•Passive FMT by coprophagia attenuates paclitaxel-induced inflammation.•Gut microbes associate with chemotherapy-induced inflammation and behavior.•Gut microbial transplants from paclitaxel-treated ...mice cause anxiety-like behavior.•Chemotherapy GMT causes neuroinflammation in germ-free recipient mice.
Chemotherapy treatment is associated with acute behavioral side effects (fatigue, anorexia) that significantly reduce patient quality of life and are dose-limiting, thereby increasing mortality (Kidwell et al., 2014). Disruptions to gut homeostasis (diarrhea, constipation, microbial dysbiosis) are also observed in patients receiving chemotherapy. In non-oncological patients, facets of mental health (fatigue, anxiety, depression) correlate with alterations in the gut microbiome, suggestive of a contribution of the gut in CNS disease etiology. The potential gut-to-brain pathway is poorly understood in patients receiving chemotherapy. Our prior studies have demonstrated a correlation between chemotherapy treatment, gut changes, peripheral and central inflammation, and behavioral symptoms in mice. Here we aimed to determine the extent to which chemotherapy-associated gut manipulations modulate the behavioral and biological consequences of chemotherapy. We measured sickness behaviors, peripheral and central inflammatory mediators, and anxiety in conventional or germ-free female mice: 1) cohabitating with mice of the opposite treatment group, 2) pre-treated with broad-spectrum antibiotics, or 3) given an intra-gastric gavage of gut content from chemotherapy-treated mice. In cohabitation studies, presumed coprophagia promoted body mass recovery, however strong associations with inflammation and behavior were not observed. Reduction of gut microbial alpha diversity via antibiotics did not prevent chemotherapy-associated side effects, however the relative abundances of the genera Tyzzerella, Romboutsia, and Turicibacter correlated with circulating inflammatory (IL-1β) and behavioral outcomes (lethargy, anxiety-like behavior). A gut microbiota transplant from chemotherapy-treated mice decreased central locomotion in open field testing, increased circulating CXCL1, and increased hippocampal Il6 and Tnfa in germ-free mice compared to germ-free mice that received a transplant from vehicle-treated mice. Taken together, these data provide further evidence that the gut microbiota likely contributes to the development of chemotherapy-associated side effects. This work has significant implications in the future treatment of anxiety in patients, and warrants future studies using microbe-based treatment options.
Chemotherapy treatment negatively affects the nervous and immune systems and alters gastrointestinal function and microbial composition. Outside of the cancer field, alterations in commensal bacteria ...and immune function have been implicated in behavioral deficits; however, the extent to which intestinal changes are related to chemotherapy-associated behavioral comorbidities is not yet known. Thus, this study identified concurrent changes in behavior, central and peripheral immune activation, colon histology, and bacterial community structure in mice treated with paclitaxel chemotherapy. In paclitaxel-treated mice, increased fatigue and decreased cognitive performance occurred in parallel with reduced microglia immunoreactivity, increased circulating chemokine expression (CXCL1), as well as transient increases in pro-inflammatory cytokine/chemokine (Il-1β, Tnfα, Il-6, and Cxcl1) gene expression in the brain. Furthermore, mice treated with paclitaxel had altered colonic bacterial community composition and increased crypt depth. Relative abundances of multiple bacterial taxa were associated with paclitaxel-induced increases in colon mass, spleen mass, and microglia activation. Although microbial community composition was not directly related to available brain or behavioral measures, structural differences in colonic tissue were strongly related to microglia activation in the dentate gyrus and the prefrontal cortex. These data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis.
Abstract Adult mammalian brains are capable of some structural plasticity. Although the basic cellular mechanisms underlying learning and memory are being revealed, extrinsic factors contributing to ...this plasticity remain unspecified. White-footed mice ( Peromyscus leucopus ) are particularly well suited to investigate brain plasticity because they show marked seasonal changes in structure and function of the hippocampus induced by a distinct environmental signal, viz., photoperiod (i.e. the number of hours of light/day). Compared to animals maintained in 16 h of light/day, exposure to 8 h of light/day for 10 weeks induces several phenotypic changes in P. leucopus , including reduction in brain mass and hippocampal volume. To investigate the functional consequences of reduced hippocampal size, we examined the effects of photoperiod on spatial learning and memory in the Barnes maze, and on long-term potentiation (LTP) in the hippocampus, a leading candidate for a synaptic mechanism underlying spatial learning and memory in rodents. Exposure to short days for 10 weeks decreased LTP in the Schaffer collateral–CA1 pathway of the hippocampus and impaired spatial learning and memory ability in the Barnes maze. Taken together, these results demonstrate a functional change in the hippocampus in male white-footed mice induced by day length.
It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We ...hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1β injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.
The effects of perinatal and postweaning photoperiods on subsequent affective behaviors were examined in adult Siberian hamsters (
Phodopus sungorus
). Hamsters exposed perinatally to short days (8 ...hr light/day) exhibited mixed results for adult anxiety-like behaviors and increased some depressive-like behaviors compared with hamsters exposed to long days (16 hr light/day). Postweaning exposure to short days increased depressive- and anxiety-like behaviors compared with long days. Sex differences in affective behaviors were observed. These results suggest that anxiety-like behaviors are organized early in life and endure throughout adulthood, and anxiety- and depressive-like behaviors are modified by postweaning photoperiod. The persistence of photoperiod-induced affective behaviors in rodents supports the hypothesis that symptoms of human affective disorders may reflect ancestral adaptations to seasonal environments.
Seasonally breeding animals use a combination of photic (i.e. day length) and nonphotic (e.g. food availability, temperature) cues to regulate their reproduction. How these environmental cues are ...integrated is not understood. To assess the potential role of two candidate neuropeptides, kisspeptin and RFamide‐related peptide‐3 (RFRP), we monitored regional changes in their gene expression in a seasonally breeding mammal exposed to moderate changes in photoperiod and food availability. Adult male Siberian hamsters (Phodopus sungorus) were housed under a long (16 h light/day; 16 L) or intermediate (13.5 L) photoperiod and fed ad lib. or a progressive food restriction schedule (FR; reduced to 80% of ad lib.) for 11 weeks. Gonadal regression occurred only in FR hamsters housed under 13.5 L. Immunohistochemistry was used to identify diencephalic populations of kisspeptin‐ and RFRP‐immunoreactive cells, and quantitative PCR was used to measure gene expression in adjacent coronal brain sections. Photoperiod, but not food availability, altered RFRP mRNA expression in the dorsomedial sections, whereas food availability but not photoperiod altered Kiss1 expression in the arcuate sections; intermediate photoperiods elevated RFRP expression, and food restriction suppressed Kiss1 expression. Regional‐ and neuropeptide‐specific activity of RFamides may provide a mechanism for integration of multi‐modal environmental information in the seasonal control of reproduction.
•Chemotherapy induces microbiome disruption, inflammation, and cognitive decline.•The resulting microbiome disruption relates to cognitive decline and inflammation.•Those cognitively impaired have ...unique chemotherapy-induced microbiome alterations.
Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.
Although seasonal changes in brain morphology and function are well established in songbirds, seasonal plasticity of brain structure and function remain less well documented in mammals. Nontropical ...animals display many adaptations to reduce energy use to survive winter, including cessation of reproductive activities. Because of the high energetic costs of brain tissue, we hypothesized that male white-footed mice (Peromyscus leucopus) would reduce brain size in response to short days as well as regress their reproductive systems. Because short days may decrease hippocampal volume and impair spatial learning and memory in rodents and because of the potential for seasonal plasticity in the hippocampus, we hypothesized that photoperiod alters hippocampal morphology to affect spatial learning and memory. Mice housed in either long or short days for 10 weeks were examined for performance in a water maze; brains were then removed and weighed, and hippocampal volumes were determined. We also measured dendritic morphology and spine density in the CA1, CA3, and dentate gyrus. Short days decreased brain mass and hippocampal volume compared with long days. Short days also impaired long-term spatial learning and memory relative to long days but did not affect sensory discrimination or other types of memory. Short days decreased apical (stratum lacunosum-moleculare) CA1 spine density, as well as increased basilar (stratum oriens) CA3 spine density. Results from this study suggest that photoperiod alters brain size and morphology, as well as cognitive function. Understanding the mechanisms mediating these photoperiod-induced alterations may provide insight for treatment of seasonal cognitive and affective disorders.
Sick animals display a constellation of behaviors, including anhedonia, anorexia, and reduced social interactions. Acute infection eliminates female mating behavior, but fails to attenuate mating ...behavior in male rats. These results have been attributed to the different reproductive strategies and parental investment of the two sexes. Males putatively suppress the symptoms of infection in order to “deceive” females into mating. We sought to investigate the mechanisms responsible for this suppression. Adult male CD-1 mice were treated with lipopolysaccharide (LPS; a component of bacterial cell walls; 400
μg/kg), then paired 2
h later with a receptive female or juvenile male or remained isolated. Blood samples and brains of the males were collected 3
h post-LPS; hypothalamic interleukin-1 (
IL-
1) and tumor necrosis factor-α (
TNFα) gene expression was measured using RT-PCR. Contrary to our prediction, exposure to a female
increased hypothalamic
IL-
1 and
TNFα gene expression. LPS treatment significantly decreased testosterone and increased corticosterone secretions. Social interactions altered absolute corticosterone concentrations in saline-injected animals only. In order to determine whether increased production of hypothalamic cytokines reflected increased severity of sickness responses, body temperature was monitored in a second group of mice implanted with telemetric transmitters. Body mass, food intake, and consumption of sweetened condensed milk (a highly favored food) were also monitored in these mice for 72
h post-injection. LPS injections reduced milk intake, an effect that was modulated by social interactions; however, fever was unaltered relative to isolated animals. These results suggest that social interactions can adjust behavioral responses to infection although the ultimate cause of this adjustment remains unspecified.
Even after successful cancer treatment, survivors report distinct physical and mental health problems, which reduce quality of life. Little is known about the mechanisms underlying the enduring ...neurobehavioral consequences of a former cancer experience. The objective of this project was to develop a tumor-resected “survivor” mouse model by which to investigate these persistent effects. We hypothesized that mouse mammary tumors induce neuroinflammation, increase affective-like behaviors, and cognitive function, all of which are attenuated by tumor resection. Murine cancer cells (67NR) were injected into mammary fat pads of 9-week old, group-housed anesthetized female Balb/c mice. Non-tumor controls underwent sham surgery. Body mass and tumor size were recorded biweekly. These tumors are non-metastatic and after 2 weeks (tumors ∼ 0.75 cm3 ), tumors in some mice were surgically resected (“survivor” group) with clean margins (no recurrence). Two weeks after these treatments (sham, tumor, tumor resection), all mice were tested using a battery of standardized behavioral tests. To assess immune activation, inflammatory gene expression was quantified in various brain regions, as well as circulating inflammatory markers and immune cells. Preliminary results indicate that tumor resection attenuated IL-1beta expression in the hippocampus and specific peripheral immune measures. However, circulating immune cell trafficking and behavior did not return to levels of tumor-free control mice, suggesting that the influence of tumors endures. These immune changes may mediate prolonged behavioral comorbidities.
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