Effects of glucocorticoid on the amygdala-dependent fear memory and hippocampal neurogenesis

Abstract

Glucocorticoid (GC) is a steroid hormone playing diverse roles which enable organisms to respond to and to cope with environmental changes such as stress. The secretion of GC is primarily governed by the hypothalamus-pituitary-adrenal (HPA) axis, a major neuroendocrine circuit in the stress response system. Maternal stress-elicited elevation of GC has programming effects on the long-lasting modification of the HPA axis and brain functions in offspring. However, the prolonged impact of maternal stress on emotional learning remains largely unknown. In addition to stress responsiveness and early life programming, another apparent characteristic of GC is its robust circadian rhythm. However, the significance of the functional GC rhythm in the brain function is not well understood yet. Recently, our group generated transgenic mice with adrenal-specific knockdown of canonical clock protein BMAL1 (A-BMKD), which showed attenuated circadian GC rhythm under constant darkness (Son et al., 2008). In Chapter 1, I intended to investigate how maternal stress affects fear memory in the amygdala, a major target of stress in the brain. In Chapter 2, using A-BMKD transgenic mouse line, I investigated the effect of circadian GC oscillation on hippocampal neurogenesis implicating in cognition deficits and mood disorders in Chapter 2. 1. In Chapter 1, I examined whether maternal stress influences on the amygdala-related learning processes. Maternally stressed mice exhibit normal fear memory acquisition as well as synaptic NMDA receptor expression in the amygdala

however, fear memory consolidation and the activation of related signaling cascades are significantly attenuated. In accordance with these behavioral aspects, maintenance of long-term potentiation (LTP) evoked in the thalamo-lateral amygdala pathway is significantly attenuated in amygdalar slices from maternally stressed animals, though basal synaptic properties and LTP induction were unaffected in these slices. Interestingly, administration of GC immediately after training or LTP induction restores impaired memory consolidation and LTP maintenance, indicating the weakened aversive memory-enhancing effect of GC in maternally stressed mice. Moreover, the membrane-impermeable form of GC mimics the restorative effect in maternally stressed animals, implying the involvement of a nongenomic mechanism. Taken together, it appears that maternal stress causes dysregulation of amygdala-dependent fear memory in adult offspring by an impairment of amygdalar synaptic plasticity in association with reduced nongenomic action of GC on long-term memory formation. 2. In Chapter 2, I focused on hippocampal neurogenesis in A-BMKD transgenic mice under constant darkness for 7 days. The number of newborn neurons in the hippocampus was significantly declined in the transgenic mice. These mice showed depressive mood states, impaired safety memory, and rapidly shutting off stress reactivity, which are known to be regulated by hippocampal neurogenesis. Moreover, enhanced rhythmic translocation of activated glucocorticoid receptor (GR) into hippocampal nucleus by binding to GC was observed against hypo-GC secretion with attenuation rhythm in TG mice. In accordance with this finding, transcript levels of brain-derived neurotrophin factor (BDNF) and its receptor TrkB, which are known to be essential for adult neurogenesis and regulated by GC negatively, were reduced in the hippocampus of A-BMKD transgenic mice. Interestingly, a daily oscillation of plasma GC restored by rhythmic intake of drinking water containing GC recovered not only neurogenesis but also gene expression of BDNF and TrkB in the hippocampus, suggesting that BDNF-related signal cascade is one of candidates responsible for the impaired hippocampal neurogenesis in the transgenic mice. Taken together, GC levels as well as its rhythmic secretion are important for maintaining normal neurogenesis associated with gene expression of BDNF and TrkB in the hippocampus. In conclusion, GC has a critical role in fear memory formation via nongenomic action in the amygdala and the functional circadian rhythm of GC is required for maintaining adult neurogenesis in the hippocampus.