Early onset memory deficit of WMI rats compared to their nearly isogenic WLIs is reversed by enriched environment in females.

Unlabelled: We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a stress-hyperresponsive rat strain. The novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain demonstrates increased stress reactivity and enhanced depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited diminished fear, and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young animals (6 months) of both strains and to middle-aged WLIs.

Female Wistar Kyoto More Immobile rats with genetic stress hyper-reactivity show enhanced contextual fear memory without deficit in extinction of fear.

The prevalence of post-traumatic stress disorder (PTSD) is higher in females than males, but pre-clinical models are established almost exclusively in males. This study is aimed to investigate the stress-enhanced fear learning model of PTSD in females. The model mirrors PTSD symptomology in males, whereby prior stress leads to extinction resistant exaggerated contextual fear memory.

The WMI Rat of Premature Cognitive Aging Presents Intrinsic Vulnerability to Oxidative Stress in Primary Neurons and Astrocytes Compared to Its Nearly Isogenic WLI Control.

The primary neuronal and astrocyte culture described here is from the stress-hyperreactive Wistar Kyoto (WKY) More Immobile (WMI) rat with premature aging-related memory deficit, and its nearly isogenic control, the Less Immobile (WLI) strain. Primary WMI hippocampal neurons and cortical astrocytes are significantly more sensitive to oxidative stress (OS) generated by administration of HO compared to WLI cells as measured by the trypan blue cell viability assay. Intrinsic genetic vulnerability is also suggested by the decreased gene expression in WMI neurons of catalase (), and in WMI cortical astrocytes of insulin-like growth factor 2 (), synuclein gamma () and glutathione peroxidase 2 () compared to WLI.

Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of .

We previously identified , , as a novel adiposity gene, but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between , adiposity, and stress, we exposed wild-type (WT) and knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited metabolic and behavioral responses to chronic stress exposure.

Limited WKY chromosomal regions confer increases in anxiety and fear memory in a F344 congenic rat strain.

This study investigated the interaction between genetic differences in stress reactivity/coping and environmental challenges, such as acute stress during adolescence on adult contextual fear memory and anxiety-like behaviors. Fischer 344 (F344) and the inbred F344;WKY-/Eer congenic strain (congenic), in which chromosomal regions from the Wistar-Kyoto (WKY) strain were introgressed into the F344 background, were exposed to a modified forced swim test during adolescence, while controls were undisturbed. In adulthood, fear learning and memory, assessed by contextual fear conditioning, were significantly greater in congenic animals compared with F344 animals, and stress during adolescence increased them even further in males of both strains.

Changes in environmental stress over COVID-19 pandemic likely contributed to failure to replicate adiposity phenotype associated with .

We previously identified keratinocyte-associated protein 3, , as an obesity-related gene in female rats where a whole body knockout (KO) led to increased adiposity compared to wild-type (WT) controls when fed a high-fat diet (HFD). We sought to replicate this work to better understand the function of but were unable to reproduce the adiposity phenotype. In the current work, WT female rats ate more compared to WT in the prior study, with corresponding increases in body weight and fat mass, while there were no changes in these measures in KO females between the studies.

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated with Krtcap3.

We previously identified Keratinocyte-associated protein 3, Krtcap3, as an obesity-related gene in female rats where a whole-body Krtcap3 knock-out (KO) led to increased adiposity compared to wild-type (WT) controls when fed a high-fat diet (HFD). We sought to replicate this work to better understand the function of Krtcap3 but were unable to reproduce the adiposity phenotype. In the current work, WT female rats ate more compared to WT in the prior study, with corresponding increases in body weight and fat mass, while there were no changes in these measures in KO females between the studies.

The Wistar Kyoto Rat: A Model of Depression Traits.

There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits.

Reduced Hippocampal and Anterior Cingulate Expression of Antioxidant Enzymes and Membrane Progesterone Receptors in Alzheimer's Disease with Depression.

Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer's disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference.

Objective: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD.

Sex-Specific Behavioral Response to Early Adolescent Stress in the Genetically More Stress-Reactive Wistar Kyoto More Immobile, and Its Nearly Isogenic Wistar Kyoto Less Immobile Control Strain.

Genetic predisposition and environmental stress are known etiologies of stress-related psychiatric disorders. Environmental stress during adolescence is assumed to be particularly detrimental for adult affective behaviors. To investigate how genetic stress-reactivity differences modify the effects of stress during adolescence on adult affective behaviors we employed two inbred strains with differing stress reactivity.

Sex and heredity are determinants of drug intake in a novel model of rat oral oxycodone self-administration.

The steady rise in prescription opioids such as oxycodone has led to a virulent epidemic of widespread abuse and deaths in the United States; approximately 80% of affected individuals initiate the habitual use of oxycodone by using prescription oral oxycodone. Given the importance of drug pharmacokinetics in determining abuse potential, we designed an oral operant oxycodone self-administration (SA) procedure in rats to model drug intake by most human users/abusers of oxycodone. Key aspects of the model include limited initial drug intake followed by increasing drug concentrations during extended 4-h sessions on alternating days.

TailTimer: A device for automating data collection in the rodent tail immersion assay.

The tail immersion assay is a widely used method for measuring acute thermal pain in a way which is quantifiable and reproducible. It is non-invasive and measures response to a stimulus that may be encountered by an animal in its natural environment. However, quantification of tail withdrawal latency relies on manual timing of tail flick using a stopwatch, and precise temperatures of the water at the time of measurement are most often not recorded.

Immediate stress alters social and object interaction and recognition memory in nearly isogenic rat strains with differing stress reactivity.

Stress prior to learning and recall is known to affect both processes depending on the learning paradigm, the sex of the animal, and their reactivity to stress. Male and female animals of the inbred Wistar-Kyoto More Immobile (WMI) and Less Immobile (WLI) strains were tested in the modified novel object and spatial recognition paradigm and in the social interaction-recognition paradigm immediately after a 30 min restraint stress. The WMI strain shows enhanced stress reactivity compared to its near isogenic WLI control and thus, represents a genetically stress-susceptible rodent model.

Whole genome sequencing of nearly isogenic WMI and WLI inbred rats identifies genes potentially involved in depression and stress reactivity.

The WMI and WLI inbred rats were generated from the stress-prone, and not yet fully inbred, Wistar Kyoto (WKY) strain. These were selected using bi-directional selection for immobility in the forced swim test and were then sib-mated for over 38 generations. Despite the low level of genetic diversity among WKY progenitors, the WMI substrain is significantly more vulnerable to stress relative to the counter-selected WLI strain.

Strain Differences in Responsiveness to Repeated Restraint Stress Affect Remote Contextual Fear Memory and Blood Transcriptomics.

The role of stress in altering fear memory is not well understood. Since individual variations in stress reactivity exist, and stress alters fear memory, exposing individuals with differing stress-reactivity to repeated stress would affect their fear memory to various degrees. We explored this question using the average stress-reactive Fisher 344 (F344) rat strain and the Wistar-Kyoto (WKY) strain with its heightened stress-reactivity.

Facilitating Complex Trait Analysis via Reduced Complexity Crosses.

Genetically diverse inbred strains are frequently used in quantitative trait mapping to identify sequence variants underlying trait variation. Poor locus resolution and high genetic complexity impede variant discovery. As a solution, we explore reduced complexity crosses (RCCs) between phenotypically divergent, yet genetically similar, rodent substrains.

Cortisol awakening response and additive serotonergic genetic risk interactively predict depression in two samples: The 2019 Donald F. Klein Early Career Investigator Award Paper.

Background: The serotonin system and hypothalamic pituitary-adrenal (HPA)-axis are each implicated in the pathway to depression; human and animal research support these systems' cross-talk. Our work implicates a 5-variant additive serotoninergic multilocus genetic profile score (MGPS) and separately the cortisol awakening response (CAR) in the prospective prediction of depression; other work has shown that the serotonin transporter polymorphism 5HTTLPR predicts CAR and interacts with the CAR to predict depression.

Methods: We tested the hypothesis that a 6-variant MGPS (original plus 5HTTLPR) would interact with CAR to predict prospective depressive episode onsets in 201 emerging adults using four annual follow-up interviews.

Genetic Model to Study the Co-Morbid Phenotypes of Increased Alcohol Intake and Prior Stress-Induced Enhanced Fear Memory.

Posttraumatic Stress Disorder (PTSD) is a complex illness, frequently co-morbid with depression, caused by both genetics, and the environment. Alcohol Use Disorder (AUD), which also co-occurs with depression, is often co-morbid with PTSD. To date, very few genes have been identified for PTSD and even less for PTSD comorbidity with AUD, likely because of the phenotypic heterogeneity seen in humans, combined with each gene playing a relatively small role in disease predisposition.

Thyroid Function in Pregnant Women With Moderate to Severe Alcohol Consumption Is Related to Infant Developmental Outcomes.

Introduction: Fetal alcohol spectrum disorders (FASD) have an estimated global prevalence of 2-5% of births, but prevalence is reported to be as high as 15.5% for FASD in certain high-risk communities in South Africa. Preclinical studies demonstrate that alcohol consumption during pregnancy interferes with thyroid hormone availability and function and negatively impacts exposed offspring.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression.

Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat.

Prepubertal Ovariectomy Exaggerates Adult Affective Behaviors and Alters the Hippocampal Transcriptome in a Genetic Rat Model of Depression.

Major depressive disorder (MDD) is a debilitating illness that affects twice as many women than men postpuberty. This female bias is thought to be caused by greater heritability of MDD in women and increased vulnerability induced by female sex hormones. We tested this hypothesis by removing the ovaries from prepubertal Wistar Kyoto (WKY) more immobile (WMI) females, a genetic animal model of depression, and its genetically close control, the WKY less immobile (WLI).

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System.

Background: Fetal alcohol spectrum disorder (FASD) is the leading nongenetic cause of mental retardation. There are no treatments for FASD to date. Preclinical in vivo and in vitro studies could help in identifying novel drug targets as for other diseases.