Linked networks for learning and expressing location-specific threat

Abstract

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.

Keywords: fMRI; hippocampus; learning; location-specific threat conditioning; navigation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Task illustration and behavioral data across threat learning. (A) Overhead illustration of the circular environment that participants explored and how it was split into one-half associated with danger (red) and the other with safety. The environment included two beehives (black dots) located at opposite sides of the environment. Participants were required to collect flowers, which were generated within the environment. (B) Example of the participant’s viewpoint, showing a beehive and flower within the environment. (C) Mean tonic skin conductance level (SCL) as flowers were approached. (D) Mean phasic skin conductance responses (SCRs) during the stationary periods when flowers were picked. (E) Shock expectancy ratings at the onset of stationary periods when picking a flower. Error bars show SEM. *P < 0.01.

Fig. 2.

Activity differences between approaching flowers and objects during threat and spatial memory, respectively. (A, Upper red) Greater activity when approaching flowers compared with objects in a range of areas, including the insula, medial parietal cortex, PCC (P < 0.05, FWE), vmPFC, bilateral anterior hippocampus, and amygdala (P < 0.05, FWE SVC). (A, Lower blue) When approaching objects compared with flowers, greater activity was seen in posterior medial temporal, parietal, and prefrontal neocortical areas (P < 0.05, FWE). (B) Activity change was greater from the first to the second half of the flower task compared with activity change during the object location task in anterior hippocampus and amygdala (P < 0.05, FWE SVC; Left) and vmPFC, medial parietal cortices/precuneus, and PCC (P < 0.05, FWE; Right). All images are presented at P < 0.001, uncorrected, for display purposes. Percentage signal changes for learning about threat and object locations across early and late periods of the task extracted from anterior hippocampus (MNI coordinates: 27, −18, −15; B, Left) and vmPFC (3, 54, −9; B, Right). Error bars show SEM.

Fig. 3.

Activity differences when approaching flowers across danger and safety. (A) For flowers approached in the danger compared with the safe zone, there was greater activity in dACC across the whole test session. (B) Irrespective of the location of flowers, activity increased from the first to second half of the experiment in the anterior hippocampus (Left) and vmPFC and medial parietal areas (including precuneus, retrosplenial cortex, and PCC; Right). All images are presented at P < 0.001, uncorrected, for display purposes. Percentage signal changes for danger and safety across early and late periods of learning extracted from anterior hippocampus (MNI coordinates: 27, −18, −15; B, Left) and vmPFC (3, 54, −9; B, Right). Error bars show SEM.

Fig. 4.

Activity differences during stationary periods after picking flowers predicting danger and safety. (A) Contrasting periods when participants were stationary when flowers were picked in the dangerous vs. safe zone of the environment showed greater activity in PAG, dACC (Upper), and bilateral insula (P < 0.05, FWE; Middle). Analysis of the reverse contrast for flowers picked in the safe zone (safe > danger) showed greater activity in the vmPFC (P < 0.001, uncorrected; Lower). (B) Irrespective of the location of flowers, during the last half of learning (late > early), we saw greater activity in bilateral posterior hippocampus (P < 0.05, FWE SVC). Images are presented at P < 0.001, uncorrected, for display purposes. (B, Right) Percentage signal change during stationary periods for danger and safety across early and late parts of learning extracted posterior hippocampus (MNI coordinates: 33, −33, −3). Error bars show SEM.

Fig. 5.

Illustration of sequential network activity in the flower task. (A) During approach periods, activity in the anterior hippocampus (aHPC), amygdala (AMYG), and ventromedial prefrontal cortex (vmPFC) increased in the late compared with the early phase of learning, including greater functional connectivity between aHPC and vmPFC, irrespective of threat. (B) Approach to flowers predicting danger was associated with increased activity in the dorsal anterior cingulate cortex (dACC), and insula, with increased connectivity, also observed between dACC and aHPC. (C) When danger was imminent, during the stationary period, increased activity was evident in dACC, insula (as well as connectivity between them), and periaqueductal gray (PAG). The posterior hippocampus (pHPC) also showed greater activity during the last half of the experiment when picking the flower compared with the first half. (Left) Illustration of task phase. (Middle) Schematic of activity over time (first and second halves of experiment; approach periods in blue, stationary periods in pink). (Right) Brain activity and functional connectivity. Green lines and boxes represent activity (and green arrows functional connectivity) that increases from the first to second half of the experiment. Red lines and boxes represent activity (and red arrows functional connectivity) that increases with danger. See Tables S1–S3 for a complete breakdown of regions across these analyses.