Incomplete reminder cues trigger memory reconsolidation and sustain learned immune responses.

Abstract Immunological responses can be modulated by taste-immune associative learning paradigms, in which the presentation of a sweet taste as conditioned stimulus (CS) is paired with the injection of an immunopharmacological substance as unconditioned stimulus (US). This phenomenon provides a basis for employing conditioning paradigms as supportive therapy in clinical contexts. However, given that conditioned responses gradually weaken over time and eventually disappear following repeated exposure to the CS in the absence of the US, it is essential to understand how learned immune responses can be protected from extinction and how they can maintain on demand by CS re-exposure. Against this background, the present study aimed interfering with extinction of conditioned anti-proliferative and immunosuppressive immune responses in a taste-associative learning paradigm with the mTOR inhibitor rapamycin. By pairing sub-effective doses of the US (rapamycin) as reminder cues simultaneously with the CS (taste stimulus) at retrieval, conditioned pharmacological responses of rapamycin persisted peripherally and centrally, reflected as suppressed interleukin-10 production and T cell activity as well as diminished activity of the mTOR target protein p70s6k in the amygdala. Importantly, these effects were only observed when reminders cues where presented together with the CS, i. e. within a time frame where memories are susceptible for modification (reconsolidation window). Our results indicate, that in paradigms of taste-immune associative learning the presentation of new information in form of sub-effective drug doses strengthens the initially conditioned association between taste and drug and saves the learned immunopharmacological responses from being extinguished.