Biology subjects

Figueroa, J. D.

Publications and source records attributed to Figueroa, J. D..

10 recordsLinked to original sources

bioRxiv2024

Impact of adolescent high-fat diet and psychosocial stress on neuroendocrine stress responses and binge eating behavior in adult male Lewis rats

Childhood obesity is a multifactorial disease affecting more than 160 million adolescents worldwide. Adolescent exposure to obesogenic environments, characterized by access to high-fat diets and stress, precipitates maladaptive eating habits in adulthood such as binge eating. Evidence suggests a strong association between Western-like high-saturated-fat (WD) food consumption and dysregulated hormone fluctuations. However, few studies have explored the long-term impact of adolescent WD and psychosocial stress on brain and behavior. This longitudinal study aimed to investigate the impact of adolescent exposure to an obesogenic diet on stress resiliency and increased susceptibility for binge-like eating behaviors. Adolescent male Lewis rats were given WD (41% fat; n=40) or control diet (CD, 16% fat; n=38) for 4 weeks before undergoing a stress paradigm of predator exposure and social instability (CDE, WDE, CDU, WDU; n=16/group). Subjects were provided intermittent WD access (24 h/week) to evaluate binge eating-like behavior in adulthood. Fecal corticosterone and testosterone were measured at four timepoints throughout adolescence and adulthood. WD rats exhibited increased body weight (p = 0.0217) and elevated testosterone in mid-adolescence (p=0.0312) and blunted stress-induced corticosterone response in mid-late adolescence (CDE:WDE, p=0.028). Adolescent hormone levels were negatively correlated with bingeing and explained the variability between adult rats expressing hyperphagic and hypophagic behaviors. These results demonstrate that exposure to WD in adolescence disrupts hormone fluctuations and stress responsivity, with effects persisting into adulthood. This underscores the importance of addressing obesogenic environments early to mitigate their lasting impact on hormone regulation and stress responsiveness.

neuroscience↗

bioRxiv2024

Shifts in Naturalistic Behaviors Induced by Early Social Isolation Stress are Associated with Adult Binge-like Eating in Female Rats

Binge eating (BE) is a highly pervasive maladaptive coping strategy in response to severe early life stress such as emotional and social neglect. BE is described as repeated episodes of uncontrolled eating and is tightly linked with comorbid mental health concerns. Despite social stressors occurring at a young age, the onset of BE typically does not occur until adulthood providing an interval for potential therapeutic intervention. Currently, our knowledge of longitudinal noninvasive digital biomarkers predictive of BE needs further development. Monitoring longitudinal impacts of adolescent social isolation stress on naturalistic behaviors in rats will enable the identification of noninvasive digital markers of disease progression to predict adult eating strategies. Recognizing adolescent naturalistic behaviors shaped by social stress informs our understanding of the underlying neurocircuits most effected. This study aimed to monitor and identify longitudinal behavioral shifts to enhance predictive capabilities in a rat model of social isolation stress-induced BE. We placed Paired (n=12) and Socially Isolated (SI, n=12) female rats in observational home cages weekly for seven weeks to evaluate the effect of SI on 10 naturalistic behaviors. All 10 naturalistic behaviors were simultaneously detected and tracked using Noldus Ethovision XT automated recognition software. Composite phenotypic z-scores were calculated by standardizing all 10 behaviors. When transitioning into adulthood, all rats underwent conventional emotionality testing and were exposed to a Western-like high fat diet (WD, 43% kcal from fat) to evaluate BE. Longitudinal assessments revealed SI-induced shifts in adolescent phenotypic z-scores and that sniffing, unsupported rearing, jumping, and twitching were the most susceptible to SI. SI increased emotionality compared to the Paired controls. Finally, we identified adolescent twitching as a digital biomarker of adult WD consumption. This study employed novel approaches to identify early life predictive biomarkers of adult eating strategies and laid a foundation for future investigations.

neuroscience↗

bioRxiv2024

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naive, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

neuroscience↗

bioRxiv2023

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/537874v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1bb1277org.highwire.dtl.DTLVardef@b978dborg.highwire.dtl.DTLVardef@adafc8org.highwire.dtl.DTLVardef@efa0f3_HPS_FORMAT_FIGEXP M_FIG Early life trauma and obesogenic diet effects of feeding control.Consumption of a Western-like high-saturated fat diet (WD, 42% kcal from fat) during adolescence in combination with (2) Exposure to early-life psychosocial stress leads to (3) changes in brain neurocircuitry and metabolic dysregulation. These alterations lead to (4) stress susceptibility, (5) emotional and feeding dysregulation, and (6) obesity. Dysregulation of feeding control and obesity leads to increased hedonic feeding and engages individuals in a cycle of aberrant feeding behaviors. C_FIG BackgroundChildhood overweight/obesity is associated with the development of stress-related psychopathology. However, the pathways connecting childhood obesity to stress susceptibility remain poorly understood. Here, we used a systems biology approach to determine linkages underlying obesity-induced stress susceptibility. MethodsSixty-two (62) adolescent Lewis rats (PND21) were fed for four weeks with a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Subsequently, a group of rats (n = 32) was exposed to a well-established 31-day model of predator exposures and social instability (PSS). The effects of the WD and PSS were assessed with a comprehensive battery of behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), high throughput 16S ribosomal RNA gene sequencing for gut microbiome profiling, hippocampal microglia morphological and gene analysis, and gene methylation status of the stress marker, FKBP5. Parallel experiments were performed on human microglial cells (HMC3) to examine molecular mechanisms by which palmitic acid primes these cells to aberrant responses to cortisol. ResultsRats exposed to the WD and PSS exhibited deficits in sociability indices and increased fear and anxiety-like behaviors, food consumption, and body weight. WD and PSS interacted to alter indices of microstructural integrity within the hippocampal formation (subiculum) and subfields (CA1). Microbiome diversity and taxa distribution revealed that WD/PSS exposure caused significant shifts in the diversity of gut dominant bacteria and decreased the abundance of various members of the Firmicutes phylum, including Lachnospiracae NK4A136. Interestingly, the WD and PSS synergized to promote hippocampal microglia morphological and gene signatures implicated in neuroinflammation. These alterations were associated with changes in the microbiome, and in the expression and methylation status of the corticosterone receptor chaperone rat gene Fkbp5. HMC3 responses to cortisol were markedly disrupted after incubating cells in palmitate, shown by morphological changes and pro-inflammatory cytokine expression and release. Notably, these effects were partly mediated by the human FKBP5 gene. ConclusionsThe combination of psychosocial stress and poor diet during adolescence has a deleterious synergistic impact on brain health. This study enhances our understanding of mechanisms and adaptations by which obesogenic environments shape the maturational trajectories of common neurobiological correlates of resilience. HighlightsO_LIObesogenic diet consumption during adolescence leads to stress-induced anxiety-like behaviors in rats. C_LIO_LIExposure to an obesogenic environment during adolescence alters indices of hippocampal microstructural integrity. C_LIO_LIObesogenic diet and chronic stress promote selective gut microbiota dysbiosis. C_LIO_LIObesogenic diet and chronic stress synergize to expand putative pro-inflammatory microglia populations in the CA1 subfield of the hippocampus. C_LIO_LIObesogenic diet and chronic stress influence hippocampal Fkbp5 gene methylation status at specific sites. C_LIO_LIFKBP5 integrates microglial pro-inflammatory signals under obesogenic conditions. C_LI

neuroscience↗

bioRxiv2023

Prefrontal cortical protease TACE/ADAM17 is involved in neuroinflammation and stress-related eating alterations

Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme / a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACE/ADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACE/ADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACE/ADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACE/ADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations.

neuroscience↗

bioRxiv2021

Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities

Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether altered NRG1-ErbB4 activities may partly explain hippocampal abnormalities in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): 1) control diet+vehicle (CDV); 2) CD+NRG1 (CDN) (daily intraperitoneal injections: 5 g/kg/day; between postnatal day, PND 21-PND 41); 3) WD+VEH (WDV); 4) WD+NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-{gamma}) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1, TNF-, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Together, these data suggest a novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals. HighlightsO_LIObesogenic diet consumption during adolescence induces anxiety-like behaviors before the onset of obesity-related changes in metabolism. C_LIO_LIObesogenic diet-driven abnormal behaviors co-occurred with alterations in hippocampal pro-inflammatory cytokine profiles. C_LIO_LIObesogenic diet consumption attenuates exogenous NRG1 effects on hippocampal-related behaviors and structure. C_LIO_LIExogenous NRG1 administration during adolescence resulted in reduced hippocampal volumes and domain-specific cognitive impairments. C_LIO_LIExogenous NRG1 administration has potent immunomodulatory actions and alters hippocampal microglia morphology. C_LI

neuroscience↗

bioRxiv2020

Oxidative Stress and Neuroinflammation in a Rat Model of Co-Morbid Obesity and Psychogenic Stress

BackgroundThere is growing recognition for a reciprocal, bidirectional link between anxiety disorders and obesity. Although the mechanisms linking obesity and anxiety remain speculative, this bidirectionality suggests shared pathophysiological processes. Neuroinflammation and oxidative damage are implicated in both pathological anxiety and obesity. This study investigates the relative contribution of comorbid diet-induced obesity and stress-induced anxiety to neuroinflammation and oxidative stress. MethodsThirty-six (36) male Lewis rats were divided into four groups based on diet type and stress exposure: 1) control diet unexposed (CDU) and 2) exposed (CDE), 3) Western-like high-saturated fat diet unexposed (WDU) and 4) exposed (WDE). Neurobehavioral tests were performed to assess anxiety-like behaviors. The catalytic concentrations of glutathione peroxidase and reductase were measured from plasma samples, and neuroinflammatory/oxidative stress biomarkers were measured from brain samples using Western blot. Correlations between behavioral phenotypes and biomarkers were assessed with Pearsons correlation procedures. ResultsWe found that WDE rats exhibited markedly increased levels of glial fibrillary acidic protein (185%), catalase protein (215%), and glutathione reductase (GSR) enzymatic activity (418%) relative to CDU rats. Interestingly, the brain protein levels of glutathione peroxidase (GPx) and catalase were positively associated with body weight and behavioral indices of anxiety. ConclusionsTogether, our results support a role for neuroinflammation and oxidative stress in heightened emotional reactivity to obesogenic environments and psychogenic stress. Uncovering adaptive responses to obesogenic environments characterized by high access to high-saturated fat/high-sugar diets and toxic stress has the potential to strongly impact how we treat psychiatric disorders in at-risk populations. HighlightsO_LIPredatory odor stress heightens footshock reactivity and anxiety-like behaviors in Lewis rats. C_LIO_LIWD intake increases glutathione reductase activity in plasma. C_LIO_LIWD intake and PS exposure acted synergistically to increase the brain protein levels of catalase and the glial fibrillary acidic protein. C_LIO_LIThe protein levels and activities of some redox/neuroinflammatory biomarkers are closely associated with behavioral proxies related to fear and anxiety in rats. C_LI

neuroscience↗

bioRxiv2020

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

BackgroundEmerging evidence demonstrates that diet-induced obesity disrupts corticolimbic circuits underlying emotional regulation. Studies directed at understanding how obesity alters brain and behavior are easily confounded by a myriad of complications related to obesity. This study investigated the early neurobiological stress response triggered by an obesogenic diet. Furthermore, this study directly determined the combined impact of a short-term obesogenic diet and adolescence on critical behavioral and molecular substrates implicated in emotion regulation and stress. MethodsAdolescent (postnatal day 31) or adult (postnatal day 81) Lewis rats were fed for one week with an experimental Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). We used the acoustic fear-potentiated startle (FPS) paradigm to determine the effects of the WD on cued fear conditioning and fear extinction. We used c-Fos mapping to determine the functional influence of the diet and stress on corticolimbic circuits. ResultsWe report that one-week WD consumption was sufficient to induce fear extinction deficits in adolescent rats, but not in adult rats. We identify fear-induced alterations in corticolimbic neuronal activation and demonstrate increased prefrontal cortex CRHR1 mRNA levels in the rats that consumed the WD. ConclusionsOur findings demonstrate that short-term consumption of an obesogenic diet during adolescence heightens behavioral and molecular vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience, and that fear extinction principles are the foundation of psychological treatments for PTSD, understanding how obesogenic environments interact with the adolescent period to affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance. HIGHLIGHTSO_LIShort-term WD consumption during adolescence impairs cued fear extinction memory retention in a fear-potentiated startle paradigm. C_LIO_LIShort-term WD consumption during adolescence attenuates neuronal activation to electric footshock stress in the basomedial nuclei of the amygdala. C_LIO_LIShort-term WD consumption increases CRHR1 mRNA levels in the medial prefrontal cortex. C_LIO_LIAdult LEW rats exhibit increased basal HPA axis tone and heightened emotional reactivity to footshock stress relative to adolescent rats. C_LI

neuroscience↗

bioRxiv2019

Developmental regulation of fear memories by an obesogenic high-saturated fat/high-sugar diet

BackgroundAnxiety and stress-related disorders are strongly linked with obesity and the consumption of obesogenic diets. Paralleling clinical findings, we showed that the consumption of an obesogenic diet during adolescence disrupts the structural integrity of amygdalar and prefrontal cortex circuits underlying emotional responses to stress. These abnormalities were associated with a PTSD-like phenotype, including heightened stress reactivity to predator odor trauma, anxiety-like behaviors, and profound learning deficits. The present follow-up study investigates how an obesogenic diet alters aversion-related associative memories across adolescence.\n\nMethodsAdolescent Lewis rats were fed for eight weeks with an experimental Western-like high-saturated fat/high-sugar diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Acoustic fear-potentiated startle (FPS) responses were assessed longitudinally at weeks 1, 4, and 8 after commencing the diets to determine the effects of the WD on cued fear conditioning, fear extinction learning, and fear extinction retention.\n\nResultsWe found that the rats that consumed the WD exhibited substantial attenuation of fear extinction and fear extinction retention when remote memory was tested. One-week WD consumption was sufficient to induce impairments in fear extinction learning. This phenotype was associated with reduced dopamine receptor 1 mRNA levels in the prefrontal cortex. Interestingly, our reconditioning paradigm revealed that early-acquired fear memories were resistant to the disruptive effects of chronic WD consumption on cued fear learning.\n\nConclusionsOur findings demonstrate that consumption of an obesogenic WD during adolescence heightens behavioral vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience and that fear extinction principles are the foundation of psychological treatments for PTSD, understanding how obesity and obesogenic diets affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance.\n\nHIGHLIGHTSO_LIAcute WD consumption impairs cued fear extinction learning in a fear-potentiated startle paradigm.\nC_LIO_LIWD consumption attenuates fear extinction memory retention\nC_LIO_LIWD consumption during adolescence increases acoustic startle responsivity over time\nC_LIO_LIChronic WD consumption decreases dopamine receptor D1 mRNA levels in the prefrontal cortex.\nC_LI

neuroscience↗

bioRxiv2019

Endocrine, metabolic, and endocannabinoid alterations in rats exhibiting high anxiety-related behaviors

Anxiety disorders are major risk factors for obesity. However, the mechanisms accounting for this susceptibility remain unclear. Animal models have proved to be useful tools for understanding the role of emotional functioning in the development and maintenance of metabolic alterations implicated in obesity. Here we sought to determine the predictive value of behavioral indices of anxiety for hormonal and metabolic imbalances in rats. Adult Lewis rats were screened on the elevated plus maze (EPM). K-means clustering was used to divide the rats into two groups based on their anxiety index in the EPM: low (LA) and high anxiety (HA) rats. This proxy of anxiety combines individual EPM parameters and accepted ratios into a single score. Four weeks later, we measured markers of endocrine and metabolic function. We found that relative LA rats, the HA rats exhibited reduced latencies to exit a modified light-dark conflict test. Our results show that the HA rats displayed increased corticosterone levels when compared to LA rats. Furthermore, the HA rats weighted more and exhibited an enhanced glycemic response to exogenously administered glucose during the glucose tolerance test, indicating glucose intolerance. Notably, when compared to LA rats, the HA rats showed higher circulating levels of the endogenous cannabinoid, 2-arachidonoyl-sn-glycerol (2-AG). Together, these data indicate that patterns of emotional reactivity associated with anxiety may share common pathological pathways with metabolic complications implicated in obesity. Uncovering metabolic risk factors for anxiety disorders have the potential to strongly impact how we treat mental illnesses.\n\nObjectiveTo test the hypothesis that indices of anxiety in the elevated plus maze have predictive value for alterations implicated in obesity, which include heightened emotional reactivity, and dysregulated corticosterone, glucose metabolism, and circulating endocannabinoid levels.

animal behavior and cognition↗