Amygdala, Medial Prefrontal Cortex and Glucocorticoid Interactions Produce Stress-Like Effects on Memory

Abstract

Adverse stress effects on the hippocampal memory system are generally thought to be due to the high level of circulating glucocorticoids directly modifying the properties of hippocampal neurons and, accordingly, the results should be reproducible with exogenous administration of cortisol in humans and corticosterone in rodents. However, glucocorticoid levels increased to other events, such as exercise and environment enrichment, do not impair but instead enhance hippocampal memory, indicating that cortisol/corticosterone are not invariant causal factors of stress. To better model the complex psychophysiological attributes of stress (i.e., aversiveness, lack of controllability, and glucose metabolism), we examined the functions of the amygdala, medial prefrontal cortex (mPFC), and corticosterone on a hippocampal-based one-trial novel object recognition (OR) memory task in rats. Specifically, animals were subjected to amygdala stimulation, mPFC inactivation, and corticosterone treatments separately or in combination during behavioral testing. Collective amygdala, mPFC, and corticosterone manipulations significantly impaired OR memory comparable to behavioral stress. By contrast, single and dual treatments failed to reliably decrease memory functioning. These results suggest that negative mnemonic impacts of uncontrollable stress involve the amalgamation of heightened amygdala and diminished mPFC activities, and elevated circulating corticosterone level.

Keywords: amygdala; cognition; corticosterone; hippocampus; learning; object recognition memory; prefrontal cortex; stress.

Figure 1

Electrodes and cannulae placements and track plots. (A) Photomicrograph and histological reconstruction of cannulae medial prefrontal cortex (mPFC, each dot represents the tips of the guide cannulae) and stimulating electrodes amygdala (BLA) implantations. (B) Representative visit maps from CTRL (left) and COMB treatments (right) during the sample (S) vs. novel (N) object test session. See text for object exploration criteria.

Figure 2

Effects of mPFC inactivation, CORT administration, and amygdalar stimulation on object recognition (OR) memory. (A) Behavior and treatment procedures. (B) Mean time in seconds (± SEM) that animals subjected to CTRL, AMYG, CORT, mPFC, and COMB treatments spent exploring two identical objects during the familiarization phase. (C) Mean time in seconds that different treatment animals spent exploring novel vs. familiar objects and the mean value of discrimination index during the first 2 min of the test phase. *p < 0.05 and **p < 0.01, respectively.

Figure 3

Effects of dyad treatments on OR memory. (A) Behavior and treatment procedures. (B) Mean time in seconds (± SEM) that CTRL, AMYG + CORT, CORT + mPFC, AMYG + mPFC, and COMB treatment animals spent exploring two identical objects during the familiarization phase. (C) Mean time in seconds that different treatment animals spent exploring novel vs. familiar objects and the mean value of discrimination index during the first 2 min of the test phase. *p < 0.05 (t-test), **p < 0.01 (t-test), and ^†p < 0.05 (Wilcoxon signed ranks test), respectively.

Figure 4

Behavioral stress effects on OR memory. (A) Behavioral procedure. (B) Mean time in seconds (± SEM) that CTRL and STRESS treatment animals spent exploring two identical objects during the familiarization phase. (C) Mean time in seconds that CTRL and STRESS treatment animals spent exploring novel vs. familiar objects and the mean value of discrimination index during the first 2 min of the test phase. **p < 0.01 and ***p < 0.001. (D) A systems-level model of stress comprising of CORT, AMYG and mPFC interaction. The model posits that the CORT, AMYG and mPFC mediate the functions of excitability f(E), aversiveness f(A), and controllability f(C), respectively, and that CORT and AMYG exert excitatory stress influences while mPFC exerts inhibitory stress influence on the hippocampus (HPC). Adapted from references Kim and Diamond (2002); Kim and Haller (2007) and Kim et al. (2015).