Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression

Wolff, Brian S.; Raheem, Sumiyya; Alshawi, Sarah; Regan, Jeniece; Feng, Linyin; Saligan, Leorey N.

doi:10.1371/journal.pone.0235566

Cited by 5 publications

(9 citation statements)

References 34 publications

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“…The fact that mice do not display fatigue in a tail irradiation model is expected and does not contradict previous observations ( 42 – 45 ), as this model was used not to explain a unifying mechanism behind radiation-induced fatigue but to demonstrate a previously unidentified skin-specific mechanism contributing to fatigue, which can be reliably measured in rats. Certainly, there are multiple mechanisms contributing to fatigue in both humans and animal models.…”

Section: Discussionsupporting

confidence: 59%

β-Endorphin mediates radiation therapy fatigue

et al. 2022

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Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. β-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as β-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived β-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma β-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either β-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived β-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.

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Section: Discussionsupporting

confidence: 59%

β-Endorphin mediates radiation therapy fatigue

et al. 2022

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“…Mouse models of accelerating aging (SOD1-knockout mice) show a selective deficit in reversal learning (Logan et al, 2018), suggesting that aging may primarily cause a problem in behavioral flexibility. An interesting observation was made in reversal learning for mice in which fatigue is induced by pelvic irradiation (Wolff et al, 2020): fatigued mice showed reduced performance in the task, but not because of a learning deficit but because they engaged the task at a slower pace, illustrating the value of the PhenoTyper being able to distinguish between the two.…”

Section: Measuring Learning and Cognitive Functionsmentioning

confidence: 99%

Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives

Grieco

Bernstein

Biemans

et al. 2021

Front. Behav. Neurosci.

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The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper® home-cages and the video-based tracking software, EthoVision® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a “home-cage”, we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios.

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“…In each Y maze assessment, SV and HV mice displayed normal spontaneous alternation (Fig. 4E), suggesting comparable cognitive ability regarding exploration and acute spatial memory ( 48 ). At the Late timepoint, HV animals exhibited increased mobility assessed by total Y maze arm entries, as well as total distance travelled, average speed, and immobility (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…Interorgan crosstalk is inherently bidirectional (15,16) and vagal brain arcs likely shape neurological side effects linked to HCC. We next explored whether hepatic vagotomy altered behaviors associated with liver cancer (e.g., aberrant fatigue) (46)(47)(48)(49).…”

Section: Ach Signaling Affects Cd8+ T Cell Anti-tumor Activitymentioning

confidence: 99%

“…Following facility acclimatization, vagotomized HCC mice underwent a battery of established behavioral tests, including phenotyping, open field test (OFT), and Y-maze (Fig. 4A) (48,50,51). To address neurological behaviors elicited by vagotomy versus tumor, a "Baseline" series of tests were performed prior to RIL175 tumor implantation.…”

Section: Vagotomy Benefits Neurological Function In Hcc Tumor-bearing...mentioning

confidence: 99%

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The Gut Microbiome Controls Liver Tumors via the Vagus Nerve

Bauer,

Trehan,

Ruf

et al. 2024

Preprint

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Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of Chrm3 on CD8+ T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer-associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, increasing Desulfovibrionales and Clostridial taxa. Strikingly, in tumor-free mice, vagotomy permitted HCC-associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis.

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Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression

Cited by 5 publications

References 34 publications

β-Endorphin mediates radiation therapy fatigue

β-Endorphin mediates radiation therapy fatigue

Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives

The Gut Microbiome Controls Liver Tumors via the Vagus Nerve

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