Thyroid hormone deficiency affects anxiety-related behaviors and expression of hippocampal glutamate transporters in male congenital hypothyroid rat offspring.

Thyroid hormones are crucial for brain development and their deficiency during fetal and postnatal periods can lead to mood and cognitive disorders. We aimed to examine the consequences of thyroid hormone deficiency on anxiety-related behaviors and protein expression of hippocampal glutamate transporters in congenital hypothyroid male offspring rats. Possible beneficial effects of treadmill exercise have also been examined. Congenital hypothyroidism was induced by adding propylthiouracil (PTU) to drinking water of pregnant Wistar rats from gestational day 6 until the end of the weaning period (postnatal day 28). Next, following 4 weeks of treadmill exercise (5 days per week), anxiety-related behaviors were examined using elevated plus maze (EPM) and light/dark box tests. Thereafter, protein expression of astrocytic (GLAST and GLT-1) and neuronal (EAAC1) glutamate transporters were measured in the hippocampus by immunoblotting. Hypothyroid rats showed decreased anxiety-like behavior, as measured by longer time spent in the open arms of the EPM and in the light area of the light/dark box, compared to control rats. Hypothyroid rats had significantly higher GLAST and GLT-1 and lower EAAC1 protein levels in the hippocampus than did the euthyroid rats. Following exercise, anxiety levels decreased in the euthyroid group while protein expression of EAAC1 increased and returned to normal levels in the hypothyroid group. Our findings indicate that thyroid hormone deficiency was associated with alterations in protein expression of glutamate transporters in the hippocampus. Up-regulation of hippocampal GLAST and GLT-1 could be at least one of the mechanisms associated with the anxiolytic effects of congenital hypothyroidism.

Hypothalamus and Post-Traumatic Stress Disorder: A Review.

Humans have lived in a dynamic environment fraught with potential dangers for thousands of years. While fear and stress were crucial for the survival of our ancestors, today, they are mostly considered harmful factors, threatening both our physical and mental health. Trauma is a highly stressful, often life-threatening event or a series of events, such as sexual assault, war, natural disasters, burns, and car accidents. Trauma can cause pathological metaplasticity, leading to long-lasting behavioral changes and impairing an individual's ability to cope with future challenges. If an individual is vulnerable, a tremendously traumatic event may result in post-traumatic stress disorder (PTSD). The hypothalamus is critical in initiating hormonal responses to stressful stimuli via the hypothalamic-pituitary-adrenal (HPA) axis. Linked to the prefrontal cortex and limbic structures, especially the amygdala and hippocampus, the hypothalamus acts as a central hub, integrating physiological aspects of the stress response. Consequently, the hypothalamic functions have been attributed to the pathophysiology of PTSD. However, apart from the well-known role of the HPA axis, the hypothalamus may also play different roles in the development of PTSD through other pathways, including the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes, as well as by secreting growth hormone, prolactin, dopamine, and oxytocin. This review aims to summarize the current evidence regarding the neuroendocrine functions of the hypothalamus, which are correlated with the development of PTSD. A better understanding of the role of the hypothalamus in PTSD could help develop better treatments for this debilitating condition.

Effect of combination fluoxetine and exercise on prefrontal BDNF, anxiety-like behavior and fear extinction in a female rat model of post-traumatic stress disorder (PTSD): a comparison with male animals.

Despite significant differences between men and women in the symptoms of PTSD and the response to therapeutic interventions, most PTSD studies have been done on male subjects. Continuing our previous study in male rats, this study aimed at better understanding the effect of a combination therapy of exercise with fluoxetine on female PTSD rats. The results were then compared with our past findings in male animals. Female adult Wistar rats subjected to PTSD were treated with moderate treadmill exercise or fluoxetine, or a combination of both. PTSD was induced by the single prolonged stress (SPS) model. Elevated plus-maze (EPM), serum and prefrontal BDNF, and fear extinctions were evaluated. The results showed that exercise plus fluoxetine decreased anxiety-like behavior, improved fear extinction, and increased BDNF changes in female rats. The effects of exercise alone were comparable with those of combination therapy except that combination therapy was more effective on OAT (open arm entry). The majority of results in female rats, except for those of prefrontal BDNF, 4th extinction, and OAT, were similar to those of male rats as shown in our previous study. According to our findings, exercise as a safe and cost-effective intervention can be considered as a complementary efficient option for PTSD treatment in both sexes. To achieve better treatment outcomes in PTSD patient, considering sex differences is recommended.

Prior short-term exercise prevents behavioral and biochemical abnormalities induced by single prolonged stress in a rat model of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs following exposure to somatic or psychotic trauma. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. However, the role of exercise on acquired PTSD-like phenotype was not examined. The present study investigated the effects of prior moderate treadmill exercise on anxiety-like behaviors, serum corticosterone and BDNF levels, hippocampal BDNF and mRNA expression of apoptotic - related proteins in the single prolonged stress (SPS) as an animal model of PTSD in rats. Male and female rats underwent a regular treadmill exercise regimen (4 weeks, 5 days per week). Following the exercise, rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min and ether anesthesia), and then they were kept undisturbed for 14 days. After testing anxiety-like behaviours in the elevated plus maze, the levels of corticosterone and BDNF in serum and BDNF and apoptosis markers (Bax, Bcl-2, and Caspase) in hippocampus were measured. Sedentary male and female SPS rats significantly (Ps ranging <0.05 to <0.0001) exhibited increased anxiety levels in the elevated plus maze, enhanced serum corticosterone, reduced serum and hippocampal BDNF and enhanced hippocampal apoptosis than the corresponding control group. Prior exercise significantly (Ps ranging <0.05 to <0.001) alleviated all SPS-induced behavioral and biochemical alterations as compared with the sedentary SPS rats. There were no significant differences in serum and hippocampal BDNF and serum corticosterone levels and hippocampal apoptotic markers between male and female rats in all of groups. Our findings strongly support that short term prior exercise training can prevent the harmful effects of traumatic events, and the resulting trauma-related disorders in both sexes.

Effect of treadmill exercise on serum corticosterone, serum and hippocampal BDNF, hippocampal apoptosis and anxiety behavior in an ovariectomized rat model of post-traumatic stress disorder (PTSD).

There is a sex difference in vulnerability to PTSD and in response to therapeutic interventions. Since relation between gonadal hormones and PTSD has been revealed, this study aimed to understand the severity of PTSD-induced impairments after ovarian hormone deficiency and the influence of exercise on PTSD accompanied by ovarian hormone deficiency. Female adult Wistar rats were subjected to ovariectomy, PTSD, or combination ovariectomy plus PTSD. Twenty days after ovariectomy, PTSD was induced by single prolonged stress (SPS) model. The exercise started 14 days after SPS and continued for 4 weeks. Thirty minutes moderate treadmill exercise was planned for 5 days per week. On day 65, after assessing rats using the elevated plus-maze (EPM) test, corticosterone, BDNF, and apoptotic markers were tested. p < 0.05 was considered as significant level. The results showed that ovariectomy worsened the effect of SPS on hippocampal BDNF and led to greater increase in serum corticosterone and hippocampal caspase 3 and BAX in SPS rats. Also, ovariectomy exacerbated anxiety-like behavior in SPS rats. Exercise improved the alterations of hippocampal BDNF, corticosterone, caspase 3, and BAX in SPS ovariectomized rats. However, exercise had no statistically significant effect on anxiety-like behavior in this group. According to the results, exercise is effective to attenuate SPS-induced impairments in molecular and cellular responses even when the condition becomes more complicated due to ovarian hormone deficiency. However, exercise alone cannot help to improve behavior impairments in PTSD combined with an ovarian hormone deficiency. Therefore, exercise could likely be considered as a complementary intervention to strengthen other treatments.

Association between GFAP-positive astrocytes with clinically important parameters including neurological deficits and/or infarct volume in stroke-induced animals.

The effect of GFAP-positive astrocytes, as positive or negative factors on stroke complications such as infarct volume and neurological deficits is currently under debate. This review was aimed to evaluate and compare the frequency of studies that showed a positive or negative relationship between astrocyte activation with the improvement of neurological deficits and/or the decrease of infarct volume. In addition, we reviewed two possible causes of differences in results including timepoint of stroke and stroke severity. Time of GFAP assessment was considered as time point and type of stroke induction and duration of stroke as stroke severity. According to our review in the most relevant English-language studies in the PubMed, Web of Science, and Google Scholar databases from 2005 to 2020, the majority of studies (77 vs. 28) showed a negative coincidence or correlation between GFAP-positive cells with neurological improvement as well as between GFAP-positive cells with infarct volume reduction. In most reviewed studies, GFAP expression was reported as a marker related to or coinciding with worse neurological function, or greater infarct volume. However, there were also studies that showed helpful effects of GFAP-positive cells on neurological function or stroke lesion. Although there are some elucidations that the difference in these findings is due to the time point of stroke and stroke severity, our review did not confirm these interpretations.

Effects of Paraoxon Exposure on Expression of Apoptosis-Related Genes, Neuronal Survival, and Astrocyte Activation in Rat Prefrontal Cortex.

Paraoxon is the bioactive metabolite of organophosphate (OP) pesticide, parathion. This study aimed to evaluate the expression of apoptosis-related genes and histopathological changes in rat prefrontal cortex following exposure to three different doses of paraoxon. Paraoxon (0.3, 0.7, or 1 mg/kg) or corn oil (vehicle) were intraperitoneally injected to adult male Wistar rats. After 14 or 28 days, mRNA and protein levels of Bax, Bcl-2, and caspase-3 were measured in prefrontal cortex using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting, respectively. In addition, neuronal injury and astrocyte activation were assessed using cresyl violet staining and glial fibrillary acidic protein (GFAP) immune-positive cells, respectively. Treatment with 0.7 and 1 mg/kg of paraoxon increased mRNA and protein levels of Bax and caspase-3 at 14 and 28 days post-exposure, while mRNA and protein levels of Bcl-2 decreased only in 1 mg/kg group after 14 days. Furthermore, a significant decrease in the number of neurons and a significant increase in the number of GFAP-positive cells were observed in rats receiving 0.7 and 1 mg/kg of paraoxon at both time points. Collectively, our results showed that apoptosis is a major mechanism for neuronal damage after exposure to paraoxon. Also, paraoxon-induced neuronal loss was correlated with activation of astrocytes. Since paraoxon-induced neuronal damage is closely related to convulsion, clinical management of convulsion could protect neuronal brain damage.

Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis - related proteins in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. Currently, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are the first-line choice in PTSD drug treatment but their moderate response rates and side effects indicate an urgent need for the development of new treatment. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. The present study investigated the effects of moderate treadmill exercise, the antidepressant fluoxetine and the combined treatment on behavioural deficits, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We also examined alternations in hippocampal brain-derived neurotrophic factor (BDNF) and mRNA expression of apoptosis - related proteins in a rat model of PTSD: the single prolonged stress (SPS) model. Rats were exposed to SPS (restraint for 2h, forced swimming for 20min and ether anaesthesia) and were then kept undisturbed for 14days. After that, SPS rats were subjected to chronic treatment with fluoxetine (10mg/kg/day, for 4weeks), moderate treadmill running (4weeks, 5day per week) and the combined treatment (fluoxetine plus treadmill exercise), followed by behavioural, biochemical and apoptosis markers assessments. SPS rats exhibited increased anxiety levels in the elevated plus maze and light/dark box, impaired fear conditioning and extinction in inhibitory avoidance (IA) task, impaired spatial memory in a recognition location memory task and enhanced negative feedback on the HPA axis following a dexamethasone suppression test. SPS rats also showed reduced hippocampal BDNF and enhanced apoptosis. Moderate treadmill exercise, fluoxetine and the combined treatment alleviated the SPS-induced alterations in terms of anxiety levels, HPA axis inhibition, IA conditioning and extinction, hippocampal BDNF and apoptosis markers. Furthermore, the combined treatment was more effective than fluoxetine alone, but in most tests, the effects of the combined treatment were similar to those of exercise alone, suggesting that exercise is the main factor in the beneficial effects of the combined therapy in PTSD patients.