Young Rat Brain Research Articles

Changes in the content of dopamine, serotonin, their precurrents and derivatives in the prefrontal cortex of the brain of young male rats under chronic exposure to low-intense electromagnetic field

Changes in the content of dopamine, serotonin, their precurrents and derivatives in the prefrontal cortex of the brain of young male rats under chronic exposure to low-intense electromagnetic field

Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.

One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

Inflammatory and metabolic responses in the aging rat brain

AbstractBackgroundThe brain is an energetically demanding organ that mostly relies on glucose oxidation to sustain its sophisticated networks. Transcriptomic studies suggest metabolic‐related genes are downregulated in the aging brain but inflammation‐related genes are highly upregulated. Astrocytes are key mediators of brain inflammation and metabolism. Yet, the relationship between inflammatory signals and energy substrates consumption in the aging brain remains unclear. To address this question, we investigated the response of the young and aged rat brain metabolism to a nonsteroidal anti‐inflammatory (NSAID) drug.MethodFive young adults (4 mo), and five aged (24 mo) male Wistar rats were scanned using positron emission microtomography with 18F‐fluorodeoxyglucose ([18F]FDG‐PET). Scans were done under basal conditions or after three‐day treatment with 5mg/kg ketoprofen (i.p.), an NSAID known to cross the blood‐brain barrier. Standard uptake values ratios (SUVr, pons as reference) were calculated for the main brain regions. Synaptosome and total mitochondria preparations from the cortex had their oxygen consumption rates measured in an Oroboros Instrument, using a SUIT protocol. Results were analyzed by t‐test, with statistical significance P < 0.05.ResultUnder basal conditions, glucose uptake showed no differences between young and aged rats. After ketoprofen treatment, clusters of glucose hypermetabolism appeared in the cortex and hippocampus of the adult but not the aged brain. Synaptosomal and mitochondrial preparations did not present differences in ATP‐linked, maximal, or leak respiration between groups under basal conditions. However, aged synaptosomes (t = 3.417, p = 0.0112) and total mitochondria (t = 3.131, p = 0.0166) presented higher respiratory coupling ratios.ConclusionWe previously showed that [18F]FDG‐PET signal highly depends on astrocyte function. The lack of response to ketoprofen in aged rats may be related to astrocyte dysfunction in aging. As a counter‐response to the aging process, the brain mitochondria are highly coupled, keeping the system as efficient as necessary. Our findings indicate that brain metabolism might not be coupled to inflammation in the aged rat brain. Still, we identified a remarkable plasticity of the mitochondria, which can sustain physiological responses despite the aging process.

Experimental evidence that N-acetylglutamate and N-acetylmethionine compromises mitochondrial functions besides inhibiting citric acid cycle enzyme and respiratory chain activities in brain of young rats

Experimental evidence that N-acetylglutamate and N-acetylmethionine compromises mitochondrial functions besides inhibiting citric acid cycle enzyme and respiratory chain activities in brain of young rats

Sex differences in distribution and identity of aromatase gene expressing cells in the young adult rat brain

BackgroundAromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene (Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene.MethodsCyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied.ResultsIn the male brain, the highest percentage of Cyp19a1+ cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1+ cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1+ cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3, suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1+ cells.ConclusionsFemales show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.

Efeitos dos exercícios físicos sobre a neurogênese do cérebro de ratos adolescentes

Introduction. The neurogenesis of the brain of young rats can be affected by several factors in their development, with the practice of physical exercises being an important factor in the neurogenesis of nervous tissue. Objective. To investigate the effects of different physical exercise protocols of medium and high intensity on neurogenesis in the brain of adolescent rats. Method. The experimental study, where three groups of animals were used: a control group (RC), a group that performed medium-intensity physical exercise (R1) and a group that performed high-intensity physical exercise (R2). Each group with 8 animals, totaling 24 animals. The progressive resisted physical exercise program on the vertical ladder was carried out for 4 weeks, 5 days a week with a duration varying between 30 and 45 minutes. After the end of the experiments, the animals were euthanized for removal of the brain and subsequent processing, staining using the Nissl method and histomorphometric analysis by counting neurons in the dentate gyrus of the hippocampus and subventricular zone. Results. The data demonstrated that there was no significant difference in the area and height of the apex of the hippocampal dentate gyrus between the groups (p=0.2474 and p=0.3337; respectively). The results of the length of the apex of the hippocampal dentate gyrus showed significant differences (p=0.0172). Conclusion. The practice of medium and high intensity progressive resisted physical exercises did not modify the morphology and neuronal density in the hippocampal dentate gyrus and subventricular zone of young rats.

Ectopic bone formation in the heart and brain of young and old male Fischer-344 rats may result from circulating ossified particles

BACKGROUND: We previously reported ossified particles (OSP, i.e., bone-like particles) in the circulation of rodents and humans. Given their diameters and other characteristics, OSP may pose as emboli and contribute to vascular dysfunction and calcification. Their presence in the circulation is an enigma and leads one to speculate as to their ultimate fate. Since valvular calcification of the heart is a known pathology, we theorize that OSP can gain access to tissues and organs and elicit ectopic bone formation. The objective of the study was to assess whether OSP were detectable in the two most vital organs, i.e., the heart and the brain. We hypothesized that the volume of bone in the myocardium would augment with advancing age; however, given the blood-brain barrier, we did not anticipate the presence of bone in this organ. METHODS: The heart and brain from young (6-mon; n=11) and old (24-mon; n=12) male Fischer-344 rats were collected following euthanasia, weighed to determine mass (g), fixed in 10% formalin for 3 days at 4ºC, and stored in 70% EtOH at -20ºC until analysis. Both tissues were subsequently scanned (55 kVp, and 145 μA) at 15μm via microCT (μCT 45; Scanco Medical, Inc. Switzerland). To determine bone volume, the entire heart and brain were analyzed. One-Way ANOVAs were used to determine significant differences in body mass (g), heart mass (g), brain mass (g), bone volume in the heart (mm3), bone volume in the brain (mm3), bone volume relative to heart mass (mm3/g), and bone volume relative to brain mass (mm3/g). A p-value of 0.05 was set a priori. Data are presented as Means ± Standard Deviation. RESULTS: Body mass (404±30g vs. 347±30g, respectively), heart mass (1.11±0.11g vs. 0.99±0.10g, respectively) and brain mass (2.05±0.15g vs. 1.91±0.10g, respectively) were higher ( p<0.05) in old vs. young rats. Bone volume in the heart (0.035±0.044mm3 vs. 0.005±0.004mm3, respectively) and brain (1.19±1.16mm3 vs. 0.38±0.31mm3, respectively) were higher ( p<0.05) in the old vs. young rats, and this increase remained when bone volume was normalized to heart mass (old, 0.030±0.035 mm3/g vs. young, 0.004±0.003 mm3/g) and brain mass (old, 0.577±0.567 mm3/g vs. young, 0.202±0.173 mm3/g). The microCT scans were limited to a 15μm resolution, eliminating detection of bone of lesser thickness. Thus, the bone volumes reported herein are presumably underestimated. CONCLUSION: Bone volume in the heart and brain increased as a function of advancing age in male rodents and may contribute to a variety of diseases (e.g., myocardial infarction, stroke, cognitive impairments, neurological disorders, etc.). We speculate that circulating OSP gain access to tissues and organs, leading to ectopic bone formation. The presence of bone in the brain was unexpected and suggest that the smallest OSP (≤ 5μm in diameter) can cross the blood-brain barrier. National Science Foundation: ECCS 1710948; American Heart Association: 16IRG27550003 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute intranasal treatment with nerve growth factor limits the onset of traumatic brain injury in young rats.

Traumatic brain injury (TBI) comprises a primary injury directly induced by impact, which progresses into a secondary injury leading to neuroinflammation, reactive astrogliosis, and cognitive and motor damage. To date, treatment of TBI consists solely of palliative therapies that do not prevent and/or limit the outcomes of secondary damage and only stabilize the deficits. The neurotrophin, nerve growth factor (NGF), delivered to the brain parenchyma following intranasal application, could be a useful means of limiting or improving the outcomes of the secondary injury, as suggested by pre-clinical and clinical data. We evaluated the effect of acute intranasal treatment of young (20-postnatal day) rats, with NGF in a TBI model (weight drop/close head), aggravated by hypoxic complications. Immediately after the trauma, rats were intranasally treated with human recombinant NGF (50 μg·kg-1 ), and motor behavioural test, morphometric and biochemical assays were carried out 24 h later. Acute intranasal NGF prevented the onset of TBI-induced motor disabilities, and decreased reactive astrogliosis, microglial activation and IL-1β content, which after TBI develops to the same extent in the impact zone and the hypothalamus. Intranasal application of NGF was effective in decreasing the motor dysfunction and neuroinflammation in the brain of young rats in our model of TBI. This work forms an initial pre-clinical evaluation of the potential of early intranasal NGF treatment in preventing and limiting the disabling outcomes of TBI, a clinical condition that remains one of the unsolved problems of paediatric neurology.

Abstract TP207: Effects Of Dietary Genistein And Estrogen On Post-stroke Inflammation: Relation To Age And Length Of Estrogen Deprivation.

Background: Poststroke inflammation plays an important role in the pathophysiology and prognosis of ischemic stroke. Preclinical investigations with the soy-derived phytoestrogen genistein have shown neuroprotective effects under conditions of brain ischemia. However, little is known about how endogenous estrogen deprivation and age influence the neuroprotection of genistein following focal cerebral ischemia. In this study, we investigated the effects of dietary genistein (Gen) on chronic poststroke inflammation and the probable mechanisms underlying its inflammatory responses after hypogonadism. Method: Young adult (~3-4 months) and proven retired breeder middle-aged Sprague-Dawley rats (~9 months) were used in the study. Rats were ovariectomized and randomly assigned to different durations of hypogonadism (2 vs 12 wks) followed by a two-wk pretreatment with Gen or 17β-estradiol (E2) implant before inducing 60 min. middle cerebral artery occlusion. After 21 days post-ischemia reperfusion, brains were harvested and processed for biochemical analyses to determine the effect of Gen and E2 on the Interleukin-6 (IL-6) and Transforming Growth Factor (TGF-β1) as surrogate markers of M1 and M2 activation respectively. GAP43 was further investigated as a marker of functional recovery. Results: Although there were no significant effects in the ischemic hemisphere, Gen treatment reduced IL-6 expression in the contralateral hemisphere in young subjects while E2 did not affect IL-6 across lengths of hypogonadism in the young cohort (p%lt0.05). After short-term estrogen deprivation, E2 and Gen increased TGF-β1 at the contralateral hemisphere in both young rats and middle-aged rats (p%lt0.05). Gen but not E2 increased GAP43 at the contralateral hemisphere of the young following short-term hypogonadism (p%lt0.05). Conclusion: Our results show that Gen reduces contralateral M1 activation in young ovariectomized rat brains independent of the length of estrogen deprivation after focal cerebral ischemia. Both Gen and E2 differentially promote M2 activation as a function of age but may not influence the inflammatory response in the ischemic hemisphere following extended reperfusion poststroke.

Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats.

Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress. Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single ICV injection (10 μl) of fresh mitochondria isolated from the brain of young rats for five minutes (2 µl/min). Finally, the levels of Malondialdehyde (MDA), Cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC. Young mitochondria administration reduced neuronal apoptosis in the PFC, associated with down-regulation of MDA, Bax, and Caspase-3 and up-regulation of Bcl-2. Moreover, fresh mitochondria partially improved the chronic stress-induced mitochondrial dysfunction in aged rats, as indicated by reduced cytochrome c (Cyt c) release from the mitochondria. These results suggest mitotherapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.

Oral Delivery of miR-320-3p with Lipidic Aminoglycoside Derivatives at Mid-Lactation Alters miR-320-3p Endogenous Levels in the Gut and Brain of Adult Rats According to Early or Regular Weaning.

To investigate if the artificial delivery of microRNAs naturally present in the breastmilk can impact the gut and brain of young rats according to weaning. Animals from a new transgenic rat line expressing the green-fluorescent protein in the endocrine lineage (cholecystokinin expressing cells) received a single oral bolus of miR-320-3p or miR-375-3p embedded in DiOleyl-Succinyl-Paromomycin (DOSP) on D-12. The pups were weaned early (D-15), or regularly (D-30). The expression of relevant miRNA, mRNAs, chromatin complexes, and duodenal cell density were assessed at 8 h post-inoculation and on D-45. The miR-320-3p/DOSP induced immediate effects on H3K4me3 chromatin complexes with polr3d promoter (p < 0.05). On regular weaning, on D-45, miR-320-3p and 375-3p were found to be downregulated in the stomach and upregulated in the hypothalamus (p < 0.001), whereas miR-320-3p was upregulated in the duodenum. After early weaning, miR-320-3p and miR-375-3p were downregulated in the stomach and the duodenum, but upregulated in the hypothalamus and the hippocampus. Combination of miR-320-3p/DOSP with early weaning enhanced miR-320-3p and chromogranin A expression in the duodenum. In the female brain stem, miR-320-3p, miR-504, and miR-16-5p levels were all upregulated. Investigating the oral miRNA-320-3p loads in the duodenal cell lineage paved the way for designing new therapeutics to avoid unexpected long-term impacts on the brain.

Acute radiofrequency electromagnetic radiation exposure impairs neurogenesis and causes neuronal DNA damage in the young rat brain

A mobile phone is now a commonly used device for digital media and communication among all age groups. Young adolescents use it for longer durations, which exposes them to radiofrequency electromagnetic radiation (RF-EMR). This exposure can lead to neuropsychiatric changes. The underlying cellular mechanism behind these changes requires detailed investigation. In the present study, we investigated the effect of RF-EMR emitted from mobile phones on young adolescent rat brains. Wistar rats (5 weeks, male) were exposed to RF-EMR signal (2115 MHz) at a head average specific absorption rate (SAR) of 1.51 W/kg continuously for 8 h. Higher level of lipid peroxidation, carbon-centered lipid radicals, and single-strand DNA damage was observed in the brain of rat exposed to RF-EMR. The number of BrdU-positive cells in the dentate gyrus (DG) decreased in RF-EMR-exposed rats, indicating reduced neurogenesis. RF-EMR exposure also induced degenerative changes and neuronal loss in DG neurons but had no effect on the CA3 and CA1 neurons of the hippocampus and cerebral cortex. The activity of Pro-caspase3 did not increase upon exposure in any of the brain regions, pointing out that degeneration observed in the DG region is not dependent on caspase activation. Results indicate that short-term acute exposure to RF-EMR induced the generation of carbon-centered lipid radicals and nuclear DNA damage, both of which likely played a role in the impaired neurogenesis and neuronal degeneration seen in the young brain's hippocampus region. The understanding of RF-EMR-induced alteration in the brain at the cellular level will help develop appropriate interventions for reducing its adverse impact.

Traumatic brain injury recapitulates developmental changes of axons.

During development, half of brain white matter axons are maintained for growth, while the remainder undergo developmental axon degeneration. After traumatic brain injury (TBI), injured axons also appear to follow pathways leading to either degeneration or repair. These observations raise the intriguing, but unexamined possibility that TBI recapitulates developmental axonal programs. Here, we examined axonal changes in the developing brain in young rats and after TBI in adult rat. Multiple shared changes in axonal microtubule (MT) through tubulin post-translational modifications and MT associated proteins (MAPs), tau and MAP6, were found in both development and TBI. Specifically, degenerating axons in both development and TBI underwent phosphorylation of tau and excessive tubulin tyrosination, suggesting MT instability and depolyermization. Conversely, nearby axons without degenerating morphologies, had increased MAP6 expression and maintenance of tubulin acetylation, suggesting enhanced MT stabilization, thereby supporting survival or repair. Quantitative proteomics revealed similar signaling pathways of axon degeneration and growth/repair, including protein clusters and networks. This comparison approach demonstrates how focused evaluation of developmental processes may provide insight into pathways initiated by TBI. In particular, the data suggest that TBI may reawaken dormant axonal programs that direct axons towards either degeneration or growth/repair, supporting further study in this area.

Potential Protective Role of Curcumin on the Toxic Effect of Food Azo Dye Tartrazine on the Brain of Young Albino Rats

The use of coloring agents in food industry has dramatically increased. Children are the main consumers of colored food products and beverages and are more vulnerable to the effects of synthetic colorants. Curcumin, an active constituent of turmeric plant, has been the subject of extensive studies assessing its antioxidant properties. The present study was conducted to evaluate the protective potentials of curcumin against neurotoxicity induced by the synthetic food colorant; tartrazine. Thirty-six young male albino rats were divided into six groups; negative control (Group I), distilled water (Group II), corn oil (Group III), curcumin (Group IV), tartrazine (Group V) and tartrazine+curcumin (Group VI). At the end of the study, the rats were subjected to biochemical, histological and immunohistochemical staining for GFAP. Our results showed that tartrazine induced a significant decrease in GSH, serotonin and GABA levels and a significant increase in MDA levels in the brain as compared to control groups. Tartrazine induced apoptosis, vacuolations, congestion and cellular infiltration in the brain tissue. An immunohistochemistry study showed astrogliosis with increased expression of GFAP. Curcumin ameliorated all these effects. In conclusion, tartrazine is neurotoxic. Increased brain oxidative stress and cellular damage are contributing factors. Curcumin can prevent tartrazine-induced neurotoxicity.

No Effects of Photobiomodulation on Prefrontal Cortex and Hippocampal Cytochrome C Oxidase Activity and Expression of c-Fos Protein of Young Male and Female Rats.

The role of light in our biological processes and systems is extensively known. In addition, the use of light devices has been introduced in the field of healthcare as an opportunity to administer power light at specific wavelengths to improve our body functions and counteract light deficiency. One of these techniques is photobiomodulation (PBM), which uses red to infrared light in a non-invasive way to stimulate, heal, regenerate, and protect tissue. The main proposed mechanism of action is the stimulation of the cytochrome c oxidase (CCO), the terminal enzyme in the mitochondrial electron transport chain. PBM has achieved positive effects on brain activity and behavioral function of several adult animal models of health and disease, the potential use of this technique in developing stages is not surprising. This research aims to examine the effects of PBM on the prefrontal cortex and hippocampus of 23 day-old healthy male (n = 31) and female (n = 30) Wistar rats. Three groups of each sex were used: a PBM group which received 5 days of PBM, a device group submitted to the same conditions but without light radiation, and a control basal group. CCO histochemistry and c-Fos immunostaining were used to analyze brain metabolic activity and immediate early genes activation, respectively. Results displayed no metabolic differences between the three groups in both sexes. The same results were found in the analysis of c-Fos positive cells, reporting no differences between groups. This research, in contrast to the PBM consequences reported in healthy adult subjects, showed a lack of PBM effects in the brain markers we examined in young healthy rat brains. At this stage, brain function, specifically brain mitochondrial function, is not disturbed so it could be that the action of PBM in the mitochondria may not be detectable using the analysis of CCO activity and c-Fos protein expression. Further studies are needed to examine in depth the effects of PBM in brain development, cognitive functions and postnatal disorders, along with the exploration of the optimal light parameters.

Regional binding of [3H]‐MK801 to NMDA receptors in young and aged rat brain membranes

Norepinephrine (NE) and dopamine (DA) are essential neuromodulators in the central nervous system. They regulate several crucial physiological processes, including arousal/attention, focus, neuroendocrine functions, and the sleep‐wake cycle; they also play complex roles in regulating cognition and affect; therefore, dysfunctions in catecholaminergic neurotransmission are associated with various neurological consequences. Previously, we confirmed that in brain slices from aged Fischer 344 rats, there is an age‐related decrease in glutamate‐stimulated NE release in the cerebral cortex and hippocampus (Gonzales et al., 1991 & Dezfuli et al., 2019) and a regionally specific decline in glutamate‐stimulated DA release, with a deficit in the striatum but not in the olfactory tubercle (Aljohani et al., 2021a). Importantly, our studies demonstrated that NMDA receptors mediate glutamate‐stimulated NE and DA release. We also have shown that the alpha‐2 adrenergic receptors agonist clonidine decreases this glutamate‐stimulated NE release in a concentration‐dependent manner; while in contrast, blockade of these receptors with phentolamine, an alpha‐1 and alpha‐2 adrenergic receptor blocker, or with idazoxan, a selective alpha‐2 receptor blocker, markedly potentiates glutamate‐stimulated NE release in cortical brain slices (Aljohani et al., 2021b). Since aging has heterogeneous effects on NMDA receptors in different brain areas, we have now begun to examine [3H]‐MK801 binding to NMDA receptors to compare changes in receptor density and responsiveness during aging in the cortex, hippocampus, striatum, and olfactory tubercle, as a possible mechanistic explanation for the changes in NE and DA release. The data from cortical membrane preparations suggest that young and old rats have similar NMDA receptor densities but may differ in their response to stimulation with glutamate/glycine.

Maternal Hypoxia Increases the Excitability of Neurons in the Entorhinal Cortex and Dorsal Hippocampus of Rat Offspring.

Prenatal hypoxia is a widespread condition that causes various disturbances in later life, including aberrant central nervous system development, abnormalities in EEG rhythms, and susceptibility to seizures. Hypoxia in rats on the 14th day of embryogenesis (E14) disrupts cortical neuroblast radial migration, mainly affecting the progenitors of cortical glutamatergic neurons but not GABAergic interneurons or hippocampal neurons. Thus, hypoxia at this time point might affect the development of the neocortex to a greater extent than the hippocampus. In the present study, we investigated the long-term effects of hypoxia on the properties of the pyramidal neurons in the hippocampus and entorhinal cortex (EC) in 3-week-old rats subjected to hypoxia on E14. We observed a reduction in the total number of NeuN-positive neurons in EC but not in the CA1 field of the hippocampus, indicating an increased cell loss in EC. However, the principal neuron electrophysiological characteristics were altered in the EC and hippocampus of animals exposed to hypoxia. The whole-cell patch-clamp recordings revealed a similar increase in input resistance in neurons from the hippocampus and EC. However, the resting membrane potential was increased in the EC neurons only. The recordings of field postsynaptic potentials (fPSPs) in the CA1 hippocampal area showed that both the threshold currents inducing fPSPs and population spikes were lower in hypoxic animals compared to age-matched controls. Using the dosed electroshock paradigm, we found that seizure thresholds were lower in the hypoxic group. Thus, the obtained results suggest that maternal hypoxia during the generation of the pyramidal cortical neurons leads to the increased excitability of neuronal circuitries in the brain of young rats. The increased excitability can be attributed to the changes in intrinsic neuronal properties.

The Effect of Short-Term Exposure to Cadmium on the Expression of Vascular Endothelial Barrier Antigen in the Developing Rat Forebrain and Cerebellum: A Computerized Quantitative Immunofluorescent Study.

Clinical and laboratory studies have shown that environmental exposure to cadmium produces damage to several organs, including bones, lungs, and kidneys. The involvement of cadmium in central nervous system (CNS) disorders has also been widely reported, but the precise pathophysiological mechanism is not yet fully understood. Children who were exposed to cadmium during pregnancy are known to suffer from developmental delays, learning difficulties, attention deficit hyperactivity disorder (ADHD), and other cognitive and neurobehavioral deficits. Results from numerous studies suggest that dysfunction of the blood-brain barrier (BBB) structures is an important step in the neurotoxicity of cadmium. A rat-specific BBB marker protein, the endothelial barrier antigen (EBA), has been previously isolated and classified by Sternberger and others. The mouse IgG1 clone, anti-endothelial barrier antigen (anti-EBA), detects a protein triplet (23.5kDa, 25 kDa, and 30kDa) localized to the luminal surface of central and peripheral nervous system (CNS and PNS) vascular endothelial cells with selective permeability barrier functions. This marker has been widely used for characterizing BBB alterations under demyelinating, inflammatory, and other CNS pathologies. Many studies have been published using the rat model system for studying the neurotoxic effect of acute and chronic exposure to cadmium.We applied the indirect immunofluorescent techniques using the anti-EBA antibody in conjunction with the Olympus cellSens computerized image analysis to detect and quantify the surface areas of BBB-competent microvessel profiles in paraformaldehyde-fixed, paraffin-embedded brains of term-delivered young rats after intraperitoneal injection of a single dose of cadmium chloride. We detected a statistically significant reduction in EBA-positive microvessel surface areas in the forebrain (t = 5.86, df = 1789, p-value < 0.001) and cerebellum (t=73.40, df=1337, p < 0.001) of cadmium-treated rats compared to the normal controls. Thus, this study supports the hypothesis that the EBA is a sensitive and measurable indicator for quantitative assessment of the impact of cadmium exposure in the developing rat brain.

Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats

Impaired mitochondrial function and abnormalities in the tryptophan (Trp)-kynurenine (Kyn) pathway are linked to age-related mood disorders. This study investigated the effect of intracerebroventricular (ICV) injection of the mitochondria isolated from young rat brain on depression-like behaviors of aged rats subjected to chronic mild stress (CMS). Aged (22 months old) male rats were randomly assigned into four groups: Aged, Aged + Mit, Aged + CMS, and Aged + CMS + Mit. Anxiety- and depression-like behaviors were assessed using elevated plus maze (EPM), open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT). Mitochondrial membrane potential (MMP), ATP levels, indoleamine 2, 3-dioxygenase (IDO) levels, and Kyn metabolites were measured in the prefrontal cortex (PFC). Golgi Cox staining was used to investigate the neuronal morphology. Mitotherapy decreased immobility time and anhedonia in the FST; increased open arm time and entries in the EPM; decreased grooming and increased rearing, center time, and the entrance in the OFT. Mitotherapy also reduced IDO and Kyn metabolites, restored MMP and ATP production, and enhanced dendritic length and spine density in the PFC. Overall, mitotherapy improved anxiety-and depression-like behaviors in aged rats and it could be considered as a new therapeutic strategy for age-related depressive disorders.

Age-dependent alteration in metabolism of vitamin B6 , neurotransmitters, and amino acids after 4'-O-methylpyridoxine administration in rats.

4'-O-methylpyridoxine (MPN), a recognized antivitamin B6 compound, is a potentially poisonous substance found in Ginkgo biloba L. In this work, the effects of MPN on the metabolism of vitamin B6 , neurotransmitters, and amino acids were compared in the plasma and brain of young and adult rats under various administration times. Results showed that the contents of MPN residues in the plasma and brain of young rats were 12.72 and 14.76 µM higher than adult rats, respectively. Moreover, the levels of 5-hydroxytryptamine and dopamine in the brain of young rats have decreased by 13.78% and 7.19%, respectively, compared with the control group, at 2h after MPN administration. Furthermore, the principal component analysis revealed that MPN was an important contributor to the amino acid composition in the brain of young rats. These results suggest that age may lead to different toxic effects of MPN. PRACTICAL APPLICATION: 4'-O-methylpyridoxine is primarily responsible for poisoning due to overconsumption of Ginkgo biloba seeds. This study will provide an exploratory understanding of the age-dependent toxicity of 4'-O-methylpyridoxine.