2. Academic Validation
  3. Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury

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

  • Theranostics. 2023 May 11;13(9):2946-2961. doi: 10.7150/thno.82889.
Chenglong Ge 1 2 3,  Wei Chen 1 2 3,  Lina Zhang 1 2 3,  Yuhang Ai 1 2 3,  Yu Zou 4,  Qianyi Peng 1 2 3
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China, 410008.
  • 2 National Clinical Research Center for Geriatric Disorders, Changsha, Hunan Province, China, 410008.
  • 3 Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha, Hunan Province, China, 410008.
  • 4 Department of Anesthesia, Xiangya Hospital, Central South University, Changsha, Hunan Province, China, 410008.
PMID: 37284451 DOI: 10.7150/thno.82889
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.

Keywords

Cognitive dysfunction; Hippocampus; Lipopolysaccharide; Medial prefrontal cortex; Sepsis-associated encephalopathy.

Figures
Products