Brain: A hodgepodge?

Click on the blue word to focus on us Sepsis is a systemic inflammatory response syndrome caused by various pathogenic microorganisms such as bacteria, viruses, and fungi
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Acute damage to the central nervous system from sepsis elicits behavioral and neuroendocrine adaptive responses to systemic inflammation
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Patients with sepsis develop long-term psychiatric symptoms such as anxiety, depression, and post-traumatic stress disorder after the infection has resolved
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Sepsis affects specific brain regions: Autopsy reports reveal neuronal activation and apoptosis in brainstem and amygdala regions
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The currently widely used animal model of sepsis is the cecal ligation and puncture (CLP) model, which induces mixed intraperitoneal infection and eventually induces sepsis, which can mimic the main features of human sepsis with severe inflammatory response and disease behavior
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Mice exhibited anxiety-like behavior and altered brain responses such as fear memory a few weeks after CLP induction
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 The basolateral amygdala (BLA) and central amygdala (CeA), subregions of the amygdala, are core brain regions that regulate anxiety and fear memory
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There are two types of inhibitory neurons in CeA: expression of protein kinase Cδ (PKCδ) and somatostatin (SOM)
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April 19, 2022 The research team of Gabriel Lepousez at the University of Paris-Site-It has revealed the neural circuit mechanism that causes long-term psychiatric symptoms after sepsis
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Figure 1: Sepsis Causes Anxiety-Like Behaviors Researchers found elevated levels of inflammatory cytokines IL-1β and TNF in the brains of sepsis model mice after 2 weeks of CLP and developed anxiety- and PTSD-like behavior
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Brain regions associated with anxiety and fear memory circuits were highly activated during the acute phase of the disease: CeA and vBNST (bed nucleus of stria terminalis), while neuronal activity in the BLA region was reduced
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Figure 2: Virus tracer analysis CeA-PKCδ→vBNST loop immunofluorescence experiments found that CeA-activated neurons in sepsis model mice were mainly PKCδ+ neurons, and SOM-positive neurons were almost not activated
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Further viral tracing experiments revealed that these activated PKCδ+ neurons in the CeA region mainly projected to vBNST
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Fiber optic calcium imaging also found that CeA-PKCδ projections to the vBNST region (CeA-PKCδ→vBNST) increased neuronal activity during sepsis
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Epilepsy abnormal electrical activity is detected in the brains of more than 10% of patients with sepsis
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EEG experiments found that epileptiform activity was also present in mice with sepsis
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Levetiracetam is a new type of antiepileptic drug
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In addition to this classic antiepileptic effect, it has applications in suppressing cortical neural circuit excitability in neurodegenerative diseases and ischemic brain injury
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In sepsis model mice, levetiracetam treatment can significantly reduce the activity of neurons in the CeA region, and the activity of CeA-PKCδ→vBNST neurons is also attenuated
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Photoactivation of the CeA-PKCδ→vBNST neural circuit resulted in enhanced neuronal activity, which could be blocked by levetiracetam
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These results suggest that levetiracetam exerts an inhibitory effect on the CeA-PKCδ→vBNST loop
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Figure 3: Antiepileptic drugs alleviate sepsis-induced anxiety-like behaviors in a sepsis model.
Intraperitoneal injection of levetiracetam attenuates anxiety-like and PTSD behaviors in the acute phase
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This suggests that levetiracetam may exert the above-mentioned therapeutic effects by inhibiting the CeA-PKCδ→vBNST loop
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To further confirm this possibility, the researchers specifically inhibited the CeA-PKCδ→vBNST loop through chemogenetic techniques, which significantly attenuated anxiety-like behaviors and post-traumatic stress disorder
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Overall, we found that overactivation of the CeA-PKCδ→vBNST circuit is a key factor in sepsis-induced anxiety-like behaviors and long-term mental disorders such as post-traumatic stress disorder, and this neural circuit can be rapidly inhibited by antiepileptic drugs.
Block the above-mentioned mental disorders
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[Reference] 1.
Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours, https://doi.
org/10.
1093/brain/awab475 The pictures in the text are from the reference