Hippocampus Of Female Rats Research Articles

Beneficial Effects of Ginger Root Extract on Pain Behaviors, Inflammation, and Mitochondrial Function in the Colon and Different Brain Regions of Male and Female Neuropathic Rats: A Gut-Brain Axis Study.

Neuroinflammation and mitochondrial dysfunction have been implicated in the progression of neuropathic pain (NP) but can be mitigated by supplementation with gingerol-enriched ginger (GEG). However, the exact benefits of GEG for each sex in treating neuroinflammation and mitochondrial homeostasis in different brain regions and the colon remain to be determined. Evaluate the effects of GEG on emotional/affective pain and spontaneous pain behaviors, neuroinflammation, as well as mitochondria homeostasis in the amygdala, frontal cortex, hippocampus, and colon of male and female rats in the spinal nerve ligation (SNL) NP model. One hundred rats (fifty males and fifty females) were randomly assigned to five groups: sham + vehicle, SNL + vehicle, and SNL with three different GEG doses (200, 400, and 600 mg/kg BW) for 5 weeks. A rat grimace scale and vocalizations were used to assess spontaneous and emotional/affective pain behaviors, respectively. mRNA gene and protein expression levels for tight junction protein, neuroinflammation, mitochondria homeostasis, and oxidative stress were measured in the amygdala, frontal cortex, hippocampus, and colon using qRT-PCR and Western blot (colon). GEG supplementation mitigated spontaneous pain in both male and female rats with NP while decreasing emotional/affective responses only in male NP rats. GEG supplementation increased intestinal integrity (claudin 3) and suppressed neuroinflammation [glial activation (GFAP, CD11b, IBA1) and inflammation (TNFα, NFκB, IL1β)] in the selected brain regions and colon of male and female NP rats. GEG supplementation improved mitochondrial homeostasis [increased biogenesis (TFAM, PGC1α), increased fission (FIS, DRP1), decreased fusion (MFN2, MFN1) and mitophagy (PINK1), and increased Complex III] in the selected brain regions and colon in both sexes. Some GEG dose-response effects in gene expression were observed in NP rats of both sexes. GEG supplementation decreased emotional/affective pain behaviors of males and females via improving gut integrity, suppressing neuroinflammation, and improving mitochondrial homeostasis in the amygdala, frontal cortex, hippocampus, and colon in both male and female SNL rats in an NP model, implicating the gut-brain axis in NP. Sex differences observed in the vocalizations assay may suggest different mechanisms of evoked NP responses in females.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's disease (AD) is the fifth leading cause of death in older adults, and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a threefold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse [via a model of hindlimb immobilization (HLI)] on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-mo-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of amyloid precursor protein (APP) and tau protein in the hippocampus, 4) and reduced brain-derived neurotrophic factor (BDNF) expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.NEW & NOTEWORTHY Muscle disuse via hindlimb immobilization increased oxidative stress and insulin resistance in the hippocampus. These findings were in association with muscle iron overload in connection with iron dysregulation in the brain. Overall, our work identifies muscle disuse as a contributor to hippocampal dysfunction, potentially through an iron-based muscle-brain axis, highlighting iron dysregulation as a potential novel mechanism in the relationship between muscle health, cognitive function, and Alzheimer's disease risk.

Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner.

Alzheimer's Disease (AD) and heavy alcohol use are widely prevalent and lead to brain pathology. Both alcohol-related brain damage (ABRD) and AD result in cholinergic dysfunction, reductions in hippocampal neurogenesis, and the emergence of hippocampal-dependent cognitive impairments. It is still unknown how ARBD caused during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study utilized a longitudinal design to characterize behavioral and pathological changes in a transgenic rat model of AD (TgF344-AD) following adolescent intermittent ethanol (AIE) exposure. We found that AIE accelerates cognitive decline associated with AD transgenes in female rats at 6 months of age, and male AD-rats are impaired on spatial navigation by 3-months with no additional deficits due to AIE exposure. Protein levels of various AD-pathological markers were analyzed in the dorsal and ventral hippocampus of male and female rats. The data suggests that AIE-induced alterations of the tropomyosin-related kinase A receptor (TrkA) / p75 neurotrophin receptor (p75NTR) ratio creates a brain that is vulnerable to age- and AD-related pathologies, which leads to an acceleration of cognitive decline, particularly in female rats.

Flaxseed Oil Alleviates Trimethyltin-Induced Cell Injury and Inhibits the Pro-Inflammatory Activation of Astrocytes in the Hippocampus of Female Rats.

Exposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction.

Transgenerational effect of prenatal stress on behavior and lipid peroxidation in brain structures of female rats during the estral cycle.

The effect of stress in pregnant female Wistar rats on the behavior and lipid peroxidation (LP) in the neocortex, hippocampus and hypothalamus in the female F2 generation during the ovarian cycle was investigated. We subjected pregnant females to daily 1-hour immobilization stress from the 15th to the 19th days of pregnancy. Further, family groups were formed from prenatally stressed and control male and female rats of the F1 generation: group 1, the control female and male; group 2, the control female and the prenatally stressed male; group 3, the prenatally stressed female and the control male; group 4, the prenatally stressed female and male. The females of the F2 generation born from these couples were selected into four experimental groups in accordance with the family group. At the age of 3 months, behavior of rats was studied in the "open field" test in two stages of the ovarian cycle - estrus and diestrus. After 7-10 days, the rats were decapitated and the neocortex, hypothalamus and hippocampus were selected to determine the level of diene and triene conjugates, Schiff bases and the degree of lipid oxidation (Klein index). In F2 females with one prenatally stressed parent, there was no interstage difference in locomotor-exploratory activity and anxiety. If both F1 parents were prenatally stressed, female F2 rats retained interstage differences similar to the control pattern, while their locomotor-exploratory activity and time spent in the center of an "open field" decreased in absolute values. In the neocortex of F2 females in groups with prenatally stressed mothers, the level of primary LP products decreased and the level of Schiff bases increased in the estrus stage. In the hippocampus of F2 females in the groups with prenatally stressed fathers, the level of Schiff bases decreased in the estrus stage, and the level of primary LP products increased in group 2 and decreased in group 4. In the hypothalamus of F2 females in the groups with prenatally stressed mothers, the level of Schiff bases increased in the estrus stage and decreased in the diestrus; in addition, in group 3, the level of primary LP products in the estrus stage increased. Thus, we demonstrated the influence of prenatal stress of both F1 mother and F1 father on the behavior and the level of LP in the neocortex, hippocampus and hypothalamus in female rats of the F2 generation in estrus and diestrus.

Dysregulation of baseline and learning-dependent protein degradation in the aged hippocampus

The ubiquitin-proteasome system (UPS) controls the majority of protein degradation in cells and dysregulation of the UPS has been implicated in the pathophysiology of numerous neurodegenerative disorders, including Alzheimer’s disease. Further, strong evidence supports a critical role for the UPS in synaptic plasticity and memory formation. However, while proteasome function is known to decrease broadly in the brain across the lifespan, whether it changes in the hippocampus, a region critical for memory storage and among the first impacted in Alzheimer’s disease, at rest and following learning in the aged brain remains unknown. Further, which proteins have altered targeting for protein degradation in the aged hippocampus has yet to be explored and whether learning in advanced age interacts with changes in ubiquitin-proteasome function across the lifespan remains unknown. Here, using proteasome activity assays and unbiased proteomic analyses, we report age-dependent changes in proteasome activity and degradation-specific K48 polyubiquitin protein targeting in the hippocampus and retrosplenial cortex of male and female rats across the lifespan. In the hippocampus, the targets of altered protein degradation were involved in transcription and astrocyte structure or G-protein and Interferon signaling in males and females, respectively. Importantly, we found that contextual fear conditioning led to an increase in proteasome activity and K48 polyubiquitin protein targeting in the hippocampus of aged male rats, a result in direct contrast to what was previously reported in young adult animals. Together, these data suggest that changes in protein degradation in the hippocampus across the lifespan may be contributing to age-related memory loss.

Oxytocin attenuates cocaine-associated place preference via the dorsal hippocampus in male and female rats

Cocaine addiction is the third largest cause of overdose-related deaths in the United States. Research investigating therapeutic targets for cocaine reward processes is key to combating this issue. The neuropeptide oxytocin (OXT) has been shown to reduce cocaine reward processes, though specific mechanisms are not understood. This study examines the effect of intra-dorsal hippocampal (DH) OXT on the expression of cocaine context associations using a conditioned place preference (CPP) paradigm. In this paradigm, one of two visually distinct chambers is paired with a drug. With repeated pairings, control animals display preference for the drug-associated context by spending more time in that context at test. In the present study, four conditioning days took place where male and female rats were injected with either cocaine or saline and placed into the corresponding chamber. On test day, rats received infusions of OXT or saline (VEH) into the DH and were allowed access to both chambers. The results show that while VEH-infused rats displayed cocaine CPP, OXT-infused rats did not prefer the cocaine-paired chamber. These findings implicate the DH as necessary in the mechanism by which OXT acts to block the expression of cocaine-context associations, providing insight into how OXT may exert its therapeutic effect in cocaine reward processes.

Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats.

Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.

Alterations in hippocampal cholinergic dynamics following CRF infusions into the medial septum of male and female rats

Corticoptropin releasing factor (CRF) is implicated in stress-related physiological and behavioral changes. The septohippocampal pathway regulates hippocampal-dependent mnemonic processes, which are affected in stress-related disorders, and given the abundance of CRF receptors in the medial septum (MS), this pathway is influenced by CRF. Moreover, there are sex differences in the MS sensitivity to CRF and its impact on hippocampal function. However, the mechanisms underlying these associations remain elusive. In the present study, we utilized an in vivo biosensor-based electrochemistry approach to examine the impact of MS CRF infusions on hippocampal cholinergic signaling dynamics in male and female rats. Our results show increased amplitudes of depolarization-evoked phasic cholinergic signals in the hippocampus following MS infusion of CRF at the 3 ng dose as compared to the infusion involving artificial cerebrospinal fluid (aCSF). Moreover, a trend for a sex × infusion interaction indicated larger cholinergic transients in females. On the contrary, intraseptal infusion of a physiologically high dose (100 ng) of CRF produced a subsequent reduction in phasic cholinergic transients in both males and females. The assessment of tonic cholinergic activity over 30 min post-infusion revealed no changes at the 3 ng CRF dose in either sex, but a significant infusion × sex interaction indicated a reduction in females at the 100 ng dose of CRF as compared to the aCSF. Taken together, our results show differential, dose-dependent modulatory effects of MS CRF on the dynamics of phasic and tonic modes of cholinergic signaling in the hippocampus of male and female rats. These cholinergic signaling modes are critical for memory encoding and maintaining arousal states, and may underlie sex differences in cognitive vulnerability to stress and stress-related psychiatric disorders.

Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats.

Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

Antioxidative Effects of Hydro-Alcoholic Extract and Essential Oil of Quercus brantii Exerts Anti-Depressant-Like Effect and Improvement of Memory Defect in Progesterone-Induced Postpartum Depression in Rats

Background: Depression and memory disorders are known to be associated with increased oxidative stress. There is evidence suggesting that Quercus brantii (Q. brantii) possesses antioxidant properties. Objectives: This study aims to investigate the impact of Q. brantii hydro-alcoholic extract and oil on cognitive dysfunction in a postpartum depression (PPD) model and on oxidant/antioxidant activity in the hippocampus of adult female rats. Methods: Forty-two female Wistar rats (200 - 250 g) were randomly divided into six groups. PPD was induced by chronic intraperitoneal administration (5 days) of progesterone at a dose of 5 mg/kg, and three days after discontinuation, depressive behavior was assessed using a forced swimming test. Simultaneously, Quercus brantii hydro-alcoholic extract (100 mg/kg) and oil (45%) were administered. Spatial memory and locomotor activity were evaluated 24 hours after training using the Morris water maze and open field tests, respectively. The hippocampus tissue of all rats was used to evaluate oxidant-antioxidant factors, Vitamin D, and corticosterone levels. Results: Quercus brantii extract significantly reduced depression (P < 0.05). Treatment with Q. brantii extract and oil improved spatial memory and learning (P < 0.05). The Q. brantii extract increased levels of SOD, GSH, catalase, and vitamin D while decreasing MDA levels; additionally, Q. brantii oil increased SOD and vitamin D levels and decreased MDA levels in the brain (P < 0.05). Conclusions: Quercus brantii extract and oil appear to have beneficial effects on learning and memory impairment in a PPD-induced model, which may be associated with their biochemical effects on the brain.

Evaluation of Effect of Piroxicam on the Hippocampus of Adult Sprague-Dawley Rats

Background: Studies have shown that some non-steroidal anti-inflammatory drugs (NSAIDs) can affect the hippocampus, a brain region crucial for memory and learning. Piroxicam is a widely used NSAID for providing relief from menstrual pain and associated symptoms in women with dysmenorrhea. Its potential effect on the hippocampus requires investigation. Objective: The objective was to determine the potential neurotoxic effect of piroxicam on the hippocampus of female rats using the Sprague –Dawley rats as models. Materials and Methods: A total of twenty adult female Wistar rats weighing 110g ± 20g (n=20, A-D) were used. Group A was control, B-D received 10, 20 and 40mg/kg of Piroxicam orally respectively for 2 weeks. After this study, the rats were euthanised and their brain was harvested for histological observations. Blood samples were also taken for the analysis of the oxidative stress markers i.e. Superoxide Dismutase (SOD), Catalase (CAT) and Malondialdehyde (MDA). Results: The photomicrographs of the hippocampus of Group A-D showed normal hippocampus with normal neuronal cells, the structural organisation of the CA1- CA4 (sub-regions of the hippocampus) also appeared normal and the dentate gyrus appeared normal. There was significant increase in MDA values in the hippocampus of piroxicam-treated rats compared to the control group (p < 0.05) and no significant decrease in SOD and CAT values. Conclusion: The study showed that piroxicam did not damage the structure of the hippocampus despite the induction of oxidative stress in the rats. These findings suggest a potential neuroprotective role for piroxicam in memory impairment scenarios

Differential regulation of hippocampal transcriptome by circulating estrogen.

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.

Pro-Oxidant and Antioxidant Activity in Female Rat Cerebellum and Hippocampus on Exposure to Aluminium

Pro-Oxidant and Antioxidant Activity in Female Rat Cerebellum and Hippocampus on Exposure to Aluminium

To what extent are orally ingested nanoplastics toxic to the hippocampus in young adult rats?

As the use of plastic-containing materials in our daily lives becomes increasingly common, exposure to nanoplastics accordingly becomes inevitable. Micro and nanoplastics released from large amounts of plastic waste constitute a serious environmental problem. Therefore, this study aimed to examine the effects of polystyrene nanoplastic (PS-NP) on the hippocampus. Material and methodThirty Wistar albino rats, 15 male and 15 female, aged 6–8 weeks, were used in the research. These were randomly divided into three groups of five males and five females each. A five-minute open field test was applied to all rats on the first and last days of the study. Three groups of rats (Control, NP1 and NP2) received the standard chow and water. Additionally, rats in the first neoplastic group (NP1) received 25 mg/kg PS-NP and rats in the second nanoplastic group (NP2) received 50 mg/kg PS-NP, at the same time each day by oral gavage. The rats were sacrificed under deep anesthesia at the end of four weeks. The hippocampi were removed and subjected to histopathological and biochemical analyses. ResultsGreen fluorescent dots were detected in the hippocampi of both dose groups receiving nanoplastics (NPs) administered orally to female and male rats. Histopathological examination revealed neuronal degeneration in the hippocampi of male and female rats from both dose groups. However, while no significant difference was observed among the groups in terms of changes in antioxidant enzyme values and open-field test data in male rats, significant differences in peroxidase (POD) and glutathione S-transferase (GST) values and fecal boli and grooming numbers were determined in female rats exposed to NPs.In conclusion, exposure to NP substances extend as far as the hippocampus, causing neuronal damage and behavioral problems.

Fingolimod prevents cognitive impairments following hypoxia-induced neonatal seizure by ameliorating the inflammation and oxidative stress in male and female juvenile rats

Hypoxia-induced neonatal seizure (HINS) is associated with cognitive disorders in later life. Since the neuroinflammation following HINS leads to these deleterious effects, in the current study, the short-term outcomes of Fingolimod (FTY720) treatment as an anti-inflammatory agent was investigated in the rat model of HINS. Seizures were induced in postnatal day (P10) by exposure to 5 % O2 for 15 min. Forty-five minutes after the onset of hypoxia, pups received FTY720 (0.3 mg/kg) or normal saline for 12 consecutive days. Then, behavioral functions of the rats were assessed by commonly used tests. Subsequently, hippocampal tissue sampling at P22-P23 was done for biochemical assessments and real-time PCR. The results showed that FTY720 prevents cognitive impairments and related reduction of malondialehyde (MDA) concentration in the hippocampus of both male and female hypoxic animals. Furthermore, FTY720 administration following HINS could not prevent the decreased brain-derived neurotrophic factor (BDNF) concentration, increased nitric oxide (NO) level and decreased Interleukin-4 (IL-4) gene expression in the hippocampus of both male and female hypoxic animals. Interestingly, FTY720 showed significant interaction with sex in hippocampal Tumor necrosis factor alpha (TNF-α) gene expression and BDNF concentration. Taken together, these results suggest that FTY720 administration in the lactation period can prevent the deleterious effects of HINS on cognition in later life by ameliorating inflammation and oxidative stress in the hippocampus of both male and female juvenile rats.

Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.

Michelia Champaca L. Modulates Superoxide Dismutase and Apoptosis-Regulating Proteins in Hippocampus of Middle-Aged Female Rats.

The aging process in women is still a problem, especially in developing countries that will become developed countries, including Indonesia. Here, we investigated the action of Michelia champaca L. extract administration on antioxidant modulation to inhibit hippocampal apoptosis in middle-aged female rats. Thirty-two female Wistar rats were divided into four groups (n = 8 each group): the middle-aged rats without any treatment (control group) and three M. champaca L. extract groups (treated at doses of 100, 200, or 300 mg/kg b. w). The superoxide dismutase (SOD) levels and Bax and Bcl-2 expressions in the hippocampal region were analyzed using the technique of enzyme-linked immunosorbent assay. The second and third doses of M. champaca L. extract significantly increased the SOD hippocampal levels compared with the control (P < 0.05). This extract also decreased Bax expression (at the second and third doses) and significantly increased Bcl-2 expression (at the highest dose) than that of the control (P < 0.05). The ethanol extract of M. champaca L. could modulate SOD and regulate apoptotic-related proteins in middle-aged female rats. Thus, the extract of M. champaca L. can be an alternative to prevent the degeneration of hippocampus due to the aging process.

Scatter Irradiation of Rat Brain Triggers Sex- and Brain Region-Specific Changes in the Expression of Non-Coding RNA Fragments.

Non-coding RNA fragments (ncRFs) are small RNA fragments processed from non-coding RNAs (ncRNAs). ncRFs have various functions and are commonly tissue-specific, and their processing is altered by exposure to stress. Information about ncRFs in the brain is scarce. Recently, we reported the brain region-specific and sex-specific expression of ncRNAs and their processing into ncRFs. Here, we analyzed the expression of ncRFs in the frontal cortex (FC), hippocampus (HIP), and cerebellum (CER) of male and female rats exposed to scatter radiation. We found multiple brain region- and sex-specific changes in response to scatter radiation. Specifically, we observed decreased miRNA expression and the increased expression of ra-ncRNA reads in HIP and CER, as well as an increased number of mtR-NA-associated reads in HIP. We also observed the appearance of sense-intronic ncRNAs-in females, in HIP and FC, and in males, in CER. In this work, we also show that tRNA-GlyGCC and tRNA-GlyCCC are most frequently processed to tRFs, in CER in females, as compared to males. An analysis of the targeted pathways revealed that tRFs and snoRFs in scatter radiation samples mapped to genes in several pathways associated with various neuronal functions. While in HIP and CER these pathways were underrepresented, in FC, they were overrepresented. Such changes may play an important role in pathologies that develop in response to scatter radiation, the effect known as "radio-brain", and may in part explain the sex-specific differences observed in animals and humans exposed to radiation and scatter radiation.

Sex differences in inflammation in the hippocampus and amygdala across the lifespan in rats: associations with cognitive bias

BackgroundCognitive symptoms of major depressive disorder, such as negative cognitive bias, are more prevalent in women than in men. Cognitive bias involves pattern separation which requires hippocampal neurogenesis and is modulated by inflammation in the brain. Previously, we found sex differences in the activation of the amygdala and the hippocampus in response to negative cognitive bias in rats that varied with age. Given the association of cognitive bias to neurogenesis and inflammation, we examined associations between cognitive bias, neurogenesis in the hippocampus, and cytokine and chemokine levels in the ventral hippocampus (HPC) and basolateral amygdala (BLA) of male and female rats across the lifespan.ResultsAfter cognitive bias testing, males had more IFN-γ, IL-1β, IL-4, IL-5, and IL-10 in the ventral HPC than females in adolescence. In young adulthood, females had more IFN-γ, IL-1β, IL-6, and IL-10 in the BLA than males. Middle-aged rats had more IL-13, TNF-α, and CXCL1 in both regions than younger groups. Adolescent male rats had higher hippocampal neurogenesis than adolescent females after cognitive bias testing and young rats that underwent cognitive bias testing had higher levels of hippocampal neurogenesis than controls. Neurogenesis in the dorsal hippocampus was negatively associated with negative cognitive bias in young adult males.ConclusionsOverall, the association between negative cognitive bias, hippocampal neurogenesis, and inflammation in the brain differs by age and sex. Hippocampal neurogenesis and inflammation may play greater role in the cognitive bias of young males compared to a greater role of BLA inflammation in adult females. These findings lay the groundwork for the discovery of sex-specific novel therapeutics that target region-specific inflammation in the brain and hippocampal neurogenesis.