title: Frontal association cortex is engaged in stimulus integration during associative learning.
abstract: The frontal association cortex (FrA) is implicated in higher brain function. Aberrant FrA activity is likely to be involved in dementia pathology. However, the functional circuits both within the FrA and with other regions are unclear. A recent study showed that inactivation of the FrA impairs memory consolidation of an auditory fear conditioning in young mice. In addition, dendritic spine remodeling of FrA neurons is sensitive to paired sensory stimuli that produce associative memory. These findings suggest that the FrA is engaged in neural processes critical to associative learning. Here we characterize stimulus integration in the mouse FrA during associative learning. We experimentally separated contextual fear conditioning into context exposure and shock, and found that memory formation requires protein synthesis associated with both context exposure and shock in the FrA. Both context exposure and shock trigger Arc, an activity-dependent immediate-early gene, expression in the FrA, and a subset of FrA neurons was dually activated by both stimuli. In addition, we found that the FrA receives projections from the perirhinal (PRh) and insular (IC) cortices and basolateral amygdala (BLA), which are implicated in context and shock encoding. PRh and IC neurons projecting to the FrA were activated by context exposure and shock, respectively. Arc expression in the FrA associated with context exposure and shock depended on PRh activity and both IC and BLA activities, respectively. These findings indicate that the FrA is engaged in stimulus integration and contributes to memory formation in associative learning.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakayama
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Zohal
authors.initials: Z
authors.lastname: Baraki
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Onoue
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; Center for Information and Neural Networks, Suita City, Osaka 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuki
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: nomura@mol.f.u-tokyo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nomura
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D005625:Frontal Lobe / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D014176:Protein Biosynthesis