Biology subjects

Correa, S. M.

Publications and source records attributed to Correa, S. M..

12 recordsLinked to original sources

bioRxiv2026

Targeting Estrogen to the Brain via the Prodrug DHED does not Protect Against Metabolic Dysfunction in Obese, OVX mice.

Menopausal hormone therapy (MHT) is prescribed for climacteric symptoms including hot flushes and weight gain and contains estrogens such as 17 beta-estradiol (17{beta}E2). However, estrogen receptor activation by MHT may increase reproductive cancers and cardiovascular event risk in some people. As the protective metabolic effects of 17{beta}E2 are partly mediated through the arcuate nucleus of the hypothalamus, restricting 17{beta}E2 actions to the brain could serve as a safer mechanism of MHT. 10{beta},17{beta}-Dihydroxyestra-1,4-dien-3-one (DHED) is a prodrug of 17{beta}E2 which is enzymatically converted to the parent hormone exclusively within the brain. DHED has demonstrated positive benefit in rodent models of centrally-mediated maladies including hot flushes, depression and cognitive decline, without peripheral hormonal burden. Therefore, we hypothesized that DHED treatment in obese female mice would act within the hypothalamus to provide the same beneficial metabolic effects as 17{beta}E2. Female mice were ovariectomized, placed on a high fat diet and split into either control, DHED, or 17{beta}E2 treatment groups. Body weight, uterus weight and glucose tolerance were recorded along with gonadal hormone receptor expression in the brain. Delivery of DHED at a similar dose as 17{beta}E2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17{beta}E2. Delivery of DHED at higher doses, which elicited estrogen-like actions within the brain, still failed to improve metabolic health. Our findings suggest that peripheral actions, in addition to hypothalamic targets, may be required to mediate 17{beta}E2s protective effects on metabolism and that brain-targeted MHT may be unsuitable for improving metabolic health during menopause.

physiology↗

bioRxiv2025

A bifunctional optical reporter for tracking estrogen response dynamics in neurons

Estrogens are inherently dynamic signaling molecules whose fluctuations induce profound shifts in physiology and behavior. However, methods for tracking the dynamics of estrogen action in vivo are limited and not tissue-specific, making it difficult to directly relate dynamics to ongoing physiological, behavioral, and neural changes. Traditionally, estrogen sensitive cells have been identified by metrics such as receptor expression or radioactive ligand binding, but these measures do not capture the dynamic nature of hormone response. In addition, current methods for assessing the dynamics of estrogens in an individual, including microdialysis and vaginal cytology, lack temporal and spatial resolution.To address this need we developed a bifunctional reporter called neuro-seeER (neuronal see Estrogen Response) that can be used to track changes in exogenous and endogenous estrogen dynamics in vitro and in vivo, including longitudinally in behaving animals. We confirmed that the fluorescent response requires estrogen receptor expression, is specific to activation with estradiol, and is consistent with the timescale of transcriptional induction. Neuro-seeER expression in the hypothalamus of Esr1-Cre mice revealed dynamic labeling of estrogen-responsive cells following treatment with exogenous estradiol, and fluorescence-aided cell sorting followed by RNA-sequencing confirmed that high neuro-seeER response is associated with enriched expression of genes associated with endogenous estrogen responses. Using a novel "snapshot" photometry method to track the dynamics longitudinally in vivo, we demonstrate that we can robustly detect exogenous estrogen response across multiple hypothalamic sites simultaneously. Finally, we demonstrate that this tool is uniquely suited to capturing endogenous estrogen response dynamics in vivo across the long timescale of the estrous cycle, revealing individual differences in neural estrogen dynamics. Together, these findings reveal unexpected cellular and temporal heterogeneity of the transcriptional response and demonstrate the feasibility of tracking the dynamics of hormonal response alongside additional neural, cell signaling, or behavioral measures.

neuroscience↗

bioRxiv2024

Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells

Estrogens have considerable impact on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor alpha (ER) alters energy intake and multiple aspects of energy expenditure, effects that may be mediated by specific regions or neuronal sub-populations of the hypothalamus. This study investigates the function of ER in neurons of the lineage that expresses Rprm (Reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ER in Rprm lineage cells (Reprimo-specific estrogen receptor KO; RERKO) and report changes in core temperature in female mice, with no changes in movement or food intake. RERKO females have elevated brown adipose tissue (BAT) temperature and lower tail temperature relative to controls, suggesting increased heat production and reduced heat dissipation, respectively. Developmental expression of Rprm was detected in the brain, but not in BAT or white adipose tissue suggesting temperature changes may be mediated by the nervous system. To confirm centrally mediated effects on temperature, we ablated Rprm expressing cells in the mediobasal hypothalamus and observed a reduction in core temperature relative to controls. Taken together, these results indicate that estrogen signaling in the Rprm lineage is critical for thermoregulation, mainly through the modulation of brown adipose tissue thermogenesis in female, but not male, mice.

physiology↗

bioRxiv2024

Neural basis of collective social behavior during environmental challenge

Humans and animals have a remarkable capacity to collectively coordinate their behavior to respond to environmental challenges. However, the underlying neurobiology remains poorly understood. Here, we found that groups of mice self-organize into huddles at cold ambient temperature during the thermal challenge assay. We found that mice make active (self-initiated) and passive (partner-initiated) decisions to enter or exit a huddle. Using microendoscopic calcium imaging, we found that active and passive decisions are encoded distinctly within the dorsomedial prefrontal cortex (dmPFC). Silencing dmPFC activity in some mice reduced their active decision-making, but also induced a compensatory increase in active decisions by non-manipulated partners, conserving the groups overall huddle time. These findings reveal how collective behavior is implemented in neurobiological mechanisms to meet homeostatic needs during environmental challenges.

neuroscience↗

bioRxiv2023

Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism

Enzymes of the core energy metabolism pathways tend to assemble into transient supramolecular complexes, yet the functional significance of the interactions within these complexes, particularly between enzymes catalyzing non-consecutive reactions, remains unclear. Here, by co-localizing two non-consecutive enzymes of the TCA cycle from B. subtilis, malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICD), in highly crowded liquid-liquid phase separated droplets we discovered that MDH-ICD interaction causes an enhancement of ICD catalytic rate and an apparent sequestration of its reaction product, 2-oxoglutarate. Theory suggests that the observed phenomena are explained by the MDH-mediating clustering of ICD molecules. In vivo validation with targeted GC-MS and 13C tracer analyses revealed that when B. subtilis is grown on glucose and ammonia, overexpression of MDH leads to accumulation of 2-oxoglutarate with a concomitant reduction of fluxes flowing through both the catabolic and anabolic branches of the carbon-nitrogen intersection occupied by 2-oxoglutarate, resulting in impeded ammonium assimilation and reduced biomass production. Our findings thus suggest that in B. subtilis the MDH-ICD interaction is an important coordinator of carbon-nitrogen metabolism, thereby expanding the list of types of functionally understood unconventional enzyme-enzyme interactions.

microbiology↗

bioRxiv2023

Feeding Neurons Integrate Metabolic and Reproductive States in Mice

Trade-offs between metabolic and reproductive processes are important for survival, particularly in mammals that gestate their young. Puberty and reproduction, as energetically taxing life stages, are often gated by metabolic availability in animals with ovaries. How the nervous system coordinates these trade-offs is an active area of study. We identify somatostatin neurons of the tuberal nucleus (TNSST) as a node of the feeding circuit that alters feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of TNSST neurons increased food intake across sexes, selective ablation decreased food intake only in female mice during proestrus. Interestingly, this ablation effect was only apparent in animals with a low body mass. Fat transplantation and bioinformatics analysis of TNSST neuronal transcriptomes revealed white adipose as a key modulator of the effects of TNSST neurons on food intake. Together, these studies point to a mechanism whereby TNSST hypothalamic neurons modulate feeding by responding to varying levels of circulating estrogens differentially based on energy stores. This research provides insight into how neural circuits integrate reproductive and metabolic signals, and illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by metabolic status.

neuroscience↗

bioRxiv2022

Nuclear Receptor 5A2 Regulation of Agrp underlies Olanzapine-induced Hyperphagia

Summary/AbstractAntipsychotic (AP) drugs are highly efficacious treatments for psychiatric disorders, but a serious side effect of their use is excessive weight gain and subsequent development of metabolic disease. Increased food intake is the underlying driver of AP-induced weight gain, although the underlying mechanisms remain unknown. In previous studies, we identified hypothalamic genes whose expression level was altered following APs-induced hyperphagia. Among these genes, the orexigenic peptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) were two of the most significantly upregulated genes by APs. NR5a2 is broadly expressed throughout the body, but little is known about its role in the brain. In this study, we investigated the role of hypothalamic NR5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, OLZ treatment resulted in a dose-dependent increase in gene expression of NR5a2 and Agrp. In mice, administration of a specific Nr5a2 inhibitor decreased olanzapine-induced hyperphagia and weight gain, while knockdown of Nr5a2 in the arcuate nucleus (ARC) partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation-PCR studies showed for the first time that NR5a2 directly binds to the Agrp promoter region. In addition, in situ hybridization studies confirm that NR5a2 and Agrp are co-localized in a subset of cells in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake and these findings can be used to inform future clinical development of APs that do not activate hyperphagia and weight gain.

physiology↗

bioRxiv2021

Manipulation of carotenoid metabolism stimulates biomass and stress tolerance in tomato

Improving yield, nutritional value and tolerance to abiotic stress are major targets of current breeding and biotechnological approaches that aim at increasing crop production and ensuring food security. Metabolic engineering of carotenoids, the precursor of Vitamin-A and plant hormones that regulate plant growth and response to adverse growth conditions, has been mainly focusing on provitamin A biofortification or the production of high-value carotenoids. Here, we show that the introduction of a single gene of the carotenoid biosynthetic pathway in different tomato cultivars simultaneously improved photosynthetic capacity and tolerance to various abiotic stresses (e.g., high light, salt, and drought), caused an up to 77% fruit yield increase and enhanced fruits provitamin A content and shelf life. Our findings pave the way for developing a new generation of crops that combine high productivity and increased nutritional value with the capability to cope with climate change-related environmental challenges.

plant biology↗

bioRxiv2020

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ER), as conditional knockout of ER in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ER-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ER mediates several key side effects of tamoxifen therapy.

neuroscience↗

bioRxiv2020

Hello darkness, my old friend: 3-Ketoacyl-Coenzyme A Synthase4 is a branch point in the regulation of triacylglycerol synthesis in Arabidopsis by re-channeling fatty acids under carbon starvation

Due to their sessile lifestyle, plants have evolved unique mechanisms to deal with environmental challenges. Under stress, plant lipids are important as alternative sources of carbon and energy when sugars or starch are limited. Here, we applied combined heat and darkness and extended darkness to a panel of [~] 300 Arabidopsis accessions to study lipid remodeling under carbon starvation. Natural allelic variation at 3-KETOACYL-COENZYME A SYNTHASE4 (KCS4), a gene encoding for an enzyme involved in very long chain fatty-acid (VLCFA) synthesis, underlies a differential accumulation of polyunsaturated triacylglycerols (puTAGs) under stress. Ectopic expression in yeast and plants proved that KCS4 is a functional enzyme localized in the ER with specificity for C22 and C24 saturated acyl-CoA. Allelic mutants and transient overexpression in planta revealed the differential role of KCS4 alleles in VLCFA synthesis and wax coverage, puTAG accumulation and biomass. Moreover, the region harboring KCS4 is under high selective pressure and allelic variation at KCS4 correlated with environmental parameters from the locales of Arabidopsis accessions. Our results provide evidence that KCS4 plays a decisive role in the subsequent fate of fatty acids released from chloroplast-membrane lipids under carbon starvation. This work sheds light on both plant response mechanisms and the evolutionary events shaping the lipidome under carbon starvation. One sentence summaryNatural variation at KCS4 underlies a differential accumulation of polyunsaturated triacylglycerols under carbon starvation, by acting as a regulatory branch point in the fate of fatty acids.

genetics↗

bioRxiv2019

Estrogen Drives Melanocortin Neurons To Reduce Sedentary Behavior

Estrogen depletion in rodents and humans leads to inactivity, unhealthy fat accumulation, and diabetes1,2, underscoring the conserved metabolic benefits of estrogen that inevitably decline with aging. In rodents, the preovulatory surge in 17{beta}-estradiol (E2) temporarily allows energy expenditure to outpace energy intake, thus coordinating increased physical activity with peak sexual receptivity. To investigate how estrogen rebalances energy allocation in females, we examine estrogen receptor alpha (ER) signaling in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3-7. We uncover a small population of VMHvlER neurons expressing the melanocortin-4 receptor (MC4R) that integrates estrogen and melanocortin signals and projects to arousal centers in the hippocampus and hindbrain, enabling bursts of physical activity. ER recruitment to the Mc4r gene promotes upregulation of Mc4r in VMHvl neurons during the preovulatory surge or following E2 treatment. We leveraged three models to stimulate VMHvlMC4R neurons, restore MC4R signaling in the VMHvl of hyperphagic MC4R null females, or increase Mc4r levels in the VMHvl by CRISPR-mediated activation. All models increase spontaneous activity, whereas silencing VMHvlMC4R neurons blunts normal activity. Direct activation of the VMHvlMC4R node overrides the inactivity and hypometabolism following hormone depletion. These data extend the impact of MC4R signaling - the most common cause of monogenic human obesity8 - beyond the regulation of food intake. Our findings also rationalize reported sex differences in melanocortin signaling, including the greater disease severity of MC4R insufficiency in women9. The hormone-dependent node identified here illuminates the power of estrogen in motivating behavior during the female reproductive cycle and for maintaining an active lifestyle.

neuroscience↗

bioRxiv2019

Single cell profiling of the VMH reveals a sexually dimorphic regulatory node of energy expenditure

Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ER) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.

neuroscience↗