Context memory formed in medial prefrontal cortex during infancy enhances learning in adulthood

The influence of early-life experiences on adult behavior is well-established, but the mechanisms are not fully understood, particularly regarding seemingly forgotten infantile episodes. While the effects of aversive early-life experiences on adult behavior are well-documented, the impact of non-aversive, discrete experiences during infancy remains less clear. Most studies examining non-aversive effects have employed non-specific stimulation over extended postnatal periods. This study employs a novel approach to investigate how brief, non-emotional spatial experiences during infancy integrate into long-term knowledge systems and influence adult behavior. Using a rat model allows for controlled manipulation of early life experiences and precise assessment of their long-term consequences. The study hypothesizes that discrete, non-emotional spatial experiences during infancy enhance adult spatial learning abilities through the formation of context memories consolidated in the mPFC. This hypothesis is based on the well-known role of the mPFC in contextual processing and the developmental changes in memory systems during infancy.

Existing literature highlights the significant impact of early-life stress on brain development and adult behavior (Lupien et al., 2009; Lumertz et al., 2022). Studies also demonstrate the role of hippocampal neurogenesis in forgetting (Akers et al., 2014) and the robustness of infantile amnesia (Josselyn & Frankland, 2012). However, fewer studies focus on the long-term impact of non-aversive early experiences. Some research suggests that early life experiences can mature learning and memory abilities (Bessières et al., 2020), but these studies often use non-specific stimulation. The role of the mPFC in context memory and its development during infancy are also well-established aspects of the literature reviewed.

The study used 191 male Long-Evans rats, divided into several experimental groups. The main groups included a Spatial-experience group (infantile exposure to changes in spatial configuration of two objects), an Object-experience group (infantile exposure to changes in object identity), and a No-experience group (no infantile exposure). Additional control groups included a Stationary-experience group (no change in object location), a Context-change group (infantile spatial experience but adult testing in a different context), and a Long-term OPR group (single infantile encoding, adult retrieval). Infantile exposures occurred between postnatal days (PD) 18-24. Adult object-place recognition (OPR) tests were performed at PD80 with a 3-hour delay between encoding and retrieval. c-Fos immunohistochemistry was used to assess neuronal activity in various brain regions, including the mPFC and hippocampus, during both infancy and adulthood. To investigate the role of the mPFC, additional experiments involved muscimol infusion to inhibit the prelimbic mPFC during adult OPR testing. Developmental trajectory was assessed by exposing additional groups to similar spatial experiences during early childhood (PD25 onwards) and adolescence (PD48 onwards). A sleep-deprivation group examined the role of sleep in consolidation. Behavioral data were analyzed using ANOVAs and t-tests, while c-Fos data were analyzed using ANOVAs and post-hoc comparisons. COX histochemistry was also used to assess basal metabolic rates in brain regions. Finally, functional connectivity analyses were performed using Pearson correlation coefficients of c-Fos activity between brain regions.

Rats in the Spatial-experience group showed significantly enhanced OPR performance compared to the Object-experience and No-experience groups. This enhancement was largest during the first minute of retrieval, indicating a strong influence of the spatial context. The Stationary-experience group, with no change in object location, also showed enhanced OPR performance, suggesting that the context, not the object displacement itself, was crucial. The Context-change group, tested in a different context, did not show enhanced performance, supporting the role of context memory. The Long-term OPR group, with only a single infantile exposure, did not show enhanced performance, indicating that the effect was not due to persistent episodic memory. Increased c-Fos activity in the prelimbic mPFC (PL-mPFC) was observed during adult OPR testing in the Spatial-experience group, but not in the hippocampus. Inhibiting the PL-mPFC abolished the enhancing effect of infantile spatial experience. Infantile spatial experience also increased c-Fos activity in the PL-mPFC during encoding, suggesting rapid formation of contextual representations. The enhancing effect of early spatial experience was specific to infancy; it was not observed in rats exposed to similar experiences during early childhood or adolescence. Sleep deprivation after infantile spatial experience nullified the enhancing effect on adult OPR performance.

The findings demonstrate that discrete spatial experiences during infancy enhance adult spatial learning capabilities through the formation of context memories primarily residing in the mPFC. The lack of enhanced performance in the Context-change group and the Long-term OPR group strongly supports the importance of context-dependent retrieval. The increased c-Fos activity in the PL-mPFC, both during encoding and retrieval, and the abolishment of the enhancing effect after PL-mPFC inhibition, directly implicates this brain region. The sleep-dependent nature of the effect suggests a role for systems consolidation processes. The age-dependency indicates a critical period for the formation of these context memories during infancy, likely related to developmental changes in brain plasticity and memory system maturation. The results challenge the notion of infantile amnesia, suggesting that certain types of early experiences, specifically contextual information, are retained and used to improve subsequent learning in similar contexts.

This study reveals a novel mechanism by which early-life experiences shape adult learning. Infantile spatial experiences, consolidated in a sleep-dependent manner, create context-rich memories in the mPFC that facilitate later learning in similar contexts. This research highlights the importance of early-life environments and suggests that interventions targeting early context memory might benefit adult learning and cognitive abilities. Future research could explore the specific mechanisms of mPFC involvement and investigate the potential for therapeutic interventions based on early context manipulation.

The study was conducted on male rats, limiting the generalizability to female rats and other species. The specific contextual cues driving the enhanced performance could be further investigated. The relatively small sample size in some control groups might affect statistical power. The study’s focus on spatial learning does not rule out potential effects on other cognitive domains.