Endocrinology. 2019 Jan 22.
The hypothalamo-pituitary-adrenal (HPA) axis involves timed signaling between the hypothalamus, pituitary, adrenal glands and back to the brain, causing an inherently oscillating system. Corticosteroids like corticosterone (CORT) are secreted in a circadian rhythm, characterized by low and high levels respectively at the start of the inactive and active phase. The circadian rhythm overarches ultradian CORT pulses, with an approximate 1-hour interpulse intervals. We examined the physiological relevance of pulsatile CORT exposure for neurons of the basolateral amygdala (BLA), an area important for fear learning. We first applied four pulses of equal, high CORT concentration and measured the frequency of miniature excitatory postsynaptic currents (mEPSC) -reflecting spontaneous glutamate signaling. The results, extending earlier studies, show that BLA neurons respond differently to each pulse, showing 'meta-plasticity'. Next we mimicked the progression of the inactive and active phase by four CORT pulses of increasing or decreasing concentration respectively. CORT pulses of increasing concentration were necessary and sufficient to gradually increase baseline (between-pulse) mEPSC frequency during the mimicked inactive phase while the opposite was seen with decreasing CORT levels during the mimicked active phase. To study the relevance of changed glutamate transmission for behavior, mice were tested in tone-cued fear conditioning during the active or inactive phase. Animals tested at the inactive compared to active phase showed efficient fear learning; this was also observed when animals tested during the active phase were treated with the CORT synthesis blocker metyrapone. This suggests that natural CORT rhythms influence electrical activity in the BLA, possibly contributing to altered behavioral function.