Responses Of Male Rats Research Articles

Limited cheese intake reduces HPA axis and behavioral stress responses in male rats

Eating palatable foods reduces behavioral and hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress – an idea referred to by the colloquial term “comfort” food. To study the underlying stress-relieving mechanisms of palatable foods, we previously developed a paradigm of limited sucrose feeding in which male rats are given twice-daily access to a small amount of sucrose drink and subsequently have reduced stress responses. Prior research in humans and rodents implicates high dietary sugars/carbohydrates with reduced stress responsivity. However, it is not clear whether the stress-relieving effects of the limited sucrose paradigm depend upon its macronutrient content. To test this idea, the current work measures stress responses in male rats following the limited intermittent intake of cheese – a highly palatable food that is low in sugar and other carbohydrates. The data show that a history of limited cheese intake (LCI) reduced HPA axis responses to acute psychological (restraint) and physiological (hypoxia) stressors. LCI also reduced behavioral struggling during restraint, increased sociability during a social interaction test, and increased open arm activity in the elevated plus-maze test. Z-score analyses evaluated the extent to which these behavioral effects extended within and across assays, and indicated that there was an overall reduction in stress-related behaviors following LCI. Finally, LCI increased immunolabeling for FosB/deltaFosB (a protein associated with repeated or chronic neuronal activation) in the nucleus accumbens. These results indicate that palatable foods can provide stress blunting regardless of their sugar/carbohydrate composition, and support the idea that food reward per se contributes to stress relief.

Abstract P171: Comparison Of Modulation Of Renal Arterial Tone By Perivascular Adipose Tissue Between Two Animal Models Of Metabolic Syndrome

Sex differences have recently been noticed in the regulation of arterial tone by perivascular adipose tissue (PVAT). In SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we demonstrated that mesenteric and renal PVAT in female rats consistently have an enhancing effect on vasodilation at 23 weeks, an age by which the effect of PVAT is impaired in the male rats. This could explain the sex differences in the prevalence of cardiovascular complications in patients with MetS. Therefore, we determined whether the sex difference in PVAT response also occurs in another animal model of MetS, SHR/NDmcr-cp (SHR-cp) rats.Renal arteries were isolated from male and female 23-week-old SHR-cp rats, and ring preparations with and without PVAT were made. After a stable contraction was obtained by phenylephrine administration, vasodilation in response to acetylcholine was examined using organ bath methods.Vasodilation in arteries without PVAT from female rats was smaller than that in arteries without PVAT from male rats, and presence of PVAT in arteries from female rats increased vasodilation to the same level as that observed in arteries without PVAT from male rats. Furthermore, renal PVAT in male rats was shown to have an enhancing effect on vasodilation.The present study did not identify sex differences in renal PVAT-mediated modulation in SHR-cp rats because the enhancing effects of PVAT did not disappear in male SHR-cp rats, in contrast to that observed in male SHRSP.ZF rats at the same age. The difference in PVAT response in male rats between two MetS models may be due to differences in the severity of MetS symptoms, especially blood pressure, between the models.

Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery.

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.

Immune receptor toll-like receptor 4 contributes to stress-induced affective responses in a sex-specific manner

Stress activates innate immune Toll-like receptors (TLRs) and enhances susceptibility to depression, a condition that is more prevalent in females. The TLR4 receptor type is involved in inflammatory responses and its expression levels associate with depressive symptoms and their successful treatment. Yet, little preclinical research has examined the role of TLR4 in stress-induced affective responses to determine if these are sex-specific. One group per genotype of male and female Tlr4 knockout (KO) and wild type (WT) rats were exposed to predator odor in a place conditioning apparatus with others exposed to saline. Affective behaviors evaluated included distance traveled and center time in an open-field apparatus, sucrose preference and fluid intake in a two-bottle test, and conditioned place aversion to the odor-paired compartment. Predator odor exposed rats showed conditioned place aversion to the odor-paired compartment, demonstrating predator odor was aversive. Such exposure led to anhedonia (decreased sucrose preference) across genotypes and sex. Predator odor exposure decreased distance traveled, an effect that was greater in KO rats, especially in females. Tlr4 deletion also resulted in sex-specific effects on anxiety-like behavior. Compared to WTs, female KO rats showed lower center time after predator odor exposure whereas genotype did not affect this response in male rats. Across litters, fewer male KO and heterozygous rats and more WT rats were born whereas female rats showed the typical genotype distribution. Results suggest predator odor alters affective behaviors, consistent with the preclinical literature, and deletion of Tlr4 enhances some stress-induced affective responses, often in a sex-specific manner.

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion.

Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.

Combined nicotine and ethanol age-dependently alter neural and behavioral responses in male rats.

Use of alcohol (EtOH) and nicotine (Nic) typically begins during adolescence. Smoking and drinking often occur together and lead to a higher consumption of alcohol. Although we have shown that Nic+EtOH is reinforcing in self-administration tests in adolescent male rats, whether Nic+EtOH affects other behaviors or neuronal activity in an age-dependent manner is unknown. To address this, adolescent and adult male rats were given intravenous injections of Nic (30 µg/kg)+EtOH (4 mg/kg) and evaluated for locomotor and anxiety-like behaviors. Regional neuronal activity, assessed by cFos mRNA expression, was measured and used to evaluate functional connectivity in limbic regions associated with anxiety and motivation. Nic+EtOH increased locomotor activity and was anxiolytic in adolescents, but not adults. The posterior ventral tegmental area (pVTA), a critical regulator of drug reward, was selectively activated by Nic+EtOH in adults, while activity in its target region, the NAc-shell, was decreased. Drug-induced alterations in functional connectivity were more extensive in adults than adolescents and may act to inhibit behavioral responses to Nic+EtOH that are seen in adolescence. Overall, our findings suggest that brief, low-dose exposure to Nic+EtOH produces marked, age-dependent changes in brain and behavior and that there may be an ongoing maturation of the pVTA during adolescence that allows increased sensitivity to Nic+EtOH's reinforcing, hyperlocomotor, and anxiolytic effects. Furthermore, this work provides a potential mechanism for high rates of co-use of nicotine and alcohol by teenagers: this drug combination is anxiolytic and recruits functional networks that are unique from protective, inhibitory networks recruited in the mature and adult brain.

Maternal immune activation and repeated maternal separation alter offspring conditioned avoidance response learning and antipsychotic response in male rats

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

Cuminum cyminum L.-Mediated Synthesis of Silver Nanoparticles: Their Characterization and Effect on Formalin-Induced Nociceptive Response in Male Rats.

In this study, a simple, low-cost, rapid, and eco-friendly approach for the biosynthesis of silver nanoparticles (AgNPs) using the aqueous extract of Cuminum cyminum L. (cumin) seed (CcAgNPs) was developed. Also, the anti-nociceptive properties of these synthesized AgNPs were evaluated in vivo. The CcAgNPs characterized using Ultraviolet-visible (UV-Vis) spectrophotometer, X-ray diffraction analysis (XRD), Fourier transform infrared (FTIR) spectroscopy, atomic force microscopy (AFM), and transmission electron microscopy (TEM). The analysis of phytochemical components in the aqueous extract of cumin seeds showed high concentrations of total phenols and ascorbic acid and low concentrations of total flavonoids. The analysis of phytochemical components and FTIR spectroscopy confirmed the presence of functional groups responsible for the bioreduction of Ag+ to AgNPs. The UV-Vis absorbance spectrum of CcAgNPs showed a maximum wavelength at 442nm. The analysis of TEM images showed a spherical shape with a size of less than 50nm, while XRD spectra revealed the crystallinity of CcAgNPs. The analysis of anti-nociceptive properties of CcAgNPs showed that the first phase of formalin-induced pain was significantly reduced in the groups receiving 200, 500, and 1000mg/kg CcAgNPs compared with the controls and the group receiving 300mg/kg of sodium salicylate (SS300). The second phase of formalin pain was also significantly reduced in the groups receiving 200 and 500mg/kg CcAgNPs compared to the controls and SS300 group. Overall, we introduced a new AgNPs synthesized from cumin seeds (CcAgNPs) and showed their anti-nociceptive properties in the formalin-induced pain.

Swim therapy-induced tissue specific metabolic responses in male rats

Swim therapy in the form of moderate physical activity has general health benefits. Regular exercise prevents the progression of chronic diseases affecting the different bodily systems. The metabolic alterations associated with following such lifestyle remain not fully understood. The aim of the present study was to elucidate the metabolic changes following prolonged swim therapy. Twenty-four Sprague Dawley rats were divided into sedentary and exercise groups. Our results revealed that regular exercise significantly increased the serum levels of growth hormone (GH), glucagon and corticosterone. A reduction in the circulating levels of irisin and insulin hormones, and glucose were noticed alongside with an upregulation in the mRNA expression levels of FNDC5, PGC-1α, GLUT-4 and preptin receptors with downregulation in the expression of Enho gene in the heart of exercised rats. Liver of the exercised rats showed elevation in the transcriptional levels of Enho gene, PPARα, and preptin with reduction in the transcriptional levels of preptin receptors. Exercise induced an increase in the pancreatic mRNA of Enho gene, preptin and preptin receptors, and a reduction in FNDC5, PPARα and PGC-1α. An elevation in the gastrocnemius muscle PGC-1α mRNA expression and a decline in the soleus muscle Enho mRNA were found. Exercise diminishes the activities of SOD, CAT and GPx in the gastrocnemius muscle, liver and pancreas. Myogenin expression increased in all examined skeletal muscles. This study takes into account the complex crosstalk between different signaling pathways in skeletal muscles, heart, liver and pancreas as well as the metabolic alterations in response to regular exercise.

Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats

Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 μg, 1 μg and 2 μg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 μM, 10 μM, 30 μM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.

Programming Skeletal Muscle Metabolic Flexibility in Offspring of Male Rats in Response to Maternal Consumption of Slow Digesting Carbohydrates during Pregnancy.

Skeletal muscle plays a relevant role in metabolic flexibility and fuel usage and the associated muscle metabolic inflexibility due to high-fat diets contributing to obesity and type 2 diabetes. Previous research from our group indicates that a high-fat and rapid-digesting carbohydrate diet during pregnancy promotes an excessive adipogenesis and also increases the risk of non-alcoholic fatty liver disease in the offspring. This effect can be counteracted by diets containing carbohydrates with similar glycemic load but lower digestion rates. To address the role of the skeletal muscle in these experimental settings, pregnant rats were fed high-fat diets containing carbohydrates with similar glycemic load but different digestion rates, a high fat containing rapid-digesting carbohydrates diet (HF/RD diet) or a high fat containing slow-digesting carbohydrates diet (HF/SD diet). After weaning, male offspring were fed a standard diet for 3 weeks (weaning) or 10 weeks (adolescence) and the impact of the maternal HF/RD and HF/SD diets on the metabolism, signaling pathways and muscle transcriptome was analyzed. The HF/SD offspring displayed better muscle features compared with the HF/RD group, showing a higher muscle mass, myosin content and differentiation markers that translated into a greater grip strength. In the HF/SD group, metabolic changes such as a higher expression of fatty acids (FAT/CD36) and glucose (GLUT4) transporters, an enhanced glycogen content, as well as changes in regulatory enzymes such as muscle pyruvate kinase and pyruvate dehydrogenase kinase 4 were found, supporting an increased muscle metabolic flexibility and improved muscle performance. The analysis of signaling pathways was consistent with a better insulin sensitivity in the muscle of the HF/SD group. Furthermore, increased expression of genes involved in pathways leading to muscle differentiation, muscle mass regulation, extracellular matrix content and insulin sensitivity were detected in the HF/SD group when compared with HF/RD animals. In the HF/SD group, the upregulation of the ElaV1/HuR gene could be one of the main regulators in the positive effects of the diet in early programming on the offspring. The long-lasting programming effects of the HF/SD diet during pregnancy may depend on a coordinated gene regulation, modulation of signaling pathways and metabolic flexibility that lead to an improved muscle functionality. The dietary early programming associated to HF/SD diet has synergic and positive crosstalk effects in several tissues, mainly muscle, liver and adipose tissue, contributing to maintain the whole body homeostasis in the offspring.

Chronic unpredictable intermittent restraint stress disrupts spatial memory in male, but not female rats

Chronic stress leads to sex-dependent outcomes on spatial memory by producing deficits in males, but not in females. Recently it was reported that compared to daily restraint, intermittent restraint (IR) produced more robust stress and anxiety responses in male rats. Whether IR would be sufficiently robust to impair hippocampal-dependent spatial memory in both male and female rats was investigated. IR involved mixing restraint with non-restraint days over weeks before assessing spatial memory and anxiety profile on the radial arm water maze, object placement, novel object recognition, Y-maze, open field and novelty suppressed feeding. Experiments 1 and 2 used Sprague-Dawley male rats only and determined that IR for 6 h/d (IR6), but not 2 h/d, impaired spatial memory and that task order was important. In experiment 3, IR6 was extended for 6wks before spatial memory testing commenced using both sexes. Unexpectedly, an extended IR6 paradigm failed to impair spatial memory in either sex, suggesting that by 6wks IR6 may have become predictable. In experiment 4, an unpredictable IR (UIR) paradigm was implemented, in which restraint duration (30 or 60-min) combined with orbital shaking, time of day, and the days off from UIR were varied. UIR impaired spatial memory in males, but not in females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not in females. We interpret these findings to show that females are more resilient to chronic stress than are males as it pertains to spatial ability.

Decreased serotonin content and release in the ventral hippocampus of prenatally stressed male rats in response to forced swim test

Prenatal stress modifies the serotonergic system by altering the synthesis, metabolism, receptors and serotonin content in the hippocampus. However, it is currently unknown whether serotonin release in the ventral hippocampus of prenatally stressed rats is altered. In this study, serotonin (5-HT) and its metabolite, 5‑hydroxyindoleacetic acid (5-HIAA) levels were analysed in dialysates (in vivo) and in homogenates (in vitro) of the ventral hippocampus. This was made after the sucrose preference test and after forced swim test (FST) in male adult progeny from mothers that were stressed by immersion in cold water during the last week of gestation. Serum concentration of corticosterone was also evaluated in control and in prenatally stressed males. Sucrose preference was differently affected in prenatally stressed males: 69% showed decreased sucrose consumption, and were considered anhedonic; 31% exhibited sucrose consumption similar to control and were considered non‑anhedonic. During the FST, increased immobility and decreased swimming were observed in prenatally stressed males. After sucrose test, content and release of 5‑HT in prenatally stressed rats were similar to those in the control group, with higher metabolite. After the FST, 5-HT content increased, but its release increased slightly in anhedonic rats and did not change in non-anhedonic rats, with lower metabolite. The response of the adrenal axis to the FST was larger in anhedonic prenatally stressed males, than in control and non‑anhedonic males. These data show that behavioural disruption caused by prenatal stress is related to low release and lower metabolism of serotonin in the ventral hippocampus in adult male offspring, as well as to hyperactivity and hyperreactivity of the adrenal axis.

The Sub-acute Effect of Lead Exposure on the Auditory Brainstem Response in Male Rats

Background: Lead is a major environmental pollutant and can adversely affect humans and animals. There are conflicting data about the ototoxic effect of lead. This study experimentally examined the association between blood lead levels (BLL) and the subsequent hearing impairment in male rats. Methods: Twenty-two male rats were randomly categorized into experimental (exposed to lead acetate, 4 mg/kg by gavage) and control groups. We evaluated the groups by click and tone audiometric burst tests, comparing the data before and 30 days after exposure to lead acetate (4mg/kg). Also, blood samples were collected from the rats and analyzed for lead levels by graphite furnace atomic absorption spectrometry. Results: The study findings demonstrated remarkable increase in hearing threshold in the lead-exposed group, compared to the controls (p<0.0001). Also, the blood lead levels revealed a significant association of lead acetate with the hearing loss in rats. Conclusion: This study revealed that exposure to lead acetate can be damaging to hearing. However, future research is recommended to clarify the mechanism of action of lead toxicity on the auditory function at varying blood lead concentrations.

The lateral intercalated cell mass of the amygdala is activated during social buffering of conditioned fear responses in male rats

The presence of an affiliative conspecific reduces stress responses to a wide variety of stimuli. This phenomenon is termed “social buffering”. We previously found that the presence of another Wistar rat (associate) suppressed activation of the lateral amygdala (LA) and ameliorated stress responses to an auditory conditioned stimulus (CS) in a fear-conditioned Wistar subject rat. Subsequent analyses suggested that activation of the posterior complex of the anterior olfactory nucleus (AOP) is responsible for the suppression of the LA. However, it remains unclear how the AOP suppresses the LA. To clarify this issue, a fear-conditioned Wistar subject was exposed to the CS either alone or with a Wistar associate. We also prepared a fear-conditioned Wistar subject that was tested with a Fischer344 (F344) associate as an additional control because F344 associates do not induce social buffering. We found that the presence of a Wistar associate induced a reduction of behavioral responses and Fos expression in the paraventricular nucleus of the hypothalamus (PVN) of the subject. Although Fos expression in the AOP was increased, the expression was not biased towards the GABAergic cells. In addition, Fos expression in the lateral intercalated cell mass of the amygdala (lITC) was increased. In contrast, the presence of a F344 associate did not affect Fos expression in subjects’ PVN or lITC, whereas behavioral responses were slightly reduced. These results suggest that the lITC was activated during social buffering. Based on these findings, we propose that the AOP indirectly suppresses the LA by activating the lITC.

Association of high-fat diet with neuroinflammation, anxiety-like defensive behavioral responses, and altered thermoregulatory responses in male rats

Overweight and obesity are a worldwide pandemic affecting billions of people. These conditions have been associated with a chronic low-grade inflammatory state that is recognized as a risk factor for a range of somatic diseases as well as neurodevelopmental disorders, anxiety disorders, trauma- and stressor-related disorders, and affective disorders. We previously reported that the ingestion of a high-fat diet (HFD; 45% fat kcal/g) for nine weeks was capable of inducing obesity in rats in association with increased reactivity to stress and increased anxiety-related defensive behavior. In this study, we conducted a nine-week diet protocol to induce obesity in rats, followed by investigation of anxiety-related defensive behavioral responses using the elevated T-maze (ETM), numbers of FOS-immunoreactive cells after exposure of rats to the avoidance or escape task of the ETM, and neuroinflammatory cytokine expression in hypothalamic and amygdaloid nuclei. In addition, we investigated stress-induced cutaneous thermoregulatory responses during exposure to an open-field (OF). Here we demonstrated that nine weeks of HFD intake induced obesity, in association with increased abdominal fat pad weight, increased anxiety-related defensive behavioral responses, and increased proinflammatory cytokines in hypothalamic and amygdaloid nuclei. In addition, HFD exposure altered avoidance- or escape task-induced FOS-immunoreactivity within brain structures involved in control of neuroendocrine, autonomic, and behavioral responses to aversive stimuli, including the basolateral amygdala (BLA) and dorsomedial (DMH), paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei. Furthermore, rats exposed to HFD, relative to control diet-fed rats, responded with increased tail skin temperature at baseline and throughout exposure to an open-field apparatus. These data are consistent with the hypothesis that HFD induces neuroinflammation, alters excitability of brain nuclei controlling neuroendocrine, autonomic, and behavioral responses to stressful stimuli, and enhances stress reactivity and anxiety-like defensive behavioral responses.

Morphological Characteristics of the Thymus and Spleen and the Subpopulation Composition of Lymphocytes in Peripheral Blood during Systemic Inflammatory Response in Male Rats with Different Resistance to Hypoxia.

On the model of the systemic inflammatory response (SIRS), induced by lipopolysaccharide (LPS), the morphological and functional changes in the thymus and spleen and the subpopulation composition of peripheral blood lymphocytes of rats differing in resistance to hypoxia were studied. It was demonstrated that the level of endotoxin in blood serum after 3 hours of LPS administration in susceptible-to-hypoxia rats was 64 times higher than in the control group, while in tolerant-to-hypoxia animals it was only 8 times higher in 6 hours. After 24 hours of LPS injection, only in susceptible-to-hypoxia rats did the level of C-reactive protein in blood serum increase. There is a difference in the dynamics of morphological changes of lymphoid organs after LPS injection in tolerant- and susceptible-to-hypoxia animals. After 3 hours of LPS administration, the tolerant-to-hypoxia rats showed no changes in the thymus, spleen, and subpopulation composition of lymphocytes in peripheral blood. After 6 hours there was only a decrease in B-lymphocytes and increase in cytotoxic T-lymphocytes and NK cells. After 1 day of LPS injection, the tolerant-to-hypoxia rats had devastation in PALS of the spleen. After 3 hours of LPS injection the susceptible-to-hypoxia animals had reactive changes in the lymphoid organs: decrease of the thymus cortex, narrowing of the marginal zones of spleen lymphoid follicles, widening of their germinal centers, and a decrease in the absolute number of cytotoxic T-lymphocytes, NK cells, and B-lymphocytes. After 24 hours of LPS injection the tolerant-to-hypoxia animals had a greater absolute number of T-lymphocytes and NK cells in comparison with the susceptible rats. Thus, in animals with different resistance to hypoxia the LPS-induced SIRS is characterized by different dynamics of morphological and functional changes of the thymus and spleen. The obtained data will serve as a basis for the development of new individual approaches to the prevention and treatment of infectious and inflammatory diseases.

Altered metabolic and hormonal responses in male rats exposed to acute bright light-at-night associated with global DNA hypo-methylation

The association between light pollution and disruption of daily rhythms, metabolic and hormonal disorders, as well as cancer progression is well-recognized. These adverse effects could be due to nocturnal melatonin suppression. The signaling pathway by which light pollution affects metabolism and endocrine responses is unclear. We studied the effects of artificial light at night (ALAN11Artificial light at night.) on body mass, food and water intake, daily rhythms of body temperature, serum glucose and insulin in male rats. Daily rhythms of urine production and urinary 6-sulfatoxymelatonin (6-SMT226-sulfatoxymelatonin.), as well as global DNA methylation in pancreas and liver tissues were also assessed. Mass gain was higher in ALAN rats compared with controls. Food intake, water consumption, glucose, insulin, and 6-SMT levels markedly lessened in response to ALAN. Conversely, urine production and body temperature were elevated in ALAN rats compared with controls. Significant 24-h rhythms were detected for all variables that were altered in mesor, amplitude, and acrophase occurrences under ALAN conditions. DNA hypo-methylation was detected in ALAN pancreatic tissue compared with controls, but not in hepatic tissue. Overall, ALAN affects metabolic and hormonal physiology in different levels in which flexible crosstalk between melatonin and both epigenetics and metabolic levels expressed as body temperature rhythm, is suggested to mediate the environmental exposure at the molecular level and subsequently physiology is altered. The flexibility of epigenetic modifications provides a potential therapeutic target for rectifying ALAN adverse effects by epigenetic markers such as melatonin and behavioral lifestyle interventions for confining ALAN exposures as much as possible.

A dyad shows mutual changes during social buffering of conditioned fear responses in male rats

The presence of an affiliative conspecific reduces stress responses to a wide variety of stimuli. This phenomenon is termed “social buffering”. We previously found that the presence of another naïve rat (associate) reduced conditioned fear responses to an auditory conditioned stimulus in a conditioned subject rat. Although we subsequently conducted a series of studies to examine behavioral, physiological, and neural changes during social buffering in the conditioned subject, the changes in the associate remained unclear. Therefore, in the present study, we investigated the behavioral and neural changes in the associate. Fear-conditioned and non-conditioned rats were re-exposed to the conditioned stimulus with an associate placed in the same enclosure (Experiment 1) or separated by a wire-mesh partition (Experiment 2). In Experiment 1, the associate exhibited increased anogenital contact and allo-grooming, which were accompanied by increased c-Fos expression in the paraventricular nucleus of the hypothalamus and central amygdala. These results suggest that the subject and associate mutually affected each other during social buffering. In contrast, in Experiment 2, we found only a difference in the time course of investigation between associates tested with the conditioned and non-conditioned subjects. These results suggest that the associate was unable to acquire a sufficient amount of signal from the conditioned subject behind the wire-mesh partition necessary to show clear changes in behavior and c-Fos expression. Taken together, the current findings suggest that a dyad shows mutual changes during social buffering of conditioned fear responses in male rats.

Vitamin E Reduces Hypobaric Hypoxia-Induced Immune Responses in Male Rats.

In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects.