Prefrontal Cortex Of Female Rats Research Articles

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

Tight junction proteins in the small intestine and prefrontal cortex of female rats exposed to stress of chronic isolation starting early in life.

Simultaneous evaluation of barrier protein expression in the gut and the brain and their modulation under stress conditions have not been studied before now. As the permeability and function of the gut and blood-brain barrier are different and both express the MRs, we hypothesized that stress of post-weaning social isolation induces changes in tight junction protein expression in the gut which are (1) independent of changes in the brain and (2) are mediated via the mineralocorticoid receptor (MR). First, using UPLC-MS/MS we have successfully validated and selected a dose (1.2mg/rat/day) of the MR antagonist spironolactone to treat female rats exposed to stress of chronic isolation or control conditions from postnatal day 21 for 9weeks. Isolation stress caused an enhancement of gene expression of occludin and ZO-1 and a decrease in claudin-5 and MR expression in both the small intestine and prefrontal cortex. Isolation stress failed to decrease claudin-5 (small intestine) and MR (prefrontal cortex) gene expression in spironolactone-treated rats. MR blockade resulted in a decrease in claudin-15 expression in the small intestine. Anxiogenic effect of chronic stress, measured in elevated plus-maze test, was partly prevented by spironolactone treatment. Claudins, the main regulators of intestinal barrier permeability responded to chronic stress of social isolation and/or simultaneous blockade of MR in female rats by alterations independent of changes in the brain cortex. The results suggest a physiological role of MR in the control of claudin expression in the small intestine, but not in the brain cortex.

Protective Effects of Spirulina platensis, Voluntary Exercise and Environmental Interventions Against Adolescent Stress-Induced Anxiety and Depressive-Like Symptoms, Oxidative Stress and Alterations of BDNF and 5HT-3 Receptors of the Prefrontal Cortex in Female Rats.

Background and PurposeAmple evidence indicates that chronic adolescence stress is associated with an increased risk of developing neuropsychiatric disorders in adulthood. Given the importance of the effective therapeutic ways to overcome adolescent stress-related deficits, the present study investigated the effects of Spirulina platensis (SP), environmental enrichment (EE), and voluntary exercise (EX) and their combination on anxiety or depression-like behaviors, oxidative stress, and alterations of BDNF and 5HT-3 receptors in the prefrontal cortex (PFC) induced by adolescent stress in adult female rats.MethodsDuring the adolescent period (PNDs30-40), rats were subjected to restraint stress. Then, the animals were subjected to SP treatment (200 mg/kg/day), EX, EE, and the combined treatments (SP+EX, and SP+EE) for 15 days between PNDs41-55. Subsequently, anxiety or depression-like behaviors, BDNF levels, oxidative stress markers and mRNA expression of BDNF and 5HT3 in the PFC were assessed.ResultsStressed rats demonstrated enhanced anxiety levels and depression-like behaviors in adulthood. Regarding the oxidative stress markers, stressed rats exhibited significantly higher levels of malondialdehyde, a lipid peroxidation product, higher activities of antioxidant enzymes (glutathione peroxidase and superoxide dismutase) and significantly lower total antioxidant reactivity capacity in the PFC. Additionally, adolescent stress significantly increased 5HT3 receptor mRNA expression and decreased BDNF content and its mRNA expression in the PFC. Treatments with SP, EX, EE, and the combined interventions alleviated these deficits.ConclusionOur findings indicate that appropriate interventions during the adolescent period can protect against adolescent stress-induced behavioral, and biochemical defects and oxidative stress damage in adulthood.

The effect of standard laboratory diets on estrogen signaling and spatial memory in male and female rats

Phytoestrogens are plant-derived compounds that can modulate estrogen activity in the brain and periphery. Laboratory rodent diets are typically high in soy-based phytoestrogens and therefore may influence neurophysiological and behavioural measures that are sensitive to estrogen signaling. Here we assessed such measures in rats (males and females) fed Australian made diets that varied in their soy levels. We found that a low-soy diet promoted greater weight, and lower levels of plasma estradiol, particularly in male rats. It also produced sex-specific effects on estrogen receptor gene expression in the brain, increasing ESR2 expression in the hippocampus and prefrontal cortex in female rats, and decreasing dopamine D1 receptor gene expression in the striatum of both male and female rats. We also found a dietary effect on short-term place recognition memory, but this was independent of soy levels in the diet. These results demonstrate that the choice of rodent laboratory diet can influence physiology, neurobiology and behavior, particularly on measures related to estrogen signaling.

Affective Behavior Shows Sex Differences in Mid-adulthood Rats Following Postnatal Immune Stimulation

Mid-adulthood represents the critical window period usually associated with the development of age-related diseases. Despite several attempts to delineate the pathological mechanisms underlying postnatal immune challenge and altered brain functions, the role of sex-dependent changes in affective behaviors of middle-aged animals requires more attention. In this study, we sought to investigate behavioral and molecular response patterns at mid-adulthood linked to early-life immune activation. Using affective behavioral test batteries, we showed that lipopolysaccharide (LPS)-induced postnatal immune challenge caused anxiety-like behaviors in both male and female Wistar rats at mid-adulthood, whereas only female rats exhibited depression-like behaviors. Our data further demonstrated a significant increase in microglial complexity and increased levels of tumor necrosis factor (TNFα), nitric oxide (NOx), and lipid peroxidation in the prefrontal cortex of female rats compared to their male counterparts and phosphate-buffered saline (PBS) littermate controls. With these results, we established significant interaction between sex differences and LPS-induced alterations in behavior and associated oxidative and immunohistochemical changes. These findings may provide an insight to better understand the neuroimmunological mechanisms of sex-dependent brain pathological manifestations occurring at mid-adulthood. [Display omitted]

Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex

Increasing cannabis consumption among adolescents, studies that link its early use with mental illnesses, and the political debate on cannabis legalization together call for an urgent need to study molecular underpinnings of adolescent brain vulnerability. The emerging role of epigenetic mechanisms in psychiatric diseases led us to hypothesize that epigenetic alterations could play a role in causes and subsequent development of the depressive/psychotic-like phenotype induced by adolescent, but not adult, Δ9-tetrahydrocannabinol (THC) exposure in female rats. We performed a time-course analysis of histone modifications, chromatin remodelling enzymes and gene expression in the prefrontal cortex of female rats after adolescent and adult THC exposure. We also administered a specific epigenetic drug (chaetocin) with THC to investigate its impact on THC-induced behavioural alterations. Adolescent THC exposure induced alterations of selective histone modifications (mainly H3K9me3), impacting the expression of genes closely associated with synaptic plasticity. Changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, suggesting specific adolescent susceptibility. Adolescent THC exposure significantly increased Suv39H1 levels, which could account for the enhanced H3K9me3. Pharmacological blockade of H3K9me3 during adolescent THC treatment prevented THC-induced cognitive deficits, suggesting the relevant role played by H3K9me3 in THC-induced effects. Only female rats were investigated, and the expression studies were limited to a specific subset of genes. Through a mechanism involving SUV39H1, THC modifies histone modifications and, thereby, expression of plasticity genes. This pathway appears to be relevant for the development of cognitive deficits.

Effects of Gonadectomy and Avoidance Learning on the GABAAα1 Receptor Density in the Prefrontal Cortex of Male and Female Rats

We evaluated the effects of gonadectomy and passive avoidance learning on the density of GABAAα1 receptors in the prefrontal cortex of male and female rats. Twenty adult males weighing 200 ± 30 g and 20 adult females weighing 150 ± 20 g were divided into four groups: (i) Sham, intact rats with no learning session, (ii) Sham-L, intact rats subjected to the avoidance learning session, (iii) GE, gonadectomized rats without learning, and (iv) GE-L, gonadectomized rats with learning. A shuttle box was used for the induction of passive avoidance learning. The density of GABAAα1 receptors was investigated with an immunohistochemical technique; Image Analyzer software was used. Ovariectomy without learning led to significant reduction of the density of GABAAα1 receptors in different regions of the prefrontal cortex relative to the control intact group; at the same time, ovariectomized females with learning demonstrated a significantly higher density of GABAAα1 receptors in the prefrontal cortex as compared to the Sham group. No significant differences in the density of GABAAα1 receptors were observed in both castrated male rat groups. The comparison of male and female rats showed that the density of GABAAα1 receptors in castrated rats with learning was significantly lower than that in ovariectomized females with learning. Thus, ovariectomy exerts a more potent effect than castration on the GABAAα1 receptor density in different regions of the prefrontal cortex. Learning provides increases in the GABAAα1 receptor density in different regions of the prefrontal cortex in female rats, while castration of male rats exerts no significant effect from this aspect.

Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats.

Antipsychotic drugs (APDs) were developed to treat schizophrenia in adults; however they have been increasingly prescribed (mostly "off-label") for children and adolescents. This study aimed to investigate the effects of aripiprazole, olanzapine and risperidone on the binding of serotonin (5-HT) and dopamine receptors in juvenile rat brain regions that are involved in antipsychotic efficacy. Male and female rats were treated orally with aripiprazole (1mg/kg), olanzapine (1mg/kg), risperidone (0.3mg/kg) or vehicle 3 times/day starting from postnatal day 23 (±1day) for 20 days. Quantitative autoradiography was performed to examine the receptor binding densities. Olanzapine significantly decreased 5-HT2A (5-HT2AR) and 5-HT2C receptor (5-HT2CR) binding in the prefrontal cortex (PFC), cingulate cortex (Cg) and nucleus accumbens (NAc) of both male and female rats. In the caudate putamen (CPu), olanzapine attenuated 5-HT2AR binding in both genders, and reduced 5-HT2CR binding in male rats. Olanzapine increased D2 receptor (D2R) binding in the NAcS of male rats, but decreased it in females. Olanzapine increased D1 receptor (D1R) binding in the Cg, while aripiprazole decreased D1R binding in the PFC of males. Aripiprazole significantly reduced 5-HT2AR binding in the male PFC. Risperidone decreased 5-HT2AR binding in the PFC of female rats, while attenuating D1R binding in the PFC and Cg of males. However, APDs have no effects on the binding of serotonin and dopamine transporters. This study revealed that aripiprazole, olanzapine and risperidone affected 5-HT2AR, 5-HT2CR, 5-HTT, D1R and D2R bindings differently in the brains of juvenile male and female rats.

Changes in cannabinoid CB1 receptor functionality in the female rat prefrontal cortex following a high fat diet

AimsA high fat diet (HFD) has been found to affect neurotransmission in the prefrontal cortex, but the effects of this dietary regime upon the endocannabinoid system has not been studied in this brain region. In consequence, in the present study, we have investigated the effect of HFD for up to 20weeks upon the endocannabinoid system in the prefrontal cortex of female rats. Main methodsCB1 receptor functionality was measured using CP55,940-stimulated [35S]GTPγS autoradiography. Fatty acid amide hydrolase and monoacylglycerol lipase activities were analysed in brain regions by assessing rates of [3H]anandamide and JZL184-sensitive [3H]2-oleoylglycerol hydrolysis, respectively. Key findingsIn the prefrontal cortex, a significantly greater stimulation of [35S]GTPγS binding by CP55,940 was seen following 4–12, but not 16–20weeks of HFD. No significant changes were seen for the caudate–putamen, CA1–CA3 region of the hippocampus or the dentate gyrus. The increased response for the 12week animals was not accompanied by a significant change in the receptor density, measured with [3H]CP55,940 autoradiography. No significant changes in the activity of the endocannabinoid hydrolytic enzymes fatty acid amide or monoacylglycerol lipase were seen in the prefrontal cortex, hippocampus, amygdala or hypothalamus following either 12 or 20weeks of HFD. SignificanceIt is concluded that HFD produces an increased CB1 receptor functionality in the prefrontal cortex of female rats. Given that the endocannabinoid system regulates neurotransmission in the prefrontal cortex, the present data would implicate this system in the disturbed prefrontal cortical activity in this region following a high fat diet.

Effect of progesterone on the expression of GABAA receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere

Progesterone is a neuroactive hormone with non-genomic effects on GABA(A) receptors (GABA(A)R). Changes in the expression of GABA(A)R subunits are related to depressive-like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA(A)R α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg⁻¹) or vehicle, during two complete female estrous cycles (8-10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA(A)R γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA(A) system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA(A) R α1 subunit expression in the right prefrontal cortex of female rats.

Effect of chronic fluoxetine treatment on male and female rat erythrocyte and prefrontal cortex fatty acid composition

Omega-3 ( n-3) polyunsaturated fatty acids (PUFA) and fluoxetine (FLX) have additive effects in the treatment of major depressive disorder, and FLX up-regulates genes that regulate fatty acid biosynthesis in vitro. Although these data suggest that FLX may augment n-3 fatty acid biosynthesis, the in vivo effects of FLX treatment on PUFA biosynthesis and peripheral and central membrane compositions are not known. In the present study, male and female rats were treated with FLX (10 mg/kg/day) through their drinking water for 30 days (P60–P90). Plasma FLX and norfluoxetine (NFLX) concentrations were determined by liquid chromatography tandem mass spectrometry, and erythrocyte and prefrontal cortex (PFC) fatty acid composition determined by gas chromatography. To confirm central effects of FLX, serotonin turnover in the PFC was determined by high performance liquid chromatography. Chronic FLX treatment resulted in clinically-relevant plasma FLX concentrations in male and female rats, and significantly decreased serotonin turnover in the PFC. After correcting for multiple comparisons, chronic FLX treatment did not significantly alter erythrocyte fatty acid composition in male or female rats. Chronic FLX treatment significantly and selectively increased docosapentaenoic acid (22:5 n-6) in the PFC of female rats, but not in male rats. These preclinical findings do not support the hypothesis that chronic FLX treatment increases n-3 fatty acid biosynthesis or membrane composition.

Influence of progesterone on GAD65 and GAD67 mRNA expression in the dorsolateral striatum and prefrontal cortex of female rats repeatedly treated with cocaine

Female rats are intensely affected by cocaine, with estrogen probably playing an important role in this effect. Progesterone modulates the GABA system and attenuates the effects of cocaine; however, there is no information about its relevance in changing GABA synthesis pathways after cocaine administration to female rats. Our objective was to investigate the influence of progesterone on the effects of repeated cocaine administration on the isoenzymes of glutamic acid decarboxylase (GAD(65) and GAD(67)) mRNA in brain areas involved in the addiction circuitry. Ovariectomized, intact and progesterone replacement-treated female rats received saline or cocaine (30 mg/kg, ip) acutely or repeatedly. GAD isoenzyme mRNA levels were determined in the dorsolateral striatum (dSTR) and prefrontal cortex (PFC) by RT-PCR, showing that repeated, but not acute, cocaine decreased GADs/beta-actin mRNA ratio in the dSTR irrespective of the hormonal condition (GAD(65): P < 0.001; and GAD(67): P = 0.004). In the PFC, repeated cocaine decreased GAD(65) and increased GAD(67) mRNA ratio (P < 0.05). Progesterone replacement decreased both GAD isoenzymes mRNA ratio after acute cocaine in the PFC (P < 0.001) and repeated cocaine treatment reversed this decrease (P < 0.001). These results suggest that cocaine does not immediately affect GAD mRNA expression, while repeated cocaine decreases both GAD(65) and GAD(67) mRNA in the dSTR of female rats, independently of their hormonal conditions. In the PFC, repeated cocaine increases the expression of GAD isoenzymes, which were decreased due to progesterone replacement.

Relationship between the thymus and neurochemical changes in the hypothalamus–preoptic area and prefrontal cortex in female rats with delayed puberty

In female rats, aged 55–58 days with delayed puberty due to deficient growth and environmental stress, 5-hydroxyindoleacetic acid levels and serotonin turnover rate in the hypothalamus–preoptic area as well as body weight, body weight gain and relative weight of ovaries, uterus, adrenals and preputial glands were lower while serotonin and 5-hydroxyindoleacetic acid levels in the prefrontal cortex were higher when compared to normal rats with the latest onset of puberty aged 42–52 days. In rats with delayed puberty, multiple regression analysis revealed a significant negative dependence on dopamine turnover in the hypothalamus–preoptic area for body weight gain and, of all organs, for the relative weight of the thymus. A similar negative significant dependence on serotonin turnover rate in the prefrontal cortex was also found for the relative weight of thymus and spleen. The same analysis in the opposite direction revealed a significant negative dependence of 3,4-dihydroxyphenylacetic acid levels and dopamine turnover rate in the hypothalamus–preoptic area as well as serotonin turnover rate in the prefrontal cortex only on thymus weight. After separation of delayed pubertal rats into two groups, based on absolute ovarian weight, the rats in the low ovarian weight range and no signs of puberty exhibited: lower body weight gain, lower body weight, and lower relative weight only of thymus, ovaries and preputial glands in parallel with an increased dopamine turnover rate in the hypothalamus–preoptic area and serotonin turnover rate in the prefrontal cortex compared to the delayed pubertal rats in the high ovarian weight range and early signs of puberty. The results suggest that in rats with delayed puberty: (1) serotonergic activation in the hypothalamus–preoptic area is lower compared to normal puberty rats; (2) dopaminergic activation in the hypothalamus–preoptic area negatively affects body weight gain, thymus weight and initiation of puberty and (3) thymus weight is negatively implicated in dopaminergic activation in the hypothalamus–preoptic area and serotonergic activation in the prefrontal cortex and positively related to ovarian weight and early signs of puberty.