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

The study addresses how discrete, non-aversive spatial experiences during infancy, a period associated with infantile amnesia, can nonetheless shape adult learning. Prior work often used aversive paradigms or broad, prolonged environmental enrichment, leaving unclear whether brief episodic-like experiences in infancy persist and influence later cognition. Here, under controlled rat models, the authors exposed pups to short (5 min) object–place configurations on four days during infancy (PD18–24) and later tested spatial memory in adulthood using an object–place recognition (OPR) task. The central hypothesis is that infancy forms long-term contextual representations, particularly within medial prefrontal cortex (mPFC), that enhance adult spatial learning in similar contexts via sleep-dependent consolidation, despite the absence of detailed episodic retention.

The authors note that most early-life experience studies emphasize stress/aversive manipulations or non-specific, prolonged environmental exposures. Infantile amnesia literature indicates rapid forgetting of detailed episodic memories, often linked to immature hippocampal circuitry and elevated neurogenesis. However, infants and young animals show strong context-dependency in recall and an increasing role of neocortical, especially prefrontal, regions in remote or schema-related memory. Sleep has been implicated in systems consolidation during early development. Against this background, the present work tests whether brief, discrete, non-aversive spatial experiences in infancy can yield durable contextual memories residing in mPFC that later scaffold adult spatial learning, and distinguishes effects of object novelty versus spatial configuration changes and environmental context continuity. Prior findings referenced include mPFC involvement in memory transformation and retrieval under partial cues, developmentally shifting specificity from generalized to detailed hippocampal representations, and sleep-dependent consolidation mechanisms.

Subjects: Male Long-Evans rats (total reported across experiments ~191), maintained on 12 h light/dark, standard housing with dam until weaning (PD21). Procedures complied with EU Directive 2010/63/EU and local approvals. Experimental design (core manipulation): During infancy (PD18, PD20, PD22, PD24) pups received two 5-min arena visits per exposure day with two identical objects; between visits there was a brief interval, and at the second visit conditions varied by group: - Spatial-experience: one object displaced to a new location at the second visit (distinct configurations across days). - Object-experience: one of the two objects replaced by a different object (location unchanged). - Stationary-experience: objects and configuration unchanged across the two visits. - No-experience: no arena exposure during infancy. - Context-change: same infantile spatial experience as Spatial-experience, but adult OPR testing occurred in a different context (different room, distal cues, floor texture, and experimenter). Adult testing: Around PD80, rats were tested on an OPR task in a larger arena with different objects; encoding and retrieval were separated by a 3 h delay. OPR memory was quantified as a discrimination ratio (preference for displaced vs familiar object location), with emphasis on the first minute of retrieval. Behavior was video-recorded and tracked (ANY-Maze). Total exploration time and distance traveled were assessed as controls. One group (Long-term OPR) encoded once at PD24 and was retrieved months later in adulthood to assess remote episodic retention. Neural activity assays: c-Fos immunohistochemistry quantified activity 90 min after adult OPR retrieval across ROIs: mPFC (PL, IL, CC), posterior cortices (RSG, PAR, PRC, LEC), thalamus (RE, RTN), and hippocampus (CA1, CA3, DG). Additional cohorts assessed c-Fos during infant encoding (PD24) vs home cage controls. Cytochrome oxidase (COX) histochemistry indexed basal metabolic activity. Causal manipulation: To test mPFC necessity, bilateral cannulae were implanted in PL mPFC in adulthood; at OPR retrieval, muscimol (0.3 µg/hemisphere) or saline was infused 18 min prior. Behavioral controls (exploration time, distance) verified no nonspecific motor effects. Developmental timing and sleep: Additional cohorts received the spatial experience during early childhood (from PD25) or adolescence (from PD48) to test sensitive periods. A sleep-deprivation group was gently handled to prevent sleep during the 90-min post-experience interval on infant exposure days to assess sleep’s role in consolidation. Statistics: ANOVAs with Group and Time (retrieval minute) factors; Huynh–Feldt corrections as needed; post hoc two-sided t-tests and planned contrasts; one-sample t-tests vs chance (zero) for discrimination ratios. c-Fos/COX analyzed via ANOVAs with Group × Area; exploratory interregional c-Fos coactivation via Pearson correlations with threshold r > 0.815. Experimenters were blinded for scoring and histology.

- Infantile spatial experience enhanced adult OPR memory: Group × Minute ANOVA interaction F(4.944, 121.135) = 2.989, P = 0.014. Largest effect in first retrieval minute: main Group effect F(2, 51) = 4.464, P = 0.017; pairwise differences favored Spatial-experience over Object-experience and No-experience. - Sustained preference in Spatial-experience group across 5-min retrieval: e.g., first minute t(16) = 3.823, P < 0.003 vs chance; Object-experience showed no significant memory; No-experience showed only transient effects (2nd–3rd min). - Contextual information is critical: Stationary-experience (no object or spatial change across infant visits) showed adult OPR enhancement comparable to Spatial-experience (ANOVA main effect across Stationary vs Object vs No-experience F(2, 46) = 3.409, P = 0.042; Stationary vs Spatial P = 0.816), indicating enduring context representations drive the benefit. In contrast, Context-change group (adult testing in a different room/cues/experimenter/floor) showed no benefit (no minute above chance), confirming context specificity. - No persistent detailed episodic memory from infancy: Long-term OPR group (single infant encoding, adult retrieval) showed no significant spatial memory at any retrieval minute, arguing against survival of full episodic-like object–place memories into adulthood. - Adult neural activity: Following infantile spatial experience, adult OPR retrieval increased c-Fos in prelimbic (PL) mPFC compared with controls, without corresponding hippocampal increases; exploratory connectivity suggested reduced widespread coactivation. - Infant encoding neural activity: During the 4th infant exposure (PD24), c-Fos was elevated in PL and IL mPFC and in hippocampal CA1 and DG versus home cage controls (ANOVA Group × Area F[12,120] = 2.750, P = 0.002), indicating rapid formation of representations during infancy. - Causality: In adulthood, PL mPFC inhibition with muscimol abolished the spatial-experience benefit: Saline controls showed robust OPR memory (e.g., t(27) = 3.381, p < 0.005 for first 3 min vs chance), while Muscimol group performed at/below chance (t(17) = -0.129, p = 0.689). Between-group effect F(1, 34) = 8.4, p < 0.01; exploration and distance did not differ (p > 0.1). - Developmental sensitivity: Only spatial experience during infancy (PD18–24) enhanced adult OPR; similar manipulations during early childhood (from PD25) or adolescence (from PD48) did not yield benefits. - Sleep dependence: Preventing sleep during the 90-min post-experience period in infancy nullified the adult OPR enhancement and altered c-Fos patterns (reported significant differences; e.g., P = 0.004 between sleep vs sleep-deprived OPR performance; c-Fos pairwise P = 0.002), indicating sleep supports consolidation of contextual representations.

The findings show that brief, non-aversive experiences during infancy leave enduring contextual traces that enhance adult spatial learning, despite the lack of persistent detailed episodic memories. Enhancement occurred when adult testing matched the infant context, and even stationary infant exposures sufficed, implicating contextual memory rather than sensitivity to object displacement per se. Neural data point to the prelimbic mPFC as the locus of these long-term representations: c-Fos activity was selectively elevated in PL at adult retrieval in previously exposed rats, PL was already engaged during infant encoding, and reversible PL inactivation in adulthood abolished the benefit without affecting exploration or locomotion. This supports a model in which infant experiences rapidly form mPFC-based contextual representations that later scaffold learning under similar contexts. The hippocampus, still maturing in infancy, did not show enhanced adult retrieval activity in this paradigm, consistent with proposals that early memory relies more on neocortical schemas and context-like representations. The enhancement depended on a sensitive period in infancy and on sleep following experience, aligning with systems consolidation frameworks where sleep promotes integration of new information into cortical networks. Together, the data indicate that infant-formed mPFC context memories guide adult behavior and learning in a context-dependent manner.

The study demonstrates that discrete, brief spatial experiences during infancy create long-lasting contextual memories that reside in prelimbic mPFC and enhance adult spatial learning when contexts match. These benefits are contingent on occurrence during a sensitive infant period and on post-experience sleep. Although detailed episodic object–place memories from infancy do not persist into adulthood, their contextual scaffolds do and can guide later learning. Future work could delineate the precise circuit dynamics linking hippocampus and mPFC during infant sleep-dependent consolidation, test generalization across tasks and modalities, and define the temporal limits and boundary conditions of the sensitive period and context specificity.

- Interpretation of the Object-experience group is tentative: novel objects during infant exposures may have distracted pups from encoding context, requiring further experiments to disambiguate novelty effects from true context encoding deficits. - c-Fos and COX are indirect activity/metabolic markers; while PL inactivation establishes causality for retrieval-time PL function, c-Fos elevations alone are correlational and sensitive to procedural differences. - Context-change tested multiple contextual dimensions simultaneously (room, cues, floor, experimenter), so the specific contextual features driving the effect remain unresolved. - Some procedural details (e.g., exact inter-visit intervals across all cohorts) varied in descriptions, and group sizes differed across experiments; replication with standardized intervals and larger samples would strengthen generalizability.