Dorsal hippocampal neural immune signaling regulates heroin-conditioned immunomodulation but not heroin-conditioned place preference

摘要

Repeated pairings of heroin and a context results in Pavlovian associations which manifest as heroin-conditioned appetitive responses and peripheral immunomodulation upon re-exposure to heroin-paired conditioned stimuli (CS). The dorsal hippocampus (DH) plays a key role in the neurocircuitry governing these context-heroin associations. Within the DH, signaling of the pro-inflammatory cytokine interleukin-lβ (IL-lβ) is required for the expression of heroin-conditioned peripheral immunomodulation. However, the role of signaling via IL-1 receptor type 1 (IL-1R1) has not been examined. Furthermore, it has not been evaluated whether the involvement of IL-1 in associative learning extends to classically conditioned appetitive behaviors, such as conditioned place preference (CPP). The first set of experiments investigated whether DH IL-1R1 signaling during CS re-exposure modulates heroin-conditioned immunomodulation and CPP. The second set of experiments employed chemogenetic techniques to examine whether DH astroglial signaling during CS re-exposure alters the same responses. This line of investigation is based on previous research indicating that astrocytes facilitate hippocampal-dependent learning and memory through the expression of IL-1 β protein and IL-1R1. Interestingly, IL-1R1 antagonism disrupted heroin-conditioned suppression of peripheral immune parameters but failed to alter heroin-CPP. Similarly, chemogenetic activation of Gi-signaling in DH astrocytes attenuated heroin-conditioned peripheral immunomodulation, but failed to alter heroin-CPP. Collectively our data show that both IL-1R1 stimulation and astrocyte signaling in the DH are critically involved in the expression of heroin-conditioned immunomodulation, but not heroin-CPP. As such these findings strongly suggest hippocampal neural immune signaling differentially regulate Pavlovian immunomodulatory and appetitive behaviors.