Biology subjects

Gaudet, A. D.

Publications and source records attributed to Gaudet, A. D..

5 recordsLinked to original sources

bioRxiv2023

Effects of circadian disruption via dim light at night in C57BL6/J mice on recoveryafter spinal cord injury

Spinal cord injury (SCI) can cause long-lasting locomotor deficits, pain, and mood disorders. Anatomical and functional outcomes are exacerbated by inflammation after SCI, which causes secondary damage. One promising target after SCI is manipulating the circadian system, which optimizes biology and behavior for time of day - including neuroimmune responses and mood- related behaviors. Circadian disruption after SCI is likely worsened by a disruptive hospital environment, which typically includes dim light-at-night (dLAN). Here, we hypothesized that mice subjected to SCI, then placed in dLAN, would exhibit worsened locomotor deficits, pain- like behavior, and anxiety-depressive-like symptoms compared to mice maintained in light days with dark nights (LD). C57BL/6J mice received sham surgery or moderate T9 contusion SCI, then were placed permanently in LD or dLAN. dLAN after SCI did not worsen locomotor deficits; rather, SCI-dLAN mice showed slight improvement in open-field locomotion at the final timepoint. Although dLAN did not alter SCI-induced heat hyperalgesia, SCI-dLAN mice exhibited an increase in mechanical allodynia at 13 days post-SCI compared to SCI-LD mice. SCI-LD and SCI-dLAN mice had similar outcomes using sucrose preference (depressive-like) and open-field (anxiety-like) tests. At 21 dpo, SCI-dLAN mice had reduced preference for a novel juvenile compared to SCI-LD, implying that dLAN combined with SCI may worsen this mood-related behavior. Finally, lesion size was similar between SCI-LD and SCI-dLAN mice. Therefore, newly placing C57BL/6J mice in dLAN after SCI had modest effects on locomotor, pain-like, and mood-related behaviors. Future studies should consider whether clinically-relevant circadian disruptors, alone or in combination, could be ameliorated to enhance outcomes after SCI.

neuroscience↗

bioRxiv2023

Spinal cord injury in mice amplifies anxiety: a novel light-heat conflict test exposes increased salience of anxiety over heat

Spinal cord injury (SCI) predisposes individuals to anxiety and chronic pain. Anxiety- and pain-like behavior after SCI can be tested in rodents, yet commonly used tests assess one variable and may not replicate effects of SCI or sex differences seen in humans. Thus, novel preclinical tests should be optimized to better evaluate behaviors relating to anxiety and pain. Here, we use our newly developed conflict test - the Thermal Increments Dark-Light (TIDAL) test - to explore how SCI affects anxiety- vs. pain-like behavior, and whether sex affects post-SCI behavior. The TIDAL conflict test consists of two plates connected by a walkway; one plate remains illuminated and at an isothermic temperature, whereas the other plate is dark but is heated incrementally to aversive temperatures. Control mice are tested with both plates illuminated (thermal place preference). Female and male mice received moderate T9 contusion SCI or remained uninjured. At 7 days post-operative (dpo), mice with SCI increased dark plate preference throughout the TIDAL conflict test compared to uninjured mice. SCI increased dark plate preference for both sexes, although female (vs. male) mice remained on the heated-dark plate to higher temperatures. Mice with SCI that repeated TIDAL at 7 and 21 dpo showed reduced preference for the dark-heated plate at 21 dpo. Overall, in female and male mice, SCI enhances the salience of anxiety (vs. heat sensitivity). The TIDAL conflict test meets a need for preclinical anxiety- and pain-related tests that recapitulate the human condition; thus, future rodent behavioral studies should incorporate TIDAL or other conflict tests to help understand and treat neurologic disorders.

animal behavior and cognition↗

bioRxiv2022

Sex differences in pain: Spinal cord injury in female and male mice elicits neuropathic pain symptoms

Spinal cord injury (SCI) in humans frequently causes intractable chronic pain. Females are susceptible to worsened pain compared to males, and females may show higher pain prevalence after SCI. Despite this difference in clinical prevalence of SCI pain, few preclinical studies have systematically studied in rodents sex differences in SCI-elicited pain-related behaviors. Here, we leverage data from a large cohort of mice to test whether contusion SCI consistently causes pain symptoms in mice, and to establish whether female (vs. male) mice display heightened hypersensitivity after SCI. Mechanical and heat sensory thresholds were assessed using the von Frey test and Hargreaves test, respectively. In an initial experiment, female mice receiving moderate 60 kDyn SCI or moderate-to-severe 75 kDyn SCI at T9 both exhibited mechanical and heat pain symptoms compared to sham controls. 75 kDyn SCI caused excess motor deficits that confounded defining pain sensitivity at acute times, so the moderate SCI force was used for subsequent experiments. Next, adult female and male C57BL6/J mice received sham surgery or T9 moderate contusion SCI. Comparing female to male mice after SCI, we reveal that mice of both sexes displayed mechanical and heat hypersensitivity compared to sham controls, from acute-to-chronic post-injury times. Females had amplified SCI-elicited hypersensitivity compared to males. Our data suggest that thoracic contusion SCI elicits consistent and persistent pain-associated symptoms, which are more intense in female vs. male mice. These results have important implications for uncovering sex-specific mechanisms and therapeutic targets to ameliorate neuropathic pain after SCI.

neuroscience↗

bioRxiv2022

Anxiety-like behaviors in mice unmasked: Revealing sex differences in anxiety using a novel light-heat conflict test

Anxiety and chronic pain afflict hundreds of millions worldwide. Both anxiety and pain are more prevalent in females compared to males. Unfortunately, robust sex differences in human anxiety are not recapitulated in rodent tests, and results from rodent pain studies frequently fail to translate clinically. Therefore, there is a need to develop tests that reflect the differential salience of anxiety or pain-related stimuli between the sexes. Accordingly, here we introduce the Thermal Increments Dark-Light (TIDAL) conflict test. The TIDAL test places an anxiety-relevant stimulus (dark vs. illuminated chamber) in conflict with a heat-related stimulus (incrementally heated vs. isothermic chamber); mice freely explore the dark-heating and illuminated-isothermic chambers. Here, we aim to determine whether the TIDAL conflict test reveals in mice underappreciated sex differences in anxiety and/or heat sensitivity. We establish in four distinct experiments that females on the TIDAL conflict test persist substantially longer on the dark-heated plate, suggesting that females as compared to males exhibit elevated anxiety-like behavior. Mice more strongly prefer the dark plate on the TIDAL conflict test compared to control thermal place preference with both chambers illuminated. We also reveal that an anxiety-relieving drug, paroxetine, reduces mouse preference for the heating dark plate, supporting the validity of the TIDAL test. Therefore, our new TIDAL conflict test reliably unmasks the relative salience of anxiety (vs. heat sensitivity): mice that are female exhibit robust anxiety-like behaviors not consistently observed in classical tests. Future studies should incorporate TIDAL and other conflict tests to better understand rodent behavior and to identify mechanisms underlying anxiety and pain.

neuroscience↗

bioRxiv2021

Distinct inflammatory and transcriptomic profiles in dominant versus subordinate males in mouse social hierarchies

Social status is a critical factor determining health outcomes in human and nonhuman social species. In social hierarchies with reproductive skew, individuals compete to monopolize resources and increase mating opportunities. This can come at a significant energetic cost leading to trade-offs between different physiological systems. Particularly, changes in energetic investment in the immune system can have significant short and long-term effects on fitness and health. We have previously found that dominant alpha male mice living in social hierarchies have increased metabolic demands related to territorial defense. In this study, we tested the hypothesis that high-ranking male mice favor energetically inexpensive adaptive immunity, while subordinate mice show higher investment in innate immunity. We housed 12 groups of 10 outbred CD-1 male mice in a social housing system. All formed linear social hierarchies and subordinate mice had higher concentrations of plasma corticosterone (CORT) than alpha males. This difference was heightened in highly despotic hierarchies. Using flow cytometry, we found that dominant status was associated with a significant shift in immunophenotypes towards favoring adaptive versus innate immunity. Using Tag-Seq to profile hepatic and splenic transcriptomes of alpha and subordinate males, we identified genes that regulate metabolic and immune defense pathways that are associated with status and/or CORT concentration. In the liver, dominant animals showed an up-regulation of specific genes involved in major urinary production and catabolic processes, whereas subordinate animals showed an up-regulation of genes promoting biosynthetic processes, wound healing, and proinflammatory responses. In spleen, subordinate mice showed up-regulation of genes facilitating oxidative phosphorylation and DNA repair and CORT was negatively associated with genes involved in lymphocyte proliferation and activation. Together, our findings suggest that dominant and subordinate animals adaptively shift energy investment in immune functioning and gene expression to match their contextual energetic demands. HighlightsO_LIImmunity is shaped by stress and energetic pressures associated with social status C_LIO_LIDominant and subordinate mice favor adaptive and innate immunity, respectively C_LIO_LIDominants increase expression of genes involved in energy production C_LIO_LIWound healing and DNA repair genes are upregulated in subordinates C_LIO_LIGenes related to maintaining and signaling social status are upregulated in dominants C_LI

immunology↗