavior, possibly through nonspecific augmentation. Thus, HA 43 modulates the nonspecific augmentation, whereas acetylcholine amplifies the BF shifts. 44 These two neuromodulators may mediate differential gating of cortical plasticity.