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Neuron. 2017 Apr 19;94(2):363-374.e4. doi: 10.1016/j.neuron.2017.03.037.

Chemogenetic Interrogation of a Brain-wide Fear Memory Network in Mice.

Author information

1
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
2
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
4
Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Departments of Biochemistry, Computer Science, and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5S 3GM, Canada.
6
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5S 3GM, Canada. Electronic address: paul.frankland@sickkids.ca.

Abstract

Behavior depends on coordinated activity across multiple brain regions. Within such networks, highly connected hub regions are assumed to disproportionately influence behavioral output, although this hypothesis has not been systematically evaluated. Previously, by mapping brain-wide expression of the activity-regulated gene c-fos, we identified a network of brain regions co-activated by fear memory. To test the hypothesis that hub regions are more important for network function, here, we simulated node deletion in silico in this behaviorally defined functional network. Removal of high degree nodes produced the greatest network disruption (e.g., reduction in global efficiency). To test these predictions in vivo, we examined the impact of post-training chemogenetic silencing of different network nodes on fear memory consolidation. In a series of independent experiments encompassing 25% of network nodes (i.e., 21/84 brain regions), we found that node degree accurately predicted observed deficits in memory consolidation, with silencing of highly connected hubs producing the largest impairments.

KEYWORDS:

CA1; DREADDS; contextual fear conditioning; functional connectivity; graph theory; hippocampus; lateral septal nucleus; laterodorsal thalamic nucleus; neocortex; reuniens thalamic nucleus

PMID:
28426969
DOI:
10.1016/j.neuron.2017.03.037
[Indexed for MEDLINE]
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