Biology subjects

Tronson, N. C.

Publications and source records attributed to Tronson, N. C..

7 recordsLinked to original sources

bioRxiv2026

Region-specific regulation of glucocorticoid and mineralocorticoid receptor signaling in a mouse model of oral contraceptive exposure

Combined oral contraceptives (OCs), containing synthetic estrogen and a progestin such as levonorgestrel (LVNG), are widely used, and up to 10% of users experience adverse mood states and increased depression risk. It is well-established that OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and blunt the cortisol responses to acute stress. This interaction with stress regulatory pathways is one mechanism by which OCs might impact mood. Here, we used a mouse model of OC exposure (ethinyl estradiol (EE) + LVNG) to investigate how OCs affect regulation of the diurnal CORT cycle and stress-related signaling in the dorsal and ventral hippocampus and paraventricular nucleus of the hypothalamus (PVN). We found that EE+LVNG did not alter basal corticosterone (CORT) levels, but impaired glucocorticoid receptor (GR) - mediated negative feedback in the dexamethasone suppression test. Molecular analyses revealed distinct, region-specific effects. In the dorsal hippocampus, EE+LVNG enhanced glucocorticoid receptor (GR)-dependent gene signaling and prolonged Fkbp5 induction. In the ventral hippocampus, EE+LVNG enhanced mineralocorticoid receptor (MR)-dependent signaling and reduced stress-induced corticotropin-releasing factor expression. In the PVN, EE+LVNG reduced MR expression and modulated MR-dependent signaling. Together, these findings demonstrate that chronic OC exposure disrupts GR- and MR-dependent regulation across stress-related brain regions and impairs glucocorticoid feedback, providing potential mechanisms by which OCs blunt stress responsivity, modify long-term HPA-axis function, and increase susceptibility or resilience to stress and depression.

neuroscience↗

bioRxiv2023

A mouse model of hormonal contraceptive exposure: depression, motivation, and the stress response

Hormonal contraceptives, including oral contraceptives (OCs), regulate hormonal cycles and broadly affect physiological processes, including stress responsivity. Whereas many users describe overall improved mood, up to 10% of OC users experience adverse effects, including depression and anxiety. Given the link between regulation of hypothalamic-pituitary-adrenal (HPA) axis, stress exposure, and risk for depression, it is likely that OC-effects on stress mediate increased risk or increased resilience to these disorders. In this study, we developed and characterized a tractable mouse model of OC exposure with which to identify the mechanisms underlying OC modulation of brain, behavior, and mood. Specifically, we aimed to determine whether translationally relevant doses of OC-hormones in mice mimic changes in stress responsivity observed in humans taking OCs and describe behavioral changes during OC exposure. Young adult female C57Bl/6N mice received daily ethinyl estradiol (EE) and levonorgestrel (LVNG) in 10% sucrose, EE and drospirenone (DRSP) in 10% sucrose, or 10% sucrose alone. Translationally relevant doses of EE+LVNG-exposure, but not EE+DRSP, suppressed the acute stress response, consistent with effects observed in human OC users. EE+LVNG caused a specific anhedonia-like effect, without broad changes in stress-coping behavior, other depression-like behaviors, or anxiety-like behaviors. The suppression of regular estrous cycling, together with the blunting of the corticosterone response to acute stress, demonstrate the utility of this model for future studies to identify the mechanisms underlying OC interactions with stress, motivation, and risk for depression.

neuroscience↗

bioRxiv2022

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here we investigated a post-translational modification of CHTs - poly-ubiquitination - and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in cortex and striatum, but not spleen, were higher in STs than in GTs. Activation of the innate immune system by systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) elevated ubiquitinated CHT levels in cortex and striatum of GTs only, suggesting ceiling effects in STs. In spleen, LPS increased levels of most cytokines in both phenotypes. In cortex, LPS particularly robustly increased levels of the chemokines CCL2 and CXCL10. Phenotype-specific increases were restricted to GTs, again suggesting ceiling effects in STs. These results indicate that interactions between elevated brain immune modulator signaling and CHT regulation are essential components of the neuronal underpinnings of the addiction vulnerability trait indexed by sign-tracking. Significance StatementSign-tracking rats (STs) have emerged as a fruitful animal model for determining the neuro-behavioral foundations, including the cholinergic-attentional control deficits, which heighten the risk for the manifestation of addictive behaviors. The results from the present experiments suggest that, in STs, elevated levels of neuro-immune signaling interact with a post-translational modification of choline transporters that yields a relatively low transporter capacity. Furthermore, the effects of activation of the innate immune system, by administrating the endotoxin lipopolysaccharide, mechanistically supported such an interaction. The results extend research on the neuronal vulnerabilities for addictive behaviors to the role of neuro-immune signaling and suggests a new role of neuro-immune modulators in influencing complex cognitive-motivational traits.

neuroscience↗

bioRxiv2020

Sex differences and similarities in the neuroimmune response to central administration of poly I:C

BackgroundThe neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. MethodsHere, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6 mice. ResultsWe observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1, IL-1{beta}, IL-4, IL-6, TNF, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFN and IFN{gamma} in response to poly I:C, whereas both males and females exhibited elevations of IFN{beta}, demonstrating a specific sex difference in the anti-viral response in the hippocampus. ConclusionOur data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.

neuroscience↗

bioRxiv2019

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

Major illnesses, including heart attack and sepsis, can cause cognitive impairments, depression, and progressive memory decline that persist long after recovery from the original illness. In rodent models of sepsis or subchronic immune challenge, memory deficits also persist for weeks or months, even in the absence of ongoing neuroimmune activation. This raises the question of what mechanisms in the brain mediate such persistent changes in neural function. Here, we used RNA-sequencing as a large-scale, unbiased approach to identify changes in hippocampal gene expression long after a subchronic immune challenge previously established to cause persistent memory impairments in both males and females. We observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, Surprisingly, we also found striking sex differences in both the magnitude of changes and the specific genes and pathways altered, where males showed persistent changes in both immune- and plasticity-related genes three months after immune challenge, whereas females showed few such changes. In contrast, females showed striking differential gene expression in response to a subsequent immune challenge. Thus, immune activation has enduring and sex-specific consequences for hippocampal gene expression and the transcriptional response to subsequent stimuli. Together with findings of long-lasting memory impairments after immune challenge, these data suggest that illnesses can cause enduring vulnerability to, cognitive decline, affective disorders, and memory impairments via dysregulation of transcriptional processes in the brain.

neuroscience↗

bioRxiv2018

Sex-specific memory deficits after subchronic immune challenge

Memory impairments and cognitive decline persist long after recovery from major illness or injury, and correlate with increased risk of later dementia. Here we developed a subchronic peripheral immune challenge model to examine delayed and persistent memory impairments in females and in males. We show that intermittent injections of either lipopolysaccharide or Poly I:C cause memory decline in both sexes that are evident eight weeks after the immune challenge. Importantly, we observed sex-specific patterns of deficits. Females showed impairments in object recognition one week after challenge that persisted for at least eight weeks. In contrast, males had intact memory one week after the immune challenge but exhibited broad impairments in memory tasks including object recognition, and both context and tone fear conditioning several months later. The differential patterns of memory deficits in males and in females were observed without sustained microglial activation or changes in blood-brain barrier permeability. Together, these data suggest that transient neuroimmune activity results in differential vulnerabilities of females and males to memory decline after immune challenge. This model will be an important tool for determining the mechanisms in both sexes that contribute to memory impairments that develop over the weeks and months after recovery from illness. Future studies using this model will provide new insights into the role of chronic inflammation in the pathogenesis of long-lasting memory decline and dementias.

animal behavior and cognition↗

bioRxiv2018

Sex differences in hippocampal cytokines after systemic immune challenge

Increased production of cytokines in the in the brain during illness or injury modulates physiological processes, behavior, and cognitive function. It is likely that the pattern of cytokines, rather than the activation of any individual cytokine, determines the functional outcome of neuroimmune signaling. Cytokine networks may thus be particularly useful for understanding sex differences in immune and neuroimmune activation and outcomes. In this project, we aimed to determine the activation and resolution of hippocampal cytokine networks in both male and female mice. We measured 32 cytokines in the hippocampus and periphery of male and female mice at rest, 2, 6, 24, 48, and 168 hours after an acute systemic injection of lipopolysaccharide (LPS; 250g/kg). We hypothesized that males and females would exhibit both differences in individual cytokine levels and differences in network dynamics of hippocampal cytokines. Cytokines with sex-specific activation by LPS included male-specific elevations of IFN{gamma}, CSF1, CSF2, and IL-10; and female-specific activation of the IL-2 family and IL-4. We also observed differences in time course, where females showed more rapid elevations, and faster resolution of cytokine activity compared with males. Network analysis using ARACNE and Cytoscape demonstrated markedly different hippocampal cytokine networks across sex even at baseline, and sex differences in cytokine network activation states in response to LPS. Analysis of global shifts in cytokine concentrations further identified a period of cytokine and chemokine downregulation at 48 hours that was more pronounced in females compared with males. Together, these findings demonstrate that sex differences in neuroimmune responses include both differences in intensity of the cytokine response, and importantly differences in cytokine networks activated. Such sex differences in cytokine networks in the brain are likely critical for short and long-term functional outcomes associated with neuroimmune activation.

neuroscience↗