Markers In Cortex Research Articles

Intermittent Fasting Improves Social Interaction and Decreases Inflammatory Markers in Cortex and Hippocampus.

Autism spectrum disorder (ASD) is a psychiatric condition characterized by reduced social interaction, anxiety, and stereotypic behaviors related to neuroinflammation and microglia activation. We demonstrated that maternal exposure to Western diet (cafeteria diet or CAF) induced microglia activation, systemic proinflammatory profile, and ASD-like behavior in the offspring. Here, we aimed to identify the effect of alternate day fasting (ADF) as a non-pharmacologic strategy to modulate neuroinflammation and ASD-like behavior in the offspring prenatally exposed to CAF diet. We found that ADF increased plasma beta-hydroxybutyrate (BHB) levels in the offspring exposed to control and CAF diets but not in the cortex (Cx) and hippocampus (Hpp). We observed that ADF increased the CD45 + cells in Cx of both groups; In control individuals, ADF promoted accumulation of CD206 + microglia cells in choroid plexus (CP) and increased in CD45 + macrophages cells and lymphocytes in the Cx. Gestational exposure to CAF diet promoted defective sociability in the offspring; ADF improved social interaction and increased microglia CD206 + in the Hpp and microglia complexity in the dentate gyrus. Additionally, ADF led to attenuation of the ER stress markers (Bip/ATF6/p-JNK) in the Cx and Hpp. Finally, biological modeling showed that fasting promotes higher microglia complexity in Cx, which is related to improvement in social interaction, whereas in dentate gyrus sociability is correlated with less microglia complexity. These data suggest a contribution of intermittent fasting as a physiological stimulus capable of modulating microglia phenotype and complexity in the brain, and social interaction in male mice.

Effect of curcumin on gene expression of selected inflammatory markers in cortex and hippocampus of pilocarpine-induced seizure in rats on a routine exercise program

Effect of curcumin on gene expression of selected inflammatory markers in cortex and hippocampus of pilocarpine-induced seizure in rats on a routine exercise program

Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer’s Disease-Like Neurodegeneration in Rats

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140–160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like β-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.

Light microscopic and heterogeneity analysis of astrocytes in the common marmoset brain.

Astrocytes are abundant cells of the central nervous system (CNS) and are involved in processes including synapse formation/function, ion homeostasis, neurotransmitter uptake, and neurovascular coupling. Recent evidence indicates that astrocytes show diverse molecular, structural, and physiological properties within the CNS. This heterogeneity is reflected in differences in astrocyte structure, gene expression, functional properties, and responsiveness to injury/pathological conditions. Deeper investigation of astrocytic heterogeneity is needed to understand how astrocytes are configured to enable diverse roles in the CNS. While much has been learned about astrocytic heterogeneity in rodents, much less is known about astrocytic heterogeneity in the primate brain where astrocytes have greater size and complexity. The common marmoset (Callithrix jacchus) is a promising non‐human primate model because of similarities between marmosets and humans with respect to genetics, brain anatomy, and cognition/behavior. Here, we investigated the molecular and structural heterogeneity of marmoset astrocytes using an array of astrocytic markers, multi‐label confocal microscopy, and quantitative analysis. We used male and female marmosets and found that marmoset astrocytes show differences in expression of astrocytic markers in cortex, hippocampus, and cerebellum. These differences were accompanied by intra‐regional variation in expression of markers for glutamate/GABA transporters, and potassium and water channels. Differences in astrocyte structure were also found, along with complex interactions with blood vessels, microglia, and neurons. This study contributes to our knowledge of the cellular and molecular features of marmoset astrocytes and is useful for understanding the complex properties of astrocytes in the primate CNS.

Naringenin Ameliorates Chronic Sleep Deprivation-Induced Pain via Sirtuin1 Inhibition.

Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreasedlevels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia.

Cognitively Impaired Old Mice Display Correlated Reduction in Cortical NMDA Receptor and Complex IV

Cognitive decline in older adults represents a major challenge since cognitive impairment is found in 10% of those ≥ 65 and 50% ≥ 85. Thus it is increasingly important to understand the impact of aging on cognitive health. We performed a battery of tests to assess cognition in 6 month-old (n=12) and 24 month-old (n=8) C57BL/6J mice, equivalent to 30 and 70 year old humans, respectively, and also assessed protein markers in cortex for mitochondrial health and cognition. We found that aged mice displayed fewer spontaneous alternations in the T maze test (p=0.034) and lower recognition of novel objects (p=0.022). In addition, aged mice showed prolonged escape time in the Barnes maze (p=0.035), all of which taken together suggest reduced capacity for learning and recall. Aged mice also exhibited diminished nest building (p<0.001), revealing an impaired functional capacity analogous to the instrumental activities of daily living (IADL) geriatric assessment. We found reduced mitochondrial complex IV expression in the cortices of aged mice concomitant with less expression of N-Methyl D-Aspartate (NMDA) receptor subunits 1, 2A and 2B. The cortices from old mice also exhibited greater expression of immature brain derived neurotrophic factor (pro-BDNF). The alterations in NMDA receptors and pro BDNF are consistent with memory impairment and greater neuronal cell death. Therefore, aged mice exhibit significantly reduced recall and learning ability alongside marked alterations in mitochondrial complex, NMDA receptor, and pro-BDNF expression. Studies are underway to assess whether these molecular changes are responsible for the cognitive declines with aging.

Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis

The synergism between estrogen and histone tail acetylation-mediated memory formation is not clearly understood. Here, we attempt to study the altered histone acetylation homeostasis mediated changes in cognition following ovariectomy and evaluate the protective effect of quercetin. A significant reduction in estradiol levels with subsequent depletion in spatial memory and learning functions assessed by Morris water maze, novel object recognition test and elevated plus maze was observed in ovariectomized (OVX) mice. Correspondingly, a significant decline in neuroplasticity markers like brain-derived neurotrophic factor (BDNF), synaptophysin (SYP) and postsynaptic density-95 (PSD-95) was observed in cortex and hippocampus of OVX animals. Notably, histone acetyltransferase (HAT)/histone deacetylase (HDAC) balance was significantly disrupted in cortex and hippocampus of OVX mice. Lowered extracellular signal regulated kinases (ERK) and cAMP response element binding protein activation observed in OVX brain regions might account for HAT/HDAC imbalance. Altered HAT/HDAC homeostasis results in lowered histone 3 acetylation in OVX brain that suppressed transcriptional activation of neuroplasticity-related genes. Quercetin supplementation to OVX mice for 4 weeks was able to ameliorate cognitive impairment by restoring HAT/HDAC homeostasis through ERK activation and reversing alterations in neuroplasticity markers in cortex and hippocampus of OVX mice. Taken together, our results suggest that quercetin alleviates ovariectomy-induced cognitive decline by modulating histone acetylation homeostasis.

Early or Late Bacterial Lung Infection Increases Mortality After Traumatic Brain Injury in Male Mice and Chronically Impairs Monocyte Innate Immune Function.

Respiratory infections in the postacute phase of traumatic brain injury impede optimal recovery and contribute substantially to overall morbidity and mortality. This study investigated bidirectional innate immune responses between the injured brain and lung, using a controlled cortical impact model followed by secondary Streptococcus pneumoniae infection in mice. Experimental study. Research laboratory. Adult male C57BL/6J mice. C57BL/6J mice were subjected to sham surgery or moderate-level controlled cortical impact and infected intranasally with S. pneumoniae (1,500 colony-forming units) or vehicle (phosphate-buffered saline) at 3 or 60 days post-injury. At 3 days post-injury, S. pneumoniae-infected traumatic brain injury mice (TBI + Sp) had a 25% mortality rate, in contrast to no mortality in S. pneumoniae-infected sham (Sham + Sp) animals. TBI + Sp mice infected 60 days post-injury had a 60% mortality compared with 5% mortality in Sham + Sp mice. In both studies, TBI + Sp mice had poorer motor function recovery compared with TBI + PBS mice. There was increased expression of pro-inflammatory markers in cortex of TBI + Sp compared with TBI + PBS mice after both early and late infection, indicating enhanced post-traumatic neuroinflammation. In addition, monocytes from lungs of TBI + Sp mice were immunosuppressed acutely after traumatic brain injury and could not produce interleukin-1β, tumor necrosis factor-α, or reactive oxygen species. In contrast, after delayed infection monocytes from TBI + Sp mice had higher levels of interleukin-1β, tumor necrosis factor-α, and reactive oxygen species when compared with Sham + Sp mice. Increased bacterial burden and pathology was also found in lungs of TBI + Sp mice. Traumatic brain injury causes monocyte functional impairments that may affect the host's susceptibility to respiratory infections. Chronically injured mice had greater mortality following S. pneumoniae infection, which suggests that respiratory infections even late after traumatic brain injury may pose a more serious threat than is currently appreciated.

Stimulatory Effects of the Flavanols (−)‐Epicatechin and its Enantiomer (+)‐Epicatechin on Frontal Cortex Markers of Neurogenesis

The consumption of cocoa products rich in flavanols is associated with improvements in measures of cognition. The most abundant flavanol present in cacao is (−)‐epicatechin (Epi) which upon consumption we have demonstrated to beneficially impact measures of neuroinflammation, neurodegeneration, oxidative stress and mitochondrial biogenesis in mouse frontal cortex. The objective of this study was to analyze the effect of either (−)‐Epi or its rare stereochemical analog (+)‐epicatechin on adult mouse brain frontal cortex markers/modulators of neurogenesis. For this purpose, 3 month old male mice (n=5/group) were provided either with water (vehicle; Veh), (−)‐Epi, or (+)‐Epi at 1 mg/kg body weight for 15 days by oral gavage. After the treatment period, brain frontal cortex was isolated for nitric oxide (NO) measurements, Western blotting for nerve growth factor (NGF), eNOS and nNOS and immunohistochemistry for neuronal specific nuclear protein (NeuN), endothelial (CD31) and neurofilament (NF200) markers. Statistical analysis was performed by ANOVA. Results evidence the stimulatory capacity of (−)‐Epi and (+)‐Epi on markers of neuronal proliferation as per the significant increases in NeuN immunoreactive cells (~150% and 240% respectively) as well as an increase in NGF protein levels of ~45% and ~65% when compared to Veh. The assessment of capillary density effects as per the immunostaining of CD31 also yielded significant increases vs. Veh that were greater in magnitude with (+)‐Epi (~400%) vs. (−)‐Epi (~270%). These effects correlated with positive actions of (−)‐Epi and (+)‐Epi on NO levels (figure A, ~150 and 400% respectively) and eNOS (~25 and 50%) and nNOS (~10 and 20%) phosphorylation levels. We also observed significant increases in neuronal cytoskeleton filaments (NF200) with immunostaining which suggest the development of mature axonal extensions which were greater in magnitude in (−)‐Epi (~200%) vs. (+)‐Epi (~170%) vs. Veh. In conclusion, results suggest that flavanols which are present in cacao exert a strong positive effect on recognized markers of neurogenesis and that such effects may be linked to the stimulatory actions on NO. It also appears that (+)‐Epi is more effective in triggering this action. Further studies await to demonstrate the impact that the sustained consumption of the (−) and (+)‐Epi flavanols exerts in measures of cognition in humans and if they may prevent the early development of mild cognitive impairment as seen in the very early phases of dementia.Support or Funding InformationFunded by NIH AG47326 and DK98717 to FV and grant 20151092 to IRS. We are thankful to Cardero Therapeutics, Inc. for providing (+)‐Epi.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Combined 192 IgG-saporin and 5,7-dihydroxytryptamine lesions in the male rat brain: A neurochemical and behavioral study

In a previous experiment [Eur J Neurosci 12 (2000) 79], combined intracerebroventricular injections of 5,7-dihydroxytryptamine (5,7-DHT; 150 μg) and 192 IgG-saporin (2 μg) in female rats produced working memory impairments, which neither single lesion induced. In the present experiment, we report on an identical approach in male rats. Behavioral variables were locomotor activity, T-maze alternation, beam-walking, Morris water-maze (working and reference memory) and radial-maze performances. 192 IgG-saporin reduced cholinergic markers in the frontoparietal cortex and the hippocampus. 5,7-DHT lesions reduced serotonergic markers in the cortex, hippocampus and striatum. Cholinergic lesions induced motor deficits, hyperactivity and reduced T-maze alternation, but had no other effect. Serotonergic lesions only produced hyperactivity and reduced T-maze alternation. Beside the deficits due to cholinergic lesions, rats with combined lesions also showed impaired radial-maze performances. We confirm that 192 IgG-saporin and 5,7-DHT injections can be combined to produce concomitant damage to cholinergic and serotonergic neurons in the brain. In female rats, this technique enabled to show that interactions between serotonergic and basal forebrain cholinergic mechanisms play an important role in cognitive functions. The results of the present experiment in male rats are not as clear-cut, although they are not in obvious contradiction with our previous results in females.

Reductions in [3H]nicotinic acetylcholine binding in Alzheimer's disease and Parkinson's disease: an autoradiographic study.

In Alzheimer's disease (AD) and Parkinson's disease (PD), dysfunction in the basal forebrain cholinergic system is accompanied by a consistent loss of presynaptic cholinergic markers in cortex, but changes in cholinergic receptor binding sites are poorly understood. In the present study, we used receptor autoradiography to map the distribution of nicotinic [3H]acetylcholine binding sites in cortices of individuals with AD and PD and matched control subjects. In both diseases, a profound loss of nicotinic receptors occurs in all cortical layers, particularly the deepest layers.

Neurotransmitter receptor alterations in Alzheimer disease: a review.

In Alzheimer disease (AD), dysfunction in several neuronal systems is associated with alterations in neurotransmitter receptors. Although receptors are important components of normal neural circuitry, their role in the pathophysiology of AD is only beginning to be clarified. For example, despite the consistent loss of presynaptic cholinergic markers in cortex in AD, the pattern of changes in cortical muscarinic cholinergic receptors is unclear, although the density of nicotinic receptors appears to be reduced. In AD, reductions in serotonin, glutamate, and somatostatin receptors also occur in cortex, and an increase in corticotropin-releasing factor (CRF) receptors has been reported. Studies of neurotransmitter receptor alterations in AD are contributing to the characterization of the biology of this disorder and could result in the development of better diagnostic tests and therapeutic agents.