Abstract

We examined the enduring effects of predictable vs. unpredictable fear acquisition early in life on memory and re-learning in adulthood. At post-natal day 17 or 25 (P17 or P25), rats either remained naïve, or were fear conditioned using paired (predictable) or unpaired (unpredictable) presentations of white-noise and foot-shocks.

At 2 months of age (adulthood), each group was fear conditioned (or re-conditioned) with either paired or un-paired training, and then was tested for fear extinction the next day.

Initial findings replicate previous work from our lab and demonstrate a difference in memory retention based on age of acquisition. Specifically, rats conditioned at P25, but not P17, using paired conditioning procedures show increased freezing to the cue when tested in adulthood. Following retention tests, our results show that both paired and

unpaired conditioning at P17 potentiated adult paired conditioning using the same cue as in early life. Paired conditioning at P25 potentiated adult conditioning across both adult paired and unpaired groups, whereas unpaired training in early life did not have an effect on memory and reacquisition in adulthood. These findings suggest that early predictable vs. unpredictable aversive learning at P17 or P25 differentially modulate memory retention and future learning, such that follow up tests explored an adolescent intervention of chronic exercise to reduce the persistence of fear. Results show that average distance run during late adolescence of P17 conditioned rat’s produces a negative relationship with freezing during the memory retention test in adulthood, such that longer distances run produced less freezing. Secondly, independent of early life conditioning, there is a trend for a negative relationship in freezing after adult conditioning in P25 experimental rats based on the average distance run during late adolescence. Taken together the influence of chronic exercise may be indirectly through its influence on stress and anxiety rather than learning or memory directly.

2.2INTRODUCTION

Behavioral adjustments through experience are important for organisms to adapt and survive in changing environments. During early life development, learning and memory processes are more plastic than in adulthood, such that experiences during childhood have a profound impact on shaping adult behavior (Arenas, Fernández, &

Farina, 2009; Schäble, Poeggel, Braun, & Gruss, 2007). Importantly, evidence suggests differential modulation of fear acquisition and reduction throughout development

(Esmorís-Arranz, Méndez, & Spear, 2008; Kim, Hamlin, & Richardson, 2009; Moriceau

& Sullivan, 2006; Pattwell, Bath, Casey, Ninan, & Lee, 2011; Travaglia, Bisaz, Sweet,

Blitzer, & Alberini, 2016) with aversive experiences throughout early development producing a variety of outcomes on adult behavior (Hunt et al., 2007; Jones & Monfils, 2016; Sevelinges et al., 2007; Travaglia, Bisaz, Sweet, et al., 2016). Additionally, support from human literature indicates that early life aversive or traumatic experiences can be linked to increased rates of anxiety, depression, and other psychopathologies throughout a life-time (Anda et al., 2006; Carr, Martins, Stingel, Lemgruber, & Juruena, 2013;

Fernandes & Osório, 2015; Heim & Nemeroff, 2001).

One phenomena, known as “infantile amnesia”, first identified by Campbell and Campbell (1962), states that younger animals readily forget a cue elicited memory (within 7 days of acquisition). More recently, findings from our lab and others have shown that rats conditioned at post-natal day 24 or 25 (P24/P25), but not post-natal-day 17 (P17), show a memory for the conditioned cue in adulthood (Jones & Monfils, 2016;

Travaglia, Bisaz, Sweet, et al., 2016). Notably, rat models of fear learning and memory have found the weaning age (or the period when rats are removed from their mothers and become independent), which occurs at approximately postnatal day (P) 21, appears to be a particularly important turning point in shaping the effects of early life experience. For example, cued fear conditioning can readily be acquired before the weaning period, but contextual fear conditioning does not emerge until P23 (Rudy, 1993; Stanton, 2000). In addition, extinction of fear can be acquired in pre-weaning rats, but unlike the post-weaning period, these rats do not require the medial prefrontal cortex (Kim et al., 2009).

This recruitment of different neural substrates is thought to be due to the immaturity of relevant connections (e. g. between amygdala and hippocampus) within the circuitry that

is responsible for fear acquisition and modulation (Foster & Burman, 2010; Travaglia, Bisaz, Sweet, et al., 2016; Yap & Richardson, 2005). These immaturities may affect not only long-term retention of early fear memories but potentially lead to differences in later learning (Coulter, Collier, & Campbell, 1976).

The idea that early life fear exposure may affect later learning is supported by additional findings that rats who do not express adult fear retention after P17

conditioning exhibit a potentiation in responding when exposed to a social fear

conditioning procedure in adulthood (Jones & Monfils, 2016). This effect, however, was not seen in rats previously conditioned at P25, suggesting a difference in the effect that early life fear exposure may have on learning in adulthood. Work by Sevelinges and colleagues also indicate that contingency of early life fear exposure is critical, as paired but not unpaired conditioning to an odor-shock paradigm at P8-12 produced an

attenuation on future fear learning in adulthood (Sevelinges et al., 2007; Sevelinges, Sullivan, Messaoudi, & Mouly, 2008). Taken together, the timing and predictability of conditioning procedures in early life may produce differential effects on later learning, making behavioral disambiguation of the effects of early events on later experience important to enhance our understanding of the factors that influence memory retention and the modulation of future learning. In the current study, the goal was to specifically examine whether there are differential effects of predictable versus unpredictable (paired vs. unpaired) fear acquisition early in life (P17 and P25) on adult fear memory and conditioning (or re-conditioning).