Biology subjects

Birnbaum, S.

Publications and source records attributed to Birnbaum, S..

5 recordsLinked to original sources

bioRxiv2023

Female specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and Estrogen Receptor α

Autism manifests differently in males and females and the brain mechanisms that mediate these sex-dependent differences are unknown. Here, we demonstrate that deletion of the ASD-risk gene, Pten, in neocortical pyramidal neurons (NSEPten KO) results in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). Circuit hyperexcitability in NSEPten KO mice is mediated by enhanced and/or altered signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor (ER) to ERK and protein synthesis selectively in Pten deleted female neurons. In support of this idea, Pten deleted Layer 5 cortical neurons have female-specific increases in mGluR5 and mGluR5-driven protein synthesis. In addition, mGluR5-ER complexes are elevated in female cortex and genetic reduction of ER in Pten KO cortical neurons rescues circuit excitability, protein synthesis and enlarged neurons selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in female NSEPten KO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germline Pten+/- mice. Our results reveal molecular mechanisms by which sex and a high impact ASD-risk gene interact to affect brain function and behavior.

neuroscience↗

bioRxiv2023

Maternal Under-Nutrition During Pregnancy Alters the Molecular Response to Over-Nutrition in Multiple Organs and Tissues in Juvenile Offspring

Previous studies suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We examined whether NHP juvenile offspring of pregnancies with maternal undernutrition (MUN) had altered response to a high-fat, high-carbohydrate diet plus sugar drink challenge (HFCS) compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation, and weaned offspring fed chow diet ad libitum. Offspring of MUN were growth restricted at birth. At [~]4.5y offspring received a 7-week HFCS challenge. Baseline and HFCS gene expression in liver, omental fat, and skeletal muscle, liver glycogen content, and fat cell size were quantified. MUN offspring had lower BMI and liver glycogen compared with CON. Pathway analysis showed differences for skeletal muscle and liver, including hepatic splicing and unfolded protein response. MUN offspring consumed more sugar drink than CON. After HFCS, MUN BMIs were similar to CON. Liver showed coordinated response to HFCS in CON but not MUN. Pathway and liver glycogen differences between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin concentrations, omental adipocyte cell size, liver glycogen content, and tissue-specific molecular response to HFCS challenge suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet. O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/548121v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@b15085org.highwire.dtl.DTLVardef@11d4c1dorg.highwire.dtl.DTLVardef@704209org.highwire.dtl.DTLVardef@1ff9791_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2021

Blood pressure and the kidney cortex transcriptome response to high sodium diet challenge in female nonhuman primates

Blood pressure (BP) is influenced by genetic variation and sodium intake. Ninety percent of Americans consume more than the AHA recommended amount of sodium. Studies on the impact of genetic variation and sodium intake on BP in nonhuman primates (NHP) to date have focused on males. We hypothesized that variation in renal transcriptional networks correlate with BP response to high dietary sodium in female baboons. Sodium-naive female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 betaestradiol, and ultrasound-guided kidney biopsies for RNA-Seq BP were collected at the end of each diet. BP was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Cell type composition of renal biopsies was consistent among all animals for both diets. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. Identification of mechanisms underlying regulators that influence BP will inform better therapies towards greater precision medicine for women.

genomics↗

bioRxiv2020

Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates

BackgroundPoor nutrition during development programs kidney function. No studies on postnatal consequences of decreased perinatal nutrition exist in nonhuman primates (NHP) for translation to human renal disease. Our baboon model of moderate maternal nutrient restriction (MNR) produces intrauterine growth restricted (IUGR) and programs renal fetal phenotype. We hypothesized that the IUGR phenotype persists postnatally, influencing responses to a high-fat, high-carbohydrate, high-salt (HFCS) diet. MethodsPregnant baboons ate chow (Control; CON) or 70% of control intake (MNR) from 0.16 gestation through lactation. MNR offspring were IUGR at birth. At weaning, all offspring (CON and IUGR females and males, n=3/group) ate chow. At ~4.5 years of age, blood, urine, and kidney biopsies were collected before and after a 7-week HFCS diet challenge. Kidney function, unbiased kidney gene expression, and untargeted urine metabolomics were evaluated. ResultsIUGR female and male kidney transcriptome and urine metabolome differed from CON at 3.5 years, prior to HFCS. After the challenge, we observed sex-specific and fetal exposure-specific responses in urine creatinine, urine metabolites, and renal signaling pathways. ConclusionsWe previously showed mTOR signaling dysregulation in IUGR fetal kidneys. Before HFCS, gene expression analysis indicated that dysregulation persists postnatally in IUGR females. IUGR male offspring response to HFCS showed uncoordinated signaling pathway responses suggestive of proximal tubule injury. To our knowledge, this is the first study comparing CON and IUGR postnatal juvenile NHP and the impact of fetal and postnatal life caloric mismatch. Perinatal history needs to be taken into account when assessing renal disease risk.

genomics↗

bioRxiv2018

Analysis of 100 high coverage genomes from a pedigreed captive baboon colony

Baboons (genus Papio) are broadly studied in the wild and in captivity. They are widely used as a non-human primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 years. Unlike other model organisms though, the genomic resources for baboons are severely lacking. This has hindered the progress of studies using baboons as a model for basic biology or human disease. Here, we describe a dataset of 100 high-coverage whole-genome sequences obtained from the mixed colony of olive (P. anubis) and yellow (P. cynocephalus) baboons housed at the SNPRC. These data provide a comprehensive catalog of common genetic variation in baboons, as well as a fine-scale genetic map. We show how the data can be used to learn about ancestry and admixture, and to correct errors in the colony records. Finally, we investigated the consequences of inbreeding within the SNPRC colony and found clear evidence for increased rates of juvenile mortality and increased homozygosity of putatively deleterious alleles in inbred individuals.

genomics↗