Brown Norway Hybrid Research Articles

Exploration of the Propagation of Hippocampal Theta Oscillations in Freely Moving Rats

Comprehending the mechanisms by which theta waves propagate across the hippocampus is of utmost importance in understanding various aspects of cognition in rodent models. A popular argument made by those studying hippocampal rhythms is that they are synchronous throughout the medial temporal lobe. However, recent studies have concluded that theta oscillations travel as waves along the septotemporal axis of the hippocampus. Our experimental goal was to derive a relationship between theta oscillations in the anterior and posterior regions of the hippocampus by examining local field potential in freely moving rats. We trained a mixed-sex cohort of five Fisher Brown Norway hybrid rats to run on a circular track for a food reward and implanted them with an intracranial silicon probe in the CA1 region of the anterior dorsal hippocampus (AP: -2.8 ML: 1.5 DV: 4.0) and the CA1 region of the posterior parietal hippocampus (AP: -5.6 ML: 4.2 DV: 4.5). After a recovery period, the rats were reintroduced to the circular track where data was collected from each site. This poster presents the activity of traveling dentate spikes, ripples, theta, and gamma within these hippocampal regions. R01MH126236 1R01MH109548-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Influence of aging, macronutrient composition and time-restricted feeding on the rat gut microbiome

Declining health and cognition are hallmarks of advanced age that reduce both the quality and length of the lifespan. While caloric restriction has been highlighted as a strategy for increasing healthspan, time-restricted feeding and changes in dietary macronutrient composition may be more feasible alternatives with similar health outcomes. Furthermore, age-related changes in gut microbiome composition may reciprocally interact with several physiological systems – providing a good target for future therapeutic interventions. To begin to investigate the potential utility of a ketogenic (high fat, low carbohydrate) diet and/or time-restricted feeding, fully mature young (5 mo) and older (22 mo) adult male Fischer Brown Norway Hybrid rats were placed on a time-restricted feeding regimen of a ketogenic or micronutrient and calorically matched control diet for 7 months. A third group of rats was permitted to eat standard chow ad libitum. Fecal samples collected at the conclusion of the study were submitted for 16S microbiome analysis, which revealed significant differences across age and diet groups, as well as across feeding paradigms. Beta diversity analysis demonstrated distinct microbiome composition across the three diet groups regardless of age. Furthermore, diet group significantly impacted abundance in expression of several microbiota at the phylum level, including Verrucomicrobia, Cyanobacteria, Actinobacteria and Patescibacteria, though age did not. Verrucomicrobia was significantly increased (p=0.02) and Actinobacteria and Patescibacteria (p<0.01) were significantly decreased in animals fed in a time-restricted fashion. These results indicate the value of both altered macronutrient composition and altered feeding methodology for therapeutic interventions targeting the gut microbiome.

Altered Regulation of adipomiR Editing with Aging.

Adipose dysfunction with aging increases risk to insulin resistance and other chronic metabolic diseases. We previously showed functional changes in microRNAs involved in pre-adipocyte differentiation with aging resulting in adipose dysfunction. However, the mechanisms leading to this dysfunction in microRNAs in adipose tissue (adipomiRs) during aging are not well understood. We determined the longitudinal changes in expression of adipomiRs and studied their regulatory mechanisms, such as miRNA biogenesis and editing, in an aging rodent model, with Fischer344 × Brown-Norway hybrid rats at ages ranging from 3 to 30 months (male/females, n > 8). Expression of adipomiRs and their edited forms were determined by small-RNA sequencing. RT-qPCR was used to measure the mRNA expression of biogenesis and editing enzymes. Sanger sequencing was used to validate editing with aging. Differential expression of adipomiRs involved in adipocyte differentiation and insulin signaling was altered with aging. Sex- and age-specific changes in edited adipomiRs were observed. An increase in miRNA biogenesis and editing enzymes (ADARs and their splice variants) were observed with increasing age, more so in female than male rats. The adipose dysfunction observed with age is attributed to differences in editing of adipomiRs, suggesting a novel regulatory pathway in aging.

Differential Effect of Repeated Lipopolysaccharide Treatment and Aging on Hippocampal Function and Biomarkers of Hippocampal Senescence.

Markers of brain aging and cognitive decline are thought to be influenced by peripheral inflammation. This study compared the effects of repeated lipopolysaccharide (LPS) treatment in young rats to age-related changes in hippocampal-dependent cognition and transcription. Young Fischer 344 X Brown Norway hybrid rats were given intraperitoneal injections once a week for 7weeks with either LPS or vehicle. Older rats received a similar injection schedule of vehicle. Old vehicle and young LPS rats exhibited a delay-dependent impairment in spatial memory. Further, LPS treatment reduced the hippocampal CA3-CA1 synaptic response. RNA sequencing, performed on CA1, indicated an increase in genes linked to neuroinflammation in old vehicle and young LPS animals. In contrast to an age-related decrease in transcription of synaptic genes, young LPS animals exhibited increased expression of genes that support the growth and maintenance of synapses. We suggest that the increased expression of genes for growth and maintenance of synapses in young animals represents neuronal resilience/recovery in response to acute systemic inflammation. Thus, the results indicate that repeated LPS treatment does not completely recapitulate the aging phenotype for synaptic function, possibly due to the chronic nature of systemic inflammation in aging and resilience of young animals to acute treatments.

Reduced frequency of resistance-type exercise training promotes adaptation of the aged skeletal muscle microenvironment.

The purpose of this study was to characterize the growth and remodeling molecular signaling response in aged skeletal muscle following 1 mo of "resistance-type exercise" training. Male Fischer 344 × Brown Norway hybrid rats aged 3 (young) and 30 mo (old) underwent stretch-shortening contraction (SSC) loading 2 or 3 days/wk; muscles were removed 72 h posttraining. Young rats SSC loaded 3 (Y3x) or 2 days/wk (Y2x) adapted via increased work performance. Old rats SSC loaded 3 days/wk (O3x) maladapted via decreased negative work; however, old rats SSC loaded 2 days/wk (O2x) adapted through improved negative and positive work. Y3x, Y2x, and O2x, but not O3x, displayed hypertrophy via larger fiber area and myonuclear domains. Y3x, Y2x, and O2x differentially expressed 19, 30, and 8 phosphatidylinositol 3-kinase-Akt genes, respectively, whereas O3x only expressed 2. Bioinformatics analysis revealed that rats in the adapting groups presented growth and remodeling processes (i.e., increased protein synthesis), whereas O3x demonstrated inflammatory signaling. In conclusion, reducing SSC-loading frequency in aged rodents positively influences the molecular signaling microenvironment, promoting muscle adaptation. NEW & NOTEWORTHY Decreasing resistance-type exercise training frequency in old rodents led to adaptation through enhancements in performance, fiber areas, and myonuclear domains. Modifying frequency influenced the molecular environment through improvements in phosphatidylinositol 3-kinase-Akt pathway-specific expression and bioinformatics indicating increased protein synthesis. Reducing training frequency may be appropriate in older individuals who respond unfavorably to higher frequencies (i.e., maladaptation); overall, modifying the parameters of the exercise prescription can affect the cellular environment, ultimately leading to adaptive or maladaptive outcomes.

Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats

Despite the fact that prefrontal cortex (PFC) function declines with age, aged individuals generally show an enhanced ability to delay gratification, as evident by less discounting of delayed rewards in intertemporal choice tasks. The present study was designed to evaluate relationships between 2 aspects of PFC-dependent cognition (working memory and cognitive flexibility) and intertemporal choice in young (6 months) and aged (24 months) Fischer 344 × brown Norway F1 hybrid rats. Rats were also evaluated for motivation to earn rewards using a progressive ratio task. As previously reported, aged rats showed attenuated discounting of delayed rewards, impaired working memory, and impaired cognitive flexibility compared with young. Among aged rats, greater choice of delayed reward was associated with preserved working memory, impaired cognitive flexibility, and less motivation to work for food. These relationships suggest that age-related changes in PFC and incentive motivation contribute to variance in intertemporal choice within the aged population. Cognitive impairments mediated by PFC are unlikely, however, to fully account for the enhanced ability to delay gratification that accompanies aging.

Sexual dimorphism in obesity-related genes in the epicardial fat during aging

Aging increases the risk of cardiovascular disease and metabolic syndrome. Alterations in epicardial fat play an important pathophysiological role in coronary artery disease and hypertension. We investigated the impact of normal aging on obesity-related genes in epicardial fat. Sex-specific changes in obesity-related genes with aging in epicardial fat (EF) were determined in young (6months) and old (30/36months) female and male, Fischer 344 × Brown Norway hybrid (FBN) rats, using a rat obesity RT2 PCR Array. Circulating sex hormone levels, body and heart weights were determined. Statistical significance was determined using two-tailed Student's t test and Pearson's correlation. Our results revealed sex-specific differences in obesity-related genes with aging. Dramatic changes in the expression profile of obesity-related genes in EF with aging in female, but not in male, FBN rats were observed. The older (30months) female rats had more significant variations in the abundance of obesity-related genes in the EF compared to that seen in younger female rats or both age groups in male rats. A correlation of changes in obesity-related genes in EF to heart weights was observed in female rats, but not in male rats with aging. No correlation was observed to circulating sex hormone levels. Our findings indicate a dysfunctional EF in female rats with aging compared to male rats. These findings, with further functional validation, might help explain the sex differences in cardiovascular risk and mortality associated with aging observed in humans.

Sex- and dose-dependent effects of post-trial calcium channel blockade by magnesium chloride on memory for inhibitory avoidance conditioning

Calcium influx through voltage-dependent Ca2+ channels is critical for many neuronal processes required for learning and memory. Persistent increases in cytosolic intracellular Ca2+ concentrations in aging neurons are associated with learning impairments, while small transient subcellular changes in intracellular calcium concentrations play critical roles in neural plasticity in young neurons. In the present study, young male and female Fisher 344×Brown Norway (FBN) hybrid rats were administered different doses of magnesium chloride (0.0, 100.0, or 200.0mg/kg, i.p.) following a single inhibitory avoidance training trial. Extracellular magnesium ions can non-specifically block voltage-gated calcium channels, and/or reduce the calcium conductance gated via glutamate and serine's activation of neuronal NMDA receptors. In our study, magnesium chloride dose-dependently enhanced memory compared to controls (significantly increased latency to enter a dark compartment previously paired with an aversive stimulus) when tested 48h later as compared to controls. A leftward shift in the dose response curve for memory enhancement by magnesium chloride was observed for male compared to female rats. These findings provide further insights into calcium-dependent modulation of aversive memory, and should be considered when assessing the design of effective treatment options for both male and female patients with dementia or other memory problems.

Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg(-1)·day(-1) po) to Lewis × Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.

MicroRNA Regulation of Adipose Derived Stem Cells in Aging Rats

BackgroundPerturbations in abdominal fat secreted adipokines play a key role in metabolic syndrome. This process is further altered during the aging process, probably due to alterations in the preadipocytes (aka. stromal vascular fraction cells-SVF cells or adipose derived stem cells-ASCs) composition and/or function. Since microRNAs regulate genes involved both in development and aging processes, we hypothesized that the impaired adipose function with aging is due to altered microRNA regulation of adipogenic pathways in SVF cells.Methodology and Principal FindingsAlterations in mRNA and proteins associated with adipogenic differentiation (ERK5 and PPARg) but not osteogenic (RUNX2) pathways were observed in SVF cells isolated from visceral adipose tissue with aging (6 to 30 mo) in female Fischer 344 x Brown Norway Hybrid (FBN) rats. The impaired differentiation capacity with aging correlated with altered levels of miRNAs involved in adipocyte differentiation (miRNA-143) and osteogenic pathways (miRNA-204). Gain and loss of function studies using premir or antagomir-143 validated the age associated adipocyte dysfunction.Conclusions and SignificanceOur studies for the first time indicate a role for miRNA mediated regulation of SVF cells with aging. This discovery is important in the light of the findings that dysfunctional adipose derived stem cells contribute to age related chronic diseases.

Accurate Quantification of More Than 4000 Mouse Tissue Proteins Reveals Minimal Proteome Changes During Aging

The biological process of aging is believed to be the result of an accumulation of cellular damage to biomolecules. Although there are numerous studies addressing mutation frequencies, morphological or transcriptional changes in aging mammalian tissues, few have measured global changes at the protein level. Here, we present an in depth proteomic analysis of three brain regions as well as heart and kidney in mice aged 5 or 26 months, using stable isotope labeling of whole animals (SILAC mouse) and high resolution mass spectrometry. In the frontal cortex and hippocampal regions of the brain, more than 4200 proteins were quantitatively compared between age groups. Proteome differences between individual mice were observable within and between age groups. However, mean protein abundance changes of more than twofold between young and old mice were detected in less than 1% of all proteins and very few of these were statistically significant. Similar outcomes were obtained when comparing cerebellum, heart, and kidney between age groups. Thus, unexpectedly, our results indicate that aging-related effects on the tissue proteome composition at the bulk level are only minor and that protein homeostasis remains functional up to a relatively high age.

Akt Serves as a Signaling Pathway Integrator for Adaptation/Maladaptation in Aging Muscle Following Mechanical Loading

Even though skeletal muscle's response has been explored extensively following mechanical loading, it has been with respect to injurious loading, while more recently the effect of aging on muscle adaptation/maladaptation has been investigated implementing a novel non-injurious paradigm. Furthermore, the need for an integrated understanding of how the soft tissue response continuum is influenced is vital and must be approached by employing a systems biology approach. This is because the molecular, cellular, and functional mechanisms governing skeletal muscle adaptation/maladaptation following mechanical loading with aging are largely unknown. PURPOSE: The purpose of this study was to investigate if Akt serves as a molecular and cellular focal point for integrating both adaptive and/or maladaptive stimuli. Gene array, RT-PCR, and morphological localization, distribution, and quantification of Akt, and its influence on young and old skeletal muscle of rats following chronic high-intensity mechanical loading via stretch-shortening contractions (SSCs) was assessed. METHODS: Left dorsiflexor muscles of young (12 weeks, N=30) and old (30 months, N = 28) Fischer Brown Norway Hybrid rats, were loaded 3 times/week for 4.5-weeks using a protocol of 80 maximal SSCs per exposure in vivo. Tibialis anterior muscle was allocated for either gene expression or histology. RNA was isolated and prepared for gene array or RT-PCR. Additionally, transverse sections of the tibialis anterior muscle midbelly were cut and prepared for pan-Akt immunofluorescence and quantified using standard stereology and densitometry. RESULTS: Gene array data indicated that Akt 1 and 2 transcript levels were decreased in old rats compared with young rats. Follow-up analyses of transcript levels using RT-PCR confirmed these findings. Further, immunolabeling of tibialis anterior muscle tissue following the SSC loading period illustrated that the volume density of muscle fibers per section labeling positively for pan-Akt was decreased ∼30% and ∼35% in young and old rats, respectively. Moreover, the average percent area of pan-Akt+ labeling was decreased in both groups, but was decreased to a greater extent in old rats (∼170%). CONCLUSIONS: Together, these findings suggest that Akt may act as a key modifier of incoming mechanical stimuli, which ultimately limits the adaptive potential of skeletal muscle with advanced age. Finally, these data provide only a basis for understanding this complex network of functionally relevant genes and proteins related to the adaptive/maladaptive process, which is currently limited.

Age and sex mediated changes in epicardial fat adipokines

Aging, which is an independent risk factor for heart disease, alters body fat mass and its function. Epicardial fat plays an important physiological and pathophysiological role on cardiac structure and function. This study investigated if aging altered the abundance of epicardial (EF) and abdominal fat (AF) derived mediators in a sex dependent manner in female and male Fischer 344 × Brown Norway hybrid (FBN) rats. EF and AF were obtained from 48 female and male, young (6 months), aged (26/30 months) and very aged (30/36 months) FBN rats. Adipose derived anti-inflammatory and pro-inflammatory mediators were measured using ELISA, adipokine array and real-time qPCR. No dramatic changes in circulating lipids other than a higher triglyceride and high density lipoprotein in aged females and a significantly increased circulating adiponectin ( p < 0.005) in aged rats were observed. Real time PCR results showed that compared to 6 months old female rats, the aged (26 months) and very aged (30 months) rats had significantly lower levels of EF genes: adiponectin ( p < 0.005), PPARγ ( p < 0.01, 0.005), IL-6 ( p < 0.01) and PAI-1 ( p < 0.01, 0.01), respectively, but not in AF. In contrast, the male rats exhibited an increase in IL-6 in EF ( p < 0.005) but a decrease in adiponectin and PPARγ in AF with aging. These changes might be attributed to differences in adipocyte make-up or macrophage infiltration. In conclusion, aging had a more profound impact on EF derived mediators in female rather than male rats, which might help explain the increased risk to cardiovascular disease seen in older women.

Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats

Aged rats exhibit a decreased muscle microvascular O(2) partial pressure (Pmv(O(2))) at rest and during contractions compared with young rats. Age-related reductions in nitric oxide bioavailability due, in part, to elevated reactive O(2) species, constrain muscle blood flow (Qm). Antioxidants may restore nitric oxide bioavailability, Qm, and ameliorate the reduced Pmv(O(2)). We tested the hypothesis that antioxidants would elevate Qm and, therefore, Pmv(O(2)) in aged rats. Spinotrapezius muscle Pmv(O(2)) and Qm were measured, and oxygen consumption (Vm(O(2))) was estimated in anesthetized male Fisher 344 x Brown Norway hybrid rats at rest and during 1-Hz contractions, before and after antioxidant intravenous infusion (76 mg/kg vitamin C and 52 mg/kg tempol). Before infusion, contractions evoked a biphasic Pmv(O(2)) that fell from 30.6 +/- 0.9 Torr to a nadir of 16.8 +/- 1.2 Torr with an "undershoot" of 2.8 +/- 0.7 Torr below the subsequent steady-state (19.7 +/- 1.2 Torr). The principal effect of antioxidants was to elevate baseline Pmv(O(2)) from 30.6 +/- 0.9 to 35.7 +/- 0.8 Torr (P < 0.05) and reduce or abolish the undershoot (P < 0.05). Antioxidants reduced Qm and Vm(O(2)) during contractions (P < 0.05), while decreasing force production 16.5% (P < 0.05) and elevating the force production-to-Vm(O(2)) ratio (0.92 +/- 0.03 to 1.06 +/- 0.6, P < 0.05). Thus antioxidants increased Pmv(O(2)) by altering the balance between muscle O(2) delivery and Vm(O(2)) at rest and during contractions. It is likely that this effect arose from antioxidants reducing myocyte redox below the level optimal for contractile performance and directly (decreased tension) or indirectly (altered balance of vasoactive mediators) influencing O(2) delivery and Vm(O(2)).

Differential protein expression during aging in ventricular myocardium of Fischer 344 × Brown Norway hybrid rats

The aging heart undergoes well characterized structural changes associated with functional decline, though the underlying mechanisms are not understood. The aim of this study was to determine to what extent ventricular myocardial protein expression was altered with age and which proteins underwent protein nitration. Fischer 344 × Brown Norway F1 hybrid (FBN) rats of four age groups were used, 4, 12, 24, and 34 months. Differential protein expression was determined by 2-DE and proteins were identified by peptide mass fingerprinting. Altered protein nitration with age was assessed by immunoblotting. Over 1000 protein spots per sample were detected, and 255 were found to be differentially expressed when all aged groups were compared to young rats (4 months) ( p ⩽ 0.05). A strong positive correlation between differential protein expression and increasing age ( p = 0.03, R 2 = 0.997) indicated a progressive, rather than abrupt, change with age. Of 46 differentially expressed proteins identified, seventeen have roles in apoptosis, ten in hypertrophy, seven in fibrosis, and three in diastolic dysfunction, aging-associated processes previously reported in both human and FBN rat heart. Protein expression alterations detected here could have beneficial effects on cardiac function; thus, our data indicate a largely adaptive change in protein expression during aging. In contrast, differential protein nitration increased abruptly, rather than progressively, at 24 months of age. Altogether, the results suggest that differential myocardial protein expression occurs in a progressive manner during aging, and that a proteomic-based approach is an effective method for the identification of potential therapeutic targets to mitigate aging-related myocardial dysfunction.

Effects of Antioxidants on Contracting Spinotrapezius Muscle Force Production and Oxygen Consumption in Aged Rats

Aged rats demonstrate a decreased exercise tolerance compared to young rats. This reduction in exercise tolerance is due in part to a diminished muscle force production, which is due to, but not limited to an increase concentration of reactive oxygen species (ROS). Increases in [ROS] produces a shift in the oxidative state of muscle and produces an inhibition in force production. Since antioxidants scavenge ROS it is possible that supplementation might reduce the concentration of ROS and hence ameliorate the age-induced reduction of muscle force production. PURPOSE: To test the hypothesis that antioxidant supplementation would elevate spinotrapezius muscle force production, but maintain oxygen consumption across the rest-to contractions transition. METHODS: Muscle force production (force transducer) was measured in the isolated spinotrapezius of four old male Fisher 344 x Brown Norway hybrid rats (F344xBN) while muscle oxygen consumption (VO2m) was estimated in 20 anesthetized (35 mg/kg pentobarbital) F344xBN rats (28-30 months, body wt 563 + 19 g) during the transition from rest to muscle contractions (1 Hz, 5-7 volts, 4 min duration). Antioxidants (76 mg/kg vitamin C, 52 mg/kg tempol, i.v.) were administered and the protocol repeated. The effects of antioxidant supplementation were compared to the untreated control condition by paired t-tests with significance set at P<0.05. RESULTS: Antioxidant supplementation produced no effect on VO2m at rest or during the exercising state. However, antioxidant supplementation produced a 16.5% decrease (P<0.05) in muscle force production that occurred with the first contraction and remained throughout the duration of stimulation. In addition, the ratio of muscle force production to VO2m (F/VO2m) increased from 0.92 + 0.03 to 1.06 + 0.6 (P<0.05) after antioxidant supplementation. CONCLUSION: Antioxidant supplementation did not produce any changes in VO2m during the rest-to-exercise transition in aged rats. In contrast, muscle force production was reduced thereby producing an increase in the F/VO2m. This increase in F/VO2m suggests a greater economy for VO2 in muscle force production per unit of VO2 consumed following antioxidant supplementation in aged rats. Supported by AHA Heartland Affiliate Grant #0750090Z.

Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 × Brown Norway hybrid rats

Available studies indicate that both genetic background and aging influence collateral growth capacity, but it is not known how their combination affects collateral growth. We evaluated collateral growth induced by ileal artery ligation in Fischer 344 (F344), Brown Norway (BN), and the first generation hybrid of F344 x BN (F1) rats available for aging research from the National Institute on Aging. Collateral growth was determined by paired diameter measurements in anesthetized rats immediately and 7 days postligation. In 3-mo-old rats, significant collateral growth occurred only in BN (35% +/- 11%, P < 0.001). The endothelial cell number in arterial cross sections was also determined, since this precedes shear-mediated luminal expansion. When compared with the same animal controls, the intimal cell number was increased only in BN rats (92% +/- 21%, P < 0.001). The increase in intimal cell number and the degree of collateral luminal expansion in BN rats was not affected by age from 3 to 24 mo. Immunohistochemical studies demonstrated that intimal cell proliferation was much greater in the collaterals of BN than of F1 rats. The remarkable difference between these three strains of rats used in aging research and the lack of an age-related impairment in the BN rats are novel observations. These rat strains mimic clinical observations of interindividual variation in collateral growth capacity and the impact of age on arteriogenesis and should be useful models to investigate the molecular mechanisms responsible for such differences.

Repeated Aerosol-vapor JP-8 Jet Fuel Exposure Affects Neurobehavior and Neurotransmitter Levels in a Rat Model

Four groups of Fischer Brown Norway hybrid rats were exposed for 5, 10, 15, or 20 d to aerosolized-vapor jet propulsion fuel 8 (JP-8) compared to freely moving (5 and 10-d exposures) or sham-confined controls (15 and 20-d exposures). Behavioral testing utilized the U.S. Environmental Protection Agency Functional Observational Battery. Exploratory ethological factor analysis identified three salient factors (central nervous system [CNS] excitability, autonomic 1, and autonomic 2) for use in profiling JP-8 exposure in future studies. The factors were used as dependent variables in general linear modeling. Exposed animals were found to engage in more rearing and hyperaroused behavior compared to controls, replicating prior JP-8 exposure findings. Exposed animals also showed increasing but rapidly decelerating stool output (autonomic 1), and a significant increasing linear trend for urine output (autonomic 2). No significant trends were noted for either of the control groups for the autonomic factors. Rats from each of the groups for each of the time frames were randomly selected for tissue assay from seven brain regions for neurotransmitter levels. Hippocampal DOPAC was significantly elevated after 4-wk JP-8 exposure compared to both control groups, suggesting increased dopamine release and metabolism. Findings indicate that behavioral changes do not appear to manifest until wk 3 and 4 of exposure, suggesting the need for longitudinal studies to determine if these behaviors occur due to cumulative exposure, or due to behavioral sensitization related to repeated exposure to aerosolized-vapor JP-8.

Two months makes a difference in spatial orientation learning in very old FBNF1 rats

Age-related changes in cognitive performance may be more pronounced in the period near or exceeding the median life span. Therefore, we compared the acquisition of a Morris water escape task by two groups of very old Fischer344 × Brown Norway hybrid rats. The mean age difference between the two groups of rats (a 33- to 34-month-old group versus a 35- to 36-month-old group) was about 2 months. Both groups of rats initially had the same level of performance, but then the younger group learned to escape onto the submerged platform faster, swimming a shorter distance, than the older group. By the fifth acquisition session, the younger rats needed only half the time and swam a shorter distance before they reached the platform than the older rats. These differences in learning were not due to different locomotor abilities as both groups had a similar swimming speed. These results suggest that age-related changes in cognitive performance are indeed more pronounced in the period around the median life span. We also discussed different set-ups to perform cross-sectional age-comparison studies. If there are not sufficient animals from one batch, it may be worthwhile to combine animals from different batches per age group, provided that breeding, rearing, housing, and testing conditions are highly standardized.

The aging hippocampus: A multi-level analysis in the rat

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344×Brown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.