Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior

IntroductionChemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses.MethodsForced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers.Results and discussionWe observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut

Recent experience impacts social behavior in a novel context by adult zebrafish (Danio rerio).

Many animals exhibit behavioral plasticity as they move between habitats seasonally, reside in fluctuating environments, or respond to human-induced environmental change. We know that physical environment during early development can have a lasting impact on behavior, and on the neural mechanisms that shape behavior. In adults, social context can have similar persistent effects on behavior and the brain. Here, we asked whether physical context impacts adult social behavior in a novel environment. We placed groups of adult zebrafish (Danio rerio) in two different physical contexts. After two weeks, we measured group behavior in a novel context, and found that zebrafish with recent experience in a more-complex physical environment charged each other more often and tended to form tighter shoals than did fish that had been housed in less-complex environments. These differences were present regardless of the novel context in which we assayed behavior, and were not easily explained by differences in activity level. Our results demonstrate the impact of recent experiences on adult behavior, and highlight the importance of physical as well as social history in predicting animal behavior in novel situations

Data from: Water flow impacts group behavior in zebrafish (Danio rerio)

Constant temporal and spatial fluctuations of the physical environment pose a great challenge for individual survival, making plastic behavioral responses an important mechanism for coping with environmental fluctuations. For aquatic animals, water flow is one of the most important factors, imposing additional physiological costs and changing their relationship with the biotic environment including conspecifics, predators, and disease agents. Here, we conducted a controlled laboratory experiment to test the influence of water flow on the behavior of zebrafish (Danio rerio), considering also the impact of obstructions. Using wild-caught zebrafish, we formed groups of 6 fish and tested their behavior in 4 treatments that varied in water flow and obstructions. We used automated tracking software to estimate shoal cohesion, aggression, and activity level. Zebrafish strongly responded to the presence of even a weak flow by forming less cohesive, more aggressive, and more active groups. The effect of flow was not exaggerated by turbulence generated from obstructions. Zebrafish were also more active and more aggressive when in a structurally complex context. These findings highlight the plasticity of zebrafish social behavior and provide insight to understand the impact of water flow on behavioral plasticity of social groups

RA_EHA_DATA

Social behavior of RA zebrafish

Table_1_Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior.DOCX

IntroductionChemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses.MethodsForced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers.Results and discussionWe observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.</p