Infant Trauma Alters Social Buffering of Threat Learning: Emerging Role of Prefrontal Cortex in Preadolescence

Abstract

Within the infant-caregiver attachment system, the primary caregiver holds potent reward value to the infant, exhibited by infants' strong preference for approach responses and proximity-seeking towards the mother. A less well-understood feature of the attachment figure is the caregiver's ability to reduce fear via social buffering, commonly associated with the notion of a "safe haven" in the developmental literature. Evidence suggests this infant system overlaps with the neural network supporting social buffering (attenuation) of fear in the adults of many species, a network known to involve the prefrontal cortex (PFC). Here, using odor-shock conditioning in young developing rats, we assessed when the infant system transitions to the adult-like PFC-dependent social buffering of threat system. Rat pups were odor-shock conditioned (0.55 mA-0.6 mA) at either postnatal day (PN18; dependent on mother) or 28 (newly independent, weaned at PN23). Within each age group, the mother was present or absent during conditioning, with PFC assessment following acquisition using ¹⁴C 2-DG autoradiography and cue testing the following day. Since the human literature suggests poor attachment attenuates the mother's ability to socially buffer the infants, half of the pups at each age were reared with an abusive mother from PN8-12. The results showed that for typical control rearing, the mother attenuated fear in both PN18 and PN28 pups, although the PFC [infralimbic (IL) and ventral prelimbic (vPL) cortices] was only engaged at PN28. Abuse rearing completely disrupted social buffering of pups by the mother at PN18. The results from PN28 pups showed that while the mother modulated learning in both control and abuse-reared pups, the behavioral and PFC effects were attenuated after maltreatment. Our data suggest that pups transition to the adult-like PFC social support circuit after independence from the mother (PN28), and this circuit remains functional after early-life trauma, although its effectiveness appears reduced. This is in sharp contrast to the effects of early life trauma during infancy, where social buffering of the infant is more robustly impacted. We suggest that the infant social buffering circuit is disengaged by early-life trauma, while the adolescent PFC-dependent social buffering circuit may use a safety signal with unreliable safety value.

Keywords: early-life trauma; fear; infralimbic; prefrontal cortex; prelimbic; social buffering; social support; threat.

Figure 1

Schematic of methodology and experimental timeline. In infancy, pups received either Scarcity-Adversity Model of Low Bedding (LB) rearing or control rearing from the mother (ages PN8–12). LB rearing involved providing the mother with insufficient bedding for nest building, which produces maltreatment of pups but growth indistinguishable from controls. Pups are odor-shock conditioned in the mother’s presence or absence at one of two ages, with the goal of better understanding the neural mechanisms involved in social suppression of threat. A portion of the pups had the brain removed immediately after conditioning, while the other half were tested the next day (Cue test involving odor only presentations). The younger subjects were PN18, an age when pups are still with the mother but only for about 5 days before weaning. The other age tested was PN28, when pups have been independent for about 5 days.

Figure 2

Odor-shock cue conditioning increases freezing to odor during training. Total cumulative (seconds) freezing (±SEM) during paired odor-shock cue conditioning at (A,B) PN18 (Control: Alone n = 8; Mom n = 8; LB: Alone n = 8; Mom n = 8) and (C,D) PN28 (Control: Alone n = 9; Mom n = 8; LB: Alone n = 14; Mom n = 15). Cue conditioning increased freezing at both ages in both control and low bedding (LB) rearing conditions however increased freezing was observed in animals conditioned with the mom (except in PN28 Control group) relative to animals conditioned alone. Open circle = conditioned with the mom; filled circles = conditioned alone; blue = controls; red = LB. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Figure 3

Early abuse modulates maternal buffering of odor-shock conditioning. Total (seconds) freezing (±SEM) to a conditioned stimulus (CS) was higher in Paired odor-shock conditions than Unpaired and Odor only conditions. Maternal presence during conditioning attenuated learning at both (A,B) PN18 Control (Paired: Alone n = 12; Mom n = 12; Unpaired: Alone n = 12; Mom n = 12; odor Only: Alone n = 12; Mom n = 12) and LB (Paired: Alone n = 11; Mom n = 12; Unpaired: Alone n = 12; Mom n = 12; odor Only: Alone n = 12; Mom n = 12) and (C,D) PN28 Control (Paired: Alone n = 9; Mom n = 10; Unpaired: Alone n = 8; Mom n = 8; odor Only: Alone n = 8; Mom n = 8) and LB (Paired: Alone n = 14; Mom n = 14; Unpaired: Alone n = 8; Mom n = 8; odor Only: Alone n = 8; Mom n = 8), although this maternal presence effect was not present following early life PN18 LB maltreatment and present but attenuated following early life PN28 LB maltreatment. *p < 0.05, ****p < 0.0001.

Figure 4

Previous abuse impairs maternal regulation of vmPFC regions during threat in older pups. Average (±SEM) fold change in activity for (A,C) PN18 Control infralimbic (IL: Alone n = 40; Mom n = 44; dorsal PL: Alone n = 41; Mom n = 33; ventral PL: Alone n = 30; Mom n = 33) and LB (IL: Alone n = 28; Mom n = 28; dorsal PL: Alone n = 28; Mom n = 21; ventral PL: Alone n = 21; Mom n = 21) or (B,D) PN28 Control (IL: Alone n = 32; Mom n = 28; dorsal PL: Alone n = 24; Mom n = 24; ventral PL: Alone n = 32; Mom n = 32) and LB (IL: Alone n = 32; Mom n = 298; dorsal PL: Alone n = 24; Mom n = 27; ventral PL: Alone n = 32; Mom n = 36). Solid bars represent pups conditioned alone while hashed bars represent pups conditioned with the mother. Right, schematics of brain regions; red, subregions with statistically significant effect of abuse on 2-DG uptake. n.s., indicates a non-significant effect (p > 0.05); **p < 0.01; ***p < 0.001.

Figure 5

Developmental transitions in amygdala inputs regulating social suppression of threat. The neural circuit supporting infant fear learning and its maternal presence blockade (≤PN15) or attenuation (≥PN16) undergoes developmental changes. Social buffering in early infancy is supported by VTA-amygdala connectivity (≤PN15), while in older pups (PN28) and adults social attenuation of fear is supported by vmPFC-amygdala connectivity. This system is disrupted following early life abusive rearing. At PN18, the ability of the mother to block fear learning is abolished and VTA showed compromised suppression of the amygdala. Early life maltreatment leaves social suppression of fear learning intact at PN28, although it is effectiveness is reduced and social modulation of vmPFC engagement is significantly reduced.