Biology subjects

Hebda-Bauer, E. K.

Publications and source records attributed to Hebda-Bauer, E. K..

7 recordsLinked to original sources

bioRxiv2026

Deep in vivo brain metabolomics maps vulnerability-associated and cocaine-induced neurochemical states

Innate temperament affects vulnerability to substance use disorders (SUDs). Identifying the neurochemistry that differentiates temperaments, alongside the metabolic impact of drugs of abuse, can provide new insights into pathways to SUD and treatments. We show that heritable emotional temperaments associated with SUD vulnerability are encoded by distinct extracellular neurochemical states in the living brain. We apply untargeted metabolomics to microdialysis samples to define the chemical composition of the living brain metabolome with unprecedented depth. Using two phenotypes from a rodent model of diverging temperaments linked to SUDs, dialysate samples were collected before and after acute exposure to cocaine (15 mg/kg, i.p.). Metabolomic analysis revealed previously unknown basal differences in stress-response, bioenergetics, and amino acid neurotransmitters and their related pathways between the two phenotypes. Cocaine administration also had a profound impact on the metabolome, altering amino acid, purine, and arachidonic acid pathways along with cognition-related metabolites. Despite these broad metabolomic changes, cocaine administration narrowed several pre-existing differences between phenotypes, highlighting divergent responses across genetic lines. These findings demonstrate that in vivo metabolomics not only offers novel insights into the neurochemistry underlying temperament and drug response but also serves as framework to advance a systems-level understanding of other brain-related disorders.

neuroscience↗

bioRxiv2026

Differential acquisition of cocaine and heroin self-administration in a rat model of internalizing versus externalizing temperament

Substance Use Disorders (SUDs) constitute a major and rising public health concern. In addition, there is a growing appreciation that different classes of addictive substances are likely to lead to qualitatively different types of SUDs requiring differing treatment and relapse prevention strategies to be most effectively managed. Biological temperament, particularly on the internalizing - externalizing axis, is well established to influence addiction susceptibility. Externalizing behavior has long been understood to predispose individuals to addiction through novelty-seeking, sensation-seeking and impulsivity, while internalizing behavior provides an alternate pathway into addiction via increased occurrence of comorbid disorders (anxiety, depression). Here, we utilize a selectively bred rat model of internalizing vs externalizing temperament (bred High Responders, representing genetically mediated externalizing behavior and bred Low Responders, representing internalizing behavior) to examine differences in the acquisition of self-administration of the prototypical psychostimulant cocaine and the prototypical opioid heroin (diacetylmorphine). We found that, as predicted, cocaine and heroin drove different patterns of acquisition in the two different bred lines of rats. Further, this was influenced by temperament in complex ways. Notably, in females the "telescoping effect" for opioid addiction-like behavior was primarily specific to externalizing temperament. These findings highlight the impact and interaction of many factors, including drug class, temperament, and sex, on the acquisition of drug-taking behavior. Additionally, these findings indicate that sex differences in addiction vulnerability may be influenced in part by biological temperament.

animal behavior and cognition↗

bioRxiv2026

Genetic Architecture of Addiction-Relevant Behaviors in Outbred Sprague-Dawley Rats Reveals Loci for Anxiety-Like and Nociceptive Traits

Studies have shown that substance use liability is associated with novelty seeking, anxiety-like behavior, and pain sensitivity. We examined whether common genetic variation in outbred Sprague-Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single-nucleotide polymorphism heritability and performed genome-wide association analyses using permutation-derived significance thresholds (N=534-654 rats across traits). Heritability estimates ranged from 0.14-0.38 across eleven traits. Three independent loci were identified: chromosome 1 for elevated plus maze open-arm behavior (=0.05), chromosome 14 for elevated plus maze immobility (=0.10), and chromosome 17 for tail flick latency (=0.05). Candidate genes included Slc18a2, Gfra1, and Pdzd8 (chromosome 1); Rel and Bcl11a (chromosome 14); and Eci2 and Eci3 (chromosome 17). We compared these loci with our genome wide association study of a F2 intercross of selectively bred high- and low-responder rats, originally derived from Sprague-Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high- and low-responder F2s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction-relevant behaviors.

genetics↗

bioRxiv2023

Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the "internalizing" bred Low Responder (bLR) line versus the "externalizing" bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Male bLR and bHR rats were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused rats to display more social interaction, as well as nominally less social avoidance, less submission during defeat, and resilience to the effects of social stress on corticosterone, in a manner that seemed more notable in bLRs. For bHRs, enrichment also caused greater aggression during a neutral social encounter and nominally during defeat, and decreased anxiety-like behavior. To explore the neurobiology underlying the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. Our findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

neuroscience↗

bioRxiv2022

Transcriptional Profiling of the Hippocampus in an F2 Cross of a Genetic Rat Model of Internalizing vs. Externalizing Behavior and Addiction Liability

Selectively-bred High Responder (bHR) and Low Responder (bLR) rats model the extreme externalizing and internalizing behavior accompanying many psychiatric disorders. To elucidate gene expression underlying these heritable behavioral differences, bHRs and bLRs (generation 37) were used to produce a F0-F1-F2 cross. We measured exploratory locomotion, anxiety-like behavior, and reward cue sensitivity (Pavlovian Conditioned Approach), and performed hippocampal RNA-Seq in male and female F0s (n=24) and F2s (n=250). Behaviors that diverged during selective breeding remained correlated in F2s, implying a shared genetic basis. F0 bHR/bLR differential expression was robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. With bHR-like behavior, gene sets related to growth/proliferation were upregulated, whereas with bLR-like behavior, gene sets related to mitochondrial function, oxidative stress, and microglial activation were upregulated. This differential expression could be successfully predicted based on F0 genotype using cis-expression quantitative trait loci (cis-eQTLs) identified in the F2s. Colocalization of these cis-eQTLs with behavioral Quantitative Trait Loci pinpointed 16 differentially expressed genes that were strong candidates for mediating the influence of genetic variation on behavioral temperament. Our findings implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, modulating vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2022

Genome-Wide Association Study in a Rat Model of Temperament Identifies Multiple Loci for Exploratory Locomotion and Anxiety-Like Traits

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.

genetics↗

bioRxiv2021

Early acquisition of threat conditioning in a selectively-bred anxiety-like rat phenotype: regulation by maternal presence and FGF2

Temperament is an innate, stable predisposition towards particular emotional and behavioral responses. In humans, certain temperaments are associated with a heightened risk of developing anxiety later in life. Non-human animals, including rodents, also exhibit innate, stable dispositions; these are referred to as behavioral phenotypes. The interaction between behavioral phenotype and early life adverse events is critical for the development of maladaptive anxiety. Rodent studies of typically developing animals have identified a number of mechanisms that protect against aversive experiences in early life. One such mechanism is an early life quiescence of threat learning, which protects against the effects of stress and facilitates safety and attachment learning. However, little is known about the factors that alleviate the effects of early life aversive events on phenotypes vulnerable to pathological anxiety. Here, we examined threat learning and the stress response in selectively-bred infant rats that show an anxiety-like phenotype relative to typically developing animals. We investigated the potential roles of maternal presence and the anxiolytic neurotrophic factor fibroblast growth factor 2 (FGF2) in regulating threat learning and the stress response in infant anxiety-like phenotype animals. We observed that rats selectively-bred for anxiety-like behaviors could acquire conditioned freezing earlier in life than typically developing animals. FGF2 administration on postnatal day 1 (PND 1) and maternal presence during threat conditioning were both capable of suppressing this early emergence of conditioned freezing. However, neither FGF2 nor maternal presence during threat conditioning were associated with reduced corticosterone levels during threat conditioning. Our results suggest that although an anxiety-like phenotype may be associated with early threat learning, environmental factors (such as maternal presence) and pharmacological intervention (such as modulation of the FGF2 system) may be capable of counteracting that early aversive learning. Interventions in vulnerable infants may thus decrease the impact of aversive events.

neuroscience↗