Impairment of Fear Memory Consolidation in Maternally Stressed Male Mouse Offspring: Evidence for Nongenomic Glucocorticoid Action on the Amygdala

Abstract

The environment in early life elicits profound effects on fetal brain development that can extend into adulthood. However, the longlasting impact of maternal stress on emotional learning remains largely unknown. Here, we focus on amygdala-related learning processes in maternally stressed mice. In these mice, fear memory consolidation and certain related signaling cascades were significantly impaired, though innate fear, fear memory acquisition, and synaptic NMDA receptor expression in the amygdala were unaltered. In accordance with these findings, maintenance of long-term potentiation (LTP) at amygdala synapses, but not its induction, was significantly impaired in the maternally stressed animals. Interestingly, amygdala glucocorticoid receptor expression was reduced in the maternally stressed mice, and administration of glucocorticoids (GCs) immediately after fear conditioning and LTP induction restored memory consolidation and LTP maintenance, respectively, suggesting that a weakening of GC signaling was responsible for the observed impairment. Furthermore, microinfusion of a membrane-impermeable form of GC (BSA-conjugated GC) into the amygdala mimicked the restorative effects of GC, indicating that a nongenomic activity of GC mediates the restorative effect. Together, these findings suggest that prenatal stress induces long-term dysregulation of nongenomic GC action in the amygdala of adult offspring, resulting in the impairment of fear memory consolidation. Since modulation of amygdala activity is known to alter the consolidation of emotionally influenced memories allocated in other brain regions, the nongenomic action of GC on the amygdala shown herein may also participate in the amygdaladependent modulation of memory consolidation.

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…More severe conditions, though, are consistently linked with reduced synaptic plasticity. This is true for prenatal stress (Kamphuis et al, 2003;Son et al, 2006;Yang et al, 2006Yang et al, , 2007Lee et al, 2011a;Yeh et al, 2012;but see Noorlander et al, 2008), low and/or fragmented maternal care including situations associated with impoverished environmental conditions (Bredy et al, 2003;Brunson et al, 2005;Cui et al, 2006;Champagne et al, 2008;Bagot et al, 2009Bagot et al, , 2012Ivy et al, 2010), prolonged maternal separation (Gruss et al, 2008;Stevenson et al, 2008;Oomen et al, 2010), or traumatic events (Akers et al, 2006;Judo et al, 2010). When investigated, basal synaptic properties or paired pulse responsiveness were not much altered (Domenici et al, 1996;Kamphuis et al, 2003;Yaka et al, 2007;Lee et al, 2011).…”

“…From what is presently known about other brain properties, though, it seems likely that epigenetic programming plays an important role (Meaney and Szyf, 2005;Franklin and Mansuy, 2010). Potential molecules mediating changes in brain function include the NMDA receptor (Kamphuis et al, 2003;Son et al, 2006;Yaka et al, 2007;Ryan et al, 2009;Judo et al, 2010; but see Lee et al, 2011a), AMPA receptors (Yaka et al, 2007;Ryan et al, 2009), cell adhesion molecules (Aisa et al, 2009), and brain-derived neurotrophic factor (van Hasselt et al, 2012a;Yeh et al, 2012). We will here discuss only some of the major variables and the principles that emerge from the currently available data set on electrophysiological effects after early-life stress (summarized in Supplemental Table IV).…”

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

“…Cued fear memory encoded in the amygdala has been shown to be consolidated within 24 h and short-term fear memory is known to be maintained for up to 4 h (Schafe and LeDoux, 2000). Therefore, if there is an impairment in the consolidation of cued fear memory, memory retention assessed 24 h after conditioning would be impaired, whereas memory retention assessed within 4 h after conditioning would be intact (Lee et al, 2011). In this study, we found that the freezing behavior of AQP4 KO mice significantly reduced 24 h after training without any significant difference during the training and 2 h after training when compared with that of WT mice, indicating that AQP4 deficiency impairs the consolidation of associative fear memory without altering the normal acquisition of fear memory.…”

Possible Modulation of the Amygdala on Metaplasticity Deficits in the Hippocampal CA1 Field in Early Postnatally Stressed Rats

“…These findings suggest that the amygdala can influence stress-induced hippocampal function through inhibitory regulatory mechanisms.fear-associated learning was altered by prenatal stress exposure: Maternally stressed animals exhibited low levels of freezing behavior during the CFC retention session, a deficit in the maintenance of LTP at amygdala synapses, and decreases in glucocorticoid receptor expression in the amygdala. Based on these findings, the authors suggested that long-term deficits in amygdala function impair fear memory consolidation (17). Interestingly, we also observed that early postnatally stressed animals that received aversive footshock (FS) stimuli during postnatal days 14 to 18 (2nd week FS [2wFS] group) exhibited a marked reduction in freezing behavior during the CFC retention session (4,18).…”

“…Similar observations were also reported in a recent study by Lee et al (17): Maternally stressed mice exhibited low levels of freezing behavior during CFC retention. Based on electrophysiological and biochemical evidence, the authors suggested that prenatal stress-induced decreases in freezing behavior are attributable to the long-lasting impairment of fear memory consolidation but not acquisition that resulted from amygdala dysfunction (17).…”