NLRP3 deficiency decreases alcohol intake controlling anxiety-like behavior via modification of glutamatergic transmission in corticostriatal circuits

Abstract

Background Alcohol use disorders result from repeated binge and chronic alcohol consumption followed by negative effects, such as anxiety, upon cessation. This process is associated with the activation of NLRP3 inflammasome-mediated responses. However, whether and how inhibition of the NLRP3 inflammasome alters alcohol intake and anxiety behavior remains unclear. Methods A combination of drinking-in-the-dark and gavage was established in NLRP3-knockout and control mice. Behavior was assessed by open-field and elevated plus maze tests. Binge alcohol drinking was measured at 2 h and 4 h. A 2 h/4 h/24 h voluntary drinking was determined by a two-bottle choice paradigm. Western blotting and ELISA were applied to examine the levels of the NLRP3 inflammasome and- inflammatory factors, such as IL-1β and TNF-α. Nissl staining was used to measure neuronal injury. The electrophysiological method was used to determine glutamatergic transmission in corticostriatal circuits. In vivo optogenetic LTP and LTD were applied to control the function of corticostriatal circuits on the behavior of mice. MCC950 was used to antagonize the NLRP3 inflammasome. Results The binge alcohol intake was decreased in NLRP3 KO mice compared to the control mice. During alcohol withdrawal, NLRP3 deficiency attenuated anxiety-like behavior and neuronal injury in the mPFC and striatum. Moreover, we discovered that glutamatergic transmission to striatal neurons was reduced in NLRP3 KO mice. Importantly, in vivo optogenetic induction of long-term potentiation (LTP) of corticostriatal circuits reversed the effects of NLRP3 deficiency on glutamatergic transmission and anxiety behavior. We also demonstrated that optogenetic induction of LTD decreased anxiety-like behavior and caused a reduction in glutamatergic transmission. Interestingly, NLRP3 deficiency or inhibition (MCC950 injection) attenuated the anxiety-like behavior, but it did not prevent DID + gavage paradigm-induced a persistent enhancement of drinking in a two-bottle choice at 2 and 4 days into withdrawal. Conclusion Our results demonstrate that NLRP3 deficiency decreases binge alcohol intake and anxiety-like behavior through downregulation of glutamatergic transmission in corticostriatal circuits, which may provide an anti-inflammatory target for treating alcohol use disorders.

Sex-dependent factors of alcohol and neuroimmune mechanisms

“…Similarly, immune factors that are recruited during alcohol dependence (e.g., TNF-α, IL-6, BDNF, etc.) have been shown to modulate inhibitory and excitatory synaptic transmission via the modulation of neurotransmitter release and receptors ( Roberts et al, 2019 ; Li et al, 2022 ; Peregud et al, 2023 ; Coleman and Crews, 2018 ).…”

NLRP3 Inflammasome in Acute and Chronic Liver Diseases

“…Alcohol addiction serves as a foundational element in the development of ALD, and NLRP3 appears to play a role in this context as well. Indeed, a study conducted by Li et al demonstrated that NLRP3-knockout mice exhibit reduced binge alcohol intake and diminished anxiety-like behaviors during alcohol withdrawal compared to those observed in the control mice [59]. Other in vivo studies explored the effects of the IL-1 receptor antagonists in caspase-1, ASC, or type I IL-1β receptor-(IL-1R1) deficient mice, underlining the importance of IL-1β, a product of the NLRP3 inflammasome, in the onset of the inflammation of ALDs [60].…”

Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice

“…Research on depression in various brain regions has been conducted. Notably, the medial prefrontal cortex (MPFC) of rats subjected to chronic social defeat stress (CSDS) exhibits substantial alterations [20], and inflammation or injury in the striatum also influences depressive symptoms [21,22]. Moreover, the nucleus accumbens [23] and the hippocampus [24,25] play crucial roles in depressive behavior.…”