Dentate Gyrus Engrams in Fear and Reward: Mechanistic Principles, Critical Gaps, and Paths to Translation

The hippocampal dentate gyrus (DG) has emerged as a cornerstone of engram research. While DG fear-based engrams have been extensively studied, revealing principles of allocation, consolidation, retrieval, and valence switching, engrams encoding context-reward associations, particularly those involving drugs of abuse, remain comparatively underexplored. This knowledge gap has critical implications for understanding addiction, depression, and other disorders involving dysfunctional reward processing. In this review, we first establish the DG's unique anatomical and functional properties that position it as an ideal model system for engram research. We then systematically examine the DG fear engram literature, documenting how decades of contextual fear conditioning studies have elucidated mechanisms of competitive allocation, molecular consolidation, competing extinction ensembles, and context-dependent discrimination versus generalization. Turning to reward engrams, we synthesize emerging evidence demonstrating that drug-context associations are encoded through sparse, distributed ensembles across multiple brain regions including the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. While these studies establish foundational principles of reward engram allocation and retrieval, critical mechanistic gaps remain, particularly regarding differences between drug-associated and natural reward memories, the neural coding of context versus valence in hippocampal circuits, and the mechanisms underlying drug associated reward memory extinction. Evidence from valence switching studies demonstrates that the DG processes and stores both fear and reward memories within overlapping circuits, exhibiting remarkable plasticity in linking contextual representations to opposing emotional outcomes, a flexibility distinguishing it from structures with hardwired valence encoding. This encoding capacity positions the DG as a promising target for interventions aimed at modifying pathological emotional associations in addiction and trauma-related disorders while preserving contextual specificity. Understanding reward engram mechanisms with the same rigor applied to fear engrams is essential for developing comprehensive frameworks of how DG circuits contribute to memory-related psychopathology and for translating engram research into therapeutic applications.