Chronic mild stress induces behavioral and physiological changes,and may alter serotonin 1A receptor function,in male and cycling female rats

Rationale Interactions among stress, serotonin 1A (5-HT_1A) receptors, and the hypothalamic–pituitary–adrenocortical (HPA) system have been proposed to influence the development of depression in humans. The investigation of depression-relevant behaviors and physiological responses to environmental stressors in animal models of depression may provide valuable insight regarding these mechanisms.Objectives The purpose of these experiments was to investigate the interactions among central 5-HT_1A receptors, endocrine function, and behavior in an animal model of depression, chronic mild stress (CMS).Methods The current study examined behavioral responses to a pleasurable stimulus (sucrose), estrous cycle length (in female rats), and plasma hormone levels following systemic administration of a selective 5-HT_1A receptor agonist [(+)8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT); 40 g/kg, s.c.; administered 15 min prior to sacrifice], in male and female rats exposed to 4 weeks of CMS.Results Four weeks of CMS produced a reduction in the intake of 1% sucrose (anhedonia), as well as attenuated adrenocorticotropic hormone (ACTH) responses to 8-OH-DPAT in both male and female rats (22 and 18% lower than the control groups, respectively). Corticosterone and oxytocin responses to 8-OH-DPAT were not altered by exposure to CMS. In female rats, CMS induced a lengthening of the estrous cycle by 40%.Conclusions CMS produces minor HPA disruptions along with behavioral disruptions. Alterations in 5-HT_1A receptor function in specific populations of neurons in the central nervous system may be associated with the CMS model. The current findings contribute to our understanding of the relations that stress and neuroendocrine function have to depressive disorders.     

Disrupted G1 to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type 1 diabetic rats

Previously we reported that a nonlethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats because of irreversible acute liver injury owing to inhibited hepatic tissue repair, primarily due to blockage of G(0) to S phase progression of cell division cycle. On the other hand, DB rats receiving 30 mg TA/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic (NDB) rats receiving 300 mg TA/kg, resulting in a delay in recovery from liver injury and survival. The objective of the present study was to test the hypothesis that impaired cyclin-regulated progression of G(1) to S phase of the cell cycle may explain inhibited liver tissue repair, hepatic failure, and death, contrasted with delayed liver tissue repair but survival observed in the DB rats receiving 300 in contrast to 30 mg TA/kg. In the TA-treated NDB rats sustained MAPKs and cyclin expression resulted in higher phosphorylation of retinoblastoma (pRb), explaining prompt tissue repair and survival. In contrast, DB rats receiving the same dose of TA (300 mg/kg) exhibited suppressed MAPKs and cyclin expression that led to inhibition of pRb, inhibited tissue repair, and death. On the other hand, DB rats receiving 30 mg TA/kg exhibited delayed up regulation of MAPK signaling that delayed the expression of CD1 and pRb, explaining delayed stimulation of tissue repair observed in this group. In conclusion, the hepatotoxicant TA has a dose-dependent adverse effect on cyclin-regulated pRb signaling: the lower dose causes a recoverable delay, whereas the higher dose inhibits it with corresponding effect on the ultimate outcomes on hepatic tissue repair; this dose-dependent adverse effect is substantially shifted to the left of the dose response curve in diabetes.     

Accuracy of reported weight and menstrual status in teenage girls with eating disorders

OBJECTIVE: The current study investigated the accuracy of reported current and historical weights and of menstrual status in teenage girls with eating disorders. METHOD: Reported current weight in one interview was compared with measured weight at another occasion. Reported historical weights were compared with documented weights from growth charts of the school health services. Reports of menstrual status from two different interviews were compared. RESULTS: The overall correlation between reported and measured/documented weight was high. Current weight was reported with high accuracy in all diagnostic groups and without tendencies to underreport. Patients with bulimia nervosa, but not those with anorexia nervosa, underreported their historical top weight. The most common reason for large discrepancies between reported and documented historical weights was that the two weights compared referred to different time points. The reports on menstrual status were divergent for 13% of the patients, most notably 4 of 15 patients on oral contraceptives had been categorized as having menstruations in one of the interviews. CONCLUSION: Reported weight history and menstrual status are of high accuracy in teenage girls with eating disorders.     

Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis

BACKGROUND: RhoE/Rnd3, a recently described novel member of the Rho GTPases family, was discussed as a possible antagonist of the RhoA protein that stimulates cell cycle progression and is overexpressed and/or overactivated in prostate cancer. We investigated the expression of RhoE and its role in cell cycle regulation and apoptosis in the human prostate. METHODS: RhoE expression in cell lines and tissue specimens was assessed by immunoblot analysis, real-time PCR (RT-PCR), and immunohistochemistry. To elucidate RhoE effects on the prostate, RhoE was cloned and overexpressed in DU-145 prostate cancer. Cell cycle modulation and apoptosis was investigated by immunoblot and FACS analysis. RESULTS: Immunoblot analysis showed a strong RhoE signal in both, benign epithelial and stromal cells. In contrast, almost no protein was detected in various prostate cancer cells. On RT-PCR and microarray analysis, RhoE mRNA expression was significantly reduced in malignant tissue when compared to benign samples. RhoE immunostaining was strong in benign tissue, especially in prostate epithelial cells, whereas it was minimal or absent in malignant tissue. Forced RhoE overexpression in a prostate cancer cell line inhibits the expression of two proteins essential for G2/M transition, namely CDC2 and cyclin B1, and induces G2/M arrest. In addition, apoptotic cell death as measured by a cleavage product of caspase 3 is significantly increased in RhoE-overexpressing cells. CONCLUSION: In conclusion, our findings suggest RhoE as a tumor suppressor gene that is downregulated early in the development of prostate cancer.     

Physiologic changes in breast magnetic resonance imaging during the menstrual cycle: perfusion imaging, signal enhancement, and influence of the T1 relaxation time of breast tissue

This study was undertaken to determine the best time during the menstrual cycle to perform dynamic breast magnetic resonance imaging (MRI). The contralateral "normal" breast of 50 premenopausal women (mean age 40.4 +/- 6.4 years, range 30--52 years) were enrolled in a protocol designed to correlate an ipsilateral suspicious breast lesion with pathology. The contralateral breast in each patient was examined with palpation and mammography prior to MRI on a 1.5 T scanner using gradient echo and dynamic contrast-enhanced echo-planar without and following gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) injection. Pre-contrast T1 relaxation times were measured before calculating extraction flow product (EFP) maps using a multicompartmental model. T1, EFP, and enhancement were measured in the control breast on four slices centered around the nipple and recorded as a function of the phases of the menstrual cycle. Lesions or areas with focal enhancement were excluded. Analysis of variance and Fisher's tests were performed. The cyclic changes in T1 relaxation time were not significant (p>0.2). EFP and enhancement varied significantly during the cycle (p<0.003 and p<0.004, respectively), with low values during the first half of the cycle and high values during the second half. The lowest values of EFP and enhancement (5.5+/-2.9 ml/100 g/min and 26+/-17%) were observed during the proliferative phase (days 3--7), and the highest values (17+/-10.2 ml/100 g/min and 104+/-28%) were observed during the secretory phase (days 21-27) (p<0.0006 and p<0.0008, respectively). Dynamic breast MRI should be performed during first half of the menstrual cycle (days 3--14) in order to minimize interpretative difficulties related to the uptake of gadolinium in normal breast tissue due to hormonal fluctuations during the menstrual cycle.     

Effects on sleep of acetylcholine perfusion of the locus coeruleus of cats

The loci coeruleus of freely moving cats were perfused bilaterally with acetylcholine at a dose of 0.001 μg/μl per min, while the animals were recorded polygraphically. The controls consisted of experiments in which no perfusions were done, and experiments in which the loci coeruleus were perfused bilaterally with saline, 1 μl/min. The acetylcholine produced a sharp inhibition of rapid eye movement (REM) sleep, prolonged the sleep cycle and the REM interval and decreased the number of REM periods and the mean duration of the REM episodes. Total sleep time was increased. This was entirely due to a specific elevation by acetylcholine of deep slow-wave sleep; light slow-wave sleep was not affected. The data support the Hobson-McCarley hypothesis of how the brain controls the REM state, and also suggest that cholinergic stimulation of the locus coeruleus may be important for the shift from REM sleep into slow-wave sleep.     

Olfactory influences on the human menstrual cycle

Two groups of women were compared for the timing of the onset of their menstrual cycle. One group was rubbed on the upper lip (directly beneath the nose) with a mixture of alcohol and underarm perspiration collected from a single female donor. The other group was rubbed with plain alcohol. The group which received the perspiration showed a significant shift in the timing of their menstrual cycles which conformed closely with the donor's monthly cycle. This is a preliminary study which supports the hypothesis that the time of menstrual onset may be modified by olfactory cues.     

Cell cycle regulation and its aberrations in human lung carcinoma

Cell cycle is strictly regulated by complex and redundant mechanisms. Basically, cell cycle transition is promoted by accelerator molecules termed 'cyclin' and 'cyclin-dependent kinase' (cdk), and inhibited by brake molecules termed 'cdk-inhibitor' (CKI). Although based on the results of early experimental studies and of clinicopathological analyses, there was much speculation that gene aberration of those molecules would be common; this has not turned out to be the case. One reason may be that activation or inactivation of a single molecule by itself usually does not lead to cell transformation, but rather to apoptosis. Successful transformation and unchecked cell proliferation appears to require the coordinated up-regulation of cyclin/cdk and/or suppression of CKI. In this article, I focus on the precise regulation of the cell cycle and describe abnormalities found in these proteins in lung carcinoma. Notable findings in lung carcinoma include: (i) cyclin A/cdk2 plays a key role in cell proliferation, while protein amount of cyclin E does not necessarily reflect cellular proliferative activity, depending on the tumor type; (ii) CKI function not only as suppressors, but also as activators of cdk, depending on expression levels; and (iii) aberrant expression of cyclin/cdk can lead to apoptosis in vivo in humans. Another key point is that as lung carcinoma is composed of a mixture of heterogeneous histological subtypes, the growth control of carcinoma cells is diversely regulated, depending on each histological subtype. This diversity is also described with our experimental results.     

Stability of hippocampal place cell activity across the rat estrous cycle

Findings from both in vitro and in vivo studies have shown that estrogen exerts pronounced effects on hippocampal morphology and physiology. The degree to which these molecular findings influence hippocampal processing in freely behaving animals is unclear. The present study assessed the effect of the estrous cycle on hippocampal place cells in naturally cycling rats during two behavioral states. Female Sprague-Dawley rats were trained to alternate on a U-shaped runway for food reinforcement. Single-unit recordings of hippocampal CA1 cells were conducted under two conditions: (1) at rest on a holder, and (2) running on the maze. Spatial firing characteristics of the cells were examined at different stages of the estrous cycle (i.e., diestrus, proestrus, and estrus). Specifically, information was collected on (1) mean firing rates; (2) basic place field parameters; and (3) changes in the firing dynamics of these cells (e.g., burst properties). The findings showed a decrease in mean firing rate on the maze during proestrus. However, other basic measures of spatial tuning and burst properties were unchanged. The current study suggests that there is relative stability of hippocampal place cells across the estrous cycle during a well-trained task.