Preclinical Models of Overwhelming Sepsis Implicate the Neural System that Encodes Contextual Fear Memory

Huerta, Patricio T.; Robbiati, Sergio; Huerta, T.; Sabharwal, Anchal; Berlin, Rose A; Frankfurt, Maya; Volpe, Bruce T.

doi:10.2119/molmed.2015.00201

Cited by 25 publications

(19 citation statements)

References 74 publications

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“…These results together with our previous and submitted data [34, 59] support the idea that exposure to sepsis using the CLP model caused altered behavior. The association with reproducible and focal pathological changes reflected by the chronic loss of dendrites confined to the apical region of the CA1 hippocampus in this work describes the pathology at a new level.…”

Section: Resultssupporting

confidence: 87%

“…CLP mice spend significantly more time solving spatial memory problems, and the partial report of the neuropathological changes showed decreased spine density in the apical, but not basilar, dendritic tree [34] and [59]. …”

Section: Resultsmentioning

confidence: 99%

“…The analysis of the Sholl dendrite arbors is consistent with the spine data that we have already reported [34]; namely, the CA1 hippocampal apical spine density is diminished [by 4 weeks after CLP, the apical spine density was 0.51 ± 0.09 spines/ μ m compared to sham = 1.12 ± 0.14 spines/ μ m ( P < 0.05), and 16 weeks after CLP the apical spine density was 0.48 ± 0.02 spines/ μ m compared to sham = 0.94 ± 0.07 spines/ μ m ( P < 0.05)], yet the basal dendrite spine density was comparable across CLP and sham mice [59]. …”

Section: Resultsmentioning

confidence: 99%

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The brain at risk: the sepsis syndrome and lessons from preclinical experiments

2015

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There is a growing awareness of the chronic brain injury that results from the sepsis syndrome. We review experiments in several animal models of sepsis and show in one model, cecal ligation and puncture (CLP), that permanent structural pathology matures after the initial event. Specifically, we observed after exposure to CLP significant decreased spine density on the apical tree, but not the basal tree, of dendrites in the CA1 region of the dorsal hippocampus that was accompanied by a significantly diminished arbor of the apical dendrites, by 8 weeks, but not after 2 weeks. These novel data from dendritic arborizations elaborate information about a cohort of mice that had behaved in spatial memory tasks. These results raise questions about the relationship between long-term behavioral consequences and intervention strategies.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The brain at risk: the sepsis syndrome and lessons from preclinical experiments

2015

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“…Another mouse study saw the same delayed deterioration 2 months after CLP, but only in the apical dendritic tree of the dorsal hippocampus, and found it was specifically associated with worse spatial memory in a navigational test ( 54 ). A third study of CLP-exposed mice also saw decreased spine density in hippocampal neurons 2 months and 6 months postsurgery, and in addition, found the same effect in the basolateral amygdala (BLA) associated with impaired contextual fear memory ( 55 ). Thus, there is evidence that sepsis in particular can cause lasting hippocampal structural damage with associated impairment in cognitive function in rodents.…”

Section: Methodsmentioning

confidence: 89%

Glucocorticoids and the Brain after Critical Illness

Hill

Spencer-Segal

2021

Endocrinology

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Treatment for critical illness typically focuses on a patient’s short-term physical recovery; however, recent work has broadened our understanding of the long-term implications of illness and treatment strategies. In particular, survivors of critical illness have significantly elevated risk of developing lasting cognitive impairment and psychiatric disorders. In this review, we examine the role of endogenous and exogenous glucocorticoids in neuropsychiatric outcomes following critical illness. Illness is marked by acute elevation of free cortisol and adrenocorticotropic hormone suppression, which typically normalize after recovery; however, prolonged dysregulation can sometimes occur. High glucocorticoid levels can cause lasting alterations to the plasticity and structural integrity of the hippocampus and prefrontal cortex, and this mechanism may plausibly contribute to impaired memory and cognition in critical illness survivors, though specific evidence is lacking. Glucocorticoids may also exacerbate inflammation-associated neural damage. Conversely, current evidence indicates that glucocorticoids during illness may protect against the development of post-traumatic stress disorder. We propose future directions for research in this field, including determining the role of persistent glucocorticoid elevations after illness in neuropsychiatric outcomes, the role of systemic vs neuroinflammation, and probing unexplored lines of investigation on the role of mineralocorticoid receptors and the gut–brain axis. Progress toward personalized medicine in this area has the potential to produce tangible improvements to the lives patients after a critical illness, including Coronavirus Disease 2019.

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“…In contrast, other studies show memory deficits in the absence of ongoing neuroimmune activation in both CLP (Huerta et al, 2016;Singer et al, 2016) and LPS models (Ming et al, 2015;Tchessalova and Tronson, 2019). Here, structural changes in the brain after transient immune challenge, including dysregulation of dendritic spine turnover or density and neuronal loss have been implicated as potential mechanisms for persistent memory impairments (Semmler et al, 2007;Liu et al, 2008;Kondo et al, 2011;Volpe et al, 2015).…”

Section: Introductionmentioning

confidence: 95%

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

Tchessalova

Tronson

2019

Preprint

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Acknowledgements:We would like to acknowledge the University of Michigan Bioinformatics core for their expertise and data analysis of differentially expressed genes and the University of Michigan DNA sequencing core for their processing of samples. We would like to sincerely thank Dr. Shigeki Iwase and Christina Vallianatos for their advice, support, and assistance with prepping of the RNA samples. We would also very much like to thank them for allowing us to use their laboratory equipment for RNA extraction.We thank Ms. Brynne Raines, Ms. Melanie Gil, and Ms. Caitlin Posillico for their extensive feedback on this manuscript. ABSTRACTMajor illnesses, including major surgery, heart attack, and sepsis, can cause long-lasting cognitive impairments, depression, and progressive memory decline that persist well after recovery from the original illness. Similarly, in animal models, immune challenge results in impairments of learning and memory as well as increased depression-like behaviors. Although neuroimmune signaling is now well established as playing a crucial role in the modulation of neural functions, how transient immune signaling mediates enduring changes in cognition, memory, and emotion remains unknown. We have recently demonstrated that a series of intermittent injections of lipopolysaccharides over a two-week period resulted in sex-specific patterns of memory deficits that persist at least several months after the end of the immune challenge. Here, we examined the persistent changes in hippocampal gene expression three months after this subchronic systemic immune challenge in males and in females. We used RNA-sequencing as a large-scale, unbiased approach to identify both persistent changes in gene expression long after an immune challenge, and changes in transcriptional response to a subsequent immune challenge. Males and females differed in number and patterns of gene expression in the hippocampus. In males, we observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, in the absence of an additional insult. In contrast, females showed few persistent changes under basal conditions, but striking dysregulation of gene expression in response to an additional acute LPS injection. Striking sex differences in the specific genes, pathways, and biological processes affected were observed both after subchronic immune challenge and after a subsequent insult. Thus, subchronic systemic immune activation has enduring and sex-specific consequences for gene expression and response to subsequent stimuli. Such persistent changes in neural functions further suggest that in both males and females, neuroimmune signaling during illness contributes to subsequent vulnerability or resilience to cognitive decline, memory impairments, and affective disorders.

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Preclinical Models of Overwhelming Sepsis Implicate the Neural System that Encodes Contextual Fear Memory

Cited by 25 publications

References 74 publications

The brain at risk: the sepsis syndrome and lessons from preclinical experiments

The brain at risk: the sepsis syndrome and lessons from preclinical experiments

Glucocorticoids and the Brain after Critical Illness

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

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