Maternal separation results in early emergence of adult-like fear and extinction learning in infant rats.

Abstract

Recent studies in rats have shown that extinction occurring early in life is resistant to relapse and may represent the erasure of fear memories. In the present study we examined the effects of early life stress on extinction in the developing rat, which could have important implications for the treatment of anxiety disorders in those who have experienced early life stress. In the present study, we used maternal-separation on postnatal days (P) 2-14 as an early life stressor. On P17, maternally separated and standard-reared animals were trained to fear a noise associated with a footshock. The fear of this noise was then extinguished (through repeated nonreinforced noise presentations) on P18. Animals were tested for contextually mediated, stress-mediated, and GABA-mediated fear relapse the day after extinction. We found that young animals exposed to maternal-separation were more likely to exhibit context- and stress-mediated relapse after extinction than standard-reared animals (Experiments 1 and 2). Further, unlike standard-reared animals, maternally separated rats exhibited a return of fear when the inhibitory neurotransmitter GABA was blocked at test (Experiment 3). These effects were not the result of maternal separation increasing rats' sensitivity to footshock (Experiment 5) and may in part be related to superior long-term memory for contexts in P17 maternally separated rats (Experiment 4). Taken together, these results suggest that early life adversity may prepare young animals to respond more cautiously toward fear signals in their environment.

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

“…Although these functional connectivity measures do not directly reflect the non-linear developmental pattern observed in fear extinction and associated synaptic plasticity , they provide an indication of the pronounced maturational changes in the dynamic interaction between these regions. Interestingly, mirroring the early maturation of the fear neurocircuitry induced by maternal separation in the rodent (Callaghan and Richardson, 2011), institutionallyreared children who experienced early maternal deprivation show the more mature pattern of positive vmPFC-amygdala coupling (Gee et al, 2013a). This suggests that, as in rodents, the maturational trajectory of human fear neurocircuitry is also highly sensitive to experiential variation during early development (Tottenham, 2013).…”

“…This suggests that early-life extinction may effectively yield fear erasure. Paralleling the influence of stress on the maturation of fear learning, separation from the mother advances the onset of adult-like extinction learning, from which fears reemerge (Callaghan and Richardson, 2011). In contrast to the ease with which fears are diminished in these younger animals, both fear extinction learning and retention are attenuated during adolescence (Kim et al, 2011;McCallum et al, 2010;Pattwell et al, 2012).…”

Ontogeny of contextual fear memory formation, specificity, and persistence in mice

“…Although some studies report that rats fail to associate a shock with a context until 23-24 d of age (Spear 1979;Rudy 1993;Rudy and Morledge 1994;Raineki et al 2010;Schiffino et al 2011), others demonstrate that this type of learning can occur at 17-18 d of age under some training conditions (Brasser and Spear 2004;Esmoris-Arranz et al 2008;Pisano et al 2012) or following certain neonatal manipulations (i.e., injection of fibroblast growth factor-2, sensory stimulation) (Woodcock and Richardson 2000;Graham and Richardson 2010;Callaghan and Richardson 2011). Our finding that mice are able to associate a shock with a context as early as 13-14 d of age, however, suggests that brain and behavioral development is accelerated in mice compared to rats, consistent with previous proposals (Pellis and Iwaniuk 2000;Whishaw et al 2001).…”

Early developmental emergence of human amygdala–prefrontal connectivity after maternal deprivation

“…Early life caregiving adversity in rodents alters amygdala-medial prefrontal cortex (mPFC) circuits that in adulthood serve to regulate the activity of the amygdala (13,14), perhaps through accelerating development of the circuitry. For example, maternal deprivation results in the early emergence of adult-like fear learning based in frontoamygdala circuitry (5) and earlier emergence of amygdala function (8,15) and structural maturation (16). Maternal separation has also been associated with increased development of neurons in mPFC (17).…”

“…Adverse or deprived caregiving is an example of a highly potent early life stressor in altricial species. Animal studies of maternal deprivation have demonstrated long-term effects on socioemotional and brain development (1)(2)(3)(4)(5), with particular influences on frontoamygdala circuitry. The timing of stress exposure and cellular properties of this circuitry may render it particularly vulnerable to early adversity (6).…”