Rats were used in a conditioned-suppression paradigm to investigate why a conditioned inhibition (CS-) does not extinguish when presented alone. Experiment 1 assessed the role of blocking by excitatory contextual cues and/or an evoked representation of the conditioned excitor (CS+), which had been nonreinforced in compound with the CS-. When the CS+ and context were extinguished prior to presentations of the CS- alone, the CS- showed a retardation effect, evidently reflecting latent inhibition, because no inhibition was detected in controls for which presentations of the CS- alone had been omitted. Experiment 2 showed that the loss of conditioned inhibition (CI) was due to excitatory extinction and not to time since conditioning. Furthermore, when excitation was reconditioned to the extinguished CS+ (Experiment 1), or to a novel CS in the same context (Experiment 2), CI was restored. Two other experiments evaluated whether the maintenance of CI depended upon excitation that was generic in form or associatively tied to the training context. They showed no loss of CI when groups received CS+ extinction in that context, along with concomitant presentations in a different context of the US by itself, for a novel CS, or correlated either positively or negatively with the original CS+. Collectively, the findings argue that CI is a "slave" to excitation, for when excitation is extinguished, CI is deactivated; and yet when excitation is reconditioned to the original or a new CS+ in the same or a different context, CI is restored.

Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD.

Proinflammatory cytokines have been implicated in alcohol-induced neurodegeneration, but the role of the neuroimmune system in alcohol related behaviors has only recently come to the forefront. Herein, the effects of binge-like drinking on IL-1β mRNA and immunoreactivity within the amygdala were measured following the “drinking in the dark” (DID) paradigm, a model of binge-like ethanol drinking in C57BL/6J mice. Moreover, the role of IL-1 receptor signaling in the amygdala on ethanol consumption was assessed. Results indicated that a history of binge-like ethanol drinking promoted a significant increase of IL-1β mRNA expression within the amygdala, and immunohistochemistry analyses revealed that the basolateral amygdala (BLA), but not central amygdala (CeA), exhibited significantly increased IL-1β immunoreactivity. Fluoro-Jade® C labeling indicated that multiple cycles of the DID paradigm were not sufficient to elicit neuronal death. Bilateral infusions of IL-1 receptor antagonist (IL-1Ra) reduced ethanol consumption when infused into the BLA but not the CeA. These observations were specific to ethanol drinking as the IL-1Ra did not alter either sucrose drinking or open-field locomotor activity. The current findings highlight a specific role for IL-1 receptor signaling in modulating binge-like ethanol consumption and indicate that proinflammatory cytokines can be induced prior to dependence or any evidence of neuronal cell death. These findings provide a framework in which to understand how neuroimmune adaptations may alter ethanol consumption and therein contributing to alcohol abuse.

Post-traumatic stress disorder (PTSD) is associated with immune dysregulation. We have previously shown that severe stress exposure in a preclinical animal model of the disorder, stress-enhanced fear learning (SEFL), is associated with an increase in hippocampal interleukin-1β (IL-1β) and that blocking central IL-1 after the severe stress prevents the development of SEFL. Here, we tested whether blocking hippocampal IL-1 signaling is sufficient to prevent enhanced fear learning and identified the cellular source of stress-induced IL-1β in this region. Experiment 1 tested whether intra-dorsal hippocampal (DH) infusions of interleukin-1 receptor antagonist (IL-1RA, 1.25µg per hemisphere) 24 and 48h after stress exposure prevents the development of enhanced fear learning. Experiment 2 used triple fluorescence immunohistochemistry to examine hippocampal alterations in IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, and ionized calcium binding adaptor molecule -1 (Iba-1), a microglial-specific marker, 48h after exposure to the severe stressor of the SEFL paradigm. Intra-DH IL-1RA prevented SEFL and stress-induced IL-1β was primarily colocalized with astrocytes in the hippocampus. Further, hippocampal GFAP immunoreactivity was not altered, whereas hippocampal Iba-1 immunoreactivity was significantly attenuated following severe stress. These data suggest that hippocampal IL-1 signaling is critical to the development of SEFL and that astrocytes are a predominant source of stress-induced IL-1β.

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