Stress Response In Rats Research Articles

Differential stress response in rats subjected to chronic mild stress is accompanied by changes in CRH-family gene expression at the pituitary level

The purpose of this study was to examine molecular markers of the stress response at the pituitary and peripheral levels in animals that responded differently to chronic mild stress (CMS). Rats were subjected to 2-weeks CMS and symptoms of anhedonia was measured by the consumption of 1% sucrose solution. mRNA levels of CRH-family neuropeptides (Crh—corticotropin-releasing hormone, Ucn1—urocortin 1, Ucn2—urocortin 2, Ucn3—urocortin 3), CRH receptors (Crhr1—corticotropin-releasing hormone receptor 1, Crhr2—corticotropin-releasing hormone receptor 2) and Crhbp (corticotropin-releasing factor binding protein) in the pituitaries of rats were determined with real-time PCR. Plasma levels of ACTH (adrenocorticotropin), CRH and urocortins were measured with ELISA assays. CMS procedure led to the development of anhedonia manifested by the decreased sucrose consumption (stress-reactive, SR, stress-susceptible group). Additionally, the group of animals not exhibiting any signs of anhedonia (stress non-reactive, SNR, stress-resilient group) and the group characterized by the increased sucrose consumption (stress invert-reactive group SIR) were selected. The significant increases in ACTH plasma level accompanied by the decreases in the pituitary gene expression of the Crh, Ucn2 and Ucn3 in both stress non-reactive and stress invert-reactive groups were observed. The only molecular change observed in stress-reactive group was the increase in UCN2 plasma level. The differentiated behavioral stress responses were reflected by gene expression changes in the pituitary. Alterations in the mRNA levels of Crh, Ucn2 and Ucn3 in the pituitary might confirm the paracrine and/or autocrine effects of these peptides in stress response. The opposite behavioral effect between SNR vs. SIR groups and the surprising similarity at gene expression and plasma ACTH levels in these two groups may suggest the discrepancy between molecular and behavioral stress responses; however, there results might indicate to similarity underlying different ways to cope with stress conditions.

Nootropic and anti-stress effects of rice bran oil in male rats.

Rice bran oil (RBO) is an important product of rice bran. It is considered to be one of the most important nutritious oil due to its favorable fatty acid composition and unique composition of naturally occurring biologically active antioxidant compounds. This study was designed to monitor the effects of oral intake of RBO on stress response in rats. RBO was extracted using hexane. Rats were divided into Control and test (RBO-treated). RBO-treated rats were given 0.2ml/day RBO for 6weeks. Food intake and body weight changes were monitored weekly. After 6weeks open field activity and Morris Water Maze (MWM) test were performed. Results showed that weekly cumulative food intake but not body weight were lower in RBO-treated rats during 1st to 5th week of treatment, which were normalized at the end of treatment. Exploratory activity of RBO-treated rats in an open field was increased. Spatial memory in Morris water maze was enhanced in RBO-treated than control rats. An episode of 2h restraint stress decreased the 24h food intake of both control and RBO-treated animals. Behavioral deficits were lower in RBO-treated rats. Exposure of 2h restraint stress increased brain serotonin (5-hydroxytryptamine: 5-HT) metabolism. These increases were lower in RBO-treated restrained than their respective control animals. Serotonergic neurotransmitter mechanism is implicated in stress. The findings of the study show beneficial effects of RBO in learning and memory functions. Moreover, the study also highlights the attenuating effect of RBO on stress induced behavioral and neurochemical effects in rats.

Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats

Bisphenol A (BPA) is an estrogen-mimicking endocrine disruptor. Early-life exposures to low doses of BPA exert long-lasting effects on animals' reproductive and brain physiology. However, little is known about the effects of BPA on the stress-response system. Given the interaction of sex and stress hormones, we examined the effect of a low perinatal BPA exposure on the function of the hypothalamic-pituitary-adrenal (HPA) axis at rest and upon application of acute stress. Throughout pregnancy and lactation rats received daily 40 μg BPA/kg body weight orally via cornflakes. We studied the effect of this low but chronic exposure to BPA in the male and female offspring at puberty. BPA exposure led to abnormal adrenal histology including reduced zona reticularis especially in male offspring, hyperplasia of zona fasciculata in both sexes, and increased adrenal weight in female offspring. BPA-treated females had increased basal corticosterone and reduced hypothalamic glucocorticoid receptors (GR) levels. Stressed BPA-exposed females exhibited anxiety-like behavioral coping, a less rigorous corticosterone response, and did not downregulate GR in the hypothalamus, compared with control females. BPA-exposed males exhibited a heightened corticosterone stress response compared with females; they also displayed increased pro-opiomelanocortin mRNA levels and retained the prestress levels of pituitary corticotropin-releasing hormone-receptor 1, compared with control males. We found that perinatal chronic exposure to a low dose of BPA perturbs the basal and stress-induced activity of the HPA axis in a sexually dimorphic manner at adolescence. Exposure to BPA might contribute to increased susceptibility to stress-related disorders in later life.

Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats

Ochratoxin A (OTA) is a renal carcinogen that induces karyomegaly in target renal tubular cells of the outer stripe of the outer medulla (OSOM). This study was performed to clarify the relationship between oxidative stress and the karyomegaly-inducing potential involving cell cycle aberration of OTA in the OSOM. Rats were treated with OTA for 28 days in combination with enzymatically modified isoquercitrin (EMIQ) or α-lipoic acid (ALA) as antioxidants. OTA increased the mRNA levels of the antioxidant enzyme-related genes Gpx1, Gpx2, Gstm1 and Nfe2l2, but did not increase the levels of Gsta5, Keap1, Nqo1, Hmox1, Aldh1a1, Por, Prdx1 and Txn1. OTA also did not change the levels of thiobarbituric acid-reactive substances, glutathione disulfide/reduced glutathione, and the immunoreactive tubular cell distribution of nuclear factor erythroid 2-related factor 2 in the OSOM. Co-treatment with EMIQ or ALA did not cause any changes in these parameters. As previously reported, OTA increased cell proliferation activity, apoptosis and immunohistochemical cellular distributions of molecules suggestive of induction of DNA damage and cell cycle aberrations involving spindle checkpoint disruption and cell cycle arrest. However, co-treatment with EMIQ or ALA did not suppress these changes, and ALA co-treatment increased the cell proliferation activity induced by OTA. These results suggest that OTA facilitates cell cycling involving cell cycle aberrations and apoptosis as a basis of the mechanism behind the development of karyomegaly and subsequent carcinogenicity targeting the OSOM, without relation to induction of oxidative stress. On the other hand, ALA may promote the OTA-induced proliferation of carcinogenic target cells.

Exposure to hypergravity during the preweaning but not postweaning period reduces vestibular-related stress responses in rats

Gravitational forces, including hypergravity or microgravity, induce plasticity of vestibular-related functions. These functions are not easily reversed if exposure to the gravitational forces occurs during vestibular development. In the present study, we hypothesized that vestibular-related stress responses might be suppressed in rats exposed to hypergravity during the vestibular development period. We exposed the rats to 2 g (hypergravity) during the preweaning (BW-HG; embryonic day 14 to postnatal week 3) or postweaning (AW-HG; postnatal weeks 4-6) periods. After recovery for 4 wk at 1 g, we conducted rotarod tests and then exposed the rats to 2 g for 90 min. In BW-HG rats, vestibular-related motor coordination on the rotarod test was partially, but not fully, restored to the level of AW-HG rats or rats raised at 1 g (1-G group). Loading-induced plasma adrenocorticotropic hormone and corticosterone levels were significantly suppressed in BW-HG and in rats with a vestibular lesion compared with AW-HG and 1-G rats. Arginine vasopressin and Fos expression levels in the paraventricular hypothalamic nucleus were also significantly lower in BW-HG and vestibular lesion rats than in AW-HG and 1-G rats. By contrast, there was no difference in the electrical foot shock-induced increase in plasma corticosterone among the experimental groups, suggesting that the nonvestibular-related stress response was not suppressed by exposure to 2 g during preweaning. These results indicated that exposure to hypergravity during preweaning specifically suppressed the vestibular-related stress response, and this suppression did not recover after 4 wk at 1 g.

Do exercise and estrogens interact to alter stress responses in rats?

The beneficial effects of exercise in coping with stress/anxiety may be particularly important for women, as anxiety and depression increase after menopause. The present experiments examined anxiety‐like behaviors and corticosterone (CORT) levels induced by acute stress in female rats with or without estradiol benzoate (EB) after a single bout of exercise vs. 3 days of exercise before and after stress.Adult female Sprague Dawley rats were ovariectomized, recovered for 7 days, given EB or OIL for 2 consecutive days, and tested during the next 2 days. In Expt. 1, rats were stressed by being placed in a plastic restrainer for 40 min, then were returned to a novel cage with a running wheel attached. Software recorded distance, speed, and time spent on wheels for 14 hrs. The next morning, anxiety‐like behaviors were assessed using the Elevated Plus Maze (EPM). In Expt. 2, exercising rats had access to running wheels beginning on day 1 of EB/OIL treatment and ran throughout the experiment, including the 14 hrs after restraint stress.Exercise prior to restraint stress reduced CORT levels in EB‐treated rats compared to rats that ran after stress. However, 3 days of exercise increased anxiety‐like behaviors in both groups compared to rats exercised for only 1 day, with or without restraint stress.Thus, exercise duration affects stress hormones in EB‐treated rats, but CORT levels may not accurately predict anxiety‐like behaviors.

Low-dose neonatal domoic acid causes persistent changes in behavioural and molecular indicators of stress response in rats

Appropriate stress responses rely on a finely-tuned neuronal balance that must continually adapt to a frequently changing external environment. Alterations in this balance can result in susceptibility to a variety of stress-related disorders, as well as exacerbate already existing conditions. We have previously reported that rat pups injected with a very low dose (20μg/kg) of domoic acid during the second postnatal week of life display low-grade seizure behaviours when challenged with stressful tasks, and also exhibit a variety of structural and functional changes similar to those seen in temporal lobe epilepsy. The current study was designed to investigate markers of altered stress-response in this model. Following neonatal treatment, adult rats were tested in the elevated plus maze, as well as two water maze tasks, both of which involved a platform reversal challenge. Results indicated a modified behavioural stress/anxiety response, increased perseveration, and alterations in search strategy for all domoate-treated rats, as well as male-specific deficits in cognitive flexibility. In addition, 80% of treated males and 20% of treated females exhibited seizure behaviour. Western blot analysis revealed male-only increases in adrenergic receptor (α2a and α2c) and mineralocorticoid receptor expression, and subtle sex-specific changes in glucocorticoid receptor expression, but no differences in corticotropin-releasing factor receptors I/II, or dopamine D2 receptor expression. A significant decrease in glucocorticoid:mineralocorticoid ratio was also noted. We conclude that early exposure to DOM alters central mechanisms underlying stress response, and that this model may be valuable for investigating the connection between stress and neurological disorders.

Chronic cocaine self-administration attenuates the anxiogenic-like and stress potentiating effects of the benzodiazepine inverse agonist, FG 7142

Stress is a well-known risk factor in relapse to drug abuse. Several forms of stress in animals have been used with varied degrees of success to elicit reinstatement of drug-seeking after chronic drug self-administration. Here, we tested the ability of the benzodiazepine (BZ) inverse agonist, FG 7142, to elicit anxiety-like behavior and potentiate stress responses in rats as measured by standard behavioral and hormonal indices and for its ability to affect reinstatement of cocaine-seeking in rats with a prior history of cocaine self-administration. FG 7142 elicited anxiety-like behavior on the elevated plus maze (EPM) in cocaine-naïve rats, and cocaine-naïve rats injected with FG 7142 exhibited increased plasma corticosterone levels following EPM exposure. However, in animals with a history of cocaine self-administration, FG 7142 failed to affect elevated plus maze performance and did not affect plasma corticosterone response to the EPM. Furthermore, FG 7142 failed to reinstate cocaine-seeking, nor did it alter conditioned cue-induced reinstatement. These data indicate that the anxiety-related and stress potentiating qualities of BZ inverse agonism are attenuated in cocaine-experienced animals and do not lead to reinstatement of cocaine-seeking.

Effects of comfort food on food intake, anxiety-like behavior and the stress response in rats

It has been suggested that access to high caloric food attenuates stress response. The present paper investigates whether access to commercial chow enriched with glucose and fat, here referred to as comfort food alters behavioral, metabolic, and hormonal parameters of rats submitted to three daily sessions of foot-shock stress. Food intake, anxiety-like behaviors, and serum levels of insulin, leptin, corticosterone, glucose and triglycerides were determined. The rats submitted to stress decreased the intake of commercial chow, but kept unaltered the intake of comfort food. During the elevated plus maze (EPM) test, stressed rats increased the number of head dipping, entries into the open arms, as well as the time spent there, and decreased the number of stretched-attend posture and risk assessment. These effects of stress were independent of the type of food consumed. Non-stressed rats ingesting comfort food decreased risk assessment as well. Stress and comfort food increased time spent in the center of the open field and delayed the first crossing to a new quadrant. Stress increased the plasma level of glucose and insulin, and reduced triglycerides, although consumption of comfort food increases glucose, triglyceride and leptin levels; no effect on leptin level was associated to stress. The stress induced increase in serum corticosterone was attenuated when rats had access to comfort food. It was concluded that foot-shock stress has an anorexigenic effect that is independent of leptin and prevented upon access to comfort food. Foot-shock stress also has an anxiolytic effect that is potentiated by the ingestion of comfort food and that is evidenced by both EPM and open field tests.

Congenital absence of vasopressin and age-dependent changes in ACTH and corticosterone stress responses in rats

The hypothalamic components of the hypothalamo–pituitary–adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V1b receptor antagonist pretreatment (SSR149415). In adult di/di or V1b pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.

P.1.027 Changes of gene expression in the pituitary reflect different stress responses in rats exposed to chronic stress

P.1.027 Changes of gene expression in the pituitary reflect different stress responses in rats exposed to chronic stress

Concomitant apoptosis and regeneration of liver cells as a mechanism of liver-tumor promotion by β-naphthoflavone involving TNFα-signaling due to oxidative cellular stress in rats

β-Naphthoflavone (BNF) is a strong inducer of cytochrome P450 1A enzymes, and exerts liver tumor-promoting activity through enhancement of oxidative stress responses in rats. This study investigated the role of the tissue environment surrounding hepatocellular preneoplastic lesions in the early tumor-promotion stage by BNF, using enzymatically modified isoquercitrin (EMIQ) as an anti-oxidative chemopreventive agent. Male F344 rats were fed a diet containing BNF (0.5%) for 6 weeks, with or without EMIQ (0.2%) in the drinking water, 2 weeks after initiation with N-diethylnitrosamine, and were subjected to two-thirds partial hepatectomy 1 week after starting BNF-promotion. BNF-treatment increased concentrations of liver thiobarbituric acid-reactive substances, single liver cells expressing glutathione S-transferase placental form or heme oxygenase (HO)-1, and concomitant apoptosis and proliferation of liver cells. Transcript upregulation of anti-oxidative enzymes ( Aldh1a1 and Nqo1), cell cycle-related molecules ( Cdc20 and Cdkn2b) and inflammation-related molecules including proinflammatory cytokines ( Ccl2, Col1a1, Il6, Nos2 and Serpine1) was also evident. Furthermore, BNF increased HO-1-expressing Kupffer cells and liver cells expressing tumor necrosis factor receptor 1 (TNFR1) and the TNFR1-associated death domain. Most of these BNF-induced fluctuations disappeared or were suppressed by EMIQ in conjunction with suppression of tumor-promotion. Tnf transcript levels with BNF were also suppressed by EMIQ. These results suggest that BNF-induced oxidative stress causes single liver cell toxicity, allowing subsequent concomitant apoptosis and regeneration involving inflammatory responses including TNFα-signaling, contributing to tumor promotion. Kupffer cells may act to protect against inflammatory stimuli induced as a result of oxidative cellular stress by BNF, causing proinflammatory cytokine level fluctuations.

Relationship between CYP1A induction by indole-3-carbinol or flutamide and liver tumor-promoting potential in rats

To investigate liver tumor-promoting potentials of indole-3-carbinol (I3C) and flutamide (FLU), changes in mRNA expression of Cyp1a and genes encoding antioxidant/detoxifying enzymes in the liver, 6-week-old male F344 rats were subjected to medium-term liver bioassay. β-Naphthoflavone (BNF), a strong CYP1A inducer, was also used for comparison. Two weeks after initiation with N-diethylnitrosamine (DEN), animals were fed a basal diet (untreated controls) or a diet containing 0.5% I3C, 0.1% FLU, or 0.5% BNF for 6weeks. Each animal was subjected to a two-third partial hepatectomy 1week after the start of promoter treatments. Histopathologically, I3C and BNF increased altered liver cell foci with the incidence (3.7- and 7.3-fold) and multiplicity (8.3- and 13.8-fold) compared with the DEN-alone group, respectively. Immunohistochemically, I3C significantly increased the number (3.1-fold; P<0.01) and area (2.4-fold; P<0.05) of foci positive for glutathione-S-transferase placental form (GST-P) compared with the DEN-alone group; FLU induced a slight but significant increase in the number of GST-P-positive foci (2.8-fold; P<0.05) whereas BNF showed marked induction of the number and area of GST-P-positive foci (20- and 14-fold, respectively; P<0.01). In parallel, I3C, FLU, and BNF markedly increased mRNA levels of Cyp1a1 (50-, 23-, 299-fold) and antioxidant/detoxifying enzymes such as Gpx2 and Nqo1 as shown by real-time reverse transcription-polymerase chain reaction analysis. These results suggest that I3C and FLU could promote hepatocellular tumors in parallel with that of CYP1A's potential to cause subsequent oxidative stress responses in rats.

The Importance of Reporting Housing and Husbandry in Rat Research

In 1963, the National Institutes of Health (NIH) first issued guidelines for animal housing and husbandry. The most recent 2010 revision emphasizes animal care “in ways judged to be scientifically, technically, and humanely appropriate” (National Institutes of Health, 2010, p. XIII). The goal of these guidelines is to ensure humanitarian treatment of animals and to optimize the quality of research. Although these animal care guidelines cover a substantial amount of information regarding animal housing and husbandry, researchers generally do not report all these variables (see Table ​Table1).1). The importance of housing and husbandry conditions with respect to standardization across different research laboratories has been debated previously (Crabbe et al., 1999; Van Der Staay and Steckler, 2002; Wahlsten et al., 2003; Wolfer et al., 2004; Van Der Staay, 2006; Richter et al., 2010, 2011). This paper focuses on several animal husbandry and housing issues that are particularly relevant to stress responses in rats, including transportation, handling, cage changing, housing conditions, light levels and the light–dark cycle. We argue that these key animal housing and husbandry variables should be reported in greater detail in an effort to raise awareness about extraneous experimental variables, especially those that have the potential to interact with the stress response.

The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses

The lateral septum (LS) has been shown to have a key role in emotional processes and stress responses. However, the exact role of the LS on stress modulation is not clear, as previous lesion studies mostly used electrolytic lesions, thereby destroying the whole septal area, including medial components and/or fibers of passage. The aim of the present study was therefore, to investigate the effects of selective excitotoxic ablation of the LS on neuroendocrine and behavioral stress responses in rats. Bilateral ibotenic acid lesions of the LS increased hypothalamo–pituitary–adrenocortical (HPA) axis responses to forced swim stress indicated by enhanced plasma ACTH and corticosterone responses and higher stress-induced c-Fos-like immunoreactivity in the paraventricular hypothalamic nucleus. Moreover, LS-lesioned animals showed a more passive coping style in the forced swim test indicated by increased floating and reduced struggling/swimming behavior compared with sham-lesioned controls. Interestingly, intraseptal corticosteroid receptor blockade modulated behavioral stress coping but failed to change HPA axis stress responses. Further experiments aimed at elucidating underlying neurochemical mechanisms revealed that intraseptal administration of the selective 5-HT1A receptor antagonist WAY-100635 increased and prolonged stress-induced ACTH and corticosterone levels mimicking lesion effects, while the agonist 8-OH-DPAT suppressed HPA axis activity facilitating the inhibitory role of the LS. In addition, 8-OH-DPAT-injected animals showed increased active and decreased passive coping strategies during forced swimming suggesting antidepressant efficacy. Taken together, our data suggest that the LS promotes active stress coping behavior and is involved in a HPA-inhibitory mechanism that is at least in part mediated by septal 5-HT1A receptors and does not involve a glucocorticoid mediated feedback mechanism.

Effects of RFamide-Related Peptide (RFRP)-1 and RFRP-3 on Oxytocin Release and Anxiety-Related Behaviour in Rats

RFamide-related peptides (RFRP-1 and RFRP-3) are localised in neurones of the dorsomedial hypothalamus in rats. The dorsomedial hypothalamus plays an essential role in neuroendocrine and behavioural stress responses. In the present study, we examined the role of RFRP in the control of neuroendocrine and behavioural responses in rats. Stressful stimuli increased expression of Fos protein in RFRP-immunoreactive neurones of the dorsomedial hypothalamus, suggesting that stressful stimuli activate RFRP neurones. Intracerebroventricular injection of RFRPs increased the expression of Fos protein in oxytocin neurones in the hypothalamus and plasma concentrations of adrenocorticotrophic hormone and oxytocin. The hypothalamic paraventricular and supraoptic nuclei expressed mRNA of GPR147, the putative RFRP receptor, and application of RFRPs to isolated supraoptic nuclei facilitated oxytocin release, suggesting that RFRPs activate oxytocin neurones directly. Furthermore, the administration of RFRPs induced anxiety-related behaviour in rats in open-field tests. All these data taken together suggest that RFRPs play a role in the control of neuroendocrine and behavioural stress responses in rats.

Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.

Interhemispheric regulation of the medial prefrontal cortical glutamate stress response in rats.

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.

Mapping the brain pathways of traumatic memory: Inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats

Protein kinase M zeta (PKMzeta), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMzeta inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations. This study assessed the long-term effects of local applications of ZIP microinjected immediately (1 h) or 10 days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD. Four brain structures known to be involved in memory processes and in anxiety were investigated: lateral ventricle (LV), dorsal hippocampus (DH), basolateral amygdala and IC. The outcome measures included behavior in an elevated plus maze and acoustic startle response 7 days after microinjection, and freezing behavior upon exposure to trauma-related cue 8 days after microinjection. Previously acquired/encoded memories associated with the IC were also assessed. Inactivation of PKMzeta in the LV or DH within 1h of exposure effectively reduced PTSD-like behavioral disruption and trauma cue response 8 days later. Inactivation of PKMzeta 10 days after exposure had equivalent effects only when administered in the IC. The effect was demonstrated to be specific for trauma memories, whereas previously acquired data were unaffected by the procedure. Predator scent related memories are located in different brain areas at different times beginning with an initial hippocampus-dependent consolidation process, and are eventually stored in the IC. These bring the IC to the forefront as a potential region of significance in processes related to traumatic stress-induced disorders.

Sex differences in the impact of neonatal inflammatory injury on long-term stress responsivity in rats

Sex differences in the impact of neonatal inflammatory injury on long-term stress responsivity in rats