Sex Dependent Effects of Minocycline on Contextual Fear Memory

Recent studies have highlighted the crucial role of microglia in fear learning and memory. This supports the potential therapeutic value of the anti-inflammatory agent minocycline, which regulates microglial activity, in psychiatric disorders involving dysregulated emotional memory. To assess the impact of minocycline during a tractable intervention window, we examined its acute systemic effects on the reconsolidation, extinction, and forgetting of contextual fear memory (CFM) in rats. Our findings show that the effects of minocycline on fear memory and anxiety-like behaviours depend on sex, memory activation (i.e., whether it was retrieved), and memory age. In males with recently acquired CFM, minocycline given before retrieval enhanced extinction and reduced fear expression. When administered without retrieval, it disrupted passive forgetting, increasing evoked fear behaviour. This extinction-enhancing effect did not occur with older (28-day) memories rather it strengthened CFM through enhancing reconsolidation. In contrast, in females, minocycline increased the expression of recent fear memories regardless of retrieval, without affecting extinction or forgetting. This elevated fear expression appeared linked to heightened anxiety-like behaviour. These findings suggest that minocycline, or other microglia-targeting agents, would need to be used in a highly selective and targeted manner to therapeutically modulate pathological fear memories. Minocycline may be beneficial as an adjunct to exposure therapy in men explicitly retrieving recent fear or trauma-related memories, but outside these conditions, it may worsen fear expression. These results help explain the mixed findings from therapeutic trials using minocycline in psychiatry and support the application of a more precision approach in any future applications.