Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury

Abstract

Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.

Serotonergic neurotransmission mediated cognitive dysfunction in two mouse models of sepsis‐associated encephalopathy

“…The dosages of LPS vary among studies investigating the animal model of SAE. Some studies have employed LPS dosages ranging from 2 to 20 mg/kg 32–35 . In our study, we selected a dose of 10 mg/kg LPS (derived from Escherichia coli serotype 055:B5), as our preliminary experiments revealed no significant difference in cognitive function were observed between mice receiving 5 mg/kg LPS and healthy control mice.…”

“…Some studies have employed LPS dosages ranging from 2 to 20 mg/kg. 32 , 33 , 34 , 35 In our study, we selected a dose of 10 mg/kg LPS (derived from Escherichia coli serotype 055:B5), as our preliminary experiments revealed no significant difference in cognitive function were observed between mice receiving 5 mg/kg LPS and healthy control mice. In contrast, a recent study demonstrated noticeable cognitive impairments in mice receiving 2 mg/kg LPS (derived from Escherichia coli serotype 0111:B4).…”

Dexmedetomidine promotes NREM sleep by depressing the neuronal activity of OXT neurons in the PVN

“…OXT-hM3D(Gq)-mCherry mice were injected 1µL 2 µM DEX into internal cannulas at ZT14(22:00) and i.p injected saline or CNO at ZT15.5 (23:30) to investigate the effect of sleep-wakefulness states in PVN OXT neurons (Fig. 2c) [27,28]. Electrophysiological characteristics of PVN OXT neurons of APs were captured using the whole-cell patchclamp method in brain slices immersed in the arti cial cerebrospinal uid (aCSF) with or without 2 µM DEX.…”