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Integrative function of higher-order behaviors through interaction of brain neural circuitry

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room B(501)
Chairperson(s) 喜田 聡 / Satoshi Kida (東京農業大学 応用生物科学部バイオサイエンス学科 / Department of Bioscience, Tokyo University of Agriculture, Japan)
小林 和人 / Kazuto Kobayashi (福島県立医科大学 医学部 生体機能研究部門 / Department of Molecular Genetics, Fukushima Medical University, Japan)

Targeted pharmacogenetic interrogation of a fear memory network

  • S1-B-3-4
  • Paul Frankland:1 
  • 1:Hospital for Sick Children, Canada 

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions, but within this distributed network some regions may play more important roles than others during consolidation. Previously, we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice (Wheeler et al [2013] PLoS Comp Biol). Expression analysis of the activity-regulated gene, c-fos, across 84 brain regions allowed us to identify regions that were co-active following memory recall, and presumably form a network that is engaged by long-term memory recall. Graph theoretical analysis of this network indicated that the memory network had small-world properties, and included several highly-connected hub-like regions that may play privileged roles in memory expression. Using pharmacogenetic neuronal silencing strategies, here we test the hypothesis that these hub regions play disproportionately important roles in the consolidation of long-term contextual fear memories. To do this we virally expressed the inhibitory designer receptor exclusively activated by designer drugs (DREADD) HM4Di in different hub and non-hub regions in the memory network. DREADDs are insensitive to endogenous ligands but activated by a synthetic ligand clozapine-N-oxide (CNO). When bound to CNO, this Gi-coupled DREADD induces membrane hyperpolarization and inhibition of spiking activity. Following contextual fear conditioning training, CNO or vehicle was administered via drinking water for 14 days and then contextual fear memory was tested. We found that inhibition of several cortical and subcortical hub regions (e.g., prelimbic cortex, primary and secondary somatosensory cortex, reuniens thalamic nucleus, posterior thalamic nuclear group, laterodorsal thalamic nucleus, lateral septal nucleus, CA1 field of the hippocampus) disrupted consolidation of the contextual fear memory. In contrast, our preliminary data indicate that similar inhibition of non-hub regions in the memory network (e.g., medial geniculate nucleus) had no effect. These data support the idea that highly-connected hub regions play a disproportionately important role in the consolidation of contextual fear memories.

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