Goal-specific hippocampal inhibition gates learning

Nuri Jeong, Xiao Zheng, Abigail L. Paulson, Stephanie M. Prince, Victor P. Nguyen, Sherina R. Thomas, Caroline E. Gilpin, Matthew C. Goodson and Annabelle C. Singer ()
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Nuri Jeong: Emory University and Georgia Institute of Technology
Xiao Zheng: Emory University and Georgia Institute of Technology
Abigail L. Paulson: Emory University and Georgia Institute of Technology
Stephanie M. Prince: Emory University and Georgia Institute of Technology
Victor P. Nguyen: Emory University and Georgia Institute of Technology
Sherina R. Thomas: Emory University and Georgia Institute of Technology
Caroline E. Gilpin: Emory University and Georgia Institute of Technology
Matthew C. Goodson: Emory University and Georgia Institute of Technology
Annabelle C. Singer: Emory University and Georgia Institute of Technology

Nature, 2025, vol. 642, issue 8069, 1007-1015

Abstract: Abstract Goal-directed navigation in a new environment requires quickly identifying and exploiting important locations. Identifying new goal locations depends on neural computations that rapidly represent locations and connect location information to key outcomes such as food1. However, the mechanisms to trigger these computations at behaviourally relevant locations are not well understood. Here we show that parvalbumin (PV)-positive interneurons in the mouse hippocampal CA3 have a causal role in identifying and exploiting new food locations such that decreases in inhibitory activity around goals enable reactivation to bind goal locations to food outcomes. PV interneurons in the CA3 substantially reduce firing on approach to and at goal locations while food-deprived mice learn to find food. These inhibitory decreases anticipate reward locations as the mice learn and are more prominent on correct trials. Sparse optogenetic stimulation to prevent goal-related decreases in PV interneuron firing impaired learning of goal locations. Disrupting goal-related decreases in PV interneuron activity impaired the reactivation of new goal locations after receipt of food, a process that associates previous locations to food outcomes such that the mice know where to seek food later. These results reveal that goal-selective and goal-predictive decreases in inhibitory activity enable learning, representations and outcome associations of crucial locations.

Date: 2025
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DOI: 10.1038/s41586-025-08868-5

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