Abstract
BackgroundPersistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear.MethodWild-type and Nlrp3−/− mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1β (IL-1β) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test.ResultsWe demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1β administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior.ConclusionTaken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.
Highlights
Fear memory plays a central role in the development and onset of trauma- and stress-related disorders, such as posttraumatic stress disorder (PTSD) [1]
Electric foot shock exposure in the contextual fear paradigm induces anxiety-like behavior Freezing behavior is associated with contextual fear memory induced by electric foot shock, which has been widely used in studies of fear memory and extinction [37]
In the Elevated plus maze (EPM) test, we found that fear-conditioned mice displayed significant lower entries, time spent, and distance traveled at open arms than control mice (Fig. S1d-g)
Summary
Fear memory plays a central role in the development and onset of trauma- and stress-related disorders, such as posttraumatic stress disorder (PTSD) [1]. Extinction learning involves the modification of synaptic connections in neuronal circuits similar to fear conditioning [2, 3]. The direct association between the context and US is established under bidirectional communication between amygdala and hippocampus [4,5,6]. The projections from the hippocampus to the amygdala and the medial prefrontal cortex (mPFC) are involved in the context-dependent fear response after extinction through increasing neuronal activity [12, 13]. Method: Wild-type and Nlrp3−/− mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test
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