Browsing by Subject "Sex differences"
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Item A moderate spinal contusion injury in rats alters bone turnover both below and above the level of injury with sex-based differences apparent in long-term recovery(Elsevier, 2024-04-10) Metzger, Corinne E.; Moore, Robert C.; Pirkle, Alexander S.; Tak, Landon Y.; Rau, Josephina; Bryan, Jessica A.; Stefanov, Alexander; Allen, Matthew R.; Hook, Michelle A.; Anatomy, Cell Biology and Physiology, School of MedicineSpinal cord injury (SCI) leads to significant sublesional bone loss and high fracture rates. While loss of mechanical loading plays a significant role in SCI-induced bone loss, animal studies have demonstrated mechanical loading alone does not fully account for loss of bone following SCI. Indeed, we have shown that bone loss occurs below the level of an incomplete moderate contusion SCI, despite the resumption of weight-bearing and stepping. As systemic factors could also impact bone after SCI, bone alterations may also be present in bone sites above the level of injury. To examine this, we assessed bone microarchitecture and bone turnover in the supralesional humerus in male and female rats at two different ages following a moderate contusion injury in both sub-chronic (30 days) and chronic (180 days) time points after injury. At the 30-day timepoint, we found that both young and adult male SCI rats had decrements in trabecular bone volume at the supralesional proximal humerus (PH), while female SCI rats were not different from age-matched shams. At the 180-day timepoint, there were no statistical differences between SCI and sham groups, irrespective of age or sex, at the supralesional proximal humerus. At the 30-day timepoint, all SCI rats had lower BFR and higher osteoclast-covered trabecular surfaces in the proximal humerus compared to age-matched sham groups generally matching the pattern of SCI-induced changes in bone turnover seen in the sublesional proximal tibia. However, at the 180-day timepoint, only male SCI rats had lower BFR at the supralesional proximal humerus while female SCI rats had higher or no different BFR than their age-matched counterparts. Overall, this preclinical study demonstrates that a moderate contusion SCI leads to alterations in bone turnover above the level of injury within 30-days of injury; however male SCI rats maintained lower BFR in the supralesional humerus into long-term recovery. These data further highlight that bone loss after SCI is not driven solely by disuse. Additionally, these data allude to potential systemic factors exerting influence on bone following SCI and highlight the need to consider treatments for SCI-induced bone loss that impact both sublesional and systemic factors.Item A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection(Frontiers Media, 2024-01-11) Pattnaik, Aryamav; Dhalech, Adeeba H.; Condotta, Stephanie A.; Corn, Caleb; Richer, Martin J.; Snell, Laura M.; Robinson, Christopher M.; Microbiology and Immunology, School of MedicineBackground: Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality. Methods: We inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection. Results: We found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model. Conclusions: Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.Item Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent(Frontiers Media, 2019-02-20) Kasten, Chelsea R.; Zhang, Yanping; Boehm, Stephen L., II; Department of Psychology, School of ScienceThe rise in cannabinoid legalization and decriminalization in the US has been paired with an increase in adolescents that perceive marijuana as a "no risk" drug. However, a comprehensive review of human literature indicates that cannabinoid usage may have both beneficial and detrimental effects, with adolescent exposure being a critical window for harming cognitive development. Although the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are often used together for recreational and medical purposes, no study has previously observed the acute and long-lasting effects of THC+CBD in a battery of behavioral assays analogous to subjective human reports. The current study observed the acute and long-term effects of THC, CBD, and THC+CBD on object recognition memory, anxiety-like behavior, and activity levels in adolescent and adult mice of both sexes. Acute THC alone and in combination with CBD resulted in robust effects on anxiety-like and locomotor behavior. A history of repeated cannabinoid treatment followed by a period without drug administration resulted in minimal effects in these behavioral assays. Most notably, the strongest effects of repeated cannabinoid treatment were seen in adult females administered THC+CBD, which significantly impaired their object recognition. No effects of repeated cannabinoid history were present on hippocampal protein expression. These studies represent a detailed examination of age- and sex-effects of acute and repeated cannabinoid administration. However, the acute and long-term effects of THC with and without CBD on additional behaviors in adolescents and adults will need to be examined for a more complete picture of these drug effects.Item Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)(Wiley, 2023) Cho, Hanna; Mundada, Nidhi S.; Apostolova, Liana G.; Carrillo, Maria C.; Shankar, Ranjani; Amuiri, Alinda N.; Zeltzer, Ehud; Windon, Charles C.; Soleimani-Meigooni, David N.; Tanner, Jeremy A.; Heath, Courtney Lawhn; Lesman-Segev, Orit H.; Aisen, Paul; Eloyan, Ani; Lee, Hye Sun; Hammers, Dustin B.; Kirby, Kala; Dage, Jeffrey L.; Fagan, Anne; Foroud, Tatiana; Grinberg, Lea T.; Jack, Clifford R.; Kramer, Joel; Kukull, Walter A.; Murray, Melissa E.; Nudelman, Kelly; Toga, Arthur; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily J.; Salloway, Stephen; Sha, Sharon; Turner, Raymond Scott; Wingo, Thomas S.; Wolk, David A.; Koeppe, Robert; Iaccarino, Leonardo; Dickerson, Bradford C.; La Joie, Renaud; Rabinovici, Gil D.; LEADS Consortium; Neurology, School of MedicineIntroduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification. Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.Item APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease(Wiley, 2023) Polsinelli, Angelina J.; Logan, Paige E.; Lane, Kathleen A.; Manchella, Mohit K.; Nemes, Sára; Sanjay, Apoorva Bharthur; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of MedicineBackground: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001). Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.Item Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood(MDPI, 2019-10-17) Meyers, Jacquelyn L.; Chorlian, David B.; Johnson, Emma C.; Pandey, Ashwini K.; Kamarajan, Chella; Salvatore, Jessica E.; Aliev, Fazil; Subbie-Saenz de Viteri, Stacey; Zhang, Jian; Chao, Michael; Kapoor, Manav; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John; Tischfield, Jay; Goate, Alison; Foroud, Tatiana; Dick, Danielle M.; Edenberg, Howard J.; Agrawal, Arpana; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDifferences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18-31 (beta coefficients ranged from 0.02-0.06, p-values ranged from 10-6-10-12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective.Item Beyond Massive Univariate Tests: Covariance Regression Reveals Complex Patterns of Functional Connectivity Related to Attention-Deficit/Hyperactivity Disorder, Age, Sex, and Response Control(Elsevier, 2022) Zhao, Yi; Nebel, Mary Beth; Caffo, Brian S.; Mostofsky, Stewart H.; Rosch, Keri S.; Biostatistics and Health Data Science, School of MedicineBackground: Studies of brain functional connectivity (FC) typically involve massive univariate tests, performing statistical analysis on each individual connection. In this study we apply a novel whole-matrix regression approach referred to as Covariate Assisted Principal (CAP) regression to identify resting-state FC brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Methods: Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) who completed a resting-state fMRI scan and a go/no-go task (GNG). We modeled three sets of covariates to identify resting-state networks associated with an ADHD diagnosis, sex, and response inhibition (commission errors) and variability (ex-Gaussian parameter tau). Results: The first network includes FC between striatal-cognitive control (CC) network subregions and thalamic-default mode network (DMN) subregions and is positively related to age. The second consists of FC between CC-visual-somatomotor regions and between CC-DMN subregions and is positively associated with response variability in boys with ADHD. The third consists of FC within the DMN and between DMN-CC-visual regions and differs between boys with and without ADHD. The fourth consists of FC between visual-somatomotor regions and between visual-DMN regions and differs between girls and boys with ADHD and is associated with response inhibition and variability in boys with ADHD. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest. Conclusions: These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.Item Brain dynamics reflecting an intra-network brain state is associated with increased posttraumatic stress symptoms in the early aftermath of trauma(Research Square, 2024-03-08) Sendi, Mohammad; Fu, Zening; Harnett, Nathaniel; van Rooij, Sanne; Vergara, Victor; Pizzagalli, Diego; Daskalakis, Nikolaos; House, Stacey; Beaudoin, Francesca; An, Xinming; Neylan, Thomas; Clifford, Gari; Jovanovic, Tanja; Linnstaedt, Sarah; Germine, Laura; Bollen, Kenneth; Rauch, Scott; Haran, John; Storrow, Alan; Lewandowski, Christopher; Musey, Paul, Jr.; Hendry, Phyllis; Sheikh, Sophia; Jones, Christopher; Punches, Brittany; Swor, Robert; Gentile, Nina; Murty, Vishnu; Hudak, Lauren; Pascual, Jose; Seamon, Mark; Harris, Erica; Chang, Anna; Pearson, Claire; Peak, David; Merchant, Roland; Domeier, Robert; Rathlev, Niels; O'Neil, Brian; Sergot, Paulina; Sanchez, Leon; Bruce, Steven; Sheridan, John; Harte, Steven; Kessler, Ronald; Koenen, Karestan; McLean, Samuel; Stevens, Jennifer; Calhoun, Vince; Ressler, Kerry; Emergency Medicine, School of MedicineThis study examines the association between brain dynamic functional network connectivity (dFNC) and current/future posttraumatic stress (PTS) symptom severity, and the impact of sex on this relationship. By analyzing 275 participants' dFNC data obtained ~2 weeks after trauma exposure, we noted that brain dynamics of an inter-network brain state link negatively with current (r=-0.179, pcorrected= 0.021) and future (r=-0.166, pcorrected= 0.029) PTS symptom severity. Also, dynamics of an intra-network brain state correlated with future symptom intensity (r = 0.192, pcorrected = 0.021). We additionally observed that the association between the network dynamics of the inter-network brain state with symptom severity is more pronounced in females (r=-0.244, pcorrected = 0.014). Our findings highlight a potential link between brain network dynamics in the aftermath of trauma with current and future PTSD outcomes, with a stronger protective effect of inter-network brain states against symptom severity in females, underscoring the importance of sex differences.Item Conditioned Inhibition of Fear and Reward in Male and Female Rats(Elsevier, 2024) Krueger, Jamie N.; Patel, Nupur N.; Shim, Kevin; Ng, Ka; Sangha, Susan; Psychiatry, School of MedicineStimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue.Item Daily patterns of ethanol drinking in adolescent and adult, male and female, high alcohol drinking (HAD) replicate lines of rats(Elsevier, 2012-10) Dhaher, Ronnie; McConnell, Kathleen K.; Rodd, Zachary A.; McBride, William J.; Bell, Richard L.; Department of Psychiatry, IU School of MedicineThe rationale for our study was to determine the pattern of ethanol drinking by the high alcohol-drinking (HAD) replicate lines of rats during adolescence and adulthood in both male and female rats. Rats were given 30 days of 24 h free-choice access to ethanol (15%, v/v) and water, with ad lib access to food, starting at the beginning of adolescence (PND 30) or adulthood (PND 90). Water and alcohol drinking patterns were monitored 22 h/day with a “lickometer” set-up. The results indicated that adolescent HAD-1 and HAD-2 males consumed the greatest levels of ethanol and had the most well defined ethanol licking binges among the age and sex groups with increasing levels of ethanol consumption throughout adolescence. In addition, following the first week of adolescence, male and female HAD-1 and HAD-2 rats differed in both ethanol consumption levels and ethanol licking behavior. Adult HAD-1 male and female rats did not differ from one another and their ethanol intake or licking behaviors did not change significantly over weeks. Adult HAD-2 male rats maintained a relatively constant level of ethanol consumption across weeks, whereas adult HAD-2 female rats increased ethanol consumption levels over weeks, peaking during the third week when they consumed more than their adult male counterparts. The results indicate that the HAD rat lines could be used as an effective animal model to examine the development of ethanol consumption and binge drinking in adolescent male and female rats providing information on the long-range consequences of adolescent alcohol drinking.