Vaccination evokes gender-dependent protection against tularemia infection in C57BL/6Tac mice

Francisella tularensis (Ft) is a Category A biothreat agent for which there currently is no FDA-approved vaccine. Thus, there is a substantial effort underway to develop an effective tularemia vaccine. While it is well established that gender can significantly impact susceptibility to primary infection, the impact of gender on vaccine efficacy is not well established. Thus, development of a successful vaccine against tularemia will require an understanding of the impact gender has on vaccine-induced protection against this organism. In this study, a role for gender in vaccine-induced protection following Ft challenge is identified for the first time. In the present study, mucosal vaccination with inactivated Ft (iFt) LVS elicited gender-based protection in C57BL/6Tac mice against respiratory challenge with Ft LVS. Specifically, vaccinated male mice were more susceptible to subsequent Ft LVS challenge. This increased susceptibility in male mice correlated with increased bacterial burden, increased tissue inflammation, and increased proinflammatory cytokine production late in post-challenge infection. In contrast, improved survival of iFt-vaccinated female mice correlated with reduced bacterial burden and enhanced levels of Ft-specific Abs in serum and broncho-alveolar lavage (BAL) fluid post-challenge. Furthermore, vaccination with a live attenuated vaccine consisting of an Ft LVS superoxide dismutase (SodB) mutant, which has proven efficacious against the highly virulent Ft SchuS4 strain, demonstrated similar gender bias in protection post-Ft SchuS4 challenge. Of particular significance is the fact that these are the first studies to demonstrate that gender differences impact disease outcome in the case of lethal respiratory tularemia following mucosal vaccination. In addition, these studies further emphasize the fact that gender differences must be a serious consideration in any future tularemia vaccine development studies.     

PAHs and PM2.5 emissions and female breast cancer incidence in metro Atlanta and rural Georgia

Environmental chemical exposure could be an important etiologic factor for geographic differences in breast cancer incidence. In this study, we examined emissions of polycyclic aromatic hydrocarbons (PAHs) and PM_2.5 in relation to breast cancer incidence in metro Atlanta and rural Georgia by analyzing data from the Surveillance, Epidemiology, and End Results Program and the Environmental Protection Agency. The results showed that metro Atlanta had a significantly higher age-adjusted annual incidence rate of female breast cancer than rural Georgia (132.6 vs. 113.7 per 100,000) for 1992–2011. Emissions of both PAHs [adjusted β = 0.568 (95 % CI: 0.209, 0.927); p = 0.004] and PM_2.5 [adjusted β = 2.964 (95 % CI: 0.468, 5.459); p = 0.023] were significantly associated with breast cancer incidence in metro Atlanta area. This study suggests that ambient air pollution, especially PAHs and PM_2.5, could have a significant impact on the increased incidence of female breast cancer in urban areas.     

Spatiotemporal dynamics of EEG microstates in four- to eight-year-old children: Age- and sex-related effects

The ultrafast spatiotemporal dynamics of large-scale neural networks can be examined using resting-state electroencephalography (EEG) microstates, representing transient periods of synchronized neural activity that evolve dynamically over time. In adults, four canonical microstates have been shown to explain most topographic variance in resting-state EEG. Their temporal structures are age-, sex- and state-dependent, and are susceptible to pathological brain states. However, no studies have assessed the spatial and temporal properties of EEG microstates exclusively during early childhood, a critical period of rapid brain development. Here we sought to investigate EEG microstates recorded with high-density EEG in a large sample of 103, 4–8-year-old children. Using data-driven k-means cluster analysis, we show that the four canonical microstates reported in adult populations already exist in early childhood. Using multiple linear regressions, we demonstrate that the temporal dynamics of two microstates are associated with age and sex. Source localization suggests that attention- and cognitive control-related networks govern the topographies of the age- and sex-dependent microstates. These novel findings provide unique insights into functional brain development in children captured with EEG microstates.     

Toll‐like receptor 4 differentially regulates adult hippocampal neurogenesis in an age‐ and sex‐dependent manner

Toll‐like receptor 4 (TLR4) is primarily responsible for initiating an immune response following pathogen recognition. However, TLR4 is also expressed on neural progenitor cells and has been reported to regulate hippocampal neurogenesis as young male TLR4 knockout mice show increases in cell proliferation and doublecortin positive cells. Whether these effects occur in both sexes and are sustained with normal aging is currently unknown. The present study evaluated whether TLR4 deficiency alters adult hippocampal neurogenesis in young (3–4 months) and aged (18–20 months), male and female, TLR4 deficient (TLR4?/?; B6.B10ScN‐Tlr4lps‐del/JthJ) and wild type (WT) mice. Additionally, neurogenesis within the dorsal and the ventral hippocampal subdivisions was evaluated to determine if TLR4 has differential effects across the hippocampus. Bromodeoxyuridine (BrdU) was administered to quantify new cell survival as well as cell differentiation. Ki‐67 was measured to evaluate cell proliferation. Results show that young TLR4?/? females had higher rates of proliferation and neuronal differentiation in both the dorsal and ventral hippocampus relative to WT females. Young TLR4?/? males show elevated proliferation and neuronal differentiation mainly in the ventral hippocampus. While young TLR4?/? mice show enhanced neurogenesis compared to young WT mice, the increase was not apparent in the aged TLR4?/? mice. Both aged WT and TLR4?/? mice showed a decrease in proliferation, new cell survival, and neuronal differentiation compared to young WT and TLR4?/? mice. The data collectively indicate that TLR4 regulates hippocampal neurogenesis in young adults, but that these effects are region‐specific in males and that females show broader changes in neurogenesis throughout the hippocampus.     

Sex differences in behavior and neuropharmacology of zebrafish

Sex is an important variable in biomedical research. The zebrafish (Danio rerio) is increasingly utilized as a powerful new model organism in translational neuroscience and pharmacology. Mounting evidence indicates important sex differences in zebrafish behavioral and neuropharmacological responses. Here, we discuss the role of sex in zebrafish central nervous system (CNS) models, their molecular mechanisms, recent findings and the existing challenges in this field. We also emphasize the growing utility of zebrafish models in translational neuropharmacological research of sex differences, fostering future CNS drug discovery and the search for novel sex‐specific therapies. Finally, we highlight the interplay between sex and environment in zebrafish models of sex‐environment correlations as an important strategy of CNS disease modeling using this aquatic organism.     

The estrous cycle modulates rat caudate–putamen medium spiny neuron physiology

The neuroendocrine environment in which the brain operates is both dynamic and differs by sex. How differences in neuroendocrine state affect neuron properties has been significantly neglected in neuroscience research. Behavioral data across humans and rodents indicate that natural cyclical changes in steroid sex hormone production affect sensorimotor and cognitive behaviors in both normal and pathological contexts. These behaviors are critically mediated by the caudate–putamen. In the caudate–putamen, medium spiny neurons (MSNs) are the predominant and primary output neurons. MSNs express membrane‐associated estrogen receptors and demonstrate estrogen sensitivity. However, how the cyclical hormone changes across the estrous cycle may modulate caudate–putamen MSN electrophysiological properties remains unknown. Here, we performed whole‐cell patch‐clamp recordings on male, diestrus female, proestrus female, and estrus female caudate–putamen MSNs. Action potential, passive membrane, and miniature excitatory post‐synaptic current properties were assessed. Numerous MSN electrical properties robustly differed by cycle state, including resting membrane potential, rheobase, action potential threshold, maximum evoked action potential firing rate, and inward rectification. Strikingly, when considered independent of estrous cycle phase, all but one of these properties do not significantly differ from male MSNs. These data indicate that female caudate–putamen MSNs are sensitive to the estrous cycle, and more broadly, the importance of considering neuroendocrine state in studies of neuron physiology.