Evidence for Hippocampus-Dependent Contextual Learning at Postnatal Day 17 in the Rat

ERIC Educational Resources Information Center

Foster, Jennifer A.; Burman, Michael A.

2010-01-01

Long-term memory for fear of an environment (contextual fear conditioning) emerges later in development (postnatal day; PD 23) than long-term memory for fear of discrete stimuli (PD 17). As contextual, but not explicit cue, fear conditioning relies on the hippocampus; this has been interpreted as evidence that the hippocampus is not fully…

Therapeutic Effects of TianDiJingWan on the Aβ 25–35-Induced Alzheimer's Disease Model Rats

PubMed Central

Li, Zhijie; Tong, Qing; Xu, Huifang; Hu, Li; Zhao, Rong; Zhou, Fang; Pan, Wei; Zhou, Li

2015-01-01

The main purpose of this study was to demonstrate the therapeutic effects and mechanism of TDJW, a modern Chinese medicine prescription developed based on the basic traditional Chinese medicine theory of “tonifying the kidney essence,” on the Aβ 25–35-induced AD rats. The AD model was established by the intracerebroventricular administrations of Aβ 25–35 into the hippocampus CA1 tissue of SD male rats. 72 rats were randomly divided into six groups: sham operation, AD model, donepezil, high TDJW group, medium TDJW group, and low TDJW group. After oral administration of TDJW, the results of Morris water maze and step-down test showed that the learning and memory abilities of AD rats were significantly improved. And biochemical measurement demonstrated that Ach and Glu in hippocampus tissues of AD rats were increased as well. Moreover, the Aβ deposits and p-Tau aggregations in hippocampus CA1 tissues of AD rats were attenuated as observed in the micrographs of immunohistochemistry study, and the results of ELISA indicated that the expressions of TNF-α, IL-1β, and IL-6 in hippocampus tissues were significantly decreased. In conclusion, the present study demonstrated that TDJW could be used as a promising therapeutic agent for the clinical applications of AD treatment in patients. PMID:25815030

STS-90 Day 04 Highlights

NASA Technical Reports Server (NTRS)

1998-01-01

On this forth day of the STS-90 mission, the flight crew, Cmdr. Richard A. Searfoss, Pilot Scott D. Altman, and Mission Specialists Richard M. Linnehan, Dafydd Rhys Williams and Kathryn P. Hire, and Payload Specialists Jay C. Buckey and James A. Pawelczyk continue work with the Escher Staircase Behavior Testing of Adult Rats experiment. This is the first of two behavior testing sessions with the adult rats being used for this experiment. The rats will have a 'hyper drive' unit placed on their head which has recording electrodes made of microscopic wires that are positioned in the brain to record activity in the hippocampus. The hippocampus is that portion of the brain used to develop spatial maps to help us navigate from one place to the other. With the 'hyper drive' units in place, the rats will then be put through a maze or on a track. While the rat is maneuvering on the maze or track, the cell activity of the hippocampus will be measured and recorded.

iTRAQ proteomic analysis of the hippocampus in a rat model of nicotine-induced conditioned place preference.

PubMed

Zhu, Beibei; Li, Xiangyu; Chen, Huan; Wang, Hongjuan; Zhu, Xinchao; Hou, Hongwei; Hu, Qingyuan

2017-05-13

Repeated exposures to nicotine are known to result in persistent changes in proteins expression in addiction-related brain regions, such as the striatum, nucleus accumbens and prefrontal cortex, but the changes induced in the protein content of the hippocampus remain poorly studied. This study established a rat model of nicotine-induced conditioned place preference (CPP), and screened for proteins that were differentially expressed in the hippocampus of these rats using isobaric tags for relative and absolute quantitation labeling (iTRAQ) coupled with 2D-LC MS/MS. The nicotine-induced CPP was established by subcutaneously injecting rats with 0.2 mg/kg nicotine. Relative to the control (saline) group, the nicotine group showed 0.67- and 1.5-fold changes in 117 and 10 hippocampal proteins, respectively. These differentially expressed proteins are mainly involved in calcium-mediated signaling, neurotransmitter transport, GABAergic synapse function, long-term synaptic potentiation and nervous system development. Furthermore, RT-PCR was used to confirmed the results of the proteomic analysis. Our findings identify several proteins and cellular signaling pathways potentially involved in the molecular mechanisms in the hippocampus that underlie nicotine addiction. These results provide insights into the mechanisms of nicotine treatment in hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

The Effect of Ascorbic Acid and Garlic Administration on Lead-Induced Neural Damage in Rat Offspring's Hippocampus.

PubMed

Sadeghi, Akram; Ebrahimzadeh Bideskan, Alireza; Alipour, Fatemeh; Fazel, Alireza; Haghir, Hossein

2013-02-01

The aim of this study was to investigate ascorbic acid and garlic protective effects on lead-induced neurotoxicity during rat hippocampus development. 90 pregnant wistar rats were divided randomly into nine groups: 1- Animals received leaded water (L). 2- Rats received leaded water and ascorbic acid (L+AA). 3- Animals received leaded water and garlic juice (L+G). 4-Animals received leaded water, ascorbic acid and garlic juice (L+G+AA). 5- Rats treated with ascorbic acid (AA). 6- Rats treated with garlic juice (G). 7- Rats treated with ascorbic acid and garlic juice (AA+G). 8- Rats treated with tap water plus 0.4 ml/l normal hydrogen chloride (HCl) and 0.5 mg/l Glucose (Sham). 9- Normal group (N). Leaded water (1500 ppm), garlic juice (1 ml/100g/day, gavage) and ascorbic acid (500 mg/kg/day, IP) were used. Finally, blood lead levels (BLL) were measured in both rats and their offspring. The rat offspring brain sections were stained using Toluidine Blue and photographed. Dark neurons (DNs) were counted to compare all groups. BLL significantly increased in L group compared to control and sham groups and decreased in L+G and L+AA groups in comparison to the L group (P<0.05). the number of DNs in the CA1, CA3, and DG of rat offspring hippocampus significantly increased in L group in comparison to control and sham groups (P<0.05) and decreased in L+G and L+AA groups compared to L group (P<0.05). Garlic juice and ascorbic acid administration during pregnancy and lactation may protect lead-induced neural damage in rat offspring hippocampus.

Neuroprotective role of curcumin on the hippocampus against the structural and serological alterations of streptozotocin-induced diabetes in Sprague Dawely rats.

PubMed

Faheem, Nermeen Mohammed; El Askary, Ahmad

2017-06-01

Diabetes mellitus causes impaired memory and cognitive functions. The hippocampus plays a key role in memory and learning. Curcumin attenuates diabetic nephropathy in vivo . Curcumin has shown a neurogenic effect and cognition-enhancing potential in aged rats. The aim of this study is to evaluate the possible protective role of curcumin on the histological and serological changes of the hippocampus in diabetic rats. Forty albino rats were divided into four groups, ten rats each. Group 1 control rats, group 2 rats received curcumin orally (200 mg/kg/day for six weeks), group 3 rats were injected intraperitoneally with streptozotocin (STZ) (100 mg/kg, single dose), group 4 received a single injection of STZ and received curcumin orally for six weeks. Paraffin sections of hippocampus were prepared and stained with hematoxylin and eosin stain, and immnunohistochemical staining for GFAP and caspase-3. Morphometrical and statistical analyses were performed. Glycemic status and parameters of oxidative stress was measured. Examination of hippocampus of diabetic rats showed disorganization of small pyramidal cells in CA1, many cellular losses in the pyramidal cells of CA3, many degenerated granule cells in the dentate gyrus. GFAP positive astrocyte and caspase-3 positive neuron counts were significantly increased. There were significant serum glucose elevation and significant lowered levels of oxidative stress parameters as compared to control rats. Curcumin administration improved the structural and serological alterations of the hippocampus with significant reduction in serum glucose level. Curcumin ameliorates the deterious effect of diabetes on the hippocampus through its antioxidant, antiapoptotic and anti-inflammatory efficacies.

Ginsenoside Rb1 improves spatial learning and memory by regulation of cell genesis in the hippocampal subregions of rats.

PubMed

Liu, Lei; Hoang-Gia, Trinh; Wu, Hui; Lee, Mi-Ra; Gu, Lijuan; Wang, Chunyan; Yun, Beom-Sik; Wang, Qijun; Ye, Shengquan; Sung, Chang-Keun

2011-03-25

Ginsenoside Rb1 (Rb1) is known to improve learning and memory in hippocampus-dependent tasks. However, the cellular mechanism remains unknown. Cell genesis in hippocampus is involved in spatial learning and memory. In the present study, Rb1 was orally administrated to adult rats for 30days. The behavioral training tests indicated that Rb1 improved spatial cognitive performance of rats in Morris water maze (MWM). Furthermore, we investigated the effects of Rb1 on cell genesis in adult rats' hippocampus, using thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. It has been shown that hippocampal cell genesis can be influenced by several factors such as learning and exercise. In order to avoid the effects of the interfering factors, only the rats treated with Rb1 without training in MWM were used to investigate cell genesis in hippocampus. When BrdU was given to the rats 30days prior to being killed, it was shown that oral administration of Rb1 significantly increased cell survival in dentate gyrus and hippocampal subregion CA3. However, when BrdU was injected 2h prior to sacrifice, the results indicated that Rb1 had no significant influence on cell proliferation in the hippocampal subregions. Thus, an increase of cell survival in hippocampus stimulated by Rb1 may be one of the mechanisms by which ginseng facilitates spatial learning and memory. Our study also indicates that Rb1 may be developed as a therapeutic agent for patients with memory impairment. Copyright © 2011 Elsevier B.V. All rights reserved.

Estradiol does not influence strategy choice but place strategy choice is associated with increased cell proliferation in the hippocampus of female rats.

PubMed

Rummel, Julia; Epp, Jonathan R; Galea, Liisa A M

2010-09-01

Adult neurogenesis occurs in the hippocampus of most mammals. While the function of adult hippocampal neurogenesis is not known, there is a relationship between neurogenesis and hippocampus-dependent learning and memory. Ovarian hormones can influence learning and memory and strategy choice. In competitive memory tasks, higher levels of estradiol shift female rats towards the use of the place strategy. Previous studies using a cue-competition paradigm find that 36% of male rats will use a hippocampus-dependent place strategy and place strategy users had lower levels of cell proliferation in the hippocampus. Here, we used the same paradigm to test whether endogenous or exogenous ovarian hormones influence strategy choice in the cue-competition paradigm and whether cell proliferation was related to strategy choice. We tested ovariectomized estradiol-treated (10 microg of estradiol benzoate) or sham-operated female rats on alternating blocks of hippocampus-dependent and hippocampus-independent versions of the Morris water task. Rats were then given a probe session with the platform visible and in a novel location. Preferred strategy was classified as place strategy (hippocampus-dependent) if they swam to the old platform location or cue strategy (hippocampus-independent) if they swam to the visible platform. All groups showed a preference for the cue strategy. However, proestrous rats were more likely to be place strategy users than rats not in proestrus. Female place strategy users had increased cell proliferation in the dentate gyrus compared to cue strategy users. Our study suggests that 78% of female rats chose the cue strategy instead of the place strategy. In summary the present results suggest that estradiol does not shift strategy use in this paradigm and that cell proliferation is related to strategy use with greater cell proliferation seen in place strategy users in female rats. Copyright (c) 2010 Elsevier Inc. All rights reserved.

The Anterior Thalamus is Critical for Overcoming Interference in a Context-Dependent Odor Discrimination Task

PubMed Central

Law, L. Matthew; Smith, David M.

2012-01-01

The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory. PMID:23025833

Investigation of Propolis’ Effect on Thiobarbituric Acid Reactive Substances and Anti-Oxidant Enzyme Levels of Hippocampus in Diabetic Rats Induced by Streptozotocin

PubMed Central

Köksal, Burcu; Emre, Memet Hanifi; Polat, Alaadin

2015-01-01

BACKGROUND: Propolis is an organic resinous viscous substance collected from flower bud and plant sprig by bees. Propolis has a potential treatment agent for oxidative damage caused by diabetes in hippocampus due to its flavonoid and phenolic content. AIM: In this study effect of propolis on thiobarbituric acid reactive substances and anti-oxidative enzyme levels of hippocampus in diabetic rats induced by streptozotocin was investigated. MATERIALS AND METHODS: The study involved measuring levels of SOD, CAT, GSH-Px and TBARs in hippocampus tissue of STZ-induced diabetic rats (Adult Male Sprague Dawley rats) after applying propolis for one month. The subjects of the study were composed of 51 rats randomly assigned to four groups (Control, STZ, P+STZ and STZ+P). For analysis of data, Kruskal Wallis Test was utilized. RESULTS: The findings of the study showed that there were no significant difference in the levels of TBARS, SOD, CAT and GSH-Px of hippocampus across the groups. CONCLUSION: Propolis application in four-week duration does not have effect on TBARS, SOD, CAT and GSH-Px levels of hippocampus of diabetic rats. These findings mean that more time for observing oxidative harms on hippocampus is needed. PMID:27275196

Treatment with tianeptine induces antidepressive-like effects and alters the neurotrophin levels, mitochondrial respiratory chain and cycle Krebs enzymes in the brain of maternally deprived adult rats.

PubMed

Della, Franciela P; Abelaira, Helena M; Réus, Gislaine Z; Santos, Maria Augusta B dos; Tomaz, Débora B; Antunes, Altamir R; Scaini, Giselli; Morais, Meline O S; Streck, Emilio L; Quevedo, João

2013-03-01

Maternally deprived rats were treated with tianeptine (15 mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming and open field tests. The BDNF, NGF and energy metabolism were assessed in the rat brain. Deprived rats increased the immobility time, but tianeptine reversed this effect and increased the swimming time; the BDNF levels were decreased in the amygdala of the deprived rats treated with saline and the BDNF levels were decreased in the nucleus accumbens within all groups; the NGF was found to have decreased in the hippocampus, amygdala and nucleus accumbens of the deprived rats; citrate synthase was increased in the hippocampus of non-deprived rats treated with tianeptine and the creatine kinase was decreased in the hippocampus and amygdala of the deprived rats; the mitochondrial complex I and II-III were inhibited, and tianeptine increased the mitochondrial complex II and IV in the hippocampus of the non-deprived rats; the succinate dehydrogenase was increased in the hippocampus of non-deprived rats treated with tianeptine. So, tianeptine showed antidepressant effects conducted on maternally deprived rats, and this can be attributed to its action on the neurochemical pathways related to depression.

Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

PubMed Central

Wang, Jian-Qin; Yin, Jie; Song, Yan-Feng; Zhang, Lang; Ren, Ying-Xiang; Wang, De-Gui; Gao, Li-Ping; Jing, Yu-Hong

2014-01-01

Objective. Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer's disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies. PMID:25197672

Post-stress facilitation of serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus prevents learned helplessness development in rats.

PubMed

Joca, Sâmia Regiane Lourenço; Zanelati, Tatiane; Guimarães, Francisco Silveira

2006-05-04

Recent pieces of evidence suggest that the dorsal hippocampus may mediate adaptation to severe and inescapable stress, possibly by the facilitation of serotonergic and/or noradrenergic neurotransmission. Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing animals to learned helplessness. To test the hypothesis that increasing serotonin or noradrenaline levels in the dorsal hippocampus would attenuate the development of learned helplessness (LH), rats received inescapable foot shock (IS) and were tested in a shuttle box 24 h latter. Prestressed animals showed impairment of escape responses. This effect was prevented by bilateral intrahippocampal injections of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, immediately after IS. This effect was not observed when zimelidine was administered before or 2 h after IS. Bilateral intrahippocampal injections of desipramine (3 or 30 nmol/0.5 microl), a noradrenaline reuptake blocker, before IS or immediately after it did not prevent LH development. Desipramine (30 nmol) enhanced LH development when injected before IS. These data suggest that poststress facilitation of hippocampal serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus facilitates adaptation to severe inescapable stress. Antidepressant effects of noradrenaline-selective drugs seem to depend on other structures than the dorsal hippocampus.

[Effect of tongluo xingnao effervescent tablet on learning and memory of AD rats and expression of insulin-degrading enzyme in hippocampus].

PubMed

Zhang, Yin-Jie; Dai, Yuan; Hu, Yong; Ma, Yun-Tong; Xu, Shi-Jun; Wang, Yong-Yan

2013-09-01

To study the effect of Tongluo Xingnao effervescent tablet on learning and memory of dementia rats induced by injection of Abeta25-35 in hippocampus and expression of insulin-degrading enzyme in hippocampus, in order to provide basis for preventing and treating senile dementia. The dementia rat model was established by injecting Abeta25-35 in hippocampus. The rats were divided into the model control group, the Aricept (1.4 mg x kg(-1)) group, and Tongluo Xingnao effervescent tablet high dose (7.56 g x kg(-1)), middle dose (3.78 g x kg(-1)) and low dose (1.59 g x kg(-1)) groups. A sham operation group was established by injecting normal saline in hippocampus. The rats were orally given drugs for 90 days, once a day. Their learning and memory were tested by using Morris water maze. Immunohistochemistry and image analysis were utilized for a quantitative analysis on the expression of insulin-degrading enzyme in hippocampus. Tongluo Xingnao effervescent tablet could significantly shorten the escape latency of rats in the directional navigation test, prolong the retention time in the first quadrant dwell, decrease the retention time in the third quadrant dwell, increase the frequency of crossing the platform, show a more notable statistical significance than the model control group (P < 0.05). Additionally, it could also remarkably increase the average optical density of insulin-degrading enzyme in hippocampus, promote the expression of insulin-degrading enzyme in hippocampus, and show a more notable statistical significance than the model control group (P < 0.05). Tongluo Xingnao effervescent tablet has the effects of improving learning and memory capacity of AD rats and promoting the expression of insulin-degrading enzyme in hippocampus. Its effect in promoting intelligence will be related to increased insulin-degrading enzyme in hippocampus.

Adult neurogenesis is reduced in the dorsal hippocampus of rats displaying learned helplessness behavior.

PubMed

Ho, Y C; Wang, S

2010-11-24

Clinical and preclinical studies suggest that the hippocampus has a role in the pathophysiology of major depression. In the learned helplessness (LH) animal model of depression after inescapable shocks (ISs) animals that display LH behavior have reduced cell proliferation in the hippocampus; this effect can be reversed by antidepressant treatment. Using this model, we compared rats that displayed LH behavior and rats that did not show LH behavior (NoLH) after ISs to determine whether reduced hippocampal cell proliferation is associated with the manifestation of LH behavior or is a general response to stress. Specifically, we examined cell proliferation, neurogenesis, and synaptic function in dorsal and ventral hippocampus of LH and NoLH animals and control rats that were not shocked. The LH rats had showed reduced cell proliferation, neurogenesis, and synaptic transmission in the dorsal hippocampus, whereas no changes were seen in the ventral hippocampus. These changes were not observed in the NoLH animals. In a group of NoLH rats that received the same amount of electrical shock as the LH rats to control for the unequal shocks received in these two groups, we observed changes in Ki-67(+) cells associated with acute stress. We conclude that reduced hippocampal cell proliferation and neurogenesis are associated with the manifestation of LH behavior and that the dorsal hippocampus is the most affected area. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains.

PubMed

Río-Álamos, Cristóbal; Oliveras, Ignasi; Piludu, Maria Antonietta; Gerbolés, Cristina; Cañete, Toni; Blázquez, Gloria; Lope-Piedrafita, Silvia; Martínez-Membrives, Esther; Torrubia, Rafael; Tobeña, Adolf; Fernández-Teruel, Alberto

2017-02-01

The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas.

PubMed

Réus, Gislaine Z; Dos Santos, Maria Augusta B; Abelaira, Helena M; Titus, Stephanie E; Carlessi, Anelise S; Matias, Beatriz I; Bruchchen, Livia; Florentino, Drielly; Vieira, Andriele; Petronilho, Fabricia; Ceretta, Luciane B; Zugno, Alexandra I; Quevedo, João

2016-03-01

Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of prolonged abstinence from METH on the hippocampal BDNF levels, neuronal numbers and apoptosis in methamphetamine-sensitized rats.

PubMed

Hajheidari, Samira; Sameni, Hamid Reza; Bandegi, Ahmad Reza; Miladi-Gorji, Hossein

2017-04-03

Methamphetamine (METH) use is associated with neuronal damage in various regions of brain, while effects of prolonged abstinence on METH-induced damage are not quite clear. This study evaluated serum and hippocampal BDNF levels, neuronal numbers and apoptosis in METH-sensitized and abstinent rats. Rats were sensitized to METH (2mg/kg, daily/18 days, s.c.). All rats were evaluated for neuron counting, the TUNEL test and serum and hippocampal BDNF levels after 30 days of forced abstinence from METH. The results showed that increased BDNF levels in the hippocampus and serum of METH-sensitized rats returned to control level after 30 days of abstinence. The number of neurons in the DG and CA1 of hippocampus and also, the total hippocampal perimeter and area in METH-sensitized rats were significantly lower than the saline rats. While, the number of neurons was not significantly increased in the hippocampus after prolonged abstinence from METH. Also, METH-sensitized rats showed a significant increase in TUNEL-positive cells, whereas METH-abstinent rats showed a slight but significant decrease in TUNEL-positive cells in the DG and CA3 of hippocampus. These results suggest that despite the reduction in BDNF levels, reducing the number of neurons, perimeter and area of the hippocampus were stable after abstinence. Thus, the degenerative effects of METH have been sustained even after prolonged abstinence in the hippocampus. Copyright © 2017 Elsevier B.V. All rights reserved.

Bisphenol-A rapidly enhanced passive avoidance memory and phosphorylation of NMDA receptor subunits in hippocampus of young rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu Xiaohong, E-mail: xuxh63@zjnu.cn; Li Tao; Luo Qingqing

Bisphenol-A (BPA), an endocrine disruptor, is found to influence development of brain and behaviors in rodents. The previous study indicated that perinatal exposure to BPA impaired learning-memory and inhibited N-methyl-D-aspartate receptor (NMDAR) subunits expressions in hippocampus during the postnatal development in rats; and in cultured hippocampal neurons, BPA rapidly promotes dynamic changes in dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDAR subunit NR2B. In the present study, we examined the rapid effect of BPA on passive avoidance memory and NMDAR in the developing hippocampus of Sprague-Dawley rats at the age of postnatal day 18. The results showedmore » that BPA or estradiol benzoate (EB) rapidly extended the latency to step down from the platform 1 h after footshock and increased the phosphorylation levels of NR1, NR2B, and mitogen-activated extracellular signal-regulated kinase (ERK) in hippocampus within 1 h. While 24 h after BPA or EB treatment, the improved memory and the increased phosphorylation levels of NR1, NR2B, ERK disappeared. Furthermore, pre-treatment with an estrogen receptors (ERs) antagonist, ICI182,780, or an ERK-activating kinase inhibitor, U0126, significantly attenuated EB- or BPA-induced phosphorylations of NR1, NR2B, and ERK within 1 h. These data suggest that BPA rapidly enhanced short-term passive avoidance memory in the developing rats. A non-genomic effect via ERs may mediate the modulation of the phosphorylation of NMDAR subunits NR1 and NR2B through ERK signaling pathway. - Highlights: > BPA rapidly extended the latency to step down from platform 1 h after footshock. > BPA rapidly increased pNR1, pNR2B, and pERK in hippocampus within 1 h. > ERs antagonist or MEK inhibitor attenuated BPA-induced pNR1, pNR2B, and pERK.« less

A high fat diet alters metabolic and bioenergetic function in the brain: A magnetic resonance spectroscopy study.

PubMed

Raider, Kayla; Ma, Delin; Harris, Janna L; Fuentes, Isabella; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Yeh, Hung-Wen; Choi, In-Young; Brooks, William M; Stanford, John A

2016-07-01

Diet-induced obesity and associated metabolic effects can lead to neurological dysfunction and increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Despite these risks, the effects of a high-fat diet on the central nervous system are not well understood. To better understand the mechanisms underlying the effects of high fat consumption on brain regions affected by AD and PD, we used proton magnetic resonance spectroscopy ((1)H-MRS) to measure neurochemicals in the hippocampus and striatum of rats fed a high fat diet vs. normal low fat chow. We detected lower concentrations of total creatine (tCr) and a lower glutamate-to-glutamine ratio in the hippocampus of high fat rats. Additional effects observed in the hippocampus of high fat rats included higher N-acetylaspartylglutamic acid (NAAG), and lower myo-inositol (mIns) and serine (Ser) concentrations. Post-mortem tissue analyses revealed lower phosphorylated AMP-activated protein kinase (pAMPK) in the striatum but not in the hippocampus of high fat rats. Hippocampal pAMPK levels correlated significantly with tCr, aspartate (Asp), phosphoethanolamine (PE), and taurine (Tau), indicating beneficial effects of AMPK activation on brain metabolic and energetic function, membrane turnover, and edema. A negative correlation between pAMPK and glucose (Glc) indicates a detrimental effect of brain Glc on cellular energy response. Overall, these changes indicate alterations in neurotransmission and in metabolic and bioenergetic function in the hippocampus and in the striatum of rats fed a high fat diet. Copyright © 2016 Elsevier Ltd. All rights reserved.

Temporal profiles of age-dependent changes in cytokine mRNA expression and glial cell activation after status epilepticus in postnatal rat hippocampus.

PubMed

Järvelä, Juha T; Lopez-Picon, Francisco R; Plysjuk, Anna; Ruohonen, Saku; Holopainen, Irma E

2011-04-08

Status epilepticus (SE) is proposed to lead to an age-dependent acute activation of a repertoire of inflammatory processes, which may contribute to neuronal damage in the hippocampus. The extent and temporal profiles of activation of these processes are well known in the adult brain, but less so in the developing brain. We have now further elucidated to what extent inflammation is activated by SE by investigating the acute expression of several cytokines and subacute glial reactivity in the postnatal rat hippocampus. SE was induced by an intraperitoneal (i.p.) injection of kainic acid (KA) in 9- and 21-day-old (P9 and P21) rats. The mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), glial-derived neurotrophic factor (GDNF), interferon gamma (IFN-γ), and transforming growth factor-beta 1 (TGF-β1) were measured from 4 h up to 3 days after KA injection with real-time quantitative PCR (qPCR). IL-1β protein expression was studied with ELISA, GFAP expression with western blotting, and microglial and astrocyte morphology with immunohistochemistry 3 days after SE. SE increased mRNA expression of IL-1β, TNF-α and IL-10 mRNA in hippocampus of both P9 and P21 rats, their induction being more rapid and pronounced in P21 than in P9 rats. MMP-9 expression was augmented similarly in both age groups and GDNF expression augmented only in P21 rats, whereas neither IFN-γ nor TGF-β1 expression was induced in either age group. Microglia and astrocytes exhibited activated morphology in the hippocampus of P21 rats, but not in P9 rats 3 d after SE. Microglial activation was most pronounced in the CA1 region and also detected in the basomedial amygdala. Our results suggest that SE provokes an age-specific cytokine expression in the acute phase, and age-specific glial cell activation in the subacute phase as verified now in the postnatal rat hippocampus. In the juvenile hippocampus, transient increases in cytokine mRNA expression after SE, in contrast to prolonged glial reactivity and region-specific microglial activity after SE, suggest that the inflammatory response is changed from a fulminant and general initial phase to a more moderate and specific subacute response.

Adult onset-hypothyroidism increases response latency and long-term potentiation (LTP) in rat hippocampus

EPA Science Inventory

Thyroid hormones (TH) influence central nervous system (CNS) function during both development and in adulthood. The hippocampus is critical for some types of learning and memory and is particularly sensitive to thyroid hormone deficiency. Hypothyroidism in adulthood has been ass...

The effect of chronic mild stress on tumor-bearing rats' behavior and its mechanism.

PubMed

Xiu, Li-Juan; Lin, Hui-Ming; Wei, Pin-Kang

2010-03-31

Much evidence has demonstrated that stress and tumor interact, but the mechanisms are poorly understood. The purpose of this study is to discuss the effect of unpredictable chronic mild stress (CMS) upon the behavior of Walker 256 tumor-bearing rats and its mechanism. Observe the effects of CMS on the sucrose consumption, activities, body weight and levels of serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats, and on the levels of Bcl-2 and the phosphor-ERK1/2 in their hippocampus. CMS can reduce the average sucrose consumption, behavioral scores, body weight gain, expression of Bcl-2 and p-ERK1/2 protein in hippocampus, and increase serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats. The stressed tumor-bearing rats had less sucrose consumption, body weight gain and lower behavioral scores, but higher level of serum TNF-alpha than stressed non-tumor-bearing rats. A negative correlation was found between the levels of serum TNF-alpha and sucrose consumption, while a positive correlation between the expression of Bcl-2 protein in hippocampus proper and sucrose consumption. CMS can reduce the protein levels of Bcl-2 and p-ERK1/2 in the rats' hippocampus, which contributes to the changes in the rats' behavior caused by CMS. Tumor-bearing rats are prone to behave depressively after the exposure to CMS. Our findings have suggested that the tumor, by increasing the inflammatory reaction, can be taken as a stressor, affecting the hippocampus and consequently causing depression by decreasing the expression of Bcl-2 and p-ERK1/2 in hippocampus. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Gonadectomy reduces the density of androgen receptor-immunoreactive neurons in male rat's hippocampus: testosterone replacement compensates it.

PubMed

Moghadami, Sajjad; Jahanshahi, Mehrdad; Sepehri, Hamid; Amini, Hossein

2016-01-28

In the present study, the role of gonadectomy on memory impairment and the density of androgen receptor-immunoreactive neurons in rats' hippocampus as well as the ability of testosterone to compensate of memory and the density of androgen receptors in the hippocampus was evaluated. Adult male rats (except intact-no testosterone group) were bilaterally castrated, and behavioral tests performed 2 weeks later. Animals bilaterally cannulated into lateral ventricles and then received testosterone (10, 40 and 120 µg/0.5 µl DMSO) or vehicle (DMSO; 0.5 µl) for gonadectomized-vehicle group, 30 min before training in water maze test. The androgen receptor-immunoreactive neurons were detected by immunohistochemical technique in the hippocampal areas. In the gonadectomized male rats, a memory deficit was found in Morris water maze test on test day (5th day) after DMSO administration. Gonadectomy decreased density of androgen receptor-immunoreactive neurons in the rats' hippocampus. The treatment with testosterone daily for 5 days attenuated memory deficits induced by gonadectomy. Testosterone also significantly increased the density of androgen receptor-immunoreactive neurons in the hippocampal areas. The intermediate dose of this hormone (40 µg) appeared to have a significant effect on spatial memory and the density of androgen receptor-immunoreactive neurons in gonadectomized rats' hippocampus. The present study suggests that testosterone can compensate memory failure in gonadectomized rats. Also testosterone replacement can compensate the reduction of androgen receptor-immunoreactive neurons density in the rats' hippocampus after gonadectomy.

Effects of naringin on learning and memory dysfunction induced by gp120 in rats.

PubMed

Qin, Shanshan; Chen, Qiang; Wu, Hui; Liu, Chenglong; Hu, Jing; Zhang, Dalei; Xu, Changshui

2016-06-01

The aim of the present study was to investigate the effects of naringin on learning and memory dysfunction induced by HIV-1-enveloped protein gp120 in rats, and to identify its potential mechanisms of action. Learning and memory ability was evaluated via Morris water maze test, P2X7 receptor and P65 protein expressions in the rat hippocampus were detected by western blot analysis, and P2X7 mRNA expression in the hippocampus was measured by RT-PCR. We also recorded P2X7 agonist BzATP-activated current in the hippocampus via patch clamp technique. The results showed that naringin treatment (30mg/kg/day) markedly decreased the escape latency and target platform errors of rats treated with gp120 (50ng/day), and further, that naringin treatment significantly decreased the expression of P2X7 and P65 protein and P2X7 mRNA in the hippocampus of gp120-treated rats. In addition, naringin treatment reduced BzATP-activated current in the hippocampus of gp120-treated rats. These results altogether demonstrated that naringin can improve gp120-induced learning and memory dysfunction via mechanisms involving the inhibition of P2X7 expression in the hippocampus. Copyright © 2016 Elsevier Inc. All rights reserved.

Hippocampal Regulation of Contextual Cue-Induced Reinstatement of Cocaine-Seeking Behavior

PubMed Central

Atkins, Alison L.; Mashhoon, Yasmin; Kantak, Kathleen M.

2008-01-01

Associations between cocaine and cues facilitate development and maintenance of addiction. We hypothesized that the ventral hippocampus is important for acquisition of these associations. Rats were trained to self-administer cocaine, with or without pre-exposure to distinct sets of cocaine- and saline-paired contextual cues. Next, rats were conditioned for 3 days with the distinct sets of contextual cues paired with cocaine and saline along with distinct discrete cues. Vehicle or lidocaine was infused into the ventral hippocampus prior to conditioning sessions. Following extinction, reinstatement of cocaine-seeking behavior was examined following exposure to contextual cues, discrete cues, or their combination. Inactivation of the ventral hippocampus during conditioning blocked acquisition of the association between cocaine and cocaine-paired contextual cues in that only lidocaine-treated rats with short-term cue exposure failed to reinstate responding in the presence of cocaine-paired contextual cues. Lidocaine also prevented rats in both cue exposure groups from discriminating between cocaine-and saline-paired contextual cues during reinstatement tests. Reinstatement induced by cocaine-paired discrete cues or by contextual and discrete cues together was not impaired for either cue exposure condition. The hippocampus is important for acquisition of the association between cocaine and context and in maintaining discrimination between cocaine-relevant and -irrelevant contextual cues. PMID:18499239

Study of molecular mechanisms of learning and memory impairment in neonatal rats post intrauterine distress via the pathway of Tau protein hyperphosphorylation.

PubMed

Wang, X-S; Huang, H

2018-05-01

To explore the reversion of the excitatory amino acid receptor antagonists against the impairment of learning-memory and the hyperphosphorylation of protein Tau induced by fetal intrauterine distress in neonatal rats. The analysis of variance of factorial design set up two intervention factors, fetal intrauterine distress (two levels: no fetal intrauterine distress and a course of fetal intrauterine distress) and the excitatory amino acid receptor antagonists (three levels: Saline; NMDA receptor antagonist MK-801; astragalosides). Forty-eight pregnant rats were randomly divided into six experimental groups (n=8, in each group). After the end of the fetal intrauterine distress, the pregnant rats continued until the birth of newborn rats. When the neonatal rats grow to 12W, the Morris water maze test started in order to evaluate learning-memory. The hippocampus was removed from newborn rats within 1 day after the Morris water maze test finished. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. Besides, the content of protein Tau including Tau5 (total protein Tau), p-PHF1Ser396/404, p-AT8Ser199/202, p-12E8Ser262 in the hippocampus of rats, was examined with the method of immunohistochemistry (IHC) staining (SP). Fetal intrauterine distress and the glutamate ionic receptor blockers could induce the impairment of learning-memory in neonatal rats, extending the evasive latency time and shorten the space exploration time. Both influences present subtract effect. Fetal intrauterine distress could significantly up-regulate the content of glutamate in the hippocampus of neonatal rats, which was not affected by the glutamate ionic receptor blockers. Fetal intrauterine distress and the glutamate ionic receptor blockers did not affect the total protein Tau in the hippocampus of rats. Moreover, fetal intrauterine distress could increase the hyperphosphorylation of protein Tau in the hippocampus of neonatal rats, which were reduced by the glutamate ionic receptor blockers. Both influences presented subtract effect. We showed that fetal intrauterine distress upregulates the content of glutamate in the hippocampus of neonatal rats, up-regulating the hyperphosphorylation of protein Tau and inducing the impairment of learning-memory in neonatal rats.

A comparative study on the effect of high cholesterol diet on the hippocampal CA1 area of adult and aged rats.

PubMed

Abo El-Khair, Doaa M; El-Safti, Fatma El-Nabawia A; Nooh, Hanaa Z; El-Mehi, Abeer E

2014-06-01

Dementia is one of the most important problems nowadays. Aging is associated with learning and memory impairments. Diet rich in cholesterol has been shown to be detrimental to cognitive performance. This work was carried out to compare the effect of high cholesterol diet on the hippocampus of adult and aged male albino rats. Twenty adult and twenty aged male rats were used in this study. According to age, the rats were randomly subdivided into balanced and high cholesterol diet fed groups. The diet was 15 g/rat/day for adult rats and 20 g/rat/day for aged rats for eight weeks. Serial coronal sections of hippocampus and blood samples were taken from each rat. For diet effect evaluation, Clinical, biochemical, histological, immunohistochemical, and morphometric assessments were done. In compare to a balanced diet fed rat, examination of Cornu Ammonis 1 (CA 1) area in the hippocampus of the high cholesterol diet adult rats showed degeneration, a significant decrease of the pyramidal cells, attenuation and/or thickening of small blood vessels, apparent increase of astrocytes and apparent decrease of Nissl's granules content. Moreover, the high cholesterol diet aged rats showed aggravation of senility changes of the hippocampus together with Alzheimer like pathological changes. In conclusion, the high cholesterol diet has a significant detrimental effect on the hippocampus and aging might pronounce this effect. So, we should direct our attention to limit cholesterol intake in our food to maintain a healthy life style for a successful aging.

Edaravone injection ameliorates cognitive deficits in rat model of Alzheimer's disease.

PubMed

Yang, Rui; Wang, Qingjun; Li, Fang; Li, Jian; Liu, Xuewen

2015-11-01

Oxidative stress plays important role in the pathogenesis of Alzheimer's disease (AD). Edaravone is a potent free radical scavenger that exerts antioxidant effects. Therefore, in this study we aimed to investigate neuroprotective effects of edaravone for AD. Wistar rats were randomly divided into three groups (n = 15): control group, model group, and treatment group, which were injected with phosphate buffered saline, Aβ1-40, and Aβ1-40 together with 5 mg/kg edaravone, respectively, into the right hippocampal dentate gyrus. Spatial learning and memory of the rats were examined by Morris water maze test. 4-Hydroxynonenal (4-HNE) level in rat hippocampus was analyzed by immunohistochemistry. Acetylcholinesterase (AChE) and choline acetylase (ChAT) activities were assayed by commercial kits. We found that edaravone ameliorated spatial learning and memory deficits in the rats. 4-HNE level in the hippocampus as well as AChE and ChAT activities in the hippocampus was significantly lower in treatment group than in model group. In conclusion, edaravone may be developed as a novel agent for the treatment of AD for improving cholinergic system and protecting neurons from oxidative toxicity.

Upregulation of GH, but not IGF1, in the hippocampus of the lactating dam after kainic acid injury

PubMed Central

Arellanes-Licea, Elvira C; Ávila-Mendoza, José; Ramírez-Martínez, Elizabeth C; Ramos, Eugenia; Uribe-González, Nancy; Arámburo, Carlos

2018-01-01

Lactation embodies a natural model of morphological, neurochemical, and functional brain plasticity. In this reproductive stage, the hippocampus of the female is less sensitive to excitotoxins in contrast to nulliparity. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) are known to be neuroprotective in several experimental models of brain lesion. Here, activation of the GH–IGF1 pituitary–brain axis following kainic acid (7.5 mg/kg i.p. KA) lesion was studied in lactating and nulliparous rats. Serum concentrations of GH and IGF1 were uncoupled in lactation. Compared to virgin rats, the basal concentration of GH increased up to 40% but IGF1 decreased 58% in dams, and only GH increased further after KA treatment. In the hippocampus, basal expression of GH mRNA was higher (2.8-fold) in lactating rats than in virgin rats. GH mRNA expression in lactating rats increased further after KA administration in the hippocampus and in the hypothalamus, in parallel to GH protein concentration in the hippocampus of KA-treated lactating rats (43% vs lactating control), as detected by Western blot and immunofluorescence. Except for the significantly lower mRNA concentration in the liver of lactating rats, IGF1 expression was not altered by the reproductive condition or by KA treatment in the hippocampus and hypothalamus. Present results indicate upregulation of GH expression in the hippocampus after an excitotoxic lesion, suggesting paracrine/autocrine actions of GH as a factor underlying neuroprotection in the brain of the lactating dam. Since no induction of IGF1 was detected, present data suggest a direct action of GH. PMID:29321175

Differential Effects of Intrauterine Growth Restriction on the Regional Neurochemical Profile of the Developing Rat Brain.

PubMed

Maliszewski-Hall, Anne M; Alexander, Michelle; Tkáč, Ivan; Öz, Gülin; Rao, Raghavendra

2017-01-01

Intrauterine growth restricted (IUGR) infants are at increased risk for neurodevelopmental deficits that suggest the hippocampus and cerebral cortex may be particularly vulnerable. Evaluate regional neurochemical profiles in IUGR and normally grown (NG) 7-day old rat pups using in vivo 1 H magnetic resonance (MR) spectroscopy at 9.4 T. IUGR was induced via bilateral uterine artery ligation at gestational day 19 in pregnant Sprague-Dawley dams. MR spectra were obtained from the cerebral cortex, hippocampus and striatum at P7 in IUGR (N = 12) and NG (N = 13) rats. In the cortex, IUGR resulted in lower concentrations of phosphocreatine, glutathione, taurine, total choline, total creatine (P < 0.01) and [glutamate]/[glutamine] ratio (P < 0.05). Lower taurine concentrations were observed in the hippocampus (P < 0.01) and striatum (P < 0.05). IUGR differentially affects the neurochemical profile of the P7 rat brain regions. Persistent neurochemical changes may lead to cortex-based long-term neurodevelopmental deficits in human IUGR infants.

A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats

PubMed Central

Jung, Marianna E.; Metzger, Daniel B.

2016-01-01

Ethanol withdrawal (EW) is referred to the abrupt termination of long-term heavy drinking, and provokes oxidative brain damage. Here, we investigated whether the cerebellum and hippocampus of female rats are less affected by prooxidant EW than male rats due to the antioxidant effect of 17β-estradiol (E2). Female and male rats received a four-week ethanol diet and three-week withdrawal per cycle for two cycles. Some female rats were ovariectomized with E2 or antioxidant (Vitamin E+Co-Q10) treatment. Measurements were cerebellum (Rotarod) and hippocampus (water-maze)-related behaviors, oxidative markers (O2•−, malondialdehyde, protein carbonyls), mitochondrial membrane swelling, and a key mitochondrial enzyme, cytochrome c oxidase (CcO). Separately, HT22 (hippocampal) cells were subjected to ethanol-exposure and withdrawal for two cycles to assess the effect of a CcO inhibitor on E2’s protection for mitochondrial respiration and cell viability. Ethanol-withdrawn female rats showed a smaller increase in oxidative markers in cerebellum and hippocampus than male rats, and E2 treatment decreased the oxidative markers. Compared to male counterparts, ethanol-withdrawn female rats showed better Rotarod but poorer water-maze performance, accompanied by more severe mitochondrial membrane swelling and CcO suppression in hippocampus. E2 or antioxidant treatment improved Rotarod but not water-maze performance. In the presence of a CcO inhibitor, E2 treatment failed to protect mitochondrial respiration and cell viability from EW. These data suggest that antioxidant E2 contributes to smaller oxidative stress in ethanol-withdrawn female than male rats. They also suggest that EW-induced severe mitochondrial damage in hippocampus may blunt E2’s antioxidant protection for hippocampus-related behavior. PMID:27503149

Damage to Hippocampus of Rats after Being Exposed to Infrasound.

PubMed

Zhang, Meng Yao; Chen, Chen; Xie, Xue Jun; Xu, Sheng Long; Guo, Guo Zhen; Wang, Jin

2016-06-01

The objective was to observe damage of hippocampus in rats after exposure to infrasound, and to assess HSP70 expression in hippocampus. SD rats in the experimental group were exposed to 140 dB (8 Hz) infrasound for 2 h per day for 3 days. The morphology of the hippocampus was examined by transmission electronic microscopic (TEM). Cell apoptosis was observed by TUNEL staining at 0 h, 24 h, 48 h, and 2 w after exposure. HSP70 expression was detected by immunohistochemistry (IHC) and Western blotting (WB). TEM showed that hippocampus was significantly damaged by exposure, and exhibited recovery 1 week after exposure. The TUNEL data showed that neuronal apoptosis after exposure was significantly higher than in the control rats at 24 h and 48 h, and the apoptotic cells decreased one week after exposure. IHC and WB showed HSP70 expression was significantly higher in the exposed rats, peaked at 24 h. Exposure to 140 dB (8 Hz) infrasound for 2 h per day for 3 days appeared to induce damage to the hippocampus of rats, based on changes in ultrastructure and increased cell apoptosis. However, recovery from the damage occurred overtime. HSP70 expression also increased after the exposure and decreased by 48. Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Ageing introduces a complex pattern of changes in several rat brain transcription factors depending on gender and anatomical localization.

PubMed

Sanguino, Elena; Roglans, Núria; Rodríguez-Calvo, Ricardo; Alegret, Marta; Sánchez, Rosa M; Vázquez-Carrera, Manuel; Laguna, Juan C

2006-04-01

As ageing changes the activity of several transcription factors in the rat cortex, we were interested in determining whether similar changes also appear in the hippocampus of old rats. We determined by electrophoretic gel shift assays the binding activity of nuclear factor kappa B (NFkappaB), activator protein-1 (AP-1), peroxisome proliferator-activated receptor (PPAR), and liver X receptor (LXR) in cortex and hippocampus samples from young (3-month-old), and old (18-month-old) male and female Sprague-Dawley rats. NFkappaB activity increased in old male and female rats, though only in cortex samples, while AP-1 activity decreased only in the cortex and hippocampus of old female animals. LXR activity decreased in all conditions, except in old male cortexes; whereas PPAR activity only decreased in the hippocampus of old female rats. Decreases in AP-1 and PPAR activities restricted to old female rats did not result from an age-related decline in plasma 17beta-estradiol concentration, as their activities did not change in samples obtained from ovariectomized young female rats. Our results indicate that ageing induces a complex pattern of changes in the brain-binding activity of NFkappaB, AP-1, PPAR and LXR, depending on the anatomical origin of the samples (cortex or hippocampus), and the sex of the animals studied.

Anti-acetylcholinesterase and Antioxidant Activities of Inhaled Juniper Oil on Amyloid Beta (1-42)-Induced Oxidative Stress in the Rat Hippocampus.

PubMed

Cioanca, Oana; Hancianu, Monica; Mihasan, Marius; Hritcu, Lucian

2015-05-01

Juniper volatile oil is extracted from Juniperus communis L., of the Cupressaceae family, also known as common juniper. Also, in aromatherapy the juniper volatile oil is used against anxiety, nervous tension and stress-related conditions. In the present study, we identified the effects of the juniper volatile oil on amyloid beta (1-42)-induced oxidative stress in the rat hippocampus. Rats received a single intracerebroventricular injection of amyloid beta (1-42) (400 pmol/rat) and then were exposed to juniper volatile oil (200 μl, either 1 or 3 %) for controlled 60 min period, daily, for 21 continuous days. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Additionally, the acetylcholinesterase activity in the hippocampus was assessed. The amyloid beta (1-42)-treated rats exhibited the following: increase of the acetylcholinesterase, superoxide dismutase and catalase specific activities, decrease of glutathione peroxidase specific activity and the total content of the reduced glutathione along with an elevation of malondialdehyde and protein carbonyl levels. Inhalation of the juniper volatile oil significantly decreases the acetylcholinesterase activity and exhibited antioxidant potential. These findings suggest that the juniper volatile oil may be a potential candidate for the development of therapeutic agents to manage oxidative stress associated with Alzheimer's disease through decreasing the activity of acetylcholinesterase and anti-oxidative mechanism.

Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats.

PubMed

Lin, Yu-Lung; Lin, Shu-Yi; Wang, Sabrina

2012-03-01

Maternal infection during pregnancy may affect fetal brain development and lead to neurological and mental disorders. Previously, we used lipopolysaccharide [LPS, 33 μg/kg, intraperitoneal injection] exposure on gestation day 10.5 to mimic maternal bacterial infection in rats and found reduced dopaminergic and serotoninergic neurons in the offspring. In the present study, we examined the anxiety and stress responses of the affected offspring and the neurophysiological changes in their brains. Our results show that LPS rats displayed more anxiety-like behaviors and heightened stress responses. Dopamine (DA) in the nucleus accumbens and serotonin (5-HT) in the medial prefrontal cortex and the hippocampus were significantly reduced in LPS rats. Their glucocorticoid receptors in the dorsal hippocampus and the 5-HT(1A) receptors in the dorsal and ventral hippocampus were also reduced. In addition, chronic but not acute fluoxetine treatment reversed the behavioral changes and increased hippocampal 5-HT(1A) receptor expression. This study demonstrates that LPS exposure during a critical time of embryonic development could produce long-term reduction of DA and 5-HT and other neurophysiological changes; such alterations may be associated with the increases in stress response and anxiety-like behaviors in the offspring. Copyright © 2011 Elsevier Inc. All rights reserved.

Behavioral deficit and decreased GABA receptor functional regulation in the hippocampus of epileptic rats: effect of Bacopa monnieri.

PubMed

Mathew, Jobin; Gangadharan, Gireesh; Kuruvilla, Korah P; Paulose, C S

2011-01-01

In the present study, alterations of the General GABA and GABA(A) receptors in the hippocampus of pilocarpine-induced temporal lobe epileptic rats and the therapeutic application of Bacopa monnieri and its active component Bacoside-A were investigated. Bacopa monnieri (Linn.) is a herbaceous plant belonging to the family Scrophulariaceae. Hippocampus is the major region of the brain belonging to the limbic system and plays an important role in epileptogenesis, memory and learning. Scatchard analysis of [³H]GABA and [³H]bicuculline in the hippocampus of the epileptic rat showed significant decrease in B(max) (P < 0.001) compared to control. Real Time PCR amplification of GABA(A) receptor sub-units such as GABA(Aά₁), GABA(Aά₅) GABA(Aδ), and GAD were down regulated (P < 0.001) in the hippocampus of the epileptic rats compared to control. GABA(Aγ) subunit was up regulated. Epileptic rats have deficit in the radial arm and Y maze performance. Bacopa monnieri and Bacoside-A treatment reverses all these changes near to control. Our results suggest that decreased GABA receptors in the hippocampus have an important role in epilepsy associated behavioral deficit, Bacopa monnieri and Bacoside-A have clinical significance in the management of epilepsy.

Dysfunction of Iron Metabolism and Iron-Regulatory Proteins in the Rat Hippocampus After Heat Stroke.

PubMed

Liu, Jing; Wan, Shengming; Zhang, Yun; Zhang, Shu; Zhang, Hongying; Wu, Shiwen

2018-05-11

Heat stroke, the most serious type of heat illness, refers to the presence of hyperthermia (core temperature >40°C), accompanied by central nervous system dysfunction. The hippocampus is a particularly vulnerable region in the early stage of heat stroke. Increasing evidence suggests that dysregulation of brain iron metabolism is involved in many neurodegenerative diseases. However, whether heat stroke causes dysfunction of iron metabolism, as well as iron-regulatory proteins, in the hippocampus remains unknown. The present study was conducted to explore the effects on spatial learning and memory, as well as iron content, ferroportin 1 (Fpn1), and hepcidin expression in the hippocampus after heat stroke in rats. Compared with the Sham group, learning ability and memory declined in rats after heat stroke. Iron concentration was significantly increased in the hippocampus. Expression of Fpn1 protein significantly decreased in the hippocampus, while expression of hepcidin increased. Interestingly, Fpn1 mRNA expression in the hippocampus increased. Our data thereby indicate that heat stroke can decrease learning ability and memory in rats. The mechanism may be related to changes of iron levels, as well as Fpn1 and hepcidin expression, in the hippocampus. Furthermore, hepcidin may rapidly decrease cellular Fpn1 protein levels, even under conditions of iron loading, indicating that hepcidin is a more dominant regulator of Fpn1 than is iron.

Effects of dorsal hippocampus catecholamine depletion on paired-associates learning and place learning in rats.

PubMed

Roschlau, Corinna; Hauber, Wolfgang

2017-04-14

Growing evidence suggests that the catecholamine (CA) neurotransmitters dopamine and noradrenaline support hippocampus-mediated learning and memory. However, little is known to date about which forms of hippocampus-mediated spatial learning are modulated by CA signaling in the hippocampus. Therefore, in the current study we examined the effects of 6-hydroxydopamine-induced CA depletion in the dorsal hippocampus on two prominent forms of hippocampus-based spatial learning, that is learning of object-location associations (paired-associates learning) as well as learning and choosing actions based on a representation of the context (place learning). Results show that rats with CA depletion of the dorsal hippocampus were able to learn object-location associations in an automated touch screen paired-associates learning (PAL) task. One possibility to explain this negative result is that object-location learning as tested in the touchscreen PAL task seems to require relatively little hippocampal processing. Results further show that in rats with CA depletion of the dorsal hippocampus the use of a response strategy was facilitated in a T-maze spatial learning task. We suspect that impaired hippocampus CA signaling may attenuate hippocampus-based place learning and favor dorsolateral striatum-based response learning. Copyright © 2017 Elsevier B.V. All rights reserved.

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection.

PubMed

Sil, Susmita; Ghosh, Rupsa; Sanyal, Moumita; Guha, Debjani; Ghosh, Tusharkanti

2016-01-01

Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicine-injected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNFα and IL-1β) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1β, TNFα, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and supported the fact that such rats might have the ability to serve as a sporadic model of AD.

Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus.

PubMed

Song, Xiaoyu; Liu, Bo; Cui, Lingyu; Zhou, Biao; Liu, Weiwei; Xu, Fanxing; Hayashi, Toshihiko; Hattori, Shunji; Ushiki-Kaku, Yuko; Tashiro, Shin-Ichi; Ikejima, Takashi

2017-10-01

Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin, a flavonoid derived from milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Aβ-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Aβ1-42-treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Aβ1-42-injected rats. Silibinin-treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of Aβ1-42 injection on hippocampus cells in rats and protective role of polygona-polysaccharose for Alzheimer's disease].

PubMed

Yi, Yuxin; Wu, Shixing; Ye, Maosheng; Zeng, Yi; Zhang, Ping; Xie, Yiqun

2014-04-01

To determine the effect of polygona-polysaccharose (PP) on learning and memory ability in rats with Alzheimer's disease (AD). Forty five Sprague-Dawley rats were assigned into 3 groups. Rats in the sham-operated group were injected with normal saline. Rats in the Aβ group were injected with Aβ1-42. Rats in the PP group were injected with 16% PP solution for 45 days consecutively. The Morris water maze was used to investigate the ability of learning and memory in the rats. The effect of Aβ and PP on the hippocampus cells was observed by HE and Congo red staining of methanol. Rats in the sham-operated group had no obvious morphological change; and morphology of rats in the PP group was basicaly normal. The layer of pyramidal cells in the Aβ group was decreased. The cells appeared sparse and irregular and became smaller. Karyopyknosis and vacuolar degeneration cells were also found. More positive staining materials aggradated in the Aβ group compared with the PP group by Congo red staining (P<0.05). Aβ infusion into the hippocampus results in the impairment of the neuronal degeneration in the rats, which shows similar characterizations of AD. PP can reduce the deposition of Aβ in the hippocampus.

The toxic influence of dibromoacetic acid on the hippocampus and pre-frontal cortex of rat: involvement of neuroinflammation response and oxidative stress.

PubMed

Jiang, Wenbo; Li, Bai; Chen, Yingying; Gao, Shuying

2017-12-01

Dibromoacetic acid (DBA) exsits in drinking water as a by-product of disinfection as a result of chlorination or ozonation processes. Hippocampus and pre-frontal cortex are the key structures in memory formation and weanling babies are more sensitive to environmental toxicant than adults, so this study was conducted to evaluate the potential neurotoxicity effects of DBA exposure when administered intragastrically for 4 weeks to weanling Sprague-Dawley rats, at concentration of 0, 20, 50, 125 mg/kg via the neurobehavioral and neurochemical effects. Results indicated that animals weight gain and food consumption were not significantly affected by DBA. However, morris water maze test showed varying degrees of changes between control and high-dose group. Additionally, the level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus and pre-frontal cortex of rats increased significantly. The activities of total superoxide dismutase (SOD) and the glutathione (GSH) content in the hippocampus and pre-frontal cortex of rats decreased significantly after treatment with DBA. Treatment with DBA increased the protein and mRNA expression of Iba-1, NF-κB, TNF-α, IL-6, IL-1β and HO-1 in the hippocampus and pre-frontal cortex of rats. These data suggested that DBA had a toxic influence on the hippocampus and pre-frontal cortex of rats, and that the mechanism of toxicity might be associated with the neuroinflammation response and oxidative stress.

Vasopressin V1 receptor in rat hippocampus is regulated by adrenocortical functions.

PubMed

Saito, R; Ishiharada, N; Ban, Y; Honda, K; Takano, Y; Kamiya, H

1994-05-16

Two subtypes of arginine vasopressin (AVP) receptors (V1 and V2) have been distinguished. In this study, we examined the characteristics of AVP binding in rat hippocampus and the effects of bilateral adrenalectomy and adrenal steroids on its [3H]AVP binding. [3H]AVP binding to rat liver and the hippocampal membranes was strongly inhibited by the V1 antagonist, OPC-21268. ADX resulted in a significant decrease in the Bmax of AVP binding in the hippocampus. Chronic treatment with aldosterone and corticosterone restored the ADX-induced reduction, but treatment with dexamethasone did not. These results suggest that the AVP V1 receptor in the hippocampus is regulated by adrenocortical neuroregulatory functions.

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

PubMed

Nelson, Britta S; Black, Katelyn L; Daniel, Jill M

2016-01-01

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

Noopept stimulates the expression of NGF and BDNF in rat hippocampus.

PubMed

Ostrovskaya, R U; Gudasheva, T A; Zaplina, A P; Vahitova, Ju V; Salimgareeva, M H; Jamidanov, R S; Seredenin, S B

2008-09-01

We studied the effect of original dipeptide preparation Noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) with nootropic and neuroprotective properties on the expression of mRNA for neurotropic factors NGF and BDNF in rat hippocampus. Expression of NGF and BDNF mRNA in the cerebral cortex and hippocampus was studied by Northern blot analysis. Taking into account the fact that pharmacological activity of Noopept is realized after both acute and chronic treatment, we studied the effect of single and long-term treatment (28 days) with this drug. Expression of the studied neurotropic factors in the cerebral cortex was below the control after single administration of Noopept, while chronic administration caused a slight increase in BDNF expression. In the hippocampus, expression of mRNA for both neurotrophins increased after acute administration of Noopept. Chronic treatment with Noopept was not followed by the development of tolerance, but even potentiated the neurotrophic effect. These changes probably play a role in neuronal restoration. We showed that the nootropic drug increases expression of neurotrophic factors in the hippocampus. Our results are consistent with the hypothesis that neurotrophin synthesis in the hippocampus determines cognitive function, particularly in consolidation and delayed memory retrieval. Published data show that neurotrophic factor deficiency in the hippocampus is observed not only in advanced Alzheimer's disease, but also at the stage of mild cognitive impairment (pre-disease state). In light of this our findings suggest that Noopept holds much promise to prevent the development of Alzheimer's disease in patients with mild cognitive impairment. Moreover, therapeutic effectiveness of Noopept should be evaluated at the initial stage of Alzheimer's disease.

Citalopram Ameliorates Synaptic Plasticity Deficits in Different Cognition-Associated Brain Regions Induced by Social Isolation in Middle-Aged Rats.

PubMed

Gong, Wei-Gang; Wang, Yan-Juan; Zhou, Hong; Li, Xiao-Li; Bai, Feng; Ren, Qing-Guo; Zhang, Zhi-Jun

2017-04-01

Our previous experiments demonstrated that social isolation (SI) caused AD-like tau hyperphosphorylation and spatial memory deficits in middle-aged rats. However, the underlying mechanisms of SI-induced spatial memory deficits remain elusive. Middle-aged rats (10 months) were group or isolation reared for 8 weeks. Following the initial 4-week period of rearing, citalopram (10 mg/kg i.p.) was administered for 28 days. Then, pathophysiological changes were assessed by performing behavioral, biochemical, and pathological analyses. We found that SI could cause cognitive dysfunction and decrease synaptic protein (synaptophysin or PSD93) expression in different brain regions associated with cognition, such as the prefrontal cortex, dorsal hippocampus, ventral hippocampus, amygdala, and caudal putamen, but not in the entorhinal cortex or posterior cingulate. Citalopram could significantly improve learning and memory and partially restore synaptophysin or PSD93 expression in the prefrontal cortex, hippocampus, and amygdala in SI rats. Moreover, SI decreased the number of dendritic spines in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus, which could be reversed by citalopram. Furthermore, SI reduced the levels of BDNF, serine-473-phosphorylated Akt (active form), and serine-9-phosphorylated GSK-3β (inactive form) with no significant changes in the levels of total GSK-3β and Akt in the dorsal hippocampus, but not in the posterior cingulate. Our results suggest that decreased synaptic plasticity in cognition-associated regions might contribute to SI-induced cognitive deficits, and citalopram could ameliorate these deficits by promoting synaptic plasticity mainly in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus. The BDNF/Akt/GSK-3β pathway plays an important role in regulating synaptic plasticity in SI rats.

Functional relationships between the hippocampus and dorsomedial striatum in learning a visual scene-based memory task in rats.

PubMed

Delcasso, Sébastien; Huh, Namjung; Byeon, Jung Seop; Lee, Jihyun; Jung, Min Whan; Lee, Inah

2014-11-19

The hippocampus is important for contextual behavior, and the striatum plays key roles in decision making. When studying the functional relationships with the hippocampus, prior studies have focused mostly on the dorsolateral striatum (DLS), emphasizing the antagonistic relationships between the hippocampus and DLS in spatial versus response learning. By contrast, the functional relationships between the dorsomedial striatum (DMS) and hippocampus are relatively unknown. The current study reports that lesions to both the hippocampus and DMS profoundly impaired performance of rats in a visual scene-based memory task in which the animals were required to make a choice response by using visual scenes displayed in the background. Analysis of simultaneous recordings of local field potentials revealed that the gamma oscillatory power was higher in the DMS, but not in CA1, when the rat performed the task using familiar scenes than novel ones. In addition, the CA1-DMS networks increased coherence at γ, but not at θ, rhythm as the rat mastered the task. At the single-unit level, the neuronal populations in CA1 and DMS showed differential firing patterns when responses were made using familiar visual scenes than novel ones. Such learning-dependent firing patterns were observed earlier in the DMS than in CA1 before the rat made choice responses. The present findings suggest that both the hippocampus and DMS process memory representations for visual scenes in parallel with different time courses and that flexible choice action using background visual scenes requires coordinated operations of the hippocampus and DMS at γ frequencies. Copyright © 2014 the authors 0270-6474/14/3415534-14$15.00/0.

Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats

PubMed Central

2010-01-01

Background The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined. Results Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-α, RGS2, Egr2/krox-20 and β-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration. Conclusions The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus. PMID:20105316

Levothyroxine replacement therapy with vitamin E supplementation prevents the oxidative stress and apoptosis in hippocampus of hypothyroid rats.

PubMed

Guo, Yanyun; Wan, Si Yuan; Zhong, Xing; Zhong, Ming Kui; Pan, Tian Rong

2014-01-01

To examine the effect of levothyroxine (L-T4), vitamin E or both on oxidative stress status and hippocampal apoptosis in a propylthiouracil (PTU)-induced hypothyroid rat model. Sprague-Dawley rats were randomly divided into five groups: Control, PTU+PTU+L-T4+PTU+Vit E, PTU+Vit E+L-T4. In each group we assessed levels of serum triiodothyronine (T3), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), hippocampus cellular apoptosis index (AI), hippocampus nicotinamide adenine denucleotide hydrogen (NADPH)oxidase and superoxide dismutase (SOD). 1) Compared with the control group, NADPH oxidase levels were significantly increased, and SOD levels were significantly reduced in the PTU groups (p<0.05). 2) Compared to the PTU group, SOD levels were significantly increased in the PTU+Vit E and PTU+L-T4+Vit E group (p<0.05). NADPH oxidase levels were significantly decreased in the PTU+L-T4, PTU+Vit E and PTU+ L-T4+Vit E group (p<0.05). 3) Compared with the control group, hippocampus AI increased significantly in the PTU group (p<0.05). Compared with the PTU group, hippocampus AI was significantly reduced in the PTU+L-T4 group and PTU+L-T4+Vit E group (p<0.05). 4) Hippocampus AI was positively correlated with NADPH oxidase expression levels in hippocampus tissue (r=0.644, p<0.01). Levothyroxine replacement therapy combined with vitamin E reduces hippocampus AI by improving oxidative stress. This study suggested that the mechanisms of hippocampus tissue injury in a hypothyroid rat model is related to hippocampus apoptosis from increased oxidative stress.

The effect of sodium thiopental as a GABA mimetic drug in neonatal period on expression of GAD65 and GAD67 genes in hippocampus of newborn and adult male rats.

PubMed

Naseri, Masoud; Parham, Abbas; Moghimi, Ali

2017-09-01

Development of the nervous system in human and most animals is continued after the birth. Critical role of this period in generation and specialization of the neuronal circuits is confirmed in numerous studies. Any pharmacological intervention in this period may result in structural, functional or behavioral abnormalities. In this study, sodium thiopental a GABA mimetic drug was administrated to newborn rats and their GAD65 and GAD67 expression in hippocampus was evaluated before and after puberty. Newborn male Wistar rats were received sodium thiopental (35 mg/kg) daily for 11 days (from 4 to 14 days after birth). Expression of GAD65 and GAD67 in their hippocampus was compared with control groups in 15 and 45 days after birth with RT-qPCR method. Significant down regulation of GAD65 and GAD67 gene expression was observed in treated rats compared with control group in 45 days after birth animals. But no significant difference was shown between experimental and control groups 15 days after birth animals. The effect of sodium thiopental on GAD65 and GAD67 expression only at adult rats showed a latent period of influence which can be attributed to dosage or intension of sodium thiopental neurotoxicity. Significant down regulation of GAD65 and GAD67 showed unwanted effect of sodium thiopental as GABA mimetic drug in critical period of development.

Rats Depend on Habit Memory for Discrimination Learning and Retention

ERIC Educational Resources Information Center

Broadbent, Nicola J.; Squire, Larry R.; Clark, Robert E.

2007-01-01

We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for…

Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density.

PubMed

Cortés, Claudia; Eugenin, Eliseo; Aliaga, Esteban; Carreño, Leandro J; Bueno, Susan M; Gonzalez, Pablo A; Gayol, Silvina; Naranjo, David; Noches, Verónica; Marassi, Michelle P; Rosenthal, Doris; Jadue, Cindy; Ibarra, Paula; Keitel, Cecilia; Wohllk, Nelson; Court, Felipe; Kalergis, Alexis M; Riedel, Claudia A

2012-09-01

Adult hypothyroidism is a highly prevalent condition that impairs processes, such as learning and memory. Even though tetra-iodothyronine (T(4)) treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient's learning capacity and memory. In this work, we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism. Adult male Sprague-Dawley rats were treated with 6-propyl-2-thiouracil (PTU) for 20 days to induce hypothyroidism. Neuronal and astrocyte apoptosis were analyzed in the hippocampus of control and hypothyroid adult rats by confocal microscopy. The content of brain-derived neurotrophic factor (BDNF) was analyzed using enzyme-linked immunosorbent assay (ELISA) and in situ hybridization. The glutamatergic synapse and the postsynaptic density (PSD) were analyzed by electron microscopy. The content of PSD proteins like tyrosine receptor kinase B (TrkB), p75, and N-methyl-D-aspartate receptor (NMDAr) were analyzed by immunoblot. We observed that the hippocampus of hypothyroid adult rats displayed increased apoptosis levels in neurons and astrocyte and reactive gliosis compared with controls. Moreover, we found that the amount of BDNF mRNA was higher in the hippocampus of hypothyroid rats and the content of TrkB, the receptor for BDNF, was reduced at the PSD of the CA3 region of hypothyroid rats, compared with controls. We also observed that the glutamatergic synapses from the stratum radiatum of CA3 from hypothyroid rats, contained thinner PSDs than control rats. This observation was in agreement with a reduced content of NMDAr subunits at the PSD in hypothyroid animals. Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival, and alters the content of the signaling neurotrophic factors, such as BDNF.

Neuropathological changes in brain cortex and hippocampus in a rat model of Alzheimer's disease.

PubMed

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Rahbar Rooshandel, Nahid; Omidzahir, Shila

2011-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and Beta amyloid (ABeta) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 muL of ABeta (1-40) into the hippocampal fissure. In the present study, ABeta (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. ABeta injection CA1 caused ABeta deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group.

Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

PubMed Central

Choi, Joungil; Chandrasekaran, Krish; Demarest, Tyler G; Kristian, Tibor; Xu, Su; Vijaykumar, Kadambari; Dsouza, Kevin Geoffrey; Qi, Nathan R; Yarowsky, Paul J; Gallipoli, Rao; Koch, Lauren G; Fiskum, Gary M; Britton, Steven L; Russell, James W

2014-01-01

Objectives Diabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts. Methods Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined. Results The levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus. Interpretation These data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction. PMID:25356430

The effect of Chinese Jinzhida recipe on the hippocampus in a rat model of diabetes-associated cognitive decline

PubMed Central

2013-01-01

Background To investigate the effects of treatment with Multi component Chinese Medicine Jinzhida (JZD) on behavioral deficits in diabetes-associated cognitive decline (DACD) rats and verify our hypothesis that JZD treatment improves cognitive function by suppressing the endoplasmic reticulum stress (ERS) and improving insulin signaling transduction in the rats’ hippocampus. Methods A rat model of type 2 diabetes mellitus (T2DM) was established using high fat diet and streptozotocin (30 mg/kg, ip). Insulin sensitivity was evaluated by the oral glucose tolerance test and the insulin tolerance test. After 7 weeks, the T2DM rats were treated with JZD. The step-down test and Morris water maze were used to evaluate behavior in T2DM rats after 5 weeks of treatment with JZD. Levels of phosphorylated proteins involved in the ERS and in insulin signaling transduction pathways were assessed by Western blot for T2DM rats’ hippocampus. Results Compared to healthy control rats, T2DM rats initially showed insulin resistance and had declines in acquisition and retrieval processes in the step-down test and in spatial memory in the Morris water maze after 12 weeks. Performance on both the step-down test and Morris water maze tasks improved after JZD treatment. In T2DM rats, the ERS was activated, and then inhibited the insulin signal transduction pathways through the Jun NH2-terminal kinases (JNK) mediated. JZD treatment suppressed the ERS, increased insulin signal transduction, and improved insulin resistance in the rats’ hippocampus. Conclusions Treatment with JZD improved cognitive function in the T2DM rat model. The possible mechanism for DACD was related with ERS inducing the insulin signal transduction dysfunction in T2DM rats’ hippocampus. The JZD could reduce ERS and improve insulin signal transduction and insulin resistance in T2DM rats’ hippocampus and as a result improved the cognitive function. PMID:23829668

[Effects of Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats].

PubMed

Tong, Hai-Ying; Wu, Jisiguleng; Bai, Liang-Feng; Bao, Wu-Ye; Hu, Rilebagen; Li, Jing; Zhang, Yue

2014-05-01

To observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats. Sixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg(-1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA). The AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill. The AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression.

A high-fat diet decreases GABA concentration in the frontal cortex and hippocampus of rats.

PubMed

Sandoval-Salazar, Cuauhtemoc; Ramírez-Emiliano, Joel; Trejo-Bahena, Aurora; Oviedo-Solís, Cecilia I; Solís-Ortiz, Martha Silvia

2016-02-29

It has been proposed that the γ-aminobutyric acid (GABA) plays a key role in the regulation of food intake and body weight by controlling the excitability, plasticity and the synchronization of neuronal activity in the frontal cortex (FC). It has been also proposed that the high-fat diet (HFD) could disturb the metabolism of glutamate and consequently the GABA levels, but the mechanism is not yet clearly understood. Therefore, the aim of this study was to investigate the effect of a HFD on the GABA levels in the FC and hippocampus of rats. The HFD significantly increased weight gain and blood glucose levels, whereas decreased the GABA levels in the FC and hippocampus compared with standard diet-fed rats. HFD decreases GABA levels in the FC and hippocampus of rat, which likely disrupts the GABAergic inhibitory processes, underlying feeding behavior.

[Activation of autophagy pathway in hippocampus and deterioration of learning and memory ability by intermittent hypoxia in rats after cerebral ischemia].

PubMed

Guo, Xiangfei; Zhao, Yaning; Li, Jianmin; Liu, Wenqian; Chen, Changxiang

2016-09-01

Objective To investigate the effects of different duration of intermittent hypoxia on the autophagy pathway in the hippocampus and the learning and memory ability after cerebral ischemia in rats. Methods 100 male Wistar rats were randomly divided into sham operation (SO) group, ischemia/reperfusion (I/R) group, intermittent hypoxia for 7 days combined with ischemia/reperfusion (IH7-I/R) group, intermittent hypoxia for 14 days combined with ischemia/reperfusion (IH14-I/R) group, intermittent hypoxia for 21 days combined with ischemia/reperfusion (IH21-I/R) group, n =20 in each group. The rats in IH7-I/R group, IH14-I/R group and IH21-I/R group were respectively subjected to intermittent hypoxia for 7, 14 and 21 days prior to I/R modeling by improved Pulsinelli four-vessel occlusion (4-VO). The morphological changes of nerve cells in the hippocampus of rat brain were detected by HE staining; the levels of mammalian target of rapamycin (mTOR) and beclin 1 mRNA in the hippocampus were determined by quantitative real-time PCR; the distribution of mTOR and beclin 1 in the hippocampus was observed by immunohistochemistry; the learning and memory ability of rats was assessed by the Morris water maze test. Results Compared with the SO group, the never cell morphology was damaged, the number of survival neurons in the hippocampus was reduced, the expressions of mTOR and beclin 1 in the hippocampus were strengthened, and the learning and memory ability declined in the I/R group. Compared with the I/R group, the never cell morphology was damaged seriously, the number of survival neurons in the hippocampus decreased, the expressions of mTOR and beclin 1 in the hippocampus increased, and the learning and memory ability dropped in the intermittent hypoxia groups. What's more, the above changes were dependent on the duration of intermittent hypoxia. Conclusion Intermittent hypoxia aggravates the dysfunction of learning and memory after cerebral ischemia and the damages increase with time passing, which are related to mTOR-beclin 1 activation and increasing neuronal cell death.

Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

PubMed

Jiang, Lizhu; Mao, Rongrong; Zhou, Qixin; Yang, Yuexiong; Cao, Jun; Ding, Yuqiang; Yang, Yuan; Zhang, Xia; Li, Lingjiang; Xu, Lin

2016-03-01

Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.

Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats

PubMed Central

2012-01-01

Background Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload. Methods Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl3), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d. Results Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls. Conclusion Aluminum overload increases oxidative stress (H2O2) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats. PMID:22613782

Effects of hypoxic preconditioning on expression of transcription factor NGFI-A in the rat brain after unavoidable stress in the "learned helplessness" model.

PubMed

Baranova, K A; Rybnikova, E A; Mironova, V I; Samoilov, M O

2010-07-01

We report here our immunocytochemical studies establishing that the development of a depression-like state in rats following unavoidable stress in a "learned helplessness" model is accompanied by stable activation of the expression of transcription factor NGFI-A in the dorsal hippocampus (field CA1) and the magnocellular paraventricular nucleus of the hypothalamus, along with an early wave of post-stress expression, which died down rapidly, in the ventral hippocampus (the dentate gyrus) and a long period of up to five days of high-level expression in the neocortex. In rats subjected to three sessions of preconditioning consisting of moderate hypobaric hypoxia (360 mmHg, 2 h, with intervals of 24 h), which did not form depression in these circumstances, there were significant changes in the dynamics of immunoreactive protein content in the hippocampus, with a stable increase in expression in the ventral hippocampus and only transient and delayed (by five days) expression in field CA1. In the neocortex (layer II), preconditioning eliminated the effects of stress, preventing prolongation of the first wave of NGFI-A expression to five days, while in the magnocellular hypothalamus, conversely, preconditioning stimulated a second (delayed) wave of the expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex, and hypothalamus seen in non-preconditioned rats appears to reflect the pathological reaction to aversive stress, which, rather than adaptation, produced depressive disorders. Post-stress modification of the expression of the product of the early gene NGFI-A in the brain induced by hypoxic preconditioning probably plays an important role in increased tolerance to severe psychoemotional stresses and is an important component of antidepressant mechanisms.

The antidepressant effect of running is associated with increased hippocampal cell proliferation.

PubMed

Bjørnebekk, Astrid; Mathé, Aleksander A; Brené, Stefan

2005-09-01

A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.

Images in electroconvulsive therapy: ECS dose-dependently increases cell proliferation in the subgranular region of the rat hippocampus.

PubMed

Smitha, Jangama S M; Roopa, Ravindranath; Sagar, B K Chandrasekhar; Kutty, Bindu M; Andrade, Chittaranjan

2014-09-01

Stress and depression are associated with impaired neuroplasticity in the hippocampus; there is a decrease in neurogenesis, which is hypothesized to decrease the adaptative competence of the organism. Representative light microscopy images are presented which show that 6 once-daily electroconvulsive shocks (ECS), dose-dependently increased new cell formation in the subgranular region of the hippocampus in healthy adult male Wistar rats (10 sections per rat, 3 rats in each of sham ECS, 10 mC, and 40 mC groups). These neuroplasticity changes, demonstrated 1 month after the last ECS, may explain a part of the mechanism of action of electroconvulsive therapy in conditions such as depression.

Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy

PubMed Central

Dadsetan, Sherry; Balzano, Tiziano; Forteza, Jerónimo; Cabrera-Pastor, Andrea; Taoro-Gonzalez, Lucas; Hernandez-Rabaza, Vicente; Gil-Perotín, Sara; Cubas-Núñez, Laura; García-Verdugo, José-Manuel; Agusti, Ana; Llansola, Marta; Felipo, Vicente

2016-01-01

Inflammation contributes to cognitive impairment in patients with hepatic encephalopathy (HE). However, the process by which peripheral inflammation results in cognitive impairment remains unclear. In animal models, neuroinflammation and altered neurotransmission mediate cognitive impairment. Taking into account these data, we hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering AMPA and/or NMDA receptors membrane expression; (3) reducing peripheral inflammation with infliximab (anti-TNF-a) would improve spatial learning; (4) this would be associated with reduced neuroinflammation and normalization of the membrane expression of glutamate receptors. The aims of this work were to assess these hypotheses. We analyzed in rats with portacaval shunt (PCS) and control rats, treated or not with infliximab: (a) peripheral inflammation by measuring prostaglandin E2, IL10, IL-17, and IL-6; (b) neuroinflammation in hippocampus by analyzing microglial activation and the content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; and (d) spatial learning in the Radial and Morris water mazes. We assessed the effects of treatment with infliximab on peripheral inflammation, on neuroinflammation and AMPA and NMDA receptors membrane expression in hippocampus and on spatial learning and memory. PCS rats show increased serum prostaglandin E2, IL-17, and IL-6 and reduced IL-10 levels, indicating increased peripheral inflammation. PCS rats also show microglial activation and increased nuclear NF-kB and expression of TNF-a and IL-1b in hippocampus. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory in the radial and Morris water maze. Treatment with infliximab reduces peripheral inflammation in PCS rats, normalizing prostaglandin E2, IL-17, IL-6, and IL-10 levels in serum. Infliximab also prevents neuroinflammation, reduces microglial activation, translocates NF-kB into nucleoli and normalizes TNF-a and IL-1b content in hippocampus. This was associated with normalization of AMPA receptors membrane expression in hippocampus and of spatial learning and memory. The results suggest that peripheral inflammation contributes to spatial learning impairment in PCS rats. Treatment with anti-TNF-a could be a new therapeutic approach to improve cognitive function in patients with HE. PMID:27853420

The hippocampus and memory for orderly stimulus relations

PubMed Central

Dusek, Jeffery A.; Eichenbaum, Howard

1997-01-01

Human declarative memory involves a systematic organization of information that supports generalizations and inferences from acquired knowledge. This kind of memory depends on the hippocampal region in humans, but the extent to which animals also have declarative memory, and whether inferential expression of memory depends on the hippocampus in animals, remains a major challenge in cognitive neuroscience. To examine these issues, we used a test of transitive inference pioneered by Piaget to assess capacities for systematic organization of knowledge and logical inference in children. In our adaptation of the test, rats were trained on a set of four overlapping odor discrimination problems that could be encoded either separately or as a single representation of orderly relations among the odor stimuli. Normal rats learned the problems and demonstrated the relational memory organization through appropriate transitive inferences about items not presented together during training. By contrast, after disconnection of the hippocampus from either its cortical or subcortical pathway, rats succeeded in acquiring the separate discrimination problems but did not demonstrate transitive inference, indicating that they had failed to develop or could not inferentially express the orderly organization of the stimulus elements. These findings strongly support the view that the hippocampus mediates a general declarative memory capacity in animals, as it does in humans. PMID:9192700

Inhibiting the CD38/cADPR pathway protected rats against sepsis associated brain injury.

PubMed

Peng, Qian-Yi; Wang, Yi-Min; Chen, Cai-Xia; Zou, Yu; Zhang, Li-Na; Deng, Song-Yun; Ai, Yu-Hang

2018-01-01

The CD38/cADPR pathway has been found to play roles in various inflammatory conditions. However, whether CD38 plays a protective or detrimental effect in the central nervous system (CNS) is controversial. The aim of this study was to determine the effect of CD38/cADPR pathway in sepsis associated brain injury. Male Sprague-Dawley rats were undergone cecal ligation and puncture (CLP) or sham laparotomies. NAD + , cADPR and CD38 were measured in the hippocampus of septic rats at 0, 6, 12, 24, and 48h after CLP surgery. Rats were divided into the sham, CLP group, CLP+ CD38 expression lentivirus (CLP+ CD38 LV), CLP+ CD38 interference lentivirus (CLP+ CD38 Ri), CLP+ negative control lentivirus (CLP+NC) and the CLP+8-Br-cADPR groups. The Western blots of Bcl-2, Bax and iNOS, TUNEL assays, malondialdehyde (MDA) and superoxide dismutase (SOD) assays, transmission electron microscope analysis were performed in the hippocampus of rats. NAD + , cADPR and CD38 levels increased significantly in the hippocampus of septic rats as early as 12-24h after CLP surgery. CD38 knockdown or blocking cADPR with 8-Br-cADPR significantly reduced apoptosis, MDA and SOD activity, iNOS expression and ultrastructural morphology damages in the hippocampus of septic rats. In this study, we found that the CD38/cADPR pathway was activated in sepsis associated brain injury. Blocking this pathway protected the hippocampus from apoptosis, oxidative stress and ultrastructural morphology damages in septic rats. Copyright © 2017. Published by Elsevier B.V.

Phencyclidine administration during neurodevelopment alters network activity in prefrontal cortex and hippocampus in adult rats.

PubMed

Kjaerby, Celia; Hovelsø, Nanna; Dalby, Nils Ole; Sotty, Florence

2017-08-01

Symptoms of schizophrenia have been linked to insults during neurodevelopment such as NMDA receptor (NMDAR) antagonist exposure. In animal models, this leads to schizophrenia-like behavioral symptoms as well as molecular and functional changes within hippocampal and prefrontal regions. The aim of this study was to determine how administration of the NMDAR antagonist phencyclidine (PCP) during neurodevelopment affects functional network activity within the hippocampus and medial prefrontal cortex (mPFC). We recorded field potentials in vivo after electrical brain stem stimulation and observed a suppression of evoked theta power in ventral hippocampus, while evoked gamma power in mPFC was enhanced in rats administered with PCP neonatally. In addition, increased gamma synchrony elicited by acute administration of the NMDAR antagonist MK-801 was exaggerated in neonatal PCP animals. These data suggest that NMDAR antagonist exposure during brain development alters functional networks within hippocampus and mPFC possibly contributing to the reported behavioral symptoms of this animal model of schizophrenia. NEW & NOTEWORTHY We show that insults with a NMDA receptor antagonist during neurodevelopment lead to suppressed evoked theta oscillations in ventral hippocampus in adult rats, while evoked gamma oscillations are enhanced and hypersensitive to an acute challenge with a NMDA receptor antagonist in prefrontal cortex. These observations reveal the significance of neurodevelopmental disturbances in the evolvement of schizophrenia-like symptoms and contribute to the understanding of the functional deficits underlying aberrant behavior in this disease. Copyright © 2017 the American Physiological Society.

Low Dose Prenatal Alcohol Exposure Does Not Impair Spatial Learning and Memory in Two Tests in Adult and Aged Rats

PubMed Central

Cullen, Carlie L.; Burne, Thomas H. J.; Lavidis, Nickolas A.; Moritz, Karen M.

2014-01-01

Consumption of alcohol during pregnancy can have detrimental impacts on the developing hippocampus, which can lead to deficits in learning and memory function. Although high levels of alcohol exposure can lead to severe deficits, there is a lack of research examining the effects of low levels of exposure. This study used a rat model to determine if prenatal exposure to chronic low dose ethanol would result in deficits in learning and memory performance and if this was associated with morphological changes within the hippocampus. Sprague Dawley rats were fed a liquid diet containing 6% (vol/vol) ethanol (EtOH) or an isocaloric control diet throughout gestation. Male and Female offspring underwent behavioural testing at 8 (Adult) or 15 months (Aged) of age. Brains from these animals were collected for stereological analysis of pyramidal neuron number and dendritic morphology within the CA1 and CA3 regions of the dorsal hippocampus. Prenatal ethanol exposed animals did not differ in spatial learning or memory performance in the Morris water maze or Y maze tasks compared to Control offspring. There was no effect of prenatal ethanol exposure on pyramidal cell number or density within the dorsal hippocampus. Overall, this study indicates that chronic low dose prenatal ethanol exposure in this model does not have long term detrimental effects on pyramidal cells within the dorsal hippocampus or impair spatial learning and memory performance. PMID:24978807

[The role of the opiate mechanisms of the hippocampus and substantia nigra in the behavioral and convulsive disorders in picrotoxin-induced kindling].

PubMed

Kryzhanovskiĭ, G N; Shandra, A A; Godlevskiĭ, L S; Mazarati, A M; Nguyen, T T

1991-03-01

It was shown in the experiments on rats that the repeated picrotoxin administration resulted in the kindling of generalized seizures. Generalized convulsions were followed by the development of either postictal depression or explosiveness. The injection of mu-opiate agonist met-enkephalin into hippocampus of kindled rats resulted in the increase in the severity of seizure reactions which were induced by picrotoxin and also in the increase in the number of animals with postictal explosiveness. The injection of dynorphin-A-1-13 (kappa-opiate agonist) into substantia nigra reticulata induced the locomotor depression which was like one in postictal period and resulted in the decrease of picrotoxin-induced seizures severity. It was concluded that mu-opiate system of hippocampus took part in the formation of generator of pathologically enhanced excitation in the structure during kindling and the development of seizure syndrome, providing also the postictal explosiveness. Kappa-opiate system of substantia nigra plays an important role in the activation of the antiepileptic system, limitation of seizures and the development of postictal depression.

Methylmercury chloride damage to the adult rat hippocampus cannot be detected by proton magnetic resonance spectroscopy

PubMed Central

Lu, Zhiyan; Wu, Jinwei; Cheng, Guangyuan; Tian, Jianying; Lu, Zeqing; Bi, Yongyi

2014-01-01

Previous studies have found that methylmercury can damage hippocampal neurons and accordingly cause cognitive dysfunction. However, a non-invasive, safe and accurate detection method for detecting hippocampal injury has yet to be developed. This study aimed to detect methylmercury-induced damage on hippocampal tissue using proton magnetic resonance spectroscopy. Rats were given a subcutaneous injection of 4 and 2 mg/kg methylmercury into the neck for 50 consecutive days. Water maze and pathology tests confirmed that cognitive function had been impaired and that the ultrastructure of hippocampal tissue was altered after injection. The results of proton magnetic resonance spectroscopy revealed that the nitrogen-acetyl aspartate/creatine, choline complex/creatine and myoinositol/creatine ratio in rat hippocampal tissue were unchanged. Therefore, proton magnetic resonance spectroscopy can not be used to determine structural damage in the adult rat hippocampus caused by methylmercury chloride. PMID:25368649

Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response.

PubMed

Thakare, Vishnu N; Aswar, Manoj K; Kulkarni, Yogesh P; Patil, Rajesh R; Patel, Bhoomika M

2017-10-01

Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-α and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-α significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-α in hippocampus and cerebral cortex as well as serum corticosterone. Copyright © 2017 Elsevier Inc. All rights reserved.

Applications of bioactive material from snakehead fish (Channa striata) for repairing of learning-memory capability and motoric activity: a case study of physiological aging and aging-caused oxidative stress in rats

NASA Astrophysics Data System (ADS)

Sunarno, Sunarno; Muflichatun Mardiati, Siti; Rahadian, Rully

2018-05-01

Physiological aging and aging due to oxidative stress are a major factor cause accelerated brain aging. Aging is characterized by a decrease of brain function of the hippocampus which is linked to the decline in the capability of learning-memory and motoric activity. The objective of this research is to obtain the important information about the mechanisms of brain antiaging associated with the improvement of hippocampus function, which includes aspects of learning-memory capability and motoric activity as well as mitochondrial ultrastructure profile of hippocampus cornu ammonis cells after treated by fish snakehead fish extract. Snakehead fish in Rawa Pening Semarang District allegedly holds the potential of endemic, which contains bioactive antiaging material that can prevent aging or improve the function of the hippocampus. This research has been conducted using a completely randomized design consisting of four treatments with five replications. The treatments were including rats with physiological aging or aging due to oxidative stress which was treated and without treated with meat extract of snakehead fish. The research was divided into two stages, i.e., determining of learning-memory capability, and determining motoric activity. The measured-parameters are time response to find feed, distance travel, time stereotypes, ambulatory time, and resting time. The result showed that the snakehead fish meat extract might improve function hippocampus, both in physiological aging or aging due to oxidative stress. The capability of learning and memory showed that the rats in both conditions of aging after getting treatment of meat extract of snakehead fish could get a feed in the fourth arm maze faster than rats untreated snakehead fish meat extract. Similarly, the measurement of the distance traveled, time stereotypes, ambulatory time, and resting time showed that rats which received treatment of meat extract of snakehead fish were better than the untreated rats. To conclude, the meat extract of snakehead fish can be used as antiaging material to improve the function of the hippocampus, to improve the capability of learning and memory, to improve motoric activity, and to prevent aging. These findings are expected to provide comprehensive information for the development of antiaging research as an effort to improve public health and to improve learning-memory capability and motoric activity.

Glucose Injections into the Dorsal Hippocampus or Dorsolateral Striatum of Rats Prior to T-Maze Training: Modulation of Learning Rates and Strategy Selection

ERIC Educational Resources Information Center

Canal, Clinton E.; Stutz, Sonja J.; Gold, Paul E.

2005-01-01

The present experiments examined the effects of injecting glucose into the dorsal hippocampus or dorsolateral striatum on learning rates and on strategy selection in rats trained on a T-maze that can be solved by using either a hippocampus-sensitive place or striatum-sensitive response strategy. Percentage strategy selection on a probe trial…

Mitigation of postnatal ethanol-induced neuroinflammation ameliorates trace fear memory deficits in juvenile rats.

PubMed

Goodfellow, Molly J; Shin, Youn Ju; Lindquist, Derick H

2018-02-15

Impairments in behavior and cognition are common in individuals diagnosed with fetal alcohol spectrum disorders (FASD). In this study, FASD model rats were intragastrically intubated with ethanol (5g/kg/day; 5E), sham-intubated (SI), or maintained as naïve controls (NC) over postnatal days (PD) 4-9. Ethanol exposure during this human third trimester-equivalent period induces persistent impairments in hippocampus-dependent learning and memory. The ability of ibuprofen (IBU), a non-steroidal anti-inflammatory drug, to diminish ethanol-induced neuroinflammation and rescue deficits in hippocampus-dependent trace fear conditioning (TFC) was investigated in 5E rats. Phosphate buffered saline vehicle (VEH) or IBU was injected 2h following ethanol exposure over PD4-9, followed by quantification of inflammation-related genes in the dorsal hippocampus of PD10 rats. The 5E-VEH rats exhibited significant increases in Il1b and Tnf, but not Itgam or Gfap, relative to NC, SI-VEH, and 5E-IBU rats. In separate groups of PD31-33 rats, conditioned fear (freezing) was significantly reduced in 5E-VEH rats during TFC testing, but not acquisition, compared to SI-VEH and, critically, 5E-IBU rats. Results suggest neuroimmune activation in response to ethanol within the neonate hippocampus contributes to later-life cognitive dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Α2 GABAA receptor sub-units in the ventral hippocampus and α5 GABAA receptor sub-units in the dorsal hippocampus mediate anxiety and fear memory.

PubMed

McEown, K; Treit, D

2013-11-12

Temporary neuronal inactivation of the ventral hippocampus with the GABAA agonist muscimol suppresses unconditioned fear behavior (anxiety) but inactivation of the dorsal hippocampus does not. On the other hand, inactivating the dorsal hippocampus disrupts fear memory, while inactivating the ventral hippocampus does not. Here we investigate the roles of hippocampal GABAA receptor sub-units in mediating these anxiolytic and amnesic effects of GABAA receptor agonists. We microinfused TPA023 (α2 agonist) or TB-21007 (inverse α5 agonist) into the dorsal or ventral hippocampus prior to testing rats in two animal models of anxiety: the elevated plus-maze and shock-probe burying test. Twenty-four hours later rats were re-tested in the shock-probe chamber with a non-electrified probe to assess their memory of the initial shock-probe experience (i.e., fear memory). We found that TPA023 was anxiolytic in the plus-maze and shock-probe burying tests when microinfused into the ventral hippocampus. However, TPA023 did not affect anxiety-related behavior when infused into the dorsal hippocampus. Conversely, we found that the α5 sub-unit inverse agonist TB-21007 impaired rats' memory of the initial shock-probe experience when infused into the dorsal hippocampus, but not when infused into the ventral hippocampus. This double dissociation suggests that α2 GABAA receptor sub-units in the ventral hippocampus mediate unconditioned fear or anxiety, while α5 GABAA receptor sub-units in the dorsal hippocampus mediate conditioned fear memory. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

The Research on the Relationship of RAGE, LRP-1, and Aβ Accumulation in the Hippocampus, Prefrontal Lobe, and Amygdala of STZ-Induced Diabetic Rats.

PubMed

Ma, Lou-Yan; Fei, Yu-Lang; Wang, Xiao-Ye; Wu, Song-Di; Du, Jun-Hui; Zhu, Mei; Jin, Long; Li, Ming; Li, Hai-Long; Zhai, Jia-Jia; Ji, Lu-Peng; Ma, Ran-Ran; Liu, Song-Fang; Li, Mo; Ma, Li; Ma, Xiao-Rui; Qu, Qiu-Min; Lv, Ya-Li

2017-05-01

Diabetes mellitus (DM) has been regarded as an important risk factor for Alzheimer's disease (AD), and diabetic patients and animals have shown cognitive dysfunction. More research has shown that the amyloid-β (Aβ), which is a hallmark of AD, was found deposited in the hippocampus of diabetic rats. This Aβ accumulation is regulated by the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP-1). However, the expression of RAGE and LRP-1 in diabetic rats is not very clear. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether the expression of RAGE and LRP-1 is related to Aβ 1-42 deposition at the hippocampus, prefrontal lobe, and amygdala in DM. We found that diabetic rats had longer escape latency and less frequency of entrance into the target zone than that of the control group (P < 0.05) in the Morris water maze (MWM) test. The Aβ 1-42 expression in the hippocampus and prefrontal lobe significantly increased in the DM group compared to the control group (P < 0.05). RAGE increased (P < 0.05), while LRP-1 decreased (P < 0.05) in the hippocampus tissue and prefrontal lobe tissue of DM rats. The Aβ 1-42 deposition was correlated with RAGE positively (P < 0.05), but with LRP-1 negatively (P < 0.05). Further, the expression levels of Aβ 1-42 , RAGE, and LRP-1 were not changed in the amygdala between the diabetic rats and the control group. These findings indicated that upregulating RAGE and/or downregulating LRP-1 at the hippocampus and the prefrontal lobe contributed to the Aβ 1-42 accumulation and then further promoted the cognitive impairment of diabetic rats.

Neuropathological Changes in Brain Cortex and Hippocampus in a Rat Model of Alzheimer’s Disease

PubMed Central

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Roosh, Nahid Rahbar; Omidzahir, Shila

2011-01-01

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Methods: Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and β-amyloid (Aβ) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 µL of Aβ (1-40) into the hippocampal fissure. Results: In the present study, Aβ (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. Aβ injection CA1 caused Aβ deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. Conclusion: We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group. PMID:21725500

Gender differences and lateralization in the distribution pattern of insulin-like growth factor-1 receptor in developing rat hippocampus: an immunohistochemical study.

PubMed

Hami, Javad; Kheradmand, Hamed; Haghir, Hossein

2014-03-01

Numerous investigators have provided data supporting essential roles for insulin-like growth factor-I (IGF-I) in development of the brain. The aim of this study was to immunohistochemically determine the distinct regional distribution pattern of IGF-1 receptor (IGF-IR) expression in various portions of newborn rat hippocampus on postnatal days 0 (P0), 7 (P7), and 14 (P14), with comparison between male/female and right/left hippocampi. We found an overall significant increase in distribution of IGF-IR-positive (IGF-IR+) cells in CA1 from P0 until P14. Although, no marked changes in distribution of IGF-IR+ cells in areas CA2 and CA3 were observed; IGF-IR+ cells in DG decreased until P14. The smallest number of immunoreactive cells was present in CA2 and the highest number in DG at P0. Moreover, in CA1, CA3, and DG, the number of IGF-IR+ cells was markedly higher in both sides of the hippocampus in females. Our data also showed a higher mean number of IGF-IR+ cells in the left hippocampus of female at P7. By contrast, male pups showed a significantly higher number of IGF-IR+ cells in the DG of the right hippocampus. At P14, the mean number of immunoreactive cells in CA1, CA3, and DG areas found to be significantly increased in left side of hippocampus of males, compared to females. These results indicate the existence of a differential distribution pattern of IGF-IR between left-right and male-female hippocampi. Together with other mechanisms, these differences may underlie sexual dimorphism and left-right asymmetry in the hippocampus.

Effects of preweaning environmental enrichment on hippocampus-dependent learning and memory in developing rats.

PubMed

Lu, Cheng-Qiu; Zhong, Le; Yan, Chong-Huai; Tian, Ying; Shen, Xiao-Ming

2017-02-15

Previous studies have shown that environmental enrichment (EE) improves learning and memory in adult animals. However, the effects of preweaning EE (preEE) on hippocampus-dependent learning and memory as well as its possible mechanisms are poorly understood. Here we report that preEE enhanced the exploratory activity in rats immediately after weaning, and the EE group showed greater performance in a passive avoidance task than the control group (p<0.05), but not in the locomotion activity. Electrophysiology analysis showed that rats exposed to preEE exhibited larger field excitatory postsynaptic potentials after long-term potentiation induction than those in the control group (p<0.05). The protein levels of phosphorylated extracellular signal-regulated kinases as well as activity-regulated cytoskeleton-associated protein were significantly upregulated in the preEE group compared to the control group (p<0.05). Our results indicate that preEE can enhance hippocampus-dependent learning and memory function as postweaning EE does, and the upregulated activation of the ERK signal transduction pathway may be the underlying molecular mechanism. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Hippocampus and Retrograde Amnesia in the Rat Model: A Modest Proposal for the Situation of Systems Consolidation

ERIC Educational Resources Information Center

Sutherland, Robert J.; Sparks, Fraser T.; Lehmann, Hugo

2010-01-01

The properties of retrograde amnesia after damage to the hippocampus have been explicated with some success using a rat model of human medial temporal lobe amnesia. We review the results of this experimental work with rats focusing on several areas of consensus in this growing literature. We evaluate the theoretically significant hypothesis that…

Effects of infrasound on hippocampus-dependent learning and memory in rats and some underlying mechanisms.

PubMed

Yuan, Hua; Long, Hua; Liu, Jing; Qu, Lili; Chen, Jingzao; Mou, Xiang

2009-09-01

To investigate the effect of infrasound on the hippocampus-dependent spatial learning and memory as well as its underlying mechanisms, we measured the changes of cognitive abilities, brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signal transduction pathway and neurogenesis in the hippocampus of rats. The results showed that rats exposed to infrasound of 16 Hz at 130 dB for 14 days exhibited longer escape latency from day 2 and shortened time staying in the quadrant P in Morris water maze (MWM). It was found that mRNA and protein expression levels of hippocampal BDNF and TrkB were significantly decreased in real-time PCR and Western blot, and the number of BrdU-labeled cells in hippocampus was also reduced when compared to control. These results provided novel evidences that the infrasound of a certain exposure parameter can impair hippocampus-dependent learning and memory, in which the downregulation of the neuronal plasticity-related BDNF-TrkB signal pathway and less neurogenesis in hippocampus might be involved.

Serotonin receptor 5-HT5A in rat hippocampus decrease by leptin treatment.

PubMed

García-Alcocer, Guadalupe; Rodríguez, Angelina; Moreno-Layseca, Paulina; Berumen, Laura C; Escobar, Jesica; Miledi, Ricardo

2010-12-17

5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Progestin Concentrations Are Increased following Paced Mating in Midbrain, Hippocampus, Diencephalon, and Cortex of Rats in Behavioral Estrus, but Only in Midbrain of Diestrous Rats

PubMed Central

Frye, Cheryl A.; Rhodes, Madeline E.

2013-01-01

Background The progesterone (P4 ) metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), acts in the midbrain ventral tegmental area (VTA) to modulate the intensity and duration of lordosis. 3α,5α-THP can also have anti-anxiety and anti-stress effects in part through actions in the hippocampus. Separate reports indicate that manipulating 3α,5α-THP levels in the VTA or hippocampus respectively can influence lordosis and affective behavior. 3α,5α-THP levels can also be altered by behavioral experiences, such as mating or swim stress. Whether endogenous levels of 3α,5α-THP modulate and/or are increased in response to affective and/or reproductively-relevant behaviors was investigated. Methods In Experiment 1, rats in behavioral estrus or diestrus were individually tested sequentially in the open field, elevated plus maze, partner preference, social interaction, and paced mating tasks and levels of 17 β-estradiol (E2), P4, dihydroprogesterone (DHP), and 3α,5α-THP in serum, midbrain, hippocampus, diencephalon, and cortex were examined. In Experiments 2 and 3, rats in behavioral estrus or diestrus, were individually tested in the battery indicated above, with, or without, paced mating and tissues were collected immediately after testing for later assessment of endocrine measures. Results In Experiment 1, behavioral estrous, compared to diestrous, rats demonstrated more exploratory, anti-anxiety, social, and reproductive behaviors, and had higher levels of E2 and progestins in serum, midbrain, hippocampus, diencephalon, and cortex. In Experiment 2, in midbrain and hippocampus, levels of 3α,5α-THP and its precursor DHP were increased among rats in behavioral estrus that were mated. In diencephalon, and cortex, DHP levels were increased by mating. In Experiment 3, in midbrain, levels of 3α,5α-THP and its precursor DHP were increased among diestrous rats that were tested in the behavioral battery with mating as compared to those tested in the behavioral battery without mating. Conclusions Increased levels of 3α,5α-THP in behavioral estrus versus diestrous rats are associated with enhanced exploratory, anti-anxiety, social, and reproductive behaviors. Rats in behavioral estrus that are mated have further increases in 3α,5α-THP and/or DHP levels in midbrain, hippocampus, diencephalon, and cortex than do non-mated rats in behavioral estrus, whereas diestrous rats only show 3α,5α-THP increases in midbrain in response to behavioral testing that included mating. PMID:17028418

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.

PubMed

Andrews, Jessica L; Newell, Kelly A; Matosin, Natalie; Huang, Xu-Feng; Fernandez-Enright, Francesca

2015-12-03

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia. Copyright © 2015 Elsevier Inc. All rights reserved.

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats.

PubMed

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT 4 ) administration increased the level of free triiodothyronine (FT 3 ) and free tetraiodothyroxine (FT 4 ) not only in serum but also in hippocampus. In addition, a single systemic LT 4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT 4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT 4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT 4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT 4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT 4 did not affect rats' locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders.

A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome.

PubMed

Goswami, Sonal; Samuel, Sherin; Sierra, Olga R; Cascardi, Michele; Paré, Denis

2012-01-01

Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e., that require the hippocampus or not) the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze (EPM). Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.

TEMPORAL PATTERNS OF LIPOPEROXIDATION AND ANTIOXIDANT ENZYMES ARE MODIFIED IN THE HIPPOCAMPUS OF VITAMIN A-DEFICIENT RATS

PubMed Central

Navigatore Fonzo, Lorena S.; Golini, Rebeca S.; Delgado, Silvia M.; Ponce, Ivana T.; Bonomi, Myrta R.; Rezza, Irma G.; Gimenez, María S.; Anzulovich, Ana C.

2011-01-01

Animals can adapt their behavior to predictable temporal fluctuations in the environment through both, memory-and-learning processes and an endogenous time-keeping mechanism. Hippocampus plays a key role in memory and learning and is especially susceptible to oxidative stress. In compensation, antioxidant enzymes activity, such as Catalase (CAT) and Glutathione peroxidase (GPx), has been detected in this brain region. Daily rhythms of antioxidant enzymes activitiy, as well as of glutathione and lipid peroxides levels, have been described in brain. Here, we investigate day/night variations in lipoperoxidation, CAT and GPx expression and activity, as well as the temporal fluctuations of two key components of the endogenous clock, BMAL1 and PER1, in the rat hippocampus and evaluate to which extent vitamin A deficiency may affect their amplitude or phase. Holtzman male rats from control, vitamin A-deficient and vitamin A-refed groups were sacrificed throughout a 24-h period. Daily levels of clock proteins, lipoperoxidation, CAT and GPx mRNA, protein, and activity, were determined in the rat hippocampus obtained every 4 or 5 h. Gene expression of RARα and RXRβ was also quantified in the hippocampus of the three groups of rats. Our results show significant daily variations of BMAL1 and PER1 protein expression. Rhythmic lipoperoxidation, CAT, and GPx, expression and activity, were also observed in the rat hippocampus. Vitamin A deficiency reduced RXRβ mRNA level, as well as the amplitude of BMAL1 and PER1 daily oscillation, phase-shifted the daily peak of lipoperoxidation, and had a differential effect on the oscillating CAT and GPx mRNA, protein, and activity. Learning how vitamin A deficiency affects the circadian gene expression in the hippocampus may have an impact on the neurobiology, nutritional and chronobiology fields, emphasizing for the first time the importance of nutritional factors, such as dietary micronutrients, in the regulation of circadian parameters in this brain memory-and-learning-related region. PMID:19308957

Lithium ameliorates lipopolysaccharide-induced neurotoxicity in the cortex and hippocampus of the adult rat brain.

PubMed

Khan, Muhammad Sohail; Ali, Tahir; Abid, Muhammad Noman; Jo, Myeung Hoon; Khan, Amjad; Kim, Min Woo; Yoon, Gwang Ho; Cheon, Eun Woo; Rehman, Shafiq Ur; Kim, Myeong Ok

2017-09-01

Lithium an effective mood stabilizer, primary used in the treatment of bipolar disorders, has been reported as a protective agent in various neurological disorders. In this study, we examined the neuroprotective role of lithium chloride (LiCl) against lipopolysaccharide (LPS) in the cortex and hippocampus of the adult rat brain. We determined that LiCl -attenuated LPS-induced activated toll-like receptor 4 (TLR4) signalling and significantly reduced the nuclear factor- k B (NF- K B) translation factor and various other inflammatory mediators such as interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α). We also analyzed that LiCl significantly abrogated activated gliosis via attenuation of specific markers for activated microglia, ionized calcium-binding adaptor molecule (Iba-1) and astrocytes, glial fibrillary acidic protein (GFAP) in both the cortex and hippocampus of the adult rat brain. Furthermore, we also observed that LiCl treatment significantly ameliorated the increase expression level of apoptotic neurodegeneration protein markers Bax/Bcl2, activated caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1) in the cortex and hippocampus regions of the LPS-treated adult rat brain. In addition, the morphological results of the fluoro-jade B (FJB) and Nissl staining showed that LiCl attenuated the neuronal degeneration in the cortex and hippocampus regions of the LPS-treated adult rat brain. Taken together, our Western blot and morphological results indicated that LiCl significantly prevents the LPS-induced neurotoxicity via attenuation of neuroinflammation and apoptotic neurodegeneration in the cortex and hippocampus of the adult rat brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Imaging of glial cell morphology, SOD1 distribution and elemental composition in the brainstem and hippocampus of the ALS hSOD1G93A rat.

PubMed

Stamenković, Stefan; Dučić, Tanja; Stamenković, Vera; Kranz, Alexander; Andjus, Pavle R

2017-08-15

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor and cognitive domains of the CNS. Mutations in the Cu,Zn-superoxide dismutase (SOD1) cause 20% of familial ALS and provoke formation of intracellular aggregates and copper and zinc unbinding, leading to glial activation and neurodegeneration. Therefore, we investigated glial cell morphology, intracellular SOD1 distribution, and elemental composition in the brainstem and hippocampus of the hSOD1 G93A transgenic rat model of ALS. Immunostaining for astrocytes, microglia and SOD1 revealed glial proliferation and progressive tissue accumulation of SOD1 in both brain regions of ALS rats starting already at the presymptomatic stage. Glial cell morphology analysis in the brainstem of ALS rats revealed astrocyte activation occurring before disease symptoms onset, followed by activation of microglia. Hippocampal ALS astrocytes exhibited an identical reactive profile, while microglial morphology was unchanged. Additionally, ALS brainstem astrocytes demonstrated progressive SOD1 accumulation in the cell body and processes, while microglial SOD1 levels were reduced and its distribution limited to distal cell processes. In the hippocampus both glial cell types exhibited SOD1 accumulation in the cell body. X-ray fluorescence imaging revealed decreased P and increased Ca, Cl, K, Ni, Cu and Zn in the brainstem, and higher levels of Cl, Ni and Cu, but lower levels of Zn in the hippocampus of symptomatic ALS rats. These results bring new insights into the glial response during disease development and progression in motor as well as in non-motor CNS structures, and indicate disturbed tissue elemental homeostasis as a prominent hallmark of disease pathology. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Prenatal exposure to a novel antipsychotic quetiapine: impact on neuro-architecture, apoptotic neurodegeneration in fetal hippocampus and cognitive impairment in young rats.

PubMed

Singh, K P; Tripathi, Nidhi

2015-05-01

Reports on prenatal exposure to some of the first generation antipsychotic drugs like, haloperidol, their effects on fetal neurotoxicity and functional impairments in the offspring, are well documented. But studies on in utero exposure to second generation antipsychotics, especially quetiapine, and its effects on fetal neurotoxicity, apoptotic neurodegeneration, postnatal developmental delay and neurobehavioral consequences are lacking. Therefore, the present study was undertaken to evaluate the effect of prenatal administration to equivalent therapeutic doses of quetiapine on neuro-architectural abnormalities, neurohistopathological changes, apoptotic neurodegeneration in fetal hippocampus, and postnatal development and growth as well as its long-lasting imprint on cognitive impairment in young-adult offspring. Pregnant Wistar rats (n=24) were exposed to selected doses (55 mg, 80 mg and 100mg/kg) of quetiapine, equivalent to human therapeutic doses, from gestation day 6 to 21 orally with control subjects. Half of the pregnant subjects of each group were sacrificed at gestation day 21 for histopathological, confocal and electron microscopic studies and rest of the dams were allowed to deliver naturally. Their pups were reared postnatally up to 10 weeks of age for neurobehavioral observations. In quetiapine treated groups, there was significant alterations in total and differential thickness of three typical layers of hippocampus associated with neuronal cells deficit and enhanced apoptotic neurodegeneration in the CA1 area of fetal hippocampus. Prenatally drug treated rat offspring displayed post-natal developmental delay till postnatal day 70, and these young-adult rats displayed cognitive impairment in Morris water maze and passive avoidance regimes as long-lasting impact of the drug. Therefore, quetiapine should be used with cautions considering its developmental neurotoxicological and neurobehavioral potential in animal model, rat. Copyright © 2015 Elsevier Ltd. All rights reserved.

Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus.

PubMed

Schmitz, Felipe; Pierozan, Paula; Biasibetti-Brendler, Helena; Ferreira, Fernanda Silva; Dos Santos Petry, Fernanda; Trindade, Vera Maria Treis; Pessoa-Pureur, Regina; Wyse, Angela T S

2017-12-29

Although methylphenidate (MPH) is ubiquitously prescribed to children and adolescents, the consequences of chronic utilization of this psychostimulant are poorly understood. In this study, we investigated the effects of MPH on cytoskeletal homeostasis and lipid content in rat hippocampus. Wistar rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 44th day of age. Results showed that MPH provoked hypophosphorylation of glial fibrillary acidic protein (GFAP) and reduced its immunocontent. Middle and high molecular weight neurofilament subunits (NF-M, NF-H) were hypophosphorylated by MPH on KSP repeat tail domains, while NFL, NFM and NFH immunocontents were not altered. MPH increased protein phosphatase 1 (PP1) and 2A (PP2A) immunocontents. MPH also decreased the total content of ganglioside and phospholipid, as well as the main brain gangliosides (GM1, GD1a, and GD1b) and the major brain phospholipids (sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). Total cholesterol content was also reduced in the hippocampi of juvenile rats treated with MPH. These results provide evidence that disruptions of cytoskeletal and lipid homeostasis in hippocampus of juvenile rats are triggers by chronic MPH treatment and present a new basis for understanding the effects and consequences associated with chronic use of this psychostimulant during the development of the central nervous system.

Differential effects of centrally-active antihypertensives on 5-HT1A receptors in rat dorso-lateral septum, rat hippocampus and guinea-pig hippocampus.

PubMed

Leishman, D J; Boeijinga, P H; Galvan, M

1994-01-01

1. The electrophysiological responses elicited by 5-hydroxytryptamine1A-(5-HT1A) receptor agonists in rat and guinea-pig CA1 pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2. In the presence of 1 microM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3. The hypotensive drug flesinoxan, a selective 5-HT1A receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HT1A-receptors, 5-methyl-urapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4. In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HT1A-receptor antagonist. 5. The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6. It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HT1A receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated.

Age-Dependent Effects of Acute Alcohol Administration in the Hippocampal Phosphoproteome.

PubMed

Contreras, Ana; Morales, Lidia; Tebourbi, Ali; Miguéns, Miguel; Olmo, Nuria Del; Pérez-García, Carmen

2017-12-18

Alcohol consumption during adolescence is deleterious to the developing brain and leads to persistent deficits in adulthood. Several results provide strong evidence for ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the hippocampus. Protein phosphorylation is a well-known and well-documented mechanism in memory processes, but information on phosphoprotein alterations in hippocampus after ethanol exposure is limited. This study focuses on age-related changes in the hippocampal phosphoproteome after acute alcohol administration. We have compared the phosphoprotein expression in the hippocampus of adult and adolescent Wistar rats treated with a single dose of ethanol (5 g/kg i.p.), using a proteomic approach including phosphoprotein enrichment by immobilized metal affinity chromatography (IMAC). Our proteomic analysis revealed that 13 proteins were differentially affected by age, ethanol administration, or both. Most of these proteins are involved in neuroprotection and are expressed less in young rats treated with ethanol. We conclude that acute alcohol induces important changes in the expression of phosphoproteins in the hippocampus that could increase the risk of neurodegenerative disorders, especially when the alcohol exposure begins in adolescence.

Environmental enrichment protects spatial learning and hippocampal neurons from the long-lasting effects of protein malnutrition early in life.

PubMed

Soares, Roberto O; Horiquini-Barbosa, Everton; Almeida, Sebastião S; Lachat, João-José

2017-09-29

As early protein malnutrition has a critically long-lasting impact on the hippocampal formation and its role in learning and memory, and environmental enrichment has demonstrated great success in ameliorating functional deficits, here we ask whether exposure to an enriched environment could be employed to prevent spatial memory impairment and neuroanatomical changes in the hippocampus of adult rats maintained on a protein deficient diet during brain development (P0-P35). To elucidate the protective effects of environmental enrichment, we used the Morris water task and neuroanatomical analysis to determine whether changes in spatial memory and number and size of CA1 neurons differed significantly among groups. Protein malnutrition and environmental enrichment during brain development had significant effects on the spatial memory and hippocampal anatomy of adult rats. Malnourished but non-enriched rats (MN) required more time to find the hidden platform than well-nourished but non-enriched rats (WN). Malnourished but enriched rats (ME) performed better than the MN and similarly to the WN rats. There was no difference between well-nourished but non-enriched and enriched rats (WE). Anatomically, fewer CA1 neurons were found in the hippocampus of MN rats than in those of WN rats. However, it was also observed that ME and WN rats retained a similar number of neurons. These results suggest that environmental enrichment during brain development alters cognitive task performance and hippocampal neuroanatomy in a manner that is neuroprotective against malnutrition-induced brain injury. These results could have significant implications for malnourished infants expected to be at risk of disturbed brain development. Copyright © 2017 Elsevier B.V. All rights reserved.

TIME-DEPENDENT NEUROBIOLOGICAL EFFECTS OF COLCHICINE ADMINISTERED DIRECTLY INTO THE HIPPOCAMPUS OF RATS (JOURNAL VERSION)

EPA Science Inventory

Rats were given bilateral injections of colchicine into the dorsal and ventral hippocampus. Behavioral, neurochemical and histopathological measurements were taken up to 12 weeks after surgery. Colchicine produced a consistent increase in spontaneous motor activity, enhanced acou...

The effect of silver nanoparticles on apoptosis and dark neuron production in rat hippocampus

PubMed Central

Bagheri-abassi, Farzaneh; Alavi, Hassan; Mohammadipour, Abbas; Motejaded, Fatemeh; Ebrahimzadeh-bideskan, Alireza

2015-01-01

Objective(s): Silver nanoparticles (Ag-NPs) are used widely in bedding, water purification, tooth paste and toys. These nanoparticles can enter into the body and move into the hippocampus. The aim of this study was to investigate the neurotoxicity of silver nanoparticles in the adult rat hippocampus. Materials and Methods: 12 male Wistar rats were randomly divided into two experimental and control groups (6 rats in each group). Animals in the experimental group received Ag-NPs (30 mg/kg) orally (gavage) for 28 consecutive days. Control group in the same period was treated with distilled water via gavage. At the end of experiment, animals were deeply anesthetized, sacrificed, and their brains were collected from each group. Finally the brain sections were stained using toluidine blue and TUNEL. Then to compare the groups, dark neurons (DNs) and apoptotic neurons were counted by morphometric method. Results: Results showed that the numbers of DNs and apoptotic cells in the CA1, CA2, CA3, and dentate gyrus (DG) of hippocampus significantly increased in the Ag-NPs group in comparison to the control group (P<0.05). Conclusion: Exposure to Ag-NPs can induce dark neuron and apoptotic cells in the hippocampus. PMID:26351553

Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

PubMed Central

Acosta, Gabriela Beatriz; Fernández, María Alejandra; Roselló, Diego Martín; Tomaro, María Luján; Balestrasse, Karina; Lemberg, Abraham

2009-01-01

AIM: To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension. METHODS: Male Wistar rats were divided into sham-operated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas. RESULTS: We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, significantly and persistent increase in this excitatory neurotransmitter activity. CONCLUSION: The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modifies the normal function in some brain regions. PMID:19533812

[The administration of interleukin-1beta during early postnatal develop ment impairs FGF2, but not TIMP1, mRNA expression in brain structures of adult rats].

PubMed

Trofimov, A N; Zubareva, O E; Shvarts, A P; Ishchenko, A M; Klimenko, V M

2014-09-01

According to the Neurodevelopmental hypothesis, the long-lasting cognitive deficit in schizophrenia and other types of neuropathology may occur by injurious factors, such as hypoxia, traumas, infections that take place during pre- and postnatal development, at least at early stages. These pathological conditions are often associated with the high production of pro-inflammatory cytokine interleukin-1B (IL-1B) by the cells of immune and nervous systems. We investigated the expression of genes involved in the neuroplastic regulation (Fgf2 and Timp2) in medial prefrontal cortex and dorsal and ventral regions of hippocampus of adult rats that were treated with IL-1beta between P15 and P21. The learning impairment in IL-1beta-treated rats is accompanied by lower FGF-2 mRNA levels in medial prefrontal cortex and ventral (not dorsal) hippocampus, but TIMP-1 was not affected. No differences in TIMP-1 and FGF-2 mRNA expressions were observed in untrained IL-1beta-treated when compared to control rats.

[MK-801 or DNQX reduces electroconvulsive shock-induced impairment of learning-memory and hyperphosphorylation of Tau in rats].

PubMed

Liu, Chao; Min, Su; Wei, Ke; Liu, Dong; Dong, Jun; Luo, Jie; Liu, Xiao-Bin

2012-08-25

This study explored the effect of the excitatory amino acid receptor antagonists on the impairment of learning-memory and the hyperphosphorylation of Tau protein induced by electroconvulsive shock (ECT) in depressed rats, in order to provide experimental evidence for the study on neuropsychological mechanisms improving learning and memory impairment and the clinical intervention treatment. The analysis of variance of factorial design set up two intervention factors which were the electroconvulsive shock (two level: no disposition; a course of ECT) and the excitatory amino acid receptor antagonists (three level: iv saline; iv NMDA receptor antagonist MK-801; iv AMPA receptor antagonist DNQX). Forty-eight adult Wistar-Kyoto (WKY) rats (an animal model for depressive behavior) were randomly divided into six experimental groups (n = 8 in each group): saline (iv 2 mL saline through the tail veins of WKY rats ); MK-801 (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats) ; DNQX (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats ); saline + ECT (iv 2 mL saline through the tail veins of WKY rats and giving a course of ECT); MK-801 + ECT (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats and giving a course of ECT); DNQX + ECT (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats and giving a course of ECT). The Morris water maze test started within 1 day after the finish of the course of ECT to evaluate learning and memory. The hippocampus was removed from rats within 1 day after the finish of Morris water maze test. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. The contents of Tau protein which included Tau5 (total Tau protein), p-PHF1(Ser396/404), p-AT8(Ser199/202) and p-12E8(Ser262) in the hippocampus of rats were detected by immunohistochemistry staining (SP) and Western blot. The results showed that ECT and the glutamate ionic receptor blockers (NMDA receptor antagonist MK-801 and AMPA receptor antagonist DNQX) induced the impairment of learning and memory in depressed rats with extended evasive latency time and shortened space exploration time. And the two factors presented a subtractive effect. ECT significantly up-regulated the content of glutamate in the hippocampus of depressed rats which were not affected by the glutamate ionic receptor blockers. ECT and the glutamate ionic receptor blockers did not affect the total Tau protein in the hippocampus of rats. ECT up-regulated the hyperphosphorylation of Tau protein in the hippocampus of depressed rats, while the glutamate ionic receptor blockers down-regulated it, and combination of the two factors presented a subtractive effect. Our results indicate that ECT up-regulates the content of glutamate in the hippocampus of depressed rats, which up-regulates the hyperphosphorylation of Tau protein resulting in the impairment of learning and memory in depressed rats.

Toxicological study of injuries of rat’s hippocampus after lead poisoning by synchrotron microradiography and elemental mapping

NASA Astrophysics Data System (ADS)

Liang, Feng; Zhang, Guilin; Xiao, Xianghui; Cai, Zhonghou; Lai, Barry; Hwu, Yeukuang; Yan, Chonghuai; Xu, Jian; Li, Yulan; Tan, Mingguang; Zhang, Chuanfu; Li, Yan

2010-09-01

The hippocampus, a major component of the brain, is one of the target nervous organs in lead poisoning. In this work, a rat's hippocampal injury caused by lead was studied. The lead concentrations in blood, bone and hippocampus collected from rats subject to lead poisoning were quantified by Inductively Coupled Plasma Mass Spectrometry while morphological information and elemental distributions in the hippocampus were obtained with synchrotron radiation X-ray phase contrast imaging and synchrotron radiation micro-beam X-ray fluorescence, respectively. For comparison, identical characterization of the specimens from the rats in the control group was done in parallel. Results show that the ratios between the lead content in the treated group and that in the control group of the hippocampus, bone, and blood are about 2.66, 236, and 39.6, respectively. Analysis also revealed that some health elements such as S, K, Cl and P increase in the regions with high lead content in the treated hippocampus. Morphological differences between the normal and lead-exposed hippocampus specimens in some local areas were observed. Explicitly, the structure of the lead-exposed hippocampus was tortuous and irregular, and the density of the neurons in the Dentate Gyrus was significantly lower than that from the control group. The study shows that the synchrotron radiation methods are very powerful for investigating structural injury caused by heavy metals in the nervous system.

Oxidative stress-induced cognitive impairment in obesity can be reversed by vitamin D administration in rats.

PubMed

Hajiluian, Ghazaleh; Abbasalizad Farhangi, Mahdieh; Nameni, Ghazaleh; Shahabi, Parviz; Megari-Abbasi, Mehran

2017-07-06

There is evidence that obesity leads to cognitive impairments via several markers of oxidative stress including glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase and malondialdehyde (MDA) in the hippocampus. Increased inflammatory markers in the brain have obesity triggering effects. In the current study we aimed to investigate the effects of vitamin D on cognitive function, nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α concentration and markers of oxidative stress in the hippocampus of high-fat diet-induced obese rats. Forty male Wistar rats were divided into two groups: control diet (CD) and high-fat diet (HFD) for 16 weeks; then each group subdivided into two groups including: CD, CD + vitamin D, HFD and HFD + vitamin D. Vitamin D was administered at 500 IU/kg dosage for 5 weeks. Four weeks after supplementation, Morris water maze test was performed. NF-κB and TNF-α concentration in the hippocampus were determined using ELISA kits. Moreover, oxidative stress markers in the hippocampus including GPx, SOD, MDA and CAT concentrations were measured by spectrophotometry methods. HFD significantly increased TNF-α (P = 0.04) and NF-κB (P = 0.01) concentrations in the hippocampus compared with CD. Vitamin D treatment led to a significant reduction in hippocampus NF-κB concentrations in HFD + vitamin D group (P = 0.001); however, vitamin D had no effect on TNF-α concentrations. Moreover, HFD significantly induced oxidative stress by reducing GPx, SOD and increasing MDA concentrations in the hippocampus. Vitamin D supplementation in HFD group also significantly increased GPx, SOD and reduced MDA concentrations. Vitamin D improved hippocampus oxidative stress and inflammatory markers in HFD-induced obese rats and improved cognitive performance. Further studies are needed to better clarify the underlying mechanisms.

The antidepressant effects of rosiglitazone on rats with depression induced by neuropathic pain.

PubMed

Zong, Jian; Liao, Xingzhi; Ren, Bingxu; Wang, Zhiping

2018-06-15

A growing number of studies reported that rosiglitazone (a PPARgamma agonist) could ameliorate the painful state and prevent stress-induced depression. However, whether rosiglitazone can prevent pain-induced depression is unclear. This study aimed to explore the antidepressant effects of rosiglitazone in L5 spinal nerve transection (SNT) induced neuropathic pain rats. In addition, AMPK inhibitor (Compound C) and autophagic antagonist (3-methyladenine, 3-MA) were applied to investigate the underlying therapeutic mechanisms. L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors were detected by paw pressure threshold test (PPT), open-field test (OFT), forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT). Rosiglitazone could ameliorate L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors and the effect could be reversed by Compound C or 3-MA. Compared with the sham group, the levels of BDNF, AMPK, Beclin-1 and LC3B in rats hippocampus significantly decreased in L5 SNT group. On the contrary, rosiglitazone administration significantly up-regulated the levels of AMPK, BDNF, Beclin-1 and LC3B in rats hippocampus. Compared with sham group, the levels of TNF-α, IL-1β, superoxide dismutase (SOD) and malondialdehyde (MDA) in rat hippocampus significantly increased in L5 SNT group. Besides, rosiglitazone administration significantly decreased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. Compared with rosiglitazone group, 3-MA administration, but not Compound C administration, significantly increased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. In conclusion, rosiglitazone can counteract down-regulation of AMPK and BDNF induced by L5 SNT rats in hippocampus, and activate autophagic pathway. These effects may contribute to the antidepressant effect of rosiglitazone on the rats with depression induced by L5 SNT. Copyright © 2018 Elsevier Inc. All rights reserved.

Elemental or contextual? It depends: individual difference in the hippocampal dependence of associative learning for a simple sensory stimulus

PubMed Central

Lee, Kyung J.; Park, Seong-Beom; Lee, Inah

2014-01-01

Learning theories categorize learning systems into elemental and contextual systems, the former being processed by non-hippocampal regions and the latter being processed in the hippocampus. A set of complex stimuli such as a visual background is often considered a contextual stimulus and simple sensory stimuli such as pure tone and light are considered elemental stimuli. However, this elemental-contextual categorization scheme has only been tested in limited behavioral paradigms and it is largely unknown whether it can be generalized across different learning situations. By requiring rats to respond differently to a common object in association with various types of sensory cues including contextual and elemental stimuli, we tested whether different types of elemental and contextual sensory stimuli depended on the hippocampus to different degrees. In most rats, a surrounding visual background and a tactile stimulus served as contextual (hippocampal dependent) and elemental (non-hippocampal dependent) stimuli, respectively. However, simple tone and light stimuli frequently used as elemental cues in traditional experiments required the hippocampus to varying degrees among rats. Specifically, one group of rats showed a normal contextual bias when both contextual and elemental cues were present. These rats effectively switched to using elemental cues when the hippocampus was inactivated. The other group showed a strong contextual bias (and hippocampal dependence) because these rats were not able to use elemental cues when the hippocampus was unavailable. It is possible that the latter group of rats might have interpreted the elemental cues (light and tone) as background stimuli and depended more on the hippocampus in associating the cues with choice responses. Although exact mechanisms underlying these individual variances are unclear, our findings recommend a caution for adopting a simple sensory stimulus as a non-hippocampal sensory cue only based on the literature. PMID:24982624

Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats.

PubMed

Mairesse, Jérôme; Gatta, Eleonora; Reynaert, Marie-Line; Marrocco, Jordan; Morley-Fletcher, Sara; Soichot, Marion; Deruyter, Lucie; Camp, Gilles Van; Bouwalerh, Hammou; Fagioli, Francesca; Pittaluga, Anna; Allorge, Delphine; Nicoletti, Ferdinando; Maccari, Stefania

2015-12-01

Oxytocin receptors are known to modulate synaptic transmission and network activity in the hippocampus, but their precise function has been only partially elucidated. Here, we have found that activation of presynaptic oxytocin receptor with the potent agonist, carbetocin, enhanced depolarization-evoked glutamate release in the ventral hippocampus with no effect on GABA release. This evidence paved the way for examining the effect of carbetocin treatment in "prenatally restraint stressed" (PRS) rats, i.e., the offspring of dams exposed to repeated episodes of restraint stress during pregnancy. Adult PRS rats exhibit an anxious/depressive-like phenotype associated with an abnormal glucocorticoid feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and, remarkably, with a reduced depolarization-evoked glutamate release in the ventral hippocampus. Chronic systemic treatment with carbetocin (1mg/kg, i.p., once a day for 2-3 weeks) in PRS rats corrected the defect in glutamate release, anxiety- and depressive-like behavior, and abnormalities in social behavior, in the HPA response to stress, and in the expression of stress-related genes in the hippocampus and amygdala. Of note, carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala. These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus.

PubMed

Hirayama, Koki; Oshima, Hideki; Yamashita, Akiko; Sakatani, Kaoru; Yoshino, Atsuo; Katayama, Yoichi

2016-09-01

We examined the effects of silymarin, which was extracted from Silybum marianum, on delayed neuronal cell death in the rat hippocampus. Rats were divided into four groups: sham-operated rats (sham group), rats which underwent ischemic surgery (control group), rats which were treated with silymarin before and after ischemic surgery (pre group), and rats which were treated with silymarin after ischemic surgery only (post group). We performed the ischemic surgery by occluding the bilateral carotid arteries for 20min and sacrificed the rats one week after the surgery. Silymarin was administered orally at 200mg/kg body weight. Smaller numbers of delayed cell deaths were noted in the rat CA1 region of the pre- and post-groups, and no significant difference was observed between these groups. There were few apoptotic cell deaths in all groups. Compared to the control group, significantly fewer cell deaths by autophagy were found in the pre- and post-group. We concluded that silymarin exerts a preservation effect on delayed neuronal cell death in the rat hippocampus and this effect has nothing to do with the timing of administering of silymarin. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control.

PubMed

Huang, Chunxia; Ng, Olivia Tsz-Wa; Ho, Yuen-Shan; Irwin, Michael Garnet; Chang, Raymond Chuen-Chung; Wong, Gordon Tin-Chun

2016-01-01

Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.

Treatment planning and 3D dose verification of whole brain radiation therapy with hippocampal avoidance in rats

NASA Astrophysics Data System (ADS)

Yoon, S. W.; Miles, D.; Cramer, C.; Reinsvold, M.; Kirsch, D.; Oldham, M.

2017-05-01

Despite increasing use of stereotactic radiosurgery, whole brain radiotherapy (WBRT) continues to have a therapeutic role in a selected subset of patients. Selectively avoiding the hippocampus during such treatment (HA-WBRT) emerged as a strategy to reduce the cognitive morbidity associated with WBRT and gave rise to a recently published the phase II trial (RTOG 0933) and now multiple ongoing clinical trials. While conceptually hippocampal avoidance is supported by pre-clinical evidence showing that the hippocampus plays a vital role in memory, there is minimal pre-clinic data showing that selectively avoiding the hippocampus will reduce radiation-induced cognitive decline. Largely the lack of pre-clinical evidence can be attributed to the technical hurdles associated with delivering precise conformal treatment the rat brain. In this work we develop a novel conformal HA-WBRT technique for Wistar rats, utilizing a 225kVp micro-irradiator with precise 3D-printed radiation blocks designed to spare hippocampus while delivering whole brain dose. The technique was verified on rodent-morphic Presage® 3D dosimeters created from micro-CT scans of Wistar rats with Duke Large Field-of-View Optical Scanner (DLOS) at 1mm isotropic voxel resolution. A 4-field box with parallel opposed AP-PA and two lateral opposed fields was explored with conformal hippocampal sparing aided by 3D-printed radiation blocks. The measured DVH aligned reasonably well with that calculated from SmART Plan Monte Carlo simulations with simulated blocks for 4-field HA-WBRT with both demonstrating hippocampal sparing of 20% volume receiving less than 30% the prescription dose.

Tanshinone IIA exerts neuroprotective effects on hippocampus-dependent cognitive impairments in diabetic rats by attenuating ER stress-induced apoptosis.

PubMed

Chen, Jian; Bi, Yanli; Chen, Lei; Zhang, Qi; Xu, Linhao

2018-08-01

This study aimed to investigate the mechanism by which tanshinone IIA (Tan IIA) suppresses neuronal apoptosis in the hippocampus of diabetic rats. Sprague-Dawley (SD) rats were randomly divided into the following four groups: a control group, a diabetes group and diabetes groups treated with different doses (2 or 4 mg/kg/day) of Tan IIA. Streptozotocin (STZ) was injected into the rats to induce diabetes. Two days after STZ treatment, Tan IIA was intraperitoneally administered to rats in the Tan IIA groups, whereas an equal volume of saline was administered to rats in the control and diabetes groups. After 6 weeks, a one-trial object recognition task and the Morris water maze were applied. The diabetes group displayed notably decreased learning and memory abilities compared with the control group (P < 0.05). Tan IIA rescued hippocampus-dependent memory. Superoxide dismutase (SOD) activity was reduced, and reactive oxygen species (ROS) production, malondialdehyde (MDA) content, and 78-kDa glucose-regulated protein (Grp78), growth arrest and DNA damage-inducible gene 153 (CHOP/GAD153) and cleaved caspase-3 levels were increased in the hippocampus of diabetic rats compared with that of control rats, changes that were accompanied by an increase in neuronal apoptosis in diabetic rats compared with control rats (P < 0.01). However, Tan IIA reduced the MDA content and GRP78 and CHOP expression by inducing SOD activity. Tan IIA attenuated neuronal apoptosis and improved learning and memory by suppressing endoplasmic reticulum (ER) stress activation. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The hippocampus, medial prefrontal cortex, and selective memory retrieval: evidence from a rodent model of the retrieval-induced forgetting effect.

PubMed

Wu, Jade Q; Peters, Greg J; Rittner, Pedro; Cleland, Thomas A; Smith, David M

2014-09-01

Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval-induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the nonpracticed items relative to a baseline condition that does not involve extra practice. Although counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or medial prefrontal cortex (mPFC). Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats' memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the nonpracticed odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that "sideband suppression" of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function. © 2014 Wiley Periodicals, Inc.

Neurogenic function in rats with unilateral hippocampal sclerosis that experienced early-life status epilepticus

PubMed Central

Dunleavy, Mark; Schindler, Clara K; Shinoda, Sachiko; Crilly, Shane; Henshall, David C

2014-01-01

Status epilepticus in the adult brain invariably causes an increase in hippocampal neurogenesis and the appearance of ectopic cells and this has been implicated as a causal factor in epileptogenesis. The effect of status epilepticus on neurogenesis in the developing brain is less well characterized and models of early-life seizures typically do not reproduce the hippocampal damage common to human mesial temporal sclerosis. We recently reported that evoking status epilepticus by intra-amygdala microinjection of kainic acid in post-natal (P) day 10 rats caused substantial acute neuronal death within the ipsilateral hippocampus and rats later developed unilateral hippocampal sclerosis and spontaneous recurrent seizures. Here, we examined the expression of a selection of genes associated with neurogenesis and assessed neurogenic function in this model. Protein levels of several markers of neurogenesis including polysialic acid neural cell adhesion molecule, neuroD and doublecortin were reduced in the hippocampus three days after status epilepticus in P10 rats. In contrast, protein levels of neurogenesis markers were similar to control in rats at P55. Pulse-chase experiments using thymidine analogues suggested there was a reduction in new neurons at 72 h after status epilepticus in P10 rats, whereas numbers of new neurons labelled in epileptic rats at P55 with hippocampal sclerosis were similar to controls. The present study suggests that status epilepticus in the immature brain suppresses neurogenesis but the neurogenic potential is retained in animals that later develop hippocampal sclerosis. PMID:25755841

Neuroprotective Benefits of Aerobic Exercise and Organoselenium Dietary Supplementation in Hippocampus of Old Rats.

PubMed

Cechella, José L; Leite, Marlon R; Pinton, Simone; Zeni, Gilson; Nogueira, Cristina W

2018-05-01

The progressive decline of neurological functions, such as learning and memory, is an unavoidable consequence of aging. Our previous work suggested that the combination of physical exercise and a diet supplemented with diphenyl diselenide improves age-related memory decline in rats. The present study investigated the effects of physical exercise and a diet supplemented with diphenyl diselenide on the levels of proteins involved in the hippocampal neuroprotection to figure out the mechanisms related to the beneficial effects of this intervention in aged rats. Male Wistar rats (27 months old) were fed daily with standard chow supplemented with 1 ppm of diphenyl diselenide and subjected to swimming training with a workload (1% of body weight, 20 min/day) for 4 weeks. The hippocampus was dissected from the brain and used for the western blot and immunohistochemistry analyses. The results of this study demonstrate that the association of diphenyl diselenide-supplemented diet and swimming exercise increased the levels of proteins involved in neuroprotection and decreased the activation of those related to apoptosis and neuroinflammation in the hippocampus of old rats. This study suggests that physical exercise and a diet supplemented with (PhSe) 2 promoted neuroprotection in the hippocampus of aged rats.

Neuroprotective effects of Bacopa monniera whole-plant extract against aluminum-induced hippocampus damage in rats: evidence from electron microscopic images.

PubMed

Nannepaga, John Sushma; Korivi, Mallikarjuna; Tirumanyam, Madhavi; Bommavaram, Mahitha; Kuo, Chia-Hua

2014-10-31

Impaired antioxidant system and structural changes in hippocampus are considered as key instigators of neurodegenerative diseases. The present study aimed to investigate the antioxidant and tissue protective properties of Bacopa monniera whole-plant extract (BME) against aluminum (Al)- induced oxidative stress and hippocampus damage in rats. Male Wistar rats were evenly divided into four groups, nine in each and labeled as control, Al treated (10 mg/kg), BME administered (40 mg/kg) and combination of both Al plus BME (Al+BME) treated groups. After one month of treatment by oral administration, antioxidant status was determined, and structural changes in the hippocampus were evaluated by electron microscopy. Al-induced increased oxidative damage in the hippocampus was revealed by elevated thiobarbituric acid reactive substances (TBARS). This increased lipid peroxidation was associated with significantly decreased antioxidant enzyme activities, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). However, aluminum intoxicated rats treated with BME for 30 days showed significantly restored antioxidant enzyme activities along with decreased TBARS (P < 0.01). Further evidences from electron micrographs clearly indicated that Al-induced vacuolation, lipofuscin deposition and pyramidal cell degeneration in the hippocampus was attenuated with co-administration of the whole-plant extract. Our results demonstrate that structural derangement in hippocampus by aluminum is directly proportionate with increased lipid peroxidation. Nevertheless, B. monniera treatment potentiates the antioxidant status and suppressed the tissue damage induced by Al-intoxication. These findings suggest that B. monniera whole-plant extracts can be considered as a possible remedy to counteract aluminum-associated neurological disorders.

Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus.

PubMed

Hritcu, Lucian; Ionita, Radu; Motei, Diana Elena; Babii, Cornelia; Stefan, Marius; Mihasan, Marius

2017-02-01

6-Hydroxy-l-nicotine (6HLN), a nicotine derivative from nicotine degradation by Arthrobacter nicotinovorans pAO1 strain was found to improve behavioral deficits and to reverse oxidative stress in the rat hippocampus. Rats were given CHL (10mg/kg, i.p.) were used as an Alzheimer's disease-like model. The nicotine (0.3mg/kg) and 6HLN (0.3mg/kg) were administered alone or in combination in the CHL-treated rats. Memory-related behaviors were evaluated using Y-maze and radial arm-maze tests. The antioxidant enzymes activity and the levels of the biomarkers of oxidative stress were measured in the hippocampus. Statistical analyses were performed using two-way ANOVA and Tukey's post hoc test. F values for which p<0.05 were regarded as statistically significant. CHL-caused memory deficits and oxidative stress enhancing were observed. Both nicotine and 6HLN administration attenuated the cognitive deficits and recovered the antioxidant capacity in the rat hippocampus of the CHL rat model. Our results suggest that 6HLN versus nicotine confers anti-amnesic properties in the CHL-induced a rat model of memory impairment via reversing cholinergic function and decreasing brain oxidative stress, suggesting the use of this compound as an alternative agent in AD treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Neurosteroids in Adult Hippocampus of Male and Female Rodents: Biosynthesis and Actions of Sex Steroids.

PubMed

Hojo, Yasushi; Kawato, Suguru

2018-01-01

The brain is not only the target of steroid hormones but also is able to locally synthesize steroids de novo . Evidence of the local production of steroids in the brain has been accumulating in various vertebrates, including teleost fish, amphibia, birds, rodents, non-human primates, and humans. In this review, we mainly focus on the local production of sex steroids in the hippocampal neurons of adult rodents (rats and mice), a center for learning and memory. From the data of the hippocampus of adult male rats, hippocampal principal neurons [pyramidal cells in CA1-CA3 and granule cells in dentate gyrus (DG)] have a complete system for biosynthesis of sex steroids. Liquid chromatography with tandem-mass-spectrometry (LC-MS/MS) enabled us to accurately determine the levels of hippocampal sex steroids including 17β-estradiol (17β-E2), testosterone (T), and dihydrotestosterone (DHT), which are much higher than those in blood. Next, we review the steroid synthesis in the hippocampus of female rats, since previous knowledge had been biased toward the data from males. Recently, we clarified that the levels of hippocampal steroids fluctuate in adult female rats across the estrous cycle. Accurate determination of hippocampal steroids at each stage of the estrous cycle is of importance for providing the account for the fluctuation of female hippocampal functions, including spine density, long-term potentiation (LTP) and long-term depression (LTD), and learning and memory. These functional fluctuations in female had been attributed to the level of circulation-derived steroids. LC-MS/MS analysis revealed that the dendritic spine density in CA1 of adult female hippocampus correlates with the levels of hippocampal progesterone and 17β-E2. Finally, we introduce the direct evidence of the role of hippocampus-synthesized steroids in hippocampal function including neurogenesis, LTP, and memory consolidation. Mild exercise (2 week of treadmill running) elevated synthesis of DHT in the hippocampus, but not in the testis, of male rats, resulting in enhancement of neurogenesis in DG. Concerning synaptic plasticity, hippocampus-synthesized E2 is required for LTP induction, whereas hippocampus-synthesized DHT is required for LTD induction. Furthermore, hippocampus-synthesized E2 is involved in memory consolidation tested by object recognition and object placement tasks, both of which are hippocampus-dependent.

Differential effects of massed and spaced training on place and response learning: A memory systems perspective.

PubMed

Wingard, Jeffrey C; Goodman, Jarid; Leong, Kah-Chung; Packard, Mark G

2015-09-01

Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and dorsolateral striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the dorsolateral striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a dorsolateral striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus-dependent and dorsolateral striatum-dependent learning may have differential temporal characteristics. Copyright © 2015 Elsevier B.V. All rights reserved.

[Effects of polydatin on learning and memory and Cdk5 kinase activity in the hippocampus of rats with chronic alcoholism].

PubMed

Li, Xin-juan; Zhang, Yan; Xu, Chun-yang; Li, Shuang; Du, Ai-lin; Zhang, Li-bin; Zhang, Rui-ling

2015-03-01

To observe the effects of polydatin on learning and memory and cyclin-dependent kinase 5 (Cdk5) kinase activity in the hippocampus of rats with chronic alcoholism. Forty rats were randomly divided into 4 groups: control group, chronic alcoholism group, low and high polydatin group. The rat chronic alcoholism model was established by ethanol 3.0 g/(kg · d) (intragastric administration). The abstinence scoring was used to evaluate the rats withdrawal symptoms; cognitive function was measured by Morris water maze experiment; Cdk5 protein expression in the hippocampus was detected by immunofluorescence; Cdk5 kinase activity in the hippocampus was detected by liquid scintillation counting method. The abstinence score, escape latency, Cdk5 kinase activity in chronic alcoholism group rats were significantly higher than those of control group (P < 0.05). The abstinence score, escape latency in high polydatin group rats were significantly lower than those of chronic alcoholism group (P < 0.05); Cdk5 kinase activity in high and low polydatin group rats was significantly lower than that of chronic alcoholism group( P < 0.05); immunofluorescence showed that the Cdk5 positive cells of chronic alcoholism group were significantly increased compared with control group (P < 0.05), and the Cdk5 positive cells of polydatin groups were significantly decreased compared with chronic alcoholism group ( P < 0.05). Polydatin-reduced the chronic alcoholism damage may interrelate with regulation of Cdk5 kinase activity.

Vitamin B6 prevents isocarbophos-induced vascular dementia in rats through N-methyl-D-aspartate receptor signaling.

PubMed

Li, Peng; Zhu, Mo-Li; Pan, Guo-Pin; Lu, Jun-Xiu; Zhao, Fan-Rong; Jian, Xu; Liu, Li-Ying; Wan, Guang-Rui; Chen, Yuan; Ping, Song; Wang, Shuang-Xi; Hu, Chang-Ping

2018-01-01

We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown. The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test. Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus. Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

PubMed Central

Opendak, Maya; Offit, Lily; Monari, Patrick; Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.

2016-01-01

Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior. PMID:27358459

GENE EXPRESSION PROFILES IN THE DEVELOPING RAT CEREBELLUM AND HIPPOCAMPUS

EPA Science Inventory

Development of the nervous system is a complex program, involving coordinated growth of axons and their targets. In rodents, rapid brain growth occurs during early postnatal development. At this time, several fundamental processes, such as dendritic and axonal outgrowth and the e...

Cannabis exacerbates depressive symptoms in rat model induced by reserpine.

PubMed

Khadrawy, Yasser A; Sawie, Hussein G; Abdel-Salam, Omar M E; Hosny, Eman N

2017-05-01

Cannabis sativa is one of the most widely recreational drugs and its use is more prevalent among depressed patients. Some studies reported that Cannabis has antidepressant effects while others showed increased depressive symptoms in Cannabis users. Therefore, the present study aims to investigate the effect of Cannabis extract on the depressive-like rats. Twenty four rats were divided into: control, rat model of depression induced by reserpine and depressive-like rats treated with Cannabis sativa extract (10mg/kg expressed as Δ9-tetrahydrocannabinol). The depressive-like rats showed a severe decrease in motor activity as assessed by open field test (OFT). This was accompanied by a decrease in monoamine levels and a significant increase in acetylcholinesterase activity in the cortex and hippocampus. Na + ,K + -ATPase activity increased in the cortex and decreased in the hippocampus of rat model. In addition, a state of oxidative stress was evident in the two brain regions. This was indicated from the significant increase in the levels of lipid peroxidation and nitric oxide. No signs of improvement were observed in the behavioral and neurochemical analyses in the depressive-like rats treated with Cannabis extract. Furthermore, Cannabis extract exacerbated the lipid peroxidation in the cortex and hippocampus. According to the present findings, it could be concluded that Cannabis sativa aggravates the motor deficits and neurochemical changes induced in the cortex and hippocampus of rat model of depression. Therefore, the obtained results could explain the reported increase in the depressive symptoms and memory impairment among Cannabis users. Copyright © 2017 Elsevier B.V. All rights reserved.

Neural Representations of Location Outside the Hippocampus

ERIC Educational Resources Information Center

Knierim, James J.

2006-01-01

Place cells of the rat hippocampus are a dominant model system for understanding the role of the hippocampus in learning and memory at the level of single-unit and neural ensemble responses. A complete understanding of the information processing and computations performed by the hippocampus requires detailed knowledge about the properties of the…

Neural Development Under Conditions of Spaceflight

NASA Technical Reports Server (NTRS)

Kosik, Kenneth S.; Steward, Oswald; Temple, Meredith D.; Denslow, Maria J.

2003-01-01

One of the key tasks the developing brain must learn is how to navigate within the environment. This skill depends on the brain's ability to establish memories of places and things in the environment so that it can form cognitive maps. Earth's gravity defines the plane of orientation of the spatial environment in which animals navigate, and cognitive maps are based on this plane of orientation. Given that experience during early development plays a key role in the development of other aspects of brain function, experience in a gravitational environment is likely to be essential for the proper organization of brain regions mediating learning and memory of spatial information. Since the hippocampus is the brain region responsible for cognitive mapping abilities, this study evaluated the development of hippocampal structure and function in rats that spent part of their early development in microgravity. Litters of male and female Sprague-Dawley rats were launched into space aboard the Space Shuttle Columbia on either postnatal day eight (P8) or 14 (P14) and remained in space for 16 days. Upon return to Earth, the rats were tested for their ability to remember spatial information and navigate using a variety of tests (the Morris water maze, a modified radial arm maze, and an open field apparatus). These rats were then tested physiologically to determine whether they exhibited normal synaptic plasticity in the hippocampus. In a separate group of rats (flight and controls), the hippocampus was analyzed using anatomical, molecular biological, and biochemical techniques immediately postlanding. There were remarkably few differences between the flight groups and their Earth-bound controls in either the navigation and spatial memory tasks or activity-induced synaptic plasticity. Microscopic and immunocytochemical analyses of the brain also did not reveal differences between flight animals and ground-based controls. These data suggest that, within the developmental window studied, microgravity has minimal long-term impact on cognitive mapping function and cellular substrates important for this function. Any differences due to development in microgravity were transient and returned to normal soon after return to Earth.

Melatonin mediated antidepressant-like effect in the hippocampus of chronic stress-induced depression rats: Regulating vesicular monoamine transporter 2 and monoamine oxidase A levels.

PubMed

Stefanovic, Bojana; Spasojevic, Natasa; Jovanovic, Predrag; Jasnic, Nebojsa; Djordjevic, Jelena; Dronjak, Sladjana

2016-10-01

The hippocampus is sensitive to stress which activates norepinephrine terminals deriving from the locus coeruleus. Melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behaviour. Thus, in the present study, an examination was made of the effect of chronic melatonin treatment on norepinephrine content, synthesis, uptake, vesicular transport and degradation in the hippocampus of rats exposed to CUMS. This entailed quantifying the norephinephrine, mRNA and protein levels of DBH, NET, VMAT 2, MAO-A and COMT. The results show that CUMS evoked prolonged immobility. Melatonin treatment decreased immobility in comparison with the placebo group, reflecting an antidepressant-like effect. Compared with the placebo group, a dramatic decrease in norepinephrine content, decreased VMAT2 mRNA and protein and increased MAO-A protein levels in the hippocampus of the CUMS rats were observed. However, no significant differences in the levels of DBH, NET, COMT mRNA and protein and MAO-A mRNA levels between the placebo and the stressed groups were found. The results showed the restorative effects of melatonin on the stress-induced decline in the norepinephrine content of the hippocampus. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in VMAT2 mRNA and protein levels, whereas it reduced the increase of the mRNA of COMT and protein levels of MAO-A. Chronic treatment with melatonin failed to alter the gene expression of DBH or NET in the hippocampus of the CUMS rats. Additionally, the results show that melatonin enhances VMAT2 expression and norepinephrine storage, whilst it reduces norepinephrine degrading enzymes. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Effects of developmental exposure to a Commercial PBDE mixture (DE-71) on protein networks in the rat Cerebellum and Hippocampus

EPA Science Inventory

Title (20 words): Effects of developmental exposure to a Commercial PBDE mixture (DE-71) on protein networks in the rat Cerebellum and Hippocampus. Introduction (120 words): Polybrominated diphenyl ethers (PBDE5) possess neurotoxic effects similar to those of PCBs. The cellular a...

Hippocampus, Perirhinal Cortex, and Complex Visual Discriminations in Rats and Humans

ERIC Educational Resources Information Center

Hales, Jena B.; Broadbent, Nicola J.; Velu, Priya D.; Squire, Larry R.; Clark, Robert E.

2015-01-01

Structures in the medial temporal lobe, including the hippocampus and perirhinal cortex, are known to be essential for the formation of long-term memory. Recent animal and human studies have investigated whether perirhinal cortex might also be important for visual perception. In our study, using a simultaneous oddity discrimination task, rats with…

Effect of hindlimb unloading on stereological parameters of the motor cortex and hippocampus in male rats.

PubMed

Salehi, Mohammad Saied; Mirzaii-Dizgah, Iraj; Vasaghi-Gharamaleki, Behnoosh; Zamiri, Mohammad Javad

2016-11-09

Hindlimb unloading (HU) can cause motion and cognition dysfunction, although its cellular and molecular mechanisms are not well understood. The aim of the present study was to determine the stereological parameters of the brain areas involved in motion (motor cortex) and spatial learning - memory (hippocampus) under an HU condition. Sixteen adult male rats, kept under a 12 : 12 h light-dark cycle, were divided into two groups of freely moving (n=8) and HU (n=8) rats. The volume of motor cortex and hippocampus, the numerical cell density of neurons in layers I, II-III, V, and VI of the motor cortex, the entire motor cortex as well as the primary motor cortex, and the numerical density of the CA1, CA3, and dentate gyrus subregions of the hippocampus were estimated. No significant differences were observed in the evaluated parameters. Our results thus indicated that motor cortical and hippocampal atrophy and cell loss may not necessarily be involved in the motion and spatial learning memory impairment in the rat.

Inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear.

PubMed

Jiang, Lizhu; Mao, Rongrong; Tong, Jianbin; Li, Jinnan; Chai, Anping; Zhou, Qixin; Yang, Yuexiong; Wang, Liping; Li, Lingjiang; Xu, Lin

2016-10-01

Promoting extinction of fear memory is the main treatment of fear disorders, especially post-traumatic stress disorder (PTSD). However, fear extinction is often incomplete in these patients. Our previous study had shown that Rac1 activity in hippocampus plays a crucial role in the learning of contextual fear memory in rats. Here, we further investigated whether Rac1 activity also modulated the extinction of contextual fear memory. We found that massed extinction obviously upregulated hippocampal Rac1 activity and induced long-term extinction of contextual fear in rats. Intrahippocampal injection of the Rac1 inhibitor NSC23766 prevents extinction of contextual fear in massed extinction training rats. In contrast, long-spaced extinction downregulated Rac1 activity and caused less extinction. And Rac1 activator CN04-A promotes extinction of contextual fear in long-spaced extinction rats. Our study demonstrates that inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear, suggesting that modulating Rac1 activity of the hippocampus may be promising therapy of fear disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lychee seed extract protects against neuronal injury and improves cognitive function in rats with type II diabetes mellitus with cognitive impairment

PubMed Central

Wu, Jianming; Chen, Haixia; Zeng, Yuan; Wang, Xiuling; Yang, Le; Mei, Qibing; Cao, Shousong; Qin, Dalian

2018-01-01

Lychee seed is a traditional Chinese medicine and has many beneficial effects such as modulation of blood sugar and lipids, antioxidation, antivirus and antitumor. Studies have indicated that type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) share common biological mechanisms including insulin resistance, impaired glucose metabolism, β-amyloid (Aβ) formation, oxidative stress and presence of advanced glycation end products (AGEs). The present study investigated the effects of lychee seed extract (LSE) on neuroprotection, cognitive function improvement and possible underlying mechanisms in a rat model of T2DM with cognitive impairment. We analyzed the chemical profile of LSE using a UHPLC-SPD chromatogram and evaluated its effect on the improvement of spatial learning and memory of rats by a Morris water maze. The levels of glucose, insulin, Aβ, AGEs, Tau protein and acetylcholinesterase in the blood and/or hippocampus of rats were determined by blood-glucose meter, radioimmunoassay, chemical chromatometry, enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analysis, respectively. Results demonstrated that LSE consists of eight major and around 20 minor ingredients, and it remarkably prevents neuronal injury and improves cognitive functions in T2DM rats. The levels of glucose, insulin, Aβ, AGEs and Tau protein were significantly increased in the blood and/or hippocampus of T2DM rats, while LSE remarkably decreased their levels compared to vehicle treatment (P<0.01). The possible mechanisms may be associated with IR improvement and decreased formations of Aβ, AGEs and Tau protein in the hippocampus of T2DM rats. LSE may be developed as the agent for the treatment of T2DM and/or AD clinically. PMID:29138799

Protective effects of ascorbic acid and garlic extract against lead-induced apoptosis in developing rat hippocampus.

PubMed

Ebrahimzadeh-Bideskan, Ali-Reza; Hami, Javad; Alipour, Fatemeh; Haghir, Hossein; Fazel, Ali-Reza; Sadeghi, Akram

2016-10-01

Lead exposure has negative effects on developing nervous system and induces apoptosis in newly generated neurons. Natural antioxidants (i.e. Ascorbic acid and Garlic) might protect against lead-induced neuronal cell damage. The aim of the present study was to investigate the protective effects of Ascorbic acid and Garlic administration during pregnancy and lactation on lead-induced apoptosis in rat developing hippocampus. Timed pregnant Wistar rats were administrated with Lead (1500 ppm) via drinking water (Pb group) or lead plus Ascorbic acid (Pb + AA Group, 500 mg/kg, IP), or lead plus Garlic Extract (Pb + G Group, 1 ml garlic juice/100 g BW, via Gavage) from early gestation (GD 0) until postnatal day 50 (PN 50). At the end of experiments, the pups' brains were carefully dissected. To identify neuronal death, the brain sections were stained with TUNEL assay. Mean of blood and brain lead levels increased significantly in Pb group comparing to other studied groups (P < 0.01). There was significant reduction in blood and brain lead level in Pb + AA and Pb + G groups when compared to those of Pb group (P < 0.01). The mean number of TUNEL positive cells in the CA1, CA3, and DG was significantly lower in the groups treated by either Ascorbic acid or Garlic (P < 0.05). Administration of Ascorbic acid and Garlic during pregnancy and lactation protect against lead-induced neuronal cell apoptosis in the hippocampus of rat pups partially via the reduction of Pb concentration in the blood and in the brain.

IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats

PubMed Central

Pang, Yi; Bhatt, Abhay J.; Fan, Lir-Wan

2015-01-01

We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an antiinflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist. PMID:25665855

Postnatal treadmill exercise alleviates short-term memory impairment by enhancing cell proliferation and suppressing apoptosis in the hippocampus of rat pups born to diabetic rats.

PubMed

Kim, Young Hoon; Sung, Yun-Hee; Lee, Hee-Hyuk; Ko, Il-Gyu; Kim, Sung-Eun; Shin, Mal-Soon; Kim, Bo-Kyun

2014-08-01

During pregnancy, diabetes mellitus exerts detrimental effects on the development of the fetus, especially the central nervous system. In the current study, we evaluated the effects of postnatal treadmill exercise on short-term memory in relation with cell proliferation and apoptosis in the hippocampus of rat pups born to streptozotocin (STZ)-induced diabetic maternal rats. Adult female rats were mated with male rats for 24 h. Two weeks after mating, the pregnant female rats were divided into two groups: control group and STZ injection group. The pregnant rats in the STZ injection group were administered 40 mg/kg of STZ intraperitoneally. After birth, the rat pups were divided into the following four groups: control group, control with postnatal exercise group, maternal STZ-injection group, and maternal STZ-injection with postnatal exercise group. The rat pups in the postnatal exercise groups were made to run on a treadmill for 30 min once a day, 5 times per week for 2 weeks beginning 4 weeks after birth. The rat pups born to diabetic rats were shown to have short-term memory impairment with suppressed cell proliferation and increased apoptosis in the hippocampal dentate gyrus. Postnatal treadmill exercise alleviated short-term memory impairment by increased cell proliferation and suppressed apoptosis in the rat pups born to diabetic rats. These findings indicate that postnatal treadmill exercise may be used as a valuable strategy to ameliorate neurodevelopmental problems in children born to diabetics.

Aluminium chloride impairs long-term memory and downregulates cAMP-PKA-CREB signalling in rats.

PubMed

Zhang, Lifeng; Jin, Cuihong; Lu, Xiaobo; Yang, Jinghua; Wu, Shengwen; Liu, Qiufang; Chen, Rong; Bai, Chunyu; Zhang, Di; Zheng, Linlin; Du, Yanqiu; Cai, Yuan

2014-09-02

Epidemiological investigations have indicated that aluminium (Al) is an important environmental neurotoxicant that may be involved in the aetiology of the cognitive dysfunction associated with neurodegenerative diseases. Additionally, exposure to Al is known to cause neurobehavioural abnormalities in animals. Previous studies demonstrated that Al impaired early-phase long-term potentiation (E-LTP) in vivo and in vitro. Our previous research revealed that Al could impair long-term memory via the impairment of late-phase long-term potentiation (L-LTP) in vivo. However, the exact mechanism by which Al impairs long-term memory has been poorly studied thus far. This study was designed not only to observe the effects of subchronic Al treatment on long-term memory and hippocampal ultrastructure but also to explore a possible underlying mechanism (involving the cAMP-PKA-CREB signalling pathway) in the hippocampus of rats.. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation for 3 weeks and then fed with distilled water containing 0, 0.2%, 0.4% or 0.6% Al chloride (AlCl3) for 3 postnatal months. The levels of Al in the blood and hippocampus were quantified by atomic absorption spectrophotometry. The shuttle-box test was performed to detect long-term memory. The hippocampus was collected for ultrastructure observation, and the level of cAMP-PKA-CREB signalling was examined. The results showed that the Al concentrations in the blood and hippocampus of Al-treated rats were higher than those of the control rats. Al may impair the long-term memory of rats. Hippocampal cAMP, cPKA, pCREB, BDNF and c-jun expression decreased significantly, and the neuronal and synaptic ultrastructure exhibited pathological changes after Al treatment. These results indicated that Al may induce long-term memory damage in rats by inhibiting cAMP-PKA-CREB signalling and altering the synaptic and neuronal ultrastructure in the hippocampus. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effects of hypothermia on S100B and glial fibrillary acidic protein in asphyxia rats after cardiopulmonary resuscitation.

PubMed

Liu, Sha; Zhang, Yibing; Zhao, Yong; Cui, Haifeng; Cao, Chunyu; Guo, Jianyou

2015-01-01

The aim of the study was to investigate the effects of hypothermia on S100B and glial fibrillary acidic protein (GFAP) in serum and hippocampus CA1 area in asphyxiated rats after cardiopulmonary resuscitation (CPR). A total of 100 SD rats were designated into four groups: group A, sham operation group; group B, rats received conventional resuscitation; group C, rats received conventional resuscitation and hypothermia at cardiac arrest; group D, rats received conventional resuscitation and hypothermia at 30 min after restoration of spontaneous circulation (ROSC). Rats were then killed by cardiac arrest at 2 and 4 h after ROSC; brain tissue was taken to observe dynamic changes of S100B and GFAP in serum and hippocampus CA1 area. Following ROSC, S100B levels increased from 2 to 4 h in group B, C, and D. In addition, S100B in serum and hippocampus CA1 area was all significantly increased at different time points compared with group A (P < 0.05). Following ROSC, serum S100B level at 2 h in group C was significantly decreased compared with group B, but the difference was not statistically significant (P > 0.05). Moreover, S100B in serum at 4 h after ROSC was significantly decreased (P < 0.05), S100B in cortex was significantly decreased (P < 0.05). The expression of GFAP was also examined. GFAP level in hippocampus CA1 area was significantly decreased in group B, C, and D at 4 h after ROSC compared with group A (P < 0.05). S100B and GFAP were expressed in rat serum and hippocampus CA2 area at early stage after ROSC, which can be used as sensitive markers for brain injury diagnosis and prognosis prediction. Hypothermia is also shown to reduce brain injury after CPR.

Effects of gestational ethanol inhalation on hippocampal function in rats.

EPA Science Inventory

Recent legislation has increased national emphasis on the development of renewable fuels as alternatives to petroleum fuels. The toxicity of gasoline-ethanol blended fuels to the developing nervous system is of specific concern. The hippocampus, a brain region involved in spatial...

Source memory in the rat

PubMed Central

Crystal, Jonathon D.; Alford, Wesley T.; Zhou, Wenyi; Hohmann, Andrea G.

2013-01-01

Summary Source memory is a representation of the origin (source) of information. When source information is bound together, it makes a memory episodic, allowing us to differentiate one event from another [1, 2]. Here we asked if rats remember the source of encoded information. Rats foraged for distinctive flavors of food that replenished (or failed to replenish) at its recently encountered location according to a source-information rule. To predict replenishment, rats needed to remember where they had encountered a preferred food type (chocolate) with self-generated (walking along a runway encountering chocolate) or experimenter-generated (placement of the rat at the chocolate site by an experimenter) cues. Three lines of evidence implicate the presence of source memory. First, rats selectively adjusted revisits to the chocolate location based on source information, under conditions in which familiarity of events could not produce successful performance. Second, source memory was dissociated from location memory by different decay rates. Third, temporary inactivation of the CA3 region of the hippocampus with lidocaine selectively eliminated source memory, suggesting that source memory is dependent upon an intact hippocampus. Development of an animal model of source memory may be valuable to probe the biological underpinnings of memory disorders marked by impairments in source memory. PMID:23394830

Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid.

PubMed

Gao, Jingquan; Wu, Hongmei; Cao, Yonggang; Liang, Shuang; Sun, Caihong; Wang, Peng; Wang, Ji; Sun, Hongli; Wu, Lijie

2016-09-01

Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA-induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p-CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiapoptotic and neuroprotective role of Curcumin in Pentylenetetrazole (PTZ) induced kindling model in rat.

PubMed

Saha, Lekha; Chakrabarti, Amitava; Kumari, Sweta; Bhatia, Alka; Banerjee, Dibyojyoti

2016-02-01

Kindling, a sub threshold chemical or electrical stimulation, increases seizure duration and enhances accompanied behavior until it reaches a sort of equilibrium state. The present study aimed to explore the effect of curcumin on the development of kindling in PTZ kindled rats and its role in apoptosis and neuronal damage. In a PTZ kindled Wistar rat model, different doses of curcumin (100, 200 and 300 mg/kg) were administrated orally one hour before the PTZ injections on alternate day during the whole kindling days. The following parameters were compared between control and experimental groups: the course of kindling, stages of seizures, Histopathological scoring of hippocampus, antioxidant parameters in the hippocampus, DNA fragmentation and caspase-3 expression in hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. PTZ, 30 mg/kg, induced kindling in rats after 32.0 ± 1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with curcumin in a dose-dependent manner. Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis.

Functional inactivation of the rat hippocampus disrupts avoidance of a moving object.

PubMed

Telensky, Petr; Svoboda, Jan; Blahna, Karel; Bureš, Jan; Kubik, Stepan; Stuchlik, Ales

2011-03-29

The hippocampus is well known for its critical involvement in spatial memory and information processing. In this study, we examined the effect of bilateral hippocampal inactivation with tetrodotoxin (TTX) in an "enemy avoidance" task. In this paradigm, a rat foraging on a circular platform (82 cm diameter) is trained to avoid a moving robot in 20-min sessions. Whenever the rat is located within 25 cm of the robot's center, it receives a mild electrical foot shock, which may be repeated until the subject makes an escape response to a safe distance. Seventeen young male Long-Evans rats were implanted with cannulae aimed at the dorsal hippocampus 14 d before the start of the training. After 6 d of training, each rat received a bilateral intrahippocampal infusion of TTX (5 ng in 1 μL) 40 min before the training session on day 7. The inactivation severely impaired avoidance of a moving robot (n = 8). No deficit was observed in a different group of rats (n = 9) that avoided a stable robot that was only displaced once in the middle of the session, showing that the impairment was not due to a deficit in distance estimation, object-reinforcement association, or shock sensitivity. This finding suggests a specific role of the hippocampus in dynamic cognitive processes required for flexible navigation strategies such as continuous updating of information about the position of a moving stimulus.

Effect of dietary γ-aminobutyric acid on the nerve growth factor and the choline acetyltransferase in the cerebral cortex and hippocampus of ovariectomized female rats.

PubMed

Tujioka, Kazuyo; Thanapreedawat, Panicha; Yamada, Takashi; Yokogoshi, Hidehiko; Horie, Kenji; Kim, Mujo; Tsutsui, Kazumi; Hayase, Kazutoshi

2014-01-01

The brain protein synthesis and the plasma concentration of growth hormone (GH) is sensitive to the dietary γ-aminobutyric acid (GABA) in ovariectomized female rats; however, the role of dietary GABA on biomarkers including nerve growth factor (NGF) and choline acetyltransferase for the function of cholinergic neurons remains unknown in ovariectomized female rats. The purpose of this study was to determine whether the dietary GABA affects the concentration and mRNA level of NGF, and the activity of choline acetyltransferase in the brains of ovariectomized female rats. Experiments were done on two groups of 24-wk-old ovariectomized female rats given 0 or 0.5% GABA added to a 20% casein diet. The concentrations of NGF and activities of choline acetyltransferase in the cerebral cortex and hippocampus, and mRNA level of NGF in the hippocampus increased significantly with the 20% casein+0.5% GABA compared with the 20% casein diet alone. In the hippocampus, the mRNA level of NGF significantly correlated with the NGF concentration (r=0.714, p<0.01). These results suggest that the administration of GABA to ovariectomized female rats is likely to control the mRNA level and concentration of NGF and cause an increase in the activity of choline acetyltransferase in the brains.

[The effect of hyperthyroidism on the cognition processes and the state of the glial intermediate filaments in the rat brain].

PubMed

Nedzvets'kyĭ, V S; Nerush, P O

2010-01-01

The effects of hyperthyreosis on oxidative stress, state of glial intermediate filaments and memory were investigated. We observed a significant increase in lipid peroxidation products into both hippocampus and cortex and memory worsening. The changes of GFAP polypeptides was observed in hippocampus and cortex. In group of rats with hyperthyreosis, the content of GFAP in both soluble and filamentous fractions was increased in hippocampus. This data shows, that glial cytoskeleton is reconstructed under thyroid hormone effects.

Mitochondrial impairment, apoptosis and autophagy in a rat brain as immediate and long-term effects of perinatal phencyclidine treatment - influence of restraint stress.

PubMed

Jevtić, Gordana; Nikolić, Tatjana; Mirčić, Aleksandar; Stojković, Tihomir; Velimirović, Milica; Trajković, Vladimir; Marković, Ivanka; Trbovich, Alexander M; Radonjić, Nevena V; Petronijević, Nataša D

2016-04-03

Phencyclidine (PCP) acts as a non-competitive antagonist of glutamatergic N-methyl-d-aspartate receptor. Its perinatal administration to rats causes pathophysiological changes that mimick some pathological features of schizophrenia (SCH). Numerous data indicate that abnormalities in mitochondrial structure and function could be associated with the development of SCH. Mitochondrial dysfunction could result in the activation of apoptosis and/or autophagy. The aim of this study was to assess immediate and long-term effects of perinatal PCP administration and acute restraint stress on the activity of respiratory chain enzymes, expression of apoptosis and autophagy markers and ultrastructural changes in the cortex and hippocampus of the rat brain. Six groups of rats were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal days (P), with either PCP (10mg/kg) or saline (0.9% NaCl). One NaCl and one PCP group were sacrificed on P13, while other two NaCl and PCP groups were sacrificed on P70. The remaining two NaCl and PCP groups were subjected to 1h restraint stress prior sacrifice on P70. Activities of respiratory chain enzymes were assessed spectrophotometrically. Expression of caspase 3 and AIF as markers of apoptosis and Beclin 1, p62 and LC3, as autophagy markers, was assessed by Western blot. Morphological changes of cortical and hippocampal ultrastructure were determined by transmission electron microscopy. Immediate effects of perinatal PCP administration at P13 were increased activities of complex I in the hippocampus and cytochrome c oxidase (COX) in the cortex and hippocampus implying mitochondrial dysfunction. These changes were followed by increased expression of apoptotic markers. However the measurement of autophagy markers at this time point has revealed decrease of this process in cortex and the absence of changes in hippocampus. At P70 the activity of complex I was unchanged while COX activity was significantly decreased in cortex and increased in the hippocampus. Expressions of apoptotic markers were still significantly higher in PCP perinatally treated rats in all investigated structures, but the changes of autophagy markers have indicated increased level of autophagy also in both structures. Restraint stress on P70 has caused increase of COX activity both in NaCl and PCP perinatally treated rats, but this increase was lower in PCP group. Also, restraint stress resulted in decrease of apoptotic and increase of autophagy processes especially in the hippocampus of PCP perinatally treated group. The presence of apoptosis and autophagy in the brain was confirmed by transmission electron microscopy. In this study we have demonstrated for the first time the presence of autophagy in PCP model of SCH. Also, we have shown increased sensitivity of PCP perinatally treated rats to restraint stress, manifested in alterations of apoptotic and autophagy markers. The future studies are necessary to elucidate the role of mitochondria in the pathophysiology of SCH and putative significance for development of novel therapeutic strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of taurine on the concentrations of glutamate, GABA, glutamine and alanine in the rat striatum and hippocampus.

PubMed

Molchanova, Svetlana M; Oja, Simos S; Saransaari, Pirjo

2007-01-01

Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue concentrations in both hippocampus and striatum. Glutamate and GABA also increased in the hippocampus, but not in the striatum. Glutamine increased and alanine decreased markedly in both brain structures. The results corroborate the neuromodulatory role of taurine in the brain. Taurine administration results in an imbalance in inhibitory and excitatory neurotransmission in the glutamatergic (hippocampus) and GABAergic (striatum) brain structures, affecting more markedly the neurotransmitter precursors.

Changes in gene expression in the rat hippocampus following exposure to 56 fe particles and protection by berry diets

USDA-ARS?s Scientific Manuscript database

Exposing young rats to particles of high energy and charge (HZE particles), such as 56Fe, enhances indices of oxidative stress and inflammation and disrupts behavior, including spatial learning and memory. In the present study, we examined whether gene expression in the hippocampus, an area of the b...

Biological sex influences learning strategy preference and muscarinic receptor binding in specific brain regions of prepubertal rats.

PubMed

Grissom, Elin M; Hawley, Wayne R; Hodges, Kelly S; Fawcett-Patel, Jessica M; Dohanich, Gary P

2013-04-01

According to the theory of multiple memory systems, specific brain regions interact to determine how the locations of goals are learned when rodents navigate a spatial environment. A number of factors influence the type of strategy used by rodents to remember the location of a given goal in space, including the biological sex of the learner. We recently found that prior to puberty male rats preferred a striatum-dependent stimulus-response strategy over a hippocampus-dependent place strategy when solving a dual-solution task, while age-matched females showed no strategy preference. Because the cholinergic system has been implicated in learning strategy and is known to be sexually dimorphic prior to puberty, we explored the relationship between learning strategy and muscarinic receptor binding in specific brain regions of prepubertal males and female rats. We confirmed our previous finding that at 28 days of age a significantly higher proportion of prepubertal males preferred a stimulus-response learning strategy than a place strategy to solve a dual-solution visible platform water maze task. Equal proportions of prepubertal females preferred stimulus-response or place strategies. Profiles of muscarinic receptor binding as assessed by autoradiography varied according to strategy preference. Regardless of biological sex, prepubertal rats that preferred stimulus-response strategy exhibited lower ratios of muscarinic receptor binding in the hippocampus relative to the dorsolateral striatum compared to rats that preferred place strategy. Importantly, much of the variance in this ratio was related to differences in the ventral hippocampus to a greater extent than the dorsal hippocampus. The ratios of muscarinic receptors in the hippocampus relative to the basolateral amygdala also were lower in rats that preferred stimulus-response strategy over place strategy. Results confirm that learning strategy preference varies with biological sex in prepubertal rats with males biased toward a stimulus-response strategy, and that stimulus-response strategy is associated with lower ratios of muscarinic binding in the hippocampus relative to either the striatum or amygdala. Copyright © 2012 Wiley Periodicals, Inc.

Effects of analogues of substance P fragments on the MAO activity in rat brain.

PubMed

Turska, E; Lachowicz, L; Koziołkiewicz, W; Wasiak, T

1985-01-01

The influence in vitro of analogues of Sp5-11 and SP6-11 substance P fragments on the activity of monoamine oxidase (MAO) in homogenates and crude mitochondrial fractions of rat brain was examined. The rat brain was divided into: I--cerebral cortex, II--hippocampus, III--midbrain, IV--thalamus with hypothalamus, V--cerebellum and VI--medulla oblongata. The obtained results proved that the analogues of SP fragments inhibit selectively the activity of the enzyme in the homogenates of cerebral cortex, hippocampus, midbrain and cerebellum. In the crude mitochondrial fractions the applied analogues of SP fragments caused a slight increase of the enzyme activity. The most significant changes in the activity of MAO were observed in hippocampus homogenate fraction.

Effect of Paullinia cupana Mart. Commercial Extract During the Aging of Middle Age Wistar Rats: Differential Effects on the Hippocampus and Striatum.

PubMed

Mingori, Moara Rodrigues; Heimfarth, Luana; Ferreira, Charles Francisco; Gomes, Henrique Mautone; Moresco, Karla Suzana; Delgado, Jeferson; Roncato, Sabrina; Zeidán-Chuliá, Fares; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

2017-08-01

During aging, there is a marked decline in the antioxidant capacity of brain tissue, leading to a gradual loss of the antioxidant/oxidant balance, which causes oxidative damage. The effects of Paullinia cupana Mart. extract, which is described as being rich in caffeine and many polyphenol compounds, on the central nervous system have not been extensively investigated. The aim of this study was to therefore investigate the effect of a commercial guarana extract (CGE) on cognitive function, oxidative stress, and brain homeostasis proteins related to cognitive injury and senescence in middle age, male Wistar rats. Animals were randomly assigned to a group according to their treatment (saline, CGE, or caffeine). Solutions were administered daily by oral gavage for 6 months. Open field and novel object recognition tasks were performed before and after treatment. Biochemical analyses were carried out on the hippocampus and striatum. Our open field data showed an increase in exploratory activity and a decrease in anxiety-like behavior with caffeine but not with the CGE treatment. In the CGE-treated group, catalase activity decreased in the hippocampus and increased in the striatum. Analyses of the hippocampus and striatum indicate that CGE and/or caffeine altered some of the analyzed parameters in a tissue-specific manner. Our data suggest that CGE intake does not improve cognitive development, but modifies the oxidative stress machinery and neurodegenerative-signaling pathway, inhibiting pro-survival pathway molecules in the hippocampus and striatum. This may contribute to the development of unfavorable microenvironments in the brain and neurodegenerative disorders.

Possible involvements of glutamate and adrenergic receptors on acute toxicity of methylphenidate in isolated hippocampus and cerebral cortex of adult rats.

PubMed

Motaghinejad, Majid; Motevalian, Manijeh; Shabab, Behnaz

2017-04-01

Neurodegeneration induced by methylphenidate (MPH), as a central stimulant with unknown long-term consequences, in adult rats' brain and the possible mechanisms involved were studied. Rats were acutely treated with MPH in the presence and absence of some receptor antagonists such as ketamine, topiramate, yohimbine, and haloperidol. Motor activity and anxiety level in rats were monitored. Antioxidant and inflammatory parameters were also measured in isolated hippocampus and cerebral cortex. MPH-treated groups (10 and 20 mg/kg) demonstrated anxiety-like behavior and increased motor activity. MPH significantly increased lipid peroxidation, GSSG content, IL-1β and TNF-α levels in isolated tissues, and also significantly reduced GSH content, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in hippocampus and cerebral cortex. Pretreatment of animals by receptor antagonists caused inhibition of MPH-induced motor activity disturbances and anxiety-like behavior. Pretreatment of animals by ketamine, topiramate, and yohimbine inhibited the MPH-induced oxidative stress and inflammation; it significantly decreased lipid peroxidation, GSSG level, IL-1β and TNF-α levels and increased GSH content, SOD, GPx, and GR activities in hippocampus and cerebral cortex of acutely MPH-treated rats. Pretreatment with haloperidol did not cause any change in MPH-induced oxidative stress and inflammation. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats and these changes might probably be mediated by glutamate (NMDA or AMPA) and/or α 2 -adrenergic receptors. © 2016 Société Française de Pharmacologie et de Thérapeutique.

[Effects of nano-lead exposure on learning and memory as well as iron homeostasis in brain of offspring rats].

PubMed

Gao, Jing; Su, Hong; Yin, Jingwen; Cao, Fuyuan; Feng, Peipei; Liu, Nan; Xue, Ling; Zheng, Guoying; Li, Qingzhao; Zhang, Yanshu

2015-06-01

To investigate the effects of nano-lead exposure on learning and memory and iron homeostasis in the brain of the offspring rats on postnatal day 21 (PND21) and postnatal day 42 (PND42). Twenty adult pregnant female Sprague-Dawley rats were randomly divided into control group and nano-lead group. Rats in the nano-lead group were orally administrated 10 mg/kg nano-lead, while rats in the control group were administrated an equal volume of normal saline until PND21. On PND21, the offspring rats were weaned and given the same treatment as the pregnant rats until 42 days after birth. The learning and memory ability of offspring rats on PND21 and PND42 was evaluated by Morris water maze test. The hippocampus and cortex s amples of offspring rats on PND21 and PND42 were collected to determine iron and lead levels in the hippocampus and cortex by inductively coupled plasma-mass spectrometry. The distributions of iron in the hippocampus and cortex were observed by Perl's iron staining. The expression levels of ferritin, ferroportin 1 (FPN1), hephaestin (HP), and ceruloplasmin (CP) were measured by enzyme-linked immunosorbent assay. After nano-lead exposure, the iron content in the cortex of offspring rats on PND21 and PND42 in the nano-lead group was significantly higher than those in the control group (32.63 ± 6.03 µg/g vs 27.04 ± 5.82 µg/g, P<0.05; 46.20 ±10.60 µg/g vs 36.61 ± 10.2µg/g, P<0.05). The iron content in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly higher than that in the control group (56.9 ± 4.37µg/g vs 37.71 ± 6.92µg/g, P<0.05). The Perl's staining showed massive iron deposition in the cortex and hippocampus in the nano-lead group. FPNl level in the cotfex of offspring rats on PND21 in the nano-lead group was significantly lower than that in the control group (3.64 ± 0.23 ng/g vs 4.99 ± 0.95 ng/g, P<0.05). FPN1 level in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly lower than that in the control group (2.28 ± 0.51 ng/g vs 3.69 ± 0.69 ng/g, P<0.05). The escape latencies of offspring rats on PND21 and PND42 in the nano-lead group were longer than those in the control group (15.54 ± 2.89 s vs 9.01 ± 4.66 s; 6.16 ± 1.42 s vs 4.26 ± 1.51 s). The numbers of platform crossings of offspring rats on PND21 and PND42 in the nano- lead group were significantly lower than those in the control group (7.77 ± 2.16 times vs 11.2 ± 1.61 times, P<0.05; 8.12 ± 1.51 times vs 13.0 ± 2.21 times, P<0.05). n Nano-lead exposure can result in iron homeostasis disorders in the hippocampus and cortex of offspring rats and affect their learning and memory ability.

The central responsiveness of the acute cerveau isolé rat.

PubMed

User, P; Gottesmann, C

1982-01-01

The electrophysiological patterns of the frontal cortex and dorsal hippocampus were studied in the acute cerveau isolé rat. Central and peripheral stimulations were performed in order to modulate these patterns. The results showed that the permanent alternation of high amplitude spindle bursts and low voltage activity in the anterior neocortex of the acute cerveau isolé was influenced neither by olfactory nor by posterior hypothalamic stimulation. In contrast, these two kinds of stimulation easily modulated the continuous low frequency theta rhythm, recorded in the dorsal hippocampus, in terms of amplitude and in overall frequency. This modulation of the theta rhythm in the acute cerveau isolé rat mimics the changes observed when the normal rat comes from the intermediate stage of sleep (as characterized in the the acute intercollicular transected rat by high amplitude spindle bursts at frontal cortex level and low frequency theta activity in the dorsal hippocampus) to rapid sleep. These results further suggest that, during the intermediate stage (as in the cerveau isolé preparation), the hippocampus montonous theta activity appears through a brainstem disinhibitory process releasing the forebrain limbic pacemaker(s). During the following rapid sleep phase, the theta rhythm would be modulated by pontine activity influences acting on the theta generators.

Role of hippocampus in polymodal-cue guided tasks in rats.

PubMed

Miniaci, Maria Concetta; Lippiello, Pellegrino; Monda, Marcellino; Scotto, Pietro

2016-09-01

To examine how signals from different sensory modalities are integrated to generate an appropriate goal-oriented behavior, we trained rats in an eight-arm radial maze to visit a cue arm provided with intramaze cues from different sensory modalities, i.e. visual, tactile and auditory, in order to obtain a reward. When the same rats were then examined on test trials in which the cue arm contained one of the stimuli that the animals were trained with (i.e. light, sound or rough sheet), they showed a significant impairment with respect to the performance on the polymodal-cue task. The contribution of the dorsal hippocampus to the acquisition and retention of polymodal-cue guided task was also examined. We found that rats with dorsal hippocampal lesions before training showed a significant deficit in the acquisition of polymodal-cue oriented task that improved with overtraining. The selective lesion of the dorsal hippocampus after training disrupted memory retention, but the animals' performance improved following retraining of the polymodal task. All hippocampal lesioned rats displayed an impaired performance on the unimodal test. These findings suggest that the dorsal hippocampus contributes to the processing of multimodal sensory information for the associative memory formation and consolidation. Copyright © 2016 Elsevier B.V. All rights reserved.

Hippocampal Infusion of Zeta Inhibitory Peptide Impairs Recent, but Not Remote, Recognition Memory in Rats

PubMed Central

Hales, Jena B.; Ocampo, Amber C.; Broadbent, Nicola J.; Clark, Robert E.

2015-01-01

Spatial memory in rodents can be erased following the infusion of zeta inhibitory peptide (ZIP) into the dorsal hippocampus via indwelling guide cannulas. It is believed that ZIP impairs spatial memory by reversing established late-phase long-term potentiation (LTP). However, it is unclear whether other forms of hippocampus-dependent memory, such as recognition memory, are also supported by hippocampal LTP. In the current study, we tested recognition memory in rats following hippocampal ZIP infusion. In order to combat the limited targeting of infusions via cannula, we implemented a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus. Rats infused with ZIP 3–7 days after training on the novel object recognition task exhibited impaired object recognition memory compared to control rats (those infused with aCSF). In contrast, rats infused with ZIP 1 month after training performed similar to control rats. The ability to form new memories after ZIP infusions remained intact. We suggest that enhanced recognition memory for recent events is supported by hippocampal LTP, which can be reversed by hippocampal ZIP infusion. PMID:26380123

Impact of environmental noise on growth and neuropsychological development of newborn rats.

PubMed

Zheng, Yanyan; Meng, Meng; Zhao, Congmin; Liao, Wei; Zhang, Yuping; Wang, Liyan; Wen, Enyi

2014-05-01

We aimed to investigate the effects of environmental noise exposure on the growth and neuropsychological development in neonatal rats. Twenty-four postnatal 7-day-old Sprague-Dawley rats were randomly assigned into control, high-noise and reduced noise groups. The rats in the high-noise group were exposed to 90 dB white noise, and those in the control group were grown under standard condition, while those in the reduced noise group were exposed to standard condition with sound-absorbing cotton. Ten, 15, and 20 days post noise exposure, both the body weight and length of the rats in high-noise group were lower than those in the control and reduced noise groups, respectively. The secretion of growth hormone was significantly decreased in the rats exposed to high noise environment, compared to those exposed to standard condition and reduced noise. More interestingly, the swimming distance was apparently increased and the swimming speed was significantly decreased in high-noise group compared with those in control and reduced noise groups. Importantly, the mRNA and protein levels of SYP in the rats hippocampus were significantly decreased in high-noise group compare with those in control and reduced noise groups. Similarly, the positive expression of SYP in the CA1 region of hippocampus was also significantly decreased in the high noise group rats. In conclusion, our results demonstrated that high noise exposure could decrease the production of growth hormone and SYP in neonatal rats, which may retard the growth of weight and length and the capability of learning and memory. Copyright © 2014 Wiley Periodicals, Inc.

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

PubMed

Kolosova, Nataliya G; Vitovtov, Anton O; Muraleva, Natalia A; Akulov, Andrey E; Stefanova, Natalia A; Blagosklonny, Mikhail V

2013-06-01

Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

PubMed Central

Kolosova, Nataliya G.; Vitovtov, Anton O.; Muraleva, Natalia A; Akulov, Andrey E.; Stefanova, Natalia A.; Blagosklonny, Mikhail V.

2013-01-01

Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging. PMID:23817674

Soft-food diet induces oxidative stress in the rat brain.

PubMed

Yoshino, Fumihiko; Yoshida, Ayaka; Hori, Norio; Ono, Yumie; Kimoto, Katsuhiko; Onozuka, Minoru; Lee, Masaichi Chang-il

2012-02-02

Decreased dopamine (DA) release in the hippocampus may be caused by dysfunctional mastication, although the mechanisms involved remain unclear. The present study examined the effects of soft- and hard-food diets on oxidative stress in the brain, and the relationship between these effects and hippocampal DA levels. The present study showed that DA release in the hippocampus was decreased in rats fed a soft-food diet. Electron spin resonance studies using the nitroxyl spin probe 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl directly demonstrated a high level of oxidative stress in the rat brain due to soft-food diet feeding. In addition, we confirmed that DA directly react with reactive oxygen species such as hydroxyl radical and superoxide. These observations suggest that soft-food diet feeding enhances oxidative stress, which leads to oxidation and a decrease in the release of DA in the hippocampus of rats. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

PubMed

Mastropaolo, J; Nadi, N S; Ostrowski, N L; Crawley, J N

1988-12-01

Galanin coexists with acetylcholine in medial septal neurons projecting to the ventral hippocampus, a projection thought to modulate memory functions. Neurochemical lesions of the nucleus basalis-medial septal area in rats impaired choice accuracy on a delayed alternation t-maze task. Acetylcholine (7.5 or 10 micrograms intraventricularly or 1 micrograms micro-injected into the ventral hippocampus) significantly improved performance in the lesioned rats. Atropine (5 mg/kg intraperitoneally or 10 micrograms intraventricularly), but not mecamylamine (3 mg/kg intraperitoneally or 20 micrograms intraventricularly), blocked this action of acetylcholine, suggesting involvement of a muscarinic receptor. Galanin (100-500 ng intraventricularly or 200 ng into the ventral hippocampus) attenuated the ability of acetylcholine to reverse the deficit in working memory in the lesioned rats. The antagonistic interaction between galanin and acetylcholine suggests that endogenous galanin may inhibit cholinergic function in memory processes, particularly in pathologies such as Alzheimer disease that involve degeneration of basal forebrain neurons.

[Free radical modification of proteins in brain structure of Sprague-Dawley rats and some behaviour indicators after prenatal stress].

PubMed

V'iushina, A V; Pritvorova, A V; Flerov, M A

2012-08-01

We studied the influence of late prenatal stress on free radical oxidation processes in Sprague-Dawley rats cortex, striatum, hippocampus, hypothalamus proteins. It was shown that after prenatal stress most changes were observed in hypothalamus and hippocampus. It was shown that in hypothalamus spontaneous oxidation level increased, but level of induced oxidation decreased, the opposite changes were found in hippocampus. Simultaneously minor changes of protein modification were observed in cortex and striatum. It was shown that prenatal stress changed both correlation of proteins free radical oxidation in studied structures and values of these data regarding to control. In test of "open field" motor activity in rats after prenatal stress decreased and time of freezing and grooming increased; opposite, in T-labyrinth motor activity and time of grooming in rats after prenatal stress increased, but time of freezing decreased.

Effect of maternal excessive sodium intake on postnatal brain development in rat offspring.

PubMed

Shin, Jung-a; Ahn, Young-mo; Lee, Hye-ah; Park, Hyesook; Kim, Young-ju; Lee, Hwa-young

2015-04-01

Postnatal brain development is affected by the in utero environment. Modern people usually have a high sodium intake. The aim of this study was to investigate the effect of sodium hyperingestion during pregnancy on the postnatal brain development of rat offspring. The sodium-overloaded rats received 1.8% NaCl in their drinking water for 7 days during the last week of gestation. Their body weight, urine, and blood levels of sodium and other parameters were measured. Some rats were sacrificed at pregnancy day 22 and the weight and length of the placenta and foetus were measured. The cerebral cortex and hippocampus were obtained from their offspring at postnatal day 1 and at postnatal weeks 1, 2, 4, and 8. Western blot analyses were conducted with brain tissue lysates. The sodium-overloaded animals had decreased weight gain in the last week of gestation as well as decreased food intake, increased water intake, urine volume, urine sodium, and serum sodium. There were no differences in placental weight and length. The foetuses of sodium-overloaded rats showed decreased body weight and size, and this difference was maintained postnatally for 2 weeks. In the cerebral cortex and hippocampus of the offspring, the protein levels of myelin basic protein, calmodulin/calcium-dependent protein kinase II, and brain-derived neurotrophic factor were decreased or aberrantly expressed. The present data suggest that increased sodium intake during pregnancy affects the brain development of the offspring.

Antidepressant effects of Kai-Xin-San in fluoxetine-resistant depression rats.

PubMed

Dong, X Z; Wang, D X; Lu, Y P; Yuan, S; Liu, P; Hu, Y

2017-08-17

This study aimed to investigate the antidepressant effect and the mechanism of action of Kai-Xin-San (KXS) in fluoxetine-resistant depressive (FRD) rats. Two hundred male Wistar rats weighing 200±10 g were exposed to chronic and unpredictable mild stresses (CUMS) for 4 weeks and given fluoxetine treatment simultaneously. The rats that did not show significant improvement in behavioral indexes were chosen as the FRD model rats. These rats were randomly divided into four groups: FRD model control; oral fluoxetine and aspirin; oral KXS at a dose of 338 mg·kg-1·day-1; and oral KXS at a dose of 676 mg·kg-1·day-1. Rats continued to be exposed to CUMS and underwent treatment once a day for 3 weeks, then cytokine (COX-2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, TGF-β, and TNF-α) levels in the hippocampus and serum, and organ coefficients were measured. Both doses of KXS improved the crossing and rearing frequencies, sucrose-preference index, and body weight in FRD rats. KXS at a dose of 338 mg·kg-1·day-1reduced COX-2, IL-2, IL-6, TNF-α levels, increased IL-10 level in the hippocampus, and reduced IL-2 and TNF-α levels in serum. KXS at a dose of 676 mg·kg-1·day-1reduced TNF-α level in the hippocampus, reduced IL-2 and TNF-α levels in serum, and increased IFN-γ and IL-10 levels in the hippocampus and serum. There were no significant differences in organ-coefficients of the spleen among and between groups. The results suggested that oral administration of KXS in FRD rats was effective in improving behavior disorders by influencing various inflammatory pathways.

Vitamin D Supplementation Reverses DNA Damage and Telomeres Shortening Caused by Ovariectomy in Hippocampus of Wistar Rats.

PubMed

Siebert, Cassiana; Dos Santos, Tiago Marcon; Bertó, Carolina Gessinger; Parisi, Mariana Migliorini; Coelho, Ritiéle Pinto; Manfredini, Vanusa; Barbé-Tuana, Florencia M; Wyse, Angela T S

2018-05-05

The aim of this study was to investigate the effect of ovariectomy (OVX), a surgical model of menopause, and/or vitamin D (VIT D) supplementation on oxidative status, DNA damage, and telomere length in hippocampus of rats at two ages. Ninety-day-old (adult) or 180-day-old (older) female Wistar rats were divided into four groups: SHAM, OVX, VIT D, and OVX + VIT D. Thirty days after OVX, rats were supplemented with VIT D (500 IU/kg) by gavage, for a period of 30 days. Results showed that OVX altered antioxidant enzymes, increasing the activities of catalase in adult rats and superoxide dismutase in older rats. VIT D per se increased the activities of catalase and superoxide dismutase in older rats, but not in adult rats. VIT D supplementation to OVX (OVX + VIT D) rats did not reverse the effect of OVX on catalase in adult rats, but it partially reversed the increase in superoxide dismutase activity in older rats. OVX increased DNA damage in hippocampus of adult and older rats. VIT D per se reduced DNA damage, and when associated to OVX, it partially reversed this alteration. Additionally, OVX caused a telomere shortening in older rats, and VIT D was able to reverse such effect. Taken together, these results demonstrate that surgical menopause in rats causes hippocampal biochemical changes and VIT D appears, at least in part, to act in a beneficial way.

An evaluation of aversive memory and hippocampal oxidative status in streptozotocin-induced diabetic rats treated with resveratrol.

PubMed

Bagatini, Pamela Brambilla; Xavier, Léder Leal; Bertoldi, Karine; Moysés, Felipe; Lovatel, Gisele; Neves, Laura Tartari; Barbosa, Sílvia; Saur, Lisiani; de Senna, Priscylla Nunes; Souto, André Arigony; Siqueira, Ionara Rodrigues; Achaval, Matilde

2017-01-01

The present study evaluated the effects of streptozotocin (STZ)-induced diabetes on aversive memory, free radical content and enzymatic antioxidant activity in the hippocampus of adult Wistar rats submitted to oral treatment with resveratrol. Animals were divided into eight groups: non-diabetic rats treated with saline (ND SAL), non-diabetic rats treated with resveratrol at a dose 5mg/kg (ND RSV 5), non-diabetic rats treated with resveratrol at a dose 10mg/kg (ND RSV 10), non-diabetic rats treated with resveratrol at a dose 20mg/kg (ND RSV 20), diabetic rats treated with saline (D SAL), diabetic rats treated with resveratrol at a dose 5mg/kg (D RSV 5), diabetic rats treated with resveratrol at a dose 10mg/kg (D RSV 10) and diabetic rats treated with resveratrol at a dose 20mg/kg (D RSV 20). The animals received oral gavage for 35days. The contextual fear conditioning task was performed to evaluate aversive-based learning and memory. The oxidative status was evaluated in the hippocampus, by measuring the free radical content - using a 2',7'-dichlorofluorescein diacetate probe - and enzymatic antioxidant activities, such as superoxide dismutase and glutathione peroxidase. Our main behavioral results demonstrated that rats from the D RSV 10 and D RSV 20 groups showed an increase in freezing behavior when compared, respectively, to the ND RSV 10 (p<0.01) and ND RSV 20 (p<0.05). Oxidative stress parameters remained unchanged in the hippocampus of all the experimental groups. In contrast to previous experimental findings, our study was unable to detect either cognitive impairments or oxidative stress in the hippocampus of the diabetic rats. We suggest additional long-term investigations be conducted into the temporal pattern of STZ-induced diabetic disruption in memory and hippocampal oxidative status, as well as the effects of resveratrol on these parameters, in a time and dose-dependent manner. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

DAILY PATTERNS OF CLOCK AND COGNITION-RELATED FACTORS ARE MODIFIED IN THE HIPPOCAMPUS OF VITAMIN A-DEFICIENT RATS

PubMed Central

Golini, Rebeca S.; Delgado, Silvia M.; Navigatore Fonzo, Lorena S.; Ponce, Ivana T.; Lacoste, María G.; Anzulovich, Ana C.

2012-01-01

The circadian expression of clock and clock-controlled cognition-related genes in the hippocampus would be essential to achieve an optimal daily cognitive performance. There is some evidence that retinoid nuclear receptors (RARs and RXRs) can regulate circadian gene expression in different tissues. In this study, Holtzman male rats from control and vitamin A-deficient groups were sacrificed throughout a 24-h period and hippocampus samples were isolated every 4 or 5 h. RARα and RXRβ expression level was quantified and daily expression patterns of clock BMAL1, PER1, RORα and REVERB genes, RORα and REVERB proteins, as well as temporal expression of cognition-related RC3 and BDNF genes were determined in the hippocampus of the two groups of rats. Our results show significant daily variations of BMAL1, PER1, RORα and REVERB genes, RORα and REVERB proteins and, consequently, daily oscillating expression of RC3 and BDNF genes in the rat hippocampus. Vitamin A deficiency reduced RXRβ mRNA level as well as the amplitude of PER1, REVERB gene and REVERB protein rhythms, and phase-shifted the daily peaks of BMAL1 and RORα mRNA, RORα protein and RC3 and BDNF mRNA levels. Thus, nutritional factors, such as vitamin A and its derivatives the retinoids, might modulate daily patterns of BDNF and RC3 expression in the hippocampus and they could be essential to maintain an optimal daily performance at molecular level in this learning-and-memory-related brain area. PMID:22434687

Impact of Preoperative Environmental Enrichment on Prevention of Development of Cognitive Impairment following Abdominal Surgery in a Rat Model.

PubMed

Kawano, Takashi; Eguchi, Satoru; Iwata, Hideki; Tamura, Takahiko; Kumagai, Naoko; Yokoyama, Masataka

2015-07-01

Sustained neuroinflammation may contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Here, the authors evaluated the preventive effect of preoperative environmental enrichment (PEE) on the development of neuroinflammation and concomitant POCD in a rat abdominal surgery model. Young and aged rats were assigned to one of four groups using a 2 × 2 experimental design: PEE versus sedentary condition for 14 days, by abdominal surgery versus anesthesia alone (n = 8 in each group). After a 7-day postsurgical recovery period, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of proinflammatory cytokines. Under identical conditions, microglia were isolated from the hippocampus for assessment of cytokine response to lipopolysaccharide. In the sedentary group, aged, but not young, rats receiving surgery showed memory deficits (novel object preference during testing phase of 54.6 ± 7.8% vs. 76.9 ± 11.3% in nonsurgery group, P < 0.05) and increased hippocampal levels of cytokines compared with nonsurgical rats. PEE had no effects on novel object preference in nonsurgery animals (78.6 ± 10.7%), whereas it attenuated surgery-induced impairment of novel object preference (70.9 ± 15.0%, P < 0.05 vs. sedentary/surgery group) as well as increase of cytokine levels in hippocampus. Furthermore, upon ex vivo stimulation with lipopolysaccharide, cytokines release from hippocampal microglia isolated from aged rats before intervention was significantly higher in comparison with young rats. PEE resulted in reduction of these age-related microglial phenotypic changes. PEE could prevent the development of neuroinflammation and related POCD in aged rats by reversion of a proinflammatory phenotype of hippocampal microglia.

Exposure to unpredictable maternal sensory signals influences cognitive development across species.

PubMed

Davis, Elysia Poggi; Stout, Stephanie A; Molet, Jenny; Vegetabile, Brian; Glynn, Laura M; Sandman, Curt A; Heins, Kevin; Stern, Hal; Baram, Tallie Z

2017-09-26

Maternal care is a critical determinant of child development. However, our understanding of processes and mechanisms by which maternal behavior influences the developing human brain remains limited. Animal research has illustrated that patterns of sensory information is important in shaping neural circuits during development. Here we examined the relation between degree of predictability of maternal sensory signals early in life and subsequent cognitive function in both humans ( n = 128 mother/infant dyads) and rats ( n = 12 dams; 28 adolescents). Behaviors of mothers interacting with their offspring were observed in both species, and an entropy rate was calculated as a quantitative measure of degree of predictability of transitions among maternal sensory signals (visual, auditory, and tactile). Human cognitive function was assessed at age 2 y with the Bayley Scales of Infant Development and at age 6.5 y with a hippocampus-dependent delayed-recall task. Rat hippocampus-dependent spatial memory was evaluated on postnatal days 49-60. Early life exposure to unpredictable sensory signals portended poor cognitive performance in both species. The present study provides evidence that predictability of maternal sensory signals early in life impacts cognitive function in both rats and humans. The parallel between experimental animal and observational human data lends support to the argument that predictability of maternal sensory signals causally influences cognitive development.

The impact of multiple memory formation on dendritic complexity in the hippocampus and anterior cingulate cortex assessed at recent and remote time points

PubMed Central

Wartman, Brianne C.; Holahan, Matthew R.

2014-01-01

Consolidation processes, involving synaptic and systems level changes, are suggested to stabilize memories once they are formed. At the synaptic level, dendritic structural changes are associated with long-term memory storage. At the systems level, memory storage dynamics between the hippocampus and anterior cingulate cortex (ACC) may be influenced by the number of sequentially encoded memories. The present experiment utilized Golgi-Cox staining and neuron reconstruction to examine recent and remote structural changes in the hippocampus and ACC following training on three different behavioral procedures. Rats were trained on one hippocampal-dependent task only (a water maze task), two hippocampal-dependent tasks (a water maze task followed by a radial arm maze task), or one hippocampal-dependent and one non-hippocampal-dependent task (a water maze task followed by an operant conditioning task). Rats were euthanized recently or remotely. Brains underwent Golgi-Cox processing and neurons were reconstructed using Neurolucida software (MicroBrightField, Williston, VT, USA). Rats trained on two hippocampal-dependent tasks displayed increased dendritic complexity compared to control rats, in neurons examined in both the ACC and hippocampus at recent and remote time points. Importantly, this behavioral group showed consistent, significant structural differences in the ACC compared to the control group at the recent time point. These findings suggest that taxing the demand placed upon the hippocampus, by training rats on two hippocampal-dependent tasks, engages synaptic and systems consolidation processes in the ACC at an accelerated rate for recent and remote storage of spatial memories. PMID:24795581

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats

PubMed Central

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT4) administration increased the level of free triiodothyronine (FT3) and free tetraiodothyroxine (FT4) not only in serum but also in hippocampus. In addition, a single systemic LT4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT4 did not affect rats’ locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders. PMID:28824379

Similar effects of substance P on learning and memory function between hippocampus and striatal marginal division

PubMed Central

Yu, Yan; Zeng, Changchun; Shu, Siyun; Liu, Xuemei; Li, Chuhua

2014-01-01

Substance P is an endogenous neurokinin that is present in the central and peripheral nervous systems. The neuropeptide substance P and its high-affinity receptor neurokinin 1 receptor are known to play an important role in the central nervous system in inflammation, blood pressure, motor behavior and anxiety. The effects of substance P in the hippocampus and the marginal division of the striatum on memory remain poorly understood. Compared with the hippocampus as a control, immunofluorescence showed high expression of the substance P receptor, neurokinin 1, in the marginal division of the striatum of normal rats. Unilateral or bilateral injection of an antisense oligonucleotide against neurokinin 1 receptor mRNA in the rat hippocampus or marginal division of the striatum effectively reduced neurokinin 1 receptor expression. Independent of injection site, rats that received this antisense oligonucleotide showed obviously increased footshock times in a Y-maze test. These results indicate that the marginal division of the striatum plays a similar function in learning and memory to the hippocampus, which is a valuable addition to our mechanistic understanding of the learning and memory functions of the marginal division of the striatum. PMID:25206901

Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus.

PubMed

Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

2014-08-01

Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions.

Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus

PubMed Central

Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

2014-01-01

Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions. PMID:25317156

Exposure of mother rats to chronic unpredictable stress before pregnancy alters the metabolism of gamma-aminobutyric acid and glutamate in the right hippocampus of offspring in early adolescence in a sexually dimorphic manner.

PubMed

Huang, Yuejun; Shen, Zhiwei; Hu, Liu; Xia, Fang; Li, Yuewa; Zhuang, Jingwen; Chen, Peishan; Huang, Qingjun

2016-12-30

There is increasing evidence that mothers' exposure to stress before or during pregnancy is linked to an incidence of psychiatric disorders in offspring. However, a few studies have estimated the role of sex in the detrimental effects of pre-gestational stress on the offspring rats at early adolescence. Sex differences regarding the metabolism of gamma-aminobutyric acid and glutamate in the right hippocampus were investigated by MRS when the offspring rats reached 30 days. Additionally, the impact of pre-gestational stress exposed on an additional short-term acute stressor, such as forced swim, was examined in the male and female offspring rats. Our findings showed female offspring rats were more vulnerable to stressful conditions for either pre-gestational stress or acute stress in early adolescence, and had decreased GABA/Cr+PCr and Glu/Cr+PCr in the right hippocampus. Interestingly, in response to forced swim, male offspring rats whose mothers were exposed to pre-gestational stress were more affected by the short-term acute stressor and this was manifested by change of Glu/GABA and Glu/Gln in the right hippocampus. These data indicated that although female offspring rats were more vulnerable to pre-gestational stress from their mothers than males, in response to an additional acute stressor they showed better response. Therefore, both sexually dimorphic manner and combination of stressful procedures should be carefully considered in the study of stress-related psychiatric disorders in early adolescence. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats.

PubMed

He, J; Yamada, K; Zou, L B; Nabeshima, T

2001-01-01

We investigated the effects of okadaic acid (OA), a specific inhibitor of protein phosphatases 1 and 2A, on spatial memory and neuronal survival in rats. Rats were initially trained on a spatial memory task in an eight arm radial maze. Spatial reference and working memory was impaired 1 day after the unilateral microinjection of OA into the dorsal hippocampus. The impairment was transient, and had disappeared by the following day. In contrast, neurodegeneration induced by OA was persistent and extended to the contralateral side 13 days after the injection. These results suggest that OA causes spatial memory impairment and neurodegeneration when injected directly into the hippocampus. Our findings also indicate dissociation between memory impairment and neurodegeneration induced by OA.

Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brain

PubMed Central

Zhu, Meng-Yang; Wang, Wei-Ping; Cai, Zheng-Wei; Regunathan, Soundar; Ordway, Gregory

2009-01-01

Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with β-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress. PMID:18364017

Effect of three different intensities of infrared laser energy on the levels of amino acid neurotransmitters in the cortex and hippocampus of rat brain.

PubMed

Ahmed, Nawal Abd El Hay; Radwan, Nasr Mahmoud; Ibrahim, Khayria Mansour; Khedr, Mona Emam; El Aziz, Mona A; Khadrawy, Yasser Ashry

2008-10-01

The aim of this study is to investigate the effects of three different intensities of infrared diode laser radiation on amino acid neurotransmitters in the cortex and hippocampus of rat brain. Lasers are known to induce different neurological effects such as pain relief, anesthesia, and neurosuppressive effects; however, the precise mechanisms of these effects are not clearly elucidated. Amino acid neurotransmitters (glutamate, aspartate, glutamine, gamma-aminobutyric acid [GABA], glycine, and taurine) play vital roles in the central nervous system (CNS). The shaved scalp of each rat was exposed to different intensities of infrared laser energy (500, 190, and 90 mW) and then the rats were sacrificed after 1 h, 7 d, and 14 d of daily laser irradiation. The control groups were exposed to the same conditions but without exposure to laser. The concentrations of amino acid neurotransmitters were measured by high-performance liquid chromatography (HPLC). The rats subjected to 500 mW of laser irradiation had a significant decrease in glutamate, aspartate, and taurine in the cortex, and a significant decrease in hippocampal GABA. In the cortices of rats exposed to 190 mW of laser irradiation, an increase in aspartate accompanied by a decrease in glutamine were observed. In the hippocampus, other changes were seen. The rats irradiated with 90 mW showed a decrease in cortical glutamate, aspartate, and glutamine, and an increase in glycine, while in the hippocampus an increase in glutamate, aspartate, and GABA were recorded. We conclude that daily laser irradiation at 90 mW produced the most pronounced inhibitory effect in the cortex after 7 d. This finding may explain the reported neurosuppressive effect of infrared laser energy on axonal conduction of hippocampal and cortical tissues of rat brain.

Learning not to respond: Role of the hippocampus in withholding responses during omission training.

PubMed

White, Norman M; Naeem, Maliha

2017-02-01

Autoshaping is a Pavlovian learning paradigm in which rats experience pairings of a CS and a US independently of their behavior. When the CS is a lever inserted into the test cage and the US is food delivered to an adjacent magazine, many rats acquire a lever-pressing response called 'sign-tracking' even though that response has no effect on the occurrence of either the CS or the US. Since these lever presses are always followed by the US, it has been suggested that sign-tracking could be due to unintended reinforcement of the response. To eliminate the possibility of such instrumental learning the omission schedule, in which a response to the CS cancels the US, was introduced. Previous research has shown that training rats on autoshaping and switching them to an omission schedule generally reduces but does not eliminate sign-tracking, suggesting that it may be due to both Pavlovian and instrumental learning. In the present study naive rats trained on an omission schedule sign-tracked less than a control group exposed to random, unpaired CS and US presentations, suggesting that they learned to withhold the lever press response because of the negative contingency between that response and the US. In a second experiment rats with dorsal hippocampus lesions sign-tracked more than sham-lesioned rats on omission schedules, suggesting that this case of learning not to respond is hippocampus-based. This conclusion is consistent with many previous findings on the inability of hippocampal rats to withhold or suppress responding, and with studies suggesting that one form of extinction of learned responses in normal rats is due to competition from hippocampus-based learning not to respond. Copyright © 2016 Elsevier B.V. All rights reserved.

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

PubMed Central

Martínez-Galán, J R; Pedraza, P; Santacana, M; Escobar del Ray, F; Morreale de Escobar, G; Ruiz-Marcos, A

1997-01-01

The most severe brain damage associated with thyroid dysfunction during development is observed in neurological cretins from areas with marked iodine deficiency. The damage is irreversible by birth and related to maternal hypothyroxinemia before mid gestation. However, direct evidence of this etiopathogenic mechanism is lacking. Rats were fed diets with a very low iodine content (LID), or LID supplemented with KI. Other rats were fed the breeding diet with a normal iodine content plus a goitrogen, methimazole (MMI). The concentrations of -thyroxine (T4) and 3,5,3'triiodo--thyronine (T3) were determined in the brain of 21-d-old fetuses. The proportion of radial glial cell fibers expressing nestin and glial fibrillary acidic protein was determined in the CA1 region of the hippocampus. T4 and T3 were decreased in the brain of the LID and MMI fetuses, as compared to their respective controls. The number of immature glial cell fibers, expressing nestin, was not affected, but the proportion of mature glial cell fibers, expressing glial fibrillary acidic protein, was significantly decreased by both LID and MMI treatment of the dams. These results show impaired maturation of cells involved in neuronal migration in the hippocampus, a region known to be affected in cretinism, at a stage of development equivalent to mid gestation in humans. The impairment is related to fetal cerebral thyroid hormone deficiency during a period of development when maternal thyroxinemia is believed to play an important role. PMID:9169500

[Effects of electromagnetic radiation on RAF/MEK/ERK signaling pathway in rats hippocampus].

PubMed

Zuo, Hong-yan; Wang, De-wen; Peng, Rui-yun; Wang, Shui-ming; Gao, Ya-bing; Xu, Xin-ping; Ma, Jun-Jie

2009-05-01

To study the development of changes for signaling molecules related to Raf/MEK/ERK pathway in hippocampus of rats after electromagnetic radiation, and investigate the mechanisms of radiation injury. Rats were exposed to X-HPM, S-HPM and EMP radiation source respectively, and animal model of electromagnetic radiation was established. Western blot was used to detect the expression of Raf-1, phosphorylated Raf-1 and phospholylated ERK. The expression of Raf-1 down-regulated during 6 h-14 d after radiation, most significantly at 7 d, and recovered at 28 d. There was no significant difference between the radiation groups. The expression of phosphorylated Raf-1 and phosphorylated ERK both up-regulated at 6 h and 7 d after radiation, more significantly at 6 h, and the two microwave groups were more serious for phosphorylated ERK. During 6 h-14 d after S-HPM radiation, the expression of phosphorylated Raf-1 increased continuously, but phosphorylated ERK changed wavily, 6 h and 7 d were expression peak. Raf/MEK/ERK signaling pathway participates in the hippocampus injury induced by electromagnetic radiation. The excessive activation of ERK pathway may result in the apoptosis and death of neurons, which is the important mechanism of recognition disfunction caused by electromagnetic radiation.

Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits.

PubMed

Morse, Sarah J; Butler, Anderson A; Davis, Robin L; Soller, Ian J; Lubin, Farah D

2015-04-01

A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity-dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging.

Experience-Dependent Epigenomic Reorganization in the Hippocampus

ERIC Educational Resources Information Center

Duke, Corey G.; Kennedy, Andrew J.; Gavin, Cristin F.; Day, Jeremy J.; Sweatt, J. David

2017-01-01

Using a hippocampus-dependent contextual threat learning and memory task, we report widespread, coordinated DNA methylation changes in CA1 hippocampus of Sprague-Dawley rats specific to threat learning at genes involved in synaptic transmission. Experience-dependent alternations in gene expression and DNA methylation were observed as early as 1 h…

Dorsal hippocampus is necessary for visual categorization in rats.

PubMed

Kim, Jangjin; Castro, Leyre; Wasserman, Edward A; Freeman, John H

2018-02-23

The hippocampus may play a role in categorization because of the need to differentiate stimulus categories (pattern separation) and to recognize category membership of stimuli from partial information (pattern completion). We hypothesized that the hippocampus would be more crucial for categorization of low-density (few relevant features) stimuli-due to the higher demand on pattern separation and pattern completion-than for categorization of high-density (many relevant features) stimuli. Using a touchscreen apparatus, rats were trained to categorize multiple abstract stimuli into two different categories. Each stimulus was a pentagonal configuration of five visual features; some of the visual features were relevant for defining the category whereas others were irrelevant. Two groups of rats were trained with either a high (dense, n = 8) or low (sparse, n = 8) number of category-relevant features. Upon reaching criterion discrimination (≥75% correct, on 2 consecutive days), bilateral cannulas were implanted in the dorsal hippocampus. The rats were then given either vehicle or muscimol infusions into the hippocampus just prior to various testing sessions. They were tested with: the previously trained stimuli (trained), novel stimuli involving new irrelevant features (novel), stimuli involving relocated features (relocation), and a single relevant feature (singleton). In training, the dense group reached criterion faster than the sparse group, indicating that the sparse task was more difficult than the dense task. In testing, accuracy of both groups was equally high for trained and novel stimuli. However, both groups showed impaired accuracy in the relocation and singleton conditions, with a greater deficit in the sparse group. The testing data indicate that rats encode both the relevant features and the spatial locations of the features. Hippocampal inactivation impaired visual categorization regardless of the density of the category-relevant features for the trained, novel, relocation, and singleton stimuli. Hippocampus-mediated pattern completion and pattern separation mechanisms may be necessary for visual categorization involving overlapping irrelevant features. © 2018 Wiley Periodicals, Inc.

Tiliacora triandra, an Anti-Intoxication Plant, Improves Memory Impairment, Neurodegeneration, Cholinergic Function, and Oxidative Stress in Hippocampus of Ethanol Dependence Rats.

PubMed

Phunchago, Nattaporn; Wattanathorn, Jintanaporn; Chaisiwamongkol, Kowit

2015-01-01

Oxidative stress plays an important role in brain dysfunctions induced by alcohol. Since less therapeutic agent against cognitive deficit and brain damage induced by chronic alcohol consumption is less available, we aimed to assess the effect of Tiliacora triandra extract, a plant possessing antioxidant activity, on memory impairment, neuron density, cholinergic function, and oxidative stress in hippocampus of alcoholic rats. Male Wistar rats were induced ethanol dependence condition by semivoluntary intake of alcohol for 15 weeks. Alcoholic rats were orally given T. triandra at doses of 100, 200, and 400 mg·kg(-1)BW for 14 days. Memory assessment was performed every 7 days while neuron density, activities of AChE, SOD, CAT, and GSH-Px and, MDA level in hippocampus were assessed at the end of study. Interestingly, the extract mitigated the increased escape latency, AChE and MDA level. The extract also mitigated the decreased retention time, SOD, CAT, and GSH-Px activities, and neurons density in hippocampus induced by alcohol. These data suggested that the extract improved memory deficit in alcoholic rats partly via the decreased oxidative stress and the suppression of AChE. Therefore, T. triandra is the potential reagent for treating brain dysfunction induced by alcohol. However, further researches are necessary to understand the detail mechanism and possible active ingredient.

Reduced Cerebrovascular Reactivity and Increased Resting Cerebral Perfusion in Rats Exposed to a Cafeteria Diet.

PubMed

Gomez-Smith, Mariana; Janik, Rafal; Adams, Conner; Lake, Evelyn M; Thomason, Lynsie A M; Jeffers, Matthew S; Stefanovic, Bojana; Corbett, Dale

2018-02-10

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO 2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

[Changes in the activity of an epileptogenic focus in the rat hippocampus under the influence of bemitil].

PubMed

Mikhaĭlov, I B; Sharf, M Ia; Guzeva, V I

1995-01-01

Experiments performed on male rats with chronically implanted electrochemotrodes showed bemitil (12.5 and 25.0 mg/kg, intra-abdominally, 24 h prior to the locus creation) suppresses he pathological activity of (100 ED) epileptogenic locus induced by he sodium salt of penicillin in the hippocampus of the animals. Probable mechanisms of antiepileptic action of bemitil are considered.

[Effect of electromagnetic radiation on discharge activity of neurons in the hippocampus CA1 in rats].

PubMed

Tong, Jun; Chen, Su; Liu, Xiang-Ming; Hao, Dong-Mei

2013-09-01

In order to explore effect of electromagnetic radiation on learning and memory ability of hippocampus neuron in rats, the changes in discharge patterns and overall electrical activity of hippocampus neuron after electromagnetic radiation were observed. Rat neurons discharge was recorded with glass electrode extracellular recording technology and a polygraph respectively. Radiation frequency of electromagnetic wave was 900 MHZ and the power was 10 W/m2. In glass electrode extracellular recording, the rats were separately irradiated for 10, 20, 30, 40, 50 and 60 min, every points repeated 10 times and updated interval of 1h, observing the changes in neuron discharge and spontaneous discharge patterns after electromagnetic radiation. In polygraph recording experiments, irradiation group rats for five days a week, 6 hours per day, repeatedly for 10 weeks, memory electrical changes in control group and irradiation group rats when they were feeding were repeatedly monitored by the implanted electrodes, observing the changes in peak electric digits and the largest amplitude in hippocampal CA1 area, and taking some electromagnetic radiation sampling sequence for correlation analysis. (1) Electromagnetic radiation had an inhibitory role on discharge frequency of the hippocampus CA1 region neurons. After electromagnetic radiation, discharge frequency of the hippocampus CA1 region neurons was reduced, but the changes in scale was not obvious. (2) Electromagnetic radiation might change the spontaneous discharge patterns of hippocampus CA1 region neurons, which made the explosive discharge pattern increased obviously. (3) Peak potential total number within 5 min in irradiation group was significantly reduced, the largest amplitude was less than that of control group. (4) Using mathematical method to make the correlation analysis of the electromagnetic radiation sampling sequence, that of irradiation group was less than that of control group, indicating that there was a tending to be inhibitory connection between neurons in irradiation group after electromagnetic radiation. Electromagnetic radiation may cause structure and function changes of transfer synaptic in global, make hippocampal CA1 area neurons change in the overall discharge characteristic and discharge patterns, thus lead to decrease in the ability of learning and memory.

The cognitive impairment induced by zinc deficiency in rats aged 0∼2 months related to BDNF DNA methylation changes in the hippocampus.

PubMed

Hu, Yan-Dan; Pang, Wei; He, Cong-Cong; Lu, Hao; Liu, Wei; Wang, Zi-Yu; Liu, Yan-Qiang; Huang, Cheng-Yu; Jiang, Yu-Gang

2017-11-01

This study was carried out to understand the effects of zinc deficiency in rats aged 0∼2 months on learning and memory, and the brain-derived neurotrophic factor (BDNF) gene methylation status in the hippocampus. The lactating mother rats were randomly divided into three groups (n = 12): zinc-adequate group (ZA: zinc 30 mg/kg diet), zinc-deprived group (ZD: zinc 1 mg/kg diet), and a pair-fed group (PF: zinc 30 mg/kg diet), in which the rats were pair-fed to those in the ZD group. After weaning (on day 23), offspring were fed the same diets as their mothers. After 37 days, the zinc concentrations in the plasma and hippocampus were measured, and the behavioral function of the offspring rats was measured using the passive avoidance performance test. We then assessed the DNA methylation patterns of the exon IX of BDNF by methylation-specific quantitative real-time PCR and the mRNA expression of BDNF in the hippocampus by RT-PCR. Compared with the ZA and PF groups, rats in the ZD group had shorter latency period, lower zinc concentrations in the plasma and hippocampus (P < 0.05). Interestingly, the DNA methylation of the BDNF exon IX was significantly increased in the ZD group, compared with the ZA and PF groups, whereas the expression of the BDNF mRNA was decreased. In addition, the DNMT1 mRNA expression was significantly upregulated and DNMT3A was downregulated in the ZD group, but not in the ZA and PF groups. The learning and memory damage in offspring may be a result of the epigenetic changes of the BDNF genes in response to the zinc-deficient diet during 0∼2 month period. Furthermore, this work supports the speculative notion that altered DNA methylation of BDNF in the hippocampus is one of the main causes of cognitive impairment by zinc deficiency.

Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Make Rats

EPA Science Inventory

Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one i...

Maternal treatment of rats with the new pyridoindole antioxidant during pregnacy and lactation resulting in improved offspring hippocampal resistance to ischemia in vitro.

PubMed

Gáspárová, Zdenka; Snirc, Vladimír; Stolc, Svorad; Dubovický, Michal; Mach, Mojmír; Ujházy, Eduard

2010-01-01

Damage to the developing brain may be caused by maternal environment, nutritional deficiencies, failure of protective mechanisms, etc. Further, the developing brain may be damaged by intrauterine ischemia or by ischemia in newborns complicated by perinatal asphyxia. There is an effort to find agents with neuroprotective effect on the developing brain. The aim was to study the effect of the new pyridoindole antioxidant SMe1EC2 on the resistance of offspring hippocampus exposed to ischemia in vitro after treatment of mothers. The electrically evoked responses were determined by extracellular recording from offspring hippocampal slices. The effect of oral treatment of rats with SMe1EC2 over 18 consecutive days, from day 15 of gestation to day 10 post partum (PP) was analyzed in the model of ischemia in vitro measured on the hippocampus of 21-day-old pups, with focus on neuronal function recovery in reoxygenation. Increased recovery of neuronal response was found at the end of 20-min reoxygenation in offspring hippocampal slices exposed to 10-min hypoxia/hypoglycemia from rats whose mothers were treated with the dose of 50 and 250 mg/kg of SMe1EC2, compared to control offspring slices (mothers received vehicle over the same time). The increased offspring hippocampus resistance to hypoxia/hypoglycemia due to 18-day maternal treatment with SMe1EC2 might have been obtained via the transplacental way as well as in the neonatal period via breast milk, skin and saliva. The manifested neuroprotective effect of SMe1EC2 on the developing brain might find exploitation during risk pregnancy and delivery.

Property of Regenerating Serotonin Fibers in the Hippocampus of Human Migration Disorders Model

NASA Astrophysics Data System (ADS)

Ueda, Shuichi; Ehara, Ayuka; Ohmomo, Hideki

Individual mood and mental conditions exert a great influence on one's own kansei. Abnormality or dysfunction of the 5-HT neuron system in the developing and/or adult brain is closely associated with their conditions. Thus, the 5-HT neuron system may play an important role in the neuronal mechanisms underlying kansei. Interestingly, previous studies have shown that heterotopic clusters in the hippocampus (hippocampal heterotopia), deriving from neocortical neurons, after prenatally treated with methylazoxymethanol acetate in rat (MAM rat), exhibit abundant 5-HT innervation. After neonatal intracisternal 5, 7-dihydroxytryptamine (DHT) injection, these 5-HT fibers degenerate and disappear throughout the forebrain, and then regenerating 5-HT fibers densely innervate in the hippocampal heterotopia. The 5-HT fiber system in the hippocampal heterotopia of MAM rat provides useful experimental models for study the plasticity of human migration disorder. In the present study, to evaluate the properties of regenerating 5-HT fibers in the hippocampal heterotopia of MAM rats, we examined the origin of these projections by combined retrograde transport and immunohistochemical methods. Prenatal exposure to MAM resulted in the formation of hippocampal heterotopia in the dorsal hippocampus. Regenerating 5-HT fibers formed a dense innervation within the hippocampal heterotopia after neonatal DHT injection. These projections appeared to arise mainly from 5-HT neurons in the median raphe nucleus, with a small portion from 5-HT neurons in the dorsal raphe nucleus. These findings suggest a specific profile of regenerating 5-HT fibers, providing the new insights for serotonergic plasticity.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155.

PubMed

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-10-27

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14 th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155

PubMed Central

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-01-01

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain. PMID:29163801

Dysfunction in Fatty Acid Amide Hydrolase Is Associated with Depressive-Like Behavior in Wistar Kyoto Rats

PubMed Central

Vinod, K. Yaragudri; Xie, Shan; Psychoyos, Delphine; Hungund, Basalingappa L.; Cooper, Thomas B.; Tejani-Butt, Shanaz M.

2012-01-01

Background While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. Methodology/Principal Findings The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats. Conclusions/Significance These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder. PMID:22606285

Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats.

PubMed

Vinod, K Yaragudri; Xie, Shan; Psychoyos, Delphine; Hungund, Basalingappa L; Cooper, Thomas B; Tejani-Butt, Shanaz M

2012-01-01

While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats. These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.

Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat.

PubMed

Maher, F O; Nolan, Yvonne; Lynch, Marina A

2005-05-01

Ageing is characterized by deficits in learning and memory and by a deficit in long-term potentiation (LTP) in hippocampus. Several age-related changes, including dysfunction of calcium homeostatic mechanisms and upregulation of inflammatory processes are likely to contribute to these deficits. Here we exploited the fact that aged rats fall into a subgroup which fail to sustain LTP in perforant path granule cell synapses as a result of tetanic stimulation, and a subgroup which sustains LTP in a manner indistinguishable from young rats, in an effort to identify differential changes in the two subgroups. The age-related increase in IL-1beta concentration and IL-1beta-induced signalling was more profound in aged rats which failed to sustain LTP. We demonstrate that functional IL-4 receptors are expressed in rat hippocampus and that age is associated with a decrease in IL-4 concentration accompanied by a decrease in phosphorylation of JAK-1 and STAT-6. We propose that the imbalance between pro-inflammatory and anti-inflammatory cytokines in the aged brain significantly contributes to age-related deficits in synaptic function.

Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval

PubMed Central

VanElzakker, Michael B.; Zoladz, Phillip R.; Thompson, Vanessa M.; Park, Collin R.; Halonen, Joshua D.; Spencer, Robert L.; Diamond, David M.

2011-01-01

We have studied the influence of pre-training psychological stress on the expression of c-fos mRNA following long-term spatial memory retrieval. Rats were trained to learn the location of a hidden escape platform in the radial-arm water maze, and then their memory for the platform location was assessed 24 h later. Rat brains were extracted 30 min after the 24-h memory test trial for analysis of c-fos mRNA. Four groups were tested: (1) Rats given standard training (Standard); (2) Rats given cat exposure (Predator Stress) 30 min prior to training (Pre-Training Stress); (3) Rats given water exposure only (Water Yoked); and (4) Rats given no water exposure (Home Cage). The Standard trained group exhibited excellent 24 h memory which was accompanied by increased c-fos mRNA in the dorsal hippocampus and basolateral amygdala (BLA). The Water Yoked group exhibited no increase in c-fos mRNA in any brain region. Rats in the Pre-Training Stress group were classified into two subgroups: good and bad memory performers. Neither of the two Pre-Training Stress subgroups exhibited a significant change in c-fos mRNA expression in the dorsal hippocampus or BLA. Instead, stressed rats with good memory exhibited significantly greater c-fos mRNA expression in the dorsolateral striatum (DLS) compared to stressed rats with bad memory. This finding suggests that stressed rats with good memory used their DLS to generate a non-spatial (cue-based) strategy to learn and subsequently retrieve the memory of the platform location. Collectively, these findings provide evidence at a molecular level for the involvement of the hippocampus and BLA in the retrieval of spatial memory and contribute novel observations on the influence of pre-training stress in activating the DLS in response to long-term memory retrieval. PMID:21738501

Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet.

PubMed

Francis, Heather M; Mirzaei, Mehdi; Pardey, Margery C; Haynes, Paul A; Cornish, Jennifer L

2013-10-01

The typical Western diet, rich in high saturated fat and refined sugar (HFS), has been shown to increase cognitive decline with aging and Alzheimer's disease, and to affect cognitive functions that are dependent on the hippocampus, including memory processes and reversal learning. To investigate neurophysiological changes underlying these impairments, we employed a proteomic approach to identify differentially expressed proteins in the rat dorsal and ventral hippocampus following maintenance on an HFS diet. Rats maintained on the HFS diet for 8 weeks were impaired on a novel object recognition task that assesses memory and on a Morris Water Maze task assessing reversal learning. Quantitative label-free shotgun proteomic analysis was conducted on biological triplicates for each group. For the dorsal hippocampus, 59 proteins were upregulated and 36 downregulated in the HFS group compared to controls. Pathway ana-lysis revealed changes to proteins involved in molecular transport and cellular and molecular signaling, and changes to signaling pathways including calcium signaling, citrate cycle, and oxidative phosphorylation. For the ventral hippocampus, 25 proteins were upregulated and 27 downregulated in HFS fed rats. Differentially expressed proteins were involved in cell-to-cell signaling and interaction, and cellular and molecular function. Changes to signaling pathways included protein ubiquitination, ubiquinone biosynthesis, oxidative phosphorylation, and mitochondrial dysfunction. This is the first shotgun proteomics study to examine protein changes in the hippocampus following long-term consumption of a HFS diet, identifying changes to a large number of proteins including those involved in synaptic plasticity and energy metabolism. All MS data have been deposited in the ProteomeXchange with identifier PXD000028. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

NADPH oxidase and redox status in amygdala, hippocampus and cortex of male Wistar rats in an animal model of post-traumatic stress disorder.

PubMed

Petrovic, Romana; Puskas, Laslo; Jevtic Dozudic, Gordana; Stojkovic, Tihomir; Velimirovic, Milica; Nikolic, Tatjana; Zivkovic, Milica; Djorovic, Djordje J; Nenadovic, Milutin; Petronijevic, Natasa

2018-05-26

Post-traumatic stress disorder (PTSD) is a highly prevalent and impairing disorder. Oxidative stress is implicated in its pathogenesis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of free radicals. The aim of the study was to assess oxidative stress parameters, activities of respiratory chain enzymes, and the expression of NADPH oxidase subunits (gp91phox, p22phox, and p67phox) in the single prolonged stress (SPS) animal model of PTSD. Twenty-four (12 controls; 12 subjected to SPS), 9-week-old, male Wistar rats were used. SPS included physical restraint, forced swimming, and ether exposure. The rats were euthanized seven days later. Cortex, hippocampus, amygdala, and thalamus were dissected. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), Complex I, and cytochrome C oxidase were measured using spectrophotometric methods, while the expression of NADPH oxidase subunits was determined by Western blot. Increased MDA and decreased GSH concentrations were found in the amygdala and hippocampus of the SPS rats. SOD activity was decreased in amygdala and GPx was decreased in hippocampus. Increased expression of the NADPH oxidase subunits was seen in amygdala, while mitochondrial respiratory chain enzyme expression was unchanged both in amygdala and hippocampus. In the cortex concentrations of MDA and GSH were unchanged despite increased Complex I and decreased GPx, while in the thalamus no change of any parameter was noticed. We conclude that oxidative stress is present in hippocampus and amygdala seven days after the SPS procedure. NADPH oxidase seems to be a main source of free radicals in the amygdala.

Aged rats are more vulnerable than adolescents to "ecstasy"-induced toxicity.

PubMed

Feio-Azevedo, R; Costa, V M; Barbosa, D J; Teixeira-Gomes, A; Pita, I; Gomes, S; Pereira, F C; Duarte-Araújo, M; Duarte, J A; Marques, F; Fernandes, E; Bastos, M L; Carvalho, F; Capela, J P

2018-06-04

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a widespread drug of abuse with known neurotoxic properties. The present study aimed to evaluate the differential toxic effects of MDMA in adolescent and aged Wistar rats, using doses pharmacologically comparable to humans. Adolescent (post-natal day 40) (3 × 5 mg/kg, 2 h apart) and aged (mean 20 months old) (2 × 5 mg/kg, 2 h apart) rats received MDMA intraperitoneally. Animals were killed 7 days later, and the frontal cortex, hippocampus, striatum and cerebellum brain areas were dissected, and heart, liver and kidneys were collected. MDMA caused hyperthermia in both treated groups, but aged rats had a more dramatic temperature elevation. MDMA promoted serotonergic neurotoxicity only in the hippocampus of aged, but not in the adolescents' brain, and did not change the levels of dopamine or serotonin metabolite in the striatum of both groups. Differential responses according to age were also seen regarding brain p-Tau levels, a hallmark of a degenerative brain, since only aged animals had significant increases. MDMA evoked brain oxidative stress in the hippocampus and striatum of aged, and in the hippocampus, frontal cortex, and striatum brain areas of adolescents according to protein carbonylation, but only decreased GSH levels in the hippocampus of aged animals. The brain maturational stage seems crucial for MDMA-evoked serotonergic neurotoxicity. Aged animals were more susceptible to MDMA-induced tissue damage in the heart and kidneys, and both ages had an increase in liver fibrotic tissue content. In conclusion, age is a determinant factor for the toxic events promoted by "ecstasy". This work demonstrated special susceptibility of aged hippocampus to MDMA neurotoxicity, as well as impressive damage to the heart and kidney tissue following "ecstasy".

Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability

PubMed Central

Wiegand, Jean-Paul L.; Gray, Daniel T.; Schimanski, Lesley A.; Lipa, Peter; Barnes, C. A.

2016-01-01

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (∼70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n = 5) and young (n = 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced “vocabulary” of available representational states. SIGNIFICANCE STATEMENT The hippocampus is a structure that is critical for the formation of episodic memories. Sharp-wave ripple events generated in the hippocampus have been implicated in memory consolidation processes critical to memory stabilization. We examine here whether these ripple oscillations are altered over the course of the life span, which could contribute to hippocampus-dependent memory deficits that occur during aging. This experiment used young and aged memory-impaired rats to examine age-related changes in ripple architecture, ripple-triggered spike variance, and spike-phase coherence. We found that there are, indeed, significant changes in characteristics of ripples in older animals that could impact consolidation processes and memory stabilization in the aged brain. PMID:27194342

Source memory in the rat.

PubMed

Crystal, Jonathon D; Alford, Wesley T; Zhou, Wenyi; Hohmann, Andrea G

2013-03-04

Source memory is a representation of the origin (source) of information. When source information is bound together, it makes a memory episodic, allowing us to differentiate one event from another. Here, we asked whether rats remember the source of encoded information. Rats foraged for distinctive flavors of food that replenished (or failed to replenish) at its recently encountered location according to a source-information rule. To predict replenishment, rats needed to remember where they had encountered a preferred food type (chocolate) with self-generated (walking along a runway encountering chocolate) or experimenter-generated (placement of the rat at the chocolate site by an experimenter) cues. Three lines of evidence implicate the presence of source memory. First, rats selectively adjusted revisits to the chocolate location based on source information, under conditions in which familiarity of events could not produce successful performance. Second, source memory was dissociated from location memory by different decay rates. Third, temporary inactivation of the CA3 region of the hippocampus with lidocaine selectively eliminated source memory, suggesting that source memory is dependent upon an intact hippocampus. Development of an animal model of source memory may be valuable to probe the biological underpinnings of memory disorders marked by impairments in source memory. Copyright © 2013 Elsevier Ltd. All rights reserved.

Diabetic encephalopathy-related depression: experimental evidence that insulin and clonazepam restore antioxidant status in rat brain.

PubMed

Wayhs, Carlos Alberto Yasin; Mescka, Caroline Paula; Guerreiro, Gilian; Moraes, Tarsila Barros; Jacques, Carlos Eduardo Diaz; Rosa, Andrea Pereira; Ferri, Marcelo Kneib; Nin, Maurício Schüler; Dutra-Filho, Carlos Severo; Barros, Helena Maria Tannhauser; Vargas, Carmen Regla

2014-12-01

There is increasing evidence suggesting that oxidative stress plays an important role in the development of many chronic and degenerative conditions such as diabetic encephalopathy and depression. Considering that diabetic rats and mice present higher depressive-like behaviour when submitted to the forced swimming test and that treatment with insulin and/or clonazepam is able to reverse the behavioural changes of the diabetic rats, the present work investigated the antioxidant status, specifically total antioxidant reactivity and antioxidant potential of insulin and clonazepam, as well as the effect of this drugs upon protein oxidative damage and reactive species formation in cortex, hippocampus and striatum from diabetic rats submitted to forced swimming test. It was verified that longer immobility time in diabetic rats and insulin plus clonazepam treatment reversed this depressive-like behaviour. Moreover, data obtained in this study allowed to demonstrate through different parameters such as protein carbonyl content, 2'7'-dichlorofluorescein oxidation, catalase, superoxide dismutase, glutathione peroxidase assay, total radical-trapping antioxidant potential and total antioxidant reactivity that there is oxidative stress in cortex, hippocampus and striatum from diabetic rats under depressive-like behaviour and highlight the insulin and/or clonazepam effect in these different brain areas, restoring antioxidant status and protein damage. Copyright © 2014 John Wiley & Sons, Ltd.

Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia–ischemia

PubMed Central

Rao, Raghavendra; Tkac, Ivan; Townsend, Elise L; Ennis, Kathleen; Gruetter, Rolf; Georgieff, Michael K

2008-01-01

The hippocampus is injured in both hypoxia–ischemia (HI) and perinatal iron deficiency that are comorbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were subjected to unilateral HI injury of 15, 30, or 45 mins (n = 12 to 13/HI duration) on postnatal day 14. Sixteen metabolite concentrations were measured from an 11 μL volume on the ipsilateral (HI) and contralateral (control) hippocampi 1 week later using in vivo 1H NMR spectroscopy. The concentrations of creatine, glutamate, myo-inositol, and N-acetylaspartate were lower on the control side in the iron-deficient group (P < 0.02, each). Magnetic resonance imaging showed hippocampal injury in the majority of the iron-deficient rats (58% versus 11%, P < 0.0001) with worsening severity with increasing durations of HI (P = 0.0001). Glucose, glutamate, N-acetylaspartate, and taurine concentrations were decreased and glutamine, lactate and myo-inositol concentrations, and glutamate/glutamine ratio were increased on the HI side in the iron-deficient group (P < 0.01, each), mainly in the 30 and 45 mins HI subgroups (P < 0.02, each). These neurochemical changes likely reflect the histochemically detected neuronal injury and reactive astrocytosis in the iron-deficient group and suggest that perinatal iron deficiency predisposes the hippocampus to greater injury from exposure to a relatively mild HI insult. PMID:16868555

Treadmill running prevents age-related memory deficit and alters neurotrophic factors and oxidative damage in the hippocampus of Wistar rats.

PubMed

Vanzella, Cláudia; Neves, Juliana Dalibor; Vizuete, Adriana Fernanda; Aristimunha, Dirceu; Kolling, Janaína; Longoni, Aline; Gonçalves, Carlos Alberto Saraiva; Wyse, Angela T S; Netto, Carlos Alexandre

2017-09-15

Clinical and pre-clinical studies indicate that exercise is beneficial to many aspects of brain function especially during aging. The present study investigated the effects of a treadmill running protocol in young (3month-old) and aged (22month-old) male Wistar rats, on: I) cognitive function, as assessed by spatial reference memory in the Morris water maze; II) oxidative stress parameters and the expression of neurotrophic factors BDNF, NT-3, IGF-1 and VEGF in the hippocampus. Animals of both ages were assigned to sedentary (non-exercised) and exercised (20min of daily running sessions, 3 times per week for 4weeks) groups. Cognition was assessed by a reference memory task run in the Morris water maze; twenty four hours after last session of behavioral testing hippocampi were collected for biochemical analysis. Results demonstrate that the moderate treadmill running exercise: I) prevented age-related deficits in reference memory in the Morris water maze; II) prevented the age-related increase of reactive oxygen species levels and lipid peroxidation in the hippocampus; III) caused an increase of BDNF, NT-3 and IGF-1 expression in the hippocampus of aged rats. Taken together, results suggest that both exercise molecular effects, namely the reduction of oxidative stress and the increase of neurotrophic factors expression in the hippocampus, might be related to its positive effect on memory performance in aged rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Exposure to 2.45 GHz electromagnetic fields elicits an HSP-related stress response in rat hippocampus.

PubMed

Yang, Xue-Sen; He, Gen-Lin; Hao, Yu-Tong; Xiao, Yang; Chen, Chun-Hai; Zhang, Guang-Bin; Yu, Zheng-Ping

2012-07-01

The issue of possible neurobiological effects of the electromagnetic field (EMF) exposure is highly controversial. To determine whether electromagnetic field exposure could act as an environmental stimulus capable of producing stress responses, we employed the hippocampus, a sensitive target of electromagnetic radiation, to assess the changes in its stress-related gene and protein expression after EMF exposure. Adult male Sprague-Dawley rats with body restrained were exposed to a 2.45 GHz EMF at a specific absorption rate (SAR) of 6 W/kg or sham conditions. cDNA microarray was performed to examine the changes of gene expression involved in the biological effects of electromagnetic radiation. Of 2048 candidate genes, 23 upregulated and 18 downregulated genes were identified. Of these differential expression genes, two heat shock proteins (HSP), HSP27 and HSP70, are notable because expression levels of both proteins are increased in the rat hippocampus. Result from immunocytochemistry revealed that EMF caused intensive staining for HSP27 and HSP70 in the hippocampus, especially in the pyramidal neurons of cornu ammonis 3 (CA3) and granular cells of dentate gyrus (DG). The gene and protein expression profiles of HSP27 and HSP70 were further confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Our data provide direct evidence that exposure to electromagnetic fields elicits a stress response in the rat hippocampus. Copyright © 2012 Elsevier Inc. All rights reserved.

Association of contextual cues with morphine reward increases neural and synaptic plasticity in the ventral hippocampus of rats.

PubMed

Alvandi, Mina Sadighi; Bourmpoula, Maria; Homberg, Judith R; Fathollahi, Yaghoub

2017-11-01

Drug addiction is associated with aberrant memory and permanent functional changes in neural circuits. It is known that exposure to drugs like morphine is associated with positive emotional states and reward-related memory. However, the underlying mechanisms in terms of neural plasticity in the ventral hippocampus, a region involved in associative memory and emotional behaviors, are not fully understood. Therefore, we measured adult neurogenesis, dendritic spine density and brain-derived neurotrophic factor (BDNF) and TrkB mRNA expression as parameters for synaptic plasticity in the ventral hippocampus. Male Sprague Dawley rats were subjected to the CPP (conditioned place preference) paradigm and received 10 mg/kg morphine. Half of the rats were used to evaluate neurogenesis by immunohistochemical markers Ki67 and doublecortin (DCX). The other half was used for Golgi staining to measure spine density and real-time quantitative reverse transcription-polymerase chain reaction to assess BDNF/TrkB expression levels. We found that morphine-treated rats exhibited more place conditioning as compared with saline-treated rats and animals that were exposed to the CPP without any injections. Locomotor activity did not change significantly. Morphine-induced CPP significantly increased the number of Ki67 and DCX-labeled cells in the ventral dentate gyrus. Additionally, we found increased dendritic spine density in both CA1 and dentate gyrus and an enhancement of BDNF/TrkB mRNA levels in the whole ventral hippocampus. Ki67, DCX and spine density were significantly correlated with CPP scores. In conclusion, we show that morphine-induced reward-related memory is associated with neural and synaptic plasticity changes in the ventral hippocampus. Such neural changes could underlie context-induced drug relapse. © 2017 Society for the Study of Addiction.

Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism.

PubMed

Wu, Hongmei; Wang, Xuelai; Gao, Jingquan; Liang, Shuang; Hao, Yanqiu; Sun, Caihong; Xia, Wei; Cao, Yonggang; Wu, Lijie

2017-03-15

To investigate the effect of FTY720 on the valproic acid (VPA) rat model of autism. As an animal model of autism, we used intraperitoneal injection of VPA on embryonic day 12.5 in Wistar rats. The pups were given FTY720 orally at doses of 0.25, 0.5 and 1mg/kg daily from postnatal day 15 to 35. Social behavior, spatial learning and memory were assessed at the end of FTY720 treatment. The histological change, oxidative stress, neuroinflammatory responses, and apoptosis-related proteins in the hippocampus were evaluated. FTY720 (1mg/kg) administration to VPA-exposed rats (1) improved social behavior, spatial learning and memory impairment; (2) resulted in a reduction in neuronal loss and apoptosis of pyramidal cells in hippocampal CA1 regions; (3) inhibited activation of microglial cells, in turn lowering the level of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-6 in the hippocampus; (4) changed Malondialdehyde (MDA) levels, Glutathione (GSH) levels, superoxide dismutase (SOD) activity and Glutathione Peroxidase (GSH-Px) activity in the hippocampus; (6) inhibited the elevated Bax and caspase-3 protein levels and enhanced the relative expression level of Bcl-2 in the hippocampus; and (7) increased phospho-Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), phospho-cAMP-response element binding protein (p-CREB) and Brain Derived Neurotrophic Factor (BDNF) protein expression in the hippocampus. FTY720 rescues social deficit, spatial learning and memory impairment in VPA-exposed rats. FTY720 exerts both a direct protection for neurons and an indirect modulation of inflammation-mediated neuron loss as a possible mechanism of neuroprotection. Copyright © 2017. Published by Elsevier Inc.

ELECTROACUPUNCTURE AT THE WANGU ACUPOINT SUPPRESSES EXPRESSION OF INFLAMMATORY CYTOKINES IN THE HIPPOCAMPUS OF RATS WITH VASCULAR DEMENTIA.

PubMed

Fang, Yanan; Sui, Rubo

2016-01-01

Vascular dementia (VD) is the most frequent psychiatric complication of stroke, and is often difficult to treat. Incidence rate of vascular cognition impairment is still 70% after stroke in one year (Sui R et al.2011). Stroke patients with VD suffer from a higher mortality rate and have worse functional outcomes and quality of life. However, despite the extensive literatures on this topic, there is no agreement on the causal mechanisms and effective therapy for VD. The objective of this study is to examine if electroacupuncture at the Wangu acupoint (GB 12), whose position is similar to the cerebellar fastigial nucleus, could reduce inflammatory cytokines in the hippocampus of rats with vascular dementia (VD). The 54 healthy, male, Sprague-Dawley (SD) rats, 9 months old, and of clean grade (300-450) g, were randomly divided into three groups: sham surgery group, VD group and electro-acupuncture group. The ethology scores of VD rats were evaluated and the mRNA expressions of inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the hippocampus were assessed and the hippocampal tissues were observed by hematoxylin-eosin staining. Compared with the VD group, in the electroacupuncture group, the rats' learning ability improved significantly and the mRNA expression of TNF-α, IL-6 and IL-1β decreased. Simultaneously, the damage extent of nerve cells in the hippocampal tissues decreased, with their morphology recovered to nearly normal. Electro-acupuncture at the Wangu acupoint can decrease the levels of inflammatory cytokines in the hippocampus, reduce the damage extent of nerve cells in the hippocampus, and thus provide a new neuroprotective method in VD.

Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion.

PubMed

Lee, Sun-Young; Cho, Woo-Hyun; Lee, Yo-Seob; Han, Jung-Soo

2018-05-01

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer's disease to stress since activation of NF-κB is associated with stress.

Daily rhythms of catalase and glutathione peroxidase expression and activity are endogenously driven in the hippocampus and are modified by a vitamin A-free diet.

PubMed

Navigatore-Fonzo, Lorena S; Delgado, Silvia M; Gimenez, Maria Sofia; Anzulovich, Ana C

2014-01-01

Alterations in enzymatic antioxidant defense systems lead to a deficit of cognitive functions and altered hippocampal synaptic plasticity. The objectives of this study were to investigate endogenous rhythms of catalase (CAT) and glutathione peroxidase (GPx) expression and activity, as well as CREB1 mRNA, in the rat hippocampus, and to evaluate to which extent the vitamin A deficiency could affect those temporal patterns. Rats from control and vitamin A-deficient (VAD) groups received a diet containing 4000 IU of vitamin A/kg diet, or the same diet devoid of vitamin A, respectively, during 3 months. Rats were maintained under 12-hour-dark conditions, during 10 days before the sacrifice. Circadian rhythms of CAT, GPx, RXRγ, and CREB1 mRNA levels were determined by reverse transcriptrase polymerase chain reaction in hippocampus samples isolated every 4 hours during a 24-hour period. CAT and GPx enzymatic activities were also determined by kinetic assays. Regulatory regions of clock and antioxidant enzymes genes were scanned for E-box, RXRE, and CRE sites. E-box, RXRE, and CRE sites were found on regulatory regions of GPx and CAT genes, which display a circadian expression in the rat hippocampus. VAD phase shifted CAT, GPx, and RXRγ endogenous rhythms without affecting circadian expression of CREB1. CAT and GPx expression and enzymatic activity are circadian in the rat hippocampus. The VAD affected the temporal patterns antioxidant genes expression, probably by altering circadian rhythms of its RXR receptors and clock factors; thus, it would impair the temporal orchestration of hippocampal daily cognitive performance.

Stabilization of HIF-1α modulates VEGF and Caspase-3 in the hippocampus of rats following transient global ischemia induced by asphyxial cardiac arrest.

PubMed

Liu, Xiao-Liang; Lu, Jian; Xing, Jihong

2016-04-15

Hypoxia inducible factor-1 (HIF-1) contributes to pathophysiological changes of homeostasis under conditions of oxygen deprivation as well as ischemia. In this study, we examined protein expression of subtype HIF-1α and its downstream product, namely vascular endothelial growth factor (VEGF) in the rat hippocampus after transient global ischemia induced by asphyxial cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We also examined the effects of stabilization of HIF-1α by systemic administration of dimethyloxalylglycine (DMOG) and ML228 on expression of VEGF receptor subtype 2 (VEGFR-2), Caspase-3 and NF-kB in the hippocampus. Ninety-six adult Sprague-Dawley rats were used in this study. The animals surviving from CPR were sacrificed 0, 3, 6 and 24h following CPR and the protein levels of HIF-1α and VEGF in the hippocampus were determined. VEGFR-2, Caspase-3 and NF-kB were also examined in control rats, and rats that survived for 24h after CPR and were given with DMOG/ML228. Moreover, neurological functions were estimated in control rats and rats with DMOG/ML228. Our results show that HIF-1α and VEGF were significantly increased in the hippocampus 3-24h after CA. Significant increases in VEGFR-2, Caspase-3 and NF-κB were observed in the hippocampus 24h after CA (P<0.05 vs. control group). Nonetheless, DMOG and ML228 significantly augmented VEGFR-2, attenuated Caspase-3 and neuronal apoptosis, and improved neurological Severity Score and tissue edema (P<0.05 vs. saline group), without affecting expression of NF-κB. Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that HIF-1α plays an important role in regulating expression of VEGFR-2 and Caspase-3 as well as improving neurological functions and neuronal edema. The subsequent induction of HIF-1α and its target signal pathways is likely a part of the intrinsic neuroprotective effects aimed at attenuating damage as a result of global cerebral ischemia. Thus, targeting one or more of these signaling molecules has clinical implications for treatment and management of CA-evoked global cerebral ischemia often observed in clinics. Copyright © 2016 Elsevier Inc. All rights reserved.

Hippocampal volume is decreased in adults with hypothyroidism.

PubMed

Cooke, Gillian E; Mullally, Sinead; Correia, Neuman; O'Mara, Shane M; Gibney, James

2014-03-01

Thyroid hormones are important for the adult brain, particularly regions of the hippocampus including the dentate gyrus and CA1 and CA3 regions. The hippocampus is a thyroid hormone receptor-rich region of the brain involved in learning and memory. Consequently, alterations in thyroid hormone levels have been reported to impair hippocampal-associated learning and memory, synaptic plasticity, and neurogenesis. While these effects have been shown primarily in developing rats, as well as in adult rats, little is known about the effects in adult humans. There are currently no data regarding structural changes in the hippocampus as a result of adult-onset hypothyroidism. We aimed to establish whether hippocampal volume was reduced in patients with untreated adult-onset hypothyroidism compared to age-matched healthy controls. High-resolution magnetization-prepared rapid acquisition with gradient echo (MPRAGE) scans were performed on 11 untreated hypothyroid adults and 9 age-matched control subjects. Hypothyroidism was diagnosed based on increased levels of thyrotropin (TSH) and reduced levels of free thyroxine (fT4). Volumetric analysis of the right and left hippocampal regions, using functional magnetic resonance imaging of the brain (FMRIB) integrated registration and segmentation tool (FIRST), demonstrated significant volume reduction in the right hippocampus in the hypothyroid patients relative to the control group. These findings provide preliminary evidence that hypothyroidism results in structural deficits in the adult human brain. Decreases in volume in the right hippocampus were evident in patients with adult-onset overt hypothyroidism, supporting some of the findings in animal models.

Aspartic acid in the hippocampus: a biomarker for postoperative cognitive dysfunction

PubMed Central

Hu, Rong; Huang, Dong; Tong, Jianbin; Liao, Qin; Hu, Zhonghua; Ouyang, Wen

2014-01-01

This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction. PMID:25206795

Aspartic acid in the hippocampus: a biomarker for postoperative cognitive dysfunction.

PubMed

Hu, Rong; Huang, Dong; Tong, Jianbin; Liao, Qin; Hu, Zhonghua; Ouyang, Wen

2014-01-15

This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.

Neuroprotective actions of the synthetic estrogen 17alpha-ethynylestradiol in the hippocampus.

PubMed

Picazo, Ofir; Becerril-Montes, Adriana; Huidobro-Perez, Delia; Garcia-Segura, Luis M

2010-07-01

17alpha-ethynylestradiol (EE2), a major constituent of many oral contraceptives, is similar in structure to 17beta-estradiol, which has neuroprotective properties in several animal models. This study explored the potential neuroprotective actions of EE2 against kainic and quinolinic acid toxicity in the hippocampus of adult ovariectomized Wistar rats. A decrease in the number of Nissl-stained neurons and the induction of vimentin immunoreactivity in astrocytes was observed in the hilus of the dentate gyrus of the hippocampus after the administration of either kainic acid or quinolinic acid. EE2 prevented the neuronal loss and the induction of vimentin immunoreactivity induced by kainic acid at low (1 microg/rat) and high (10-100 microg/rat) doses and exerted a protection against quinolinic acid toxicity at a low dose (1 microg/rat) only. These observations demonstrate that EE2 exerts neuroprotective actions against excitotoxic insults. This finding is relevant for the design of new neuroprotective estrogenic compounds.

Enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in rats.

PubMed

Haider, Saida; Khaliq, Saima; Haleem, Darakhshan J

2007-01-01

Increasing evidence shows that serotonin (5-hydroxytryptamine - 5-HT) plays a modulatory role in memory functions. 5-HT transmission has been implicated in learning and memory. Both 5-HT depletion and specific 5-HT agonists lower memory performance. Hippocampus is thought to be the key region involved in long-term memory. It is the major limbic target of the brainstem serotonergic neurons that modulate learning. In the present study, we examined the effects of increased hippocampal 5-HT metabolism following tryptophan (TRP) administration on short-term memory (STM) and long-term memory (LTM) in rats. Learning acquisition (LA) and memory consolidation (MC) in rats was also evaluated. TRP at 50 mg/kg and 100 mg/kg body weight was used. Assessment of memory in rats was done using the water maze test (WM) after 6 weeks of daily administration of TRP. The results showed that administration of TRP enhanced both STM and LTM. However, the effect on STM was significant only at the higher dose. Rats administered the higher dose of TRP also exhibited a significant enhancement in LA. A significant effect on MC was also observed in tryptophan-treated rats. The results suggest that serotonergic system in the hippocampus is important in LA and MC in rats.

Effects of propofol and dizocilpine maleate on the cognitive abilities and the hyperphosphorylation of Tau protein of rats after the electroconvulsive therapy.

PubMed

Liu, Chao; Min, Su; Wei, Ke; Liu, Dong; Dong, Jun; Luo, Jie; Li, Ping; Liu, Xiao-bin

2012-08-01

To explore the effects of propofol and dizocilpine maleate (MK-801) on the cognitive abilities the hyperphosphorylation of Tau protein of rats after the electroconvulsive therapy. Two intervention factors including electroconvulsive shock therapy (ECT) (two levels: not applied and one treatment course) and drug intervention (three levels: intravenous saline,intravenous MK-801, and intravenous propofol). The morris water maze test started within 1 day after ECT to evaluate the learning-memory. The glutamate level in the hippocampus of rats was determined by high-performance liquid chromatography. The Tau protein that includes Tau5 (total Tau protein), PHF-1 (pSer(396/404)), AT8 (pSer(199/202)), and 12E8 (pSer(262)) in the hippocampus of rats was determined using Western blotting. Propofol, MK-801, and ECT could induce the impairment of learning-memory in depressed rats. The electroconvulsive shock significantly up-regulated the glutamate level, which was reduces by the propofol. The ECT up-regulated the hyperphosphorylation of Tau protein in the hippocampus of depressed rats, which was reduced by propofol and MK-801. Both propofol and MK-801 could protect against the impairment of learning-memory and reduce the hyperphosphorylation of Tau protein induced by ECT in depressed rats.

Apigenin attenuates diabetes-associated cognitive decline in rats via suppressing oxidative stress and nitric oxide synthase pathway

PubMed Central

Mao, Xiao-Yuan; Yu, Jing; Liu, Zhao-Qian; Zhou, Hong-Hao

2015-01-01

Our present investigation aimed to determine the neuroprotection of apigenin (API) against diabetes-associated cognitive decline (DACD) a diabetic rat model and exploring its potential mechanism. Diabetic rat model was induced by intraperitoneal injection of streptozotocin. All experiment animals treated with vehicle or API by doses of 10, 20 and 40 mg/kg for seven weeks. Firstly, the body weight and blood glucose levels were detected. We used Morris water maze test to evaluate learning and memory function. The oxidative indicators (malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH)), cNOS, iNOS, caspase-3 and caspase-9 were measured in cerebral cortex and hippocampus using corresponding commercial kits. API can increase body weight, reduce the blood glucose levels, and improve the cognitive function in rats induced by diabetes. API decrease the MDA content, and increase SOD activity and GSH level of diabetic animals in the cerebral cortex and hippocampus of diabetic rats. Meanwhile, constitutive nitric oxide synthase (cNOS), inducible nitric oxide synthase (iNOS), caspase-3/9 were markedly exhibited in the cerebral cortex and hippocampus of diabetic rats. In summary, our current work discloses that API attenuates DACD in rats via suppressing oxidative stress, nitric oxide and apoptotic cascades synthase pathway. PMID:26629041

Hippocampal damage impairs long-term spatial memory in rats: comparison between electrolytic and neurotoxic lesions.

PubMed

Ramos, Juan M J

2008-03-18

In previous studies we have suggested that the dorsal hippocampus is involved in spatial consolidation by showing that rats with electrolytic hippocampal lesions exhibit a profound deficit in the retention of an allocentric task 24 days after the acquisition. However, in various hippocampal-dependent tasks, several studies have shown an overestimation of the behavioral deficit when electrolytic versus axon-sparing cytotoxic lesions has been used. For this reason, in this report we compare the effects on spatial retention of electrolytic and neurotoxic lesions to the dorsal hippocampus. Results showed a similar deficit in spatial retention in both groups 24 days after acquisition. Thus, the hippocampus proper and not fibers of passage or extrahippocampal damage is directly responsible for the deficit in spatial retention seen in rats with electrolytic lesions.

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

PubMed

Gemmel, Mary; Rayen, Ine; Lotus, Tiffany; van Donkelaar, Eva; Steinbusch, Harry W; De Lacalle, Sonsoles; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

2016-04-01

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc.

Acetylcholine Release in the Hippocampus and Striatum during Place and Response Training

ERIC Educational Resources Information Center

Pych, Jason C.; Chang, Qing; Colon-Rivera, Cynthia; Haag, Renee; Gold, Paul E.

2005-01-01

These experiments examined the release of acetylcholine in the hippocampus and striatum when rats were trained, within single sessions, on place or response versions of food-rewarded mazes. Microdialysis samples of extra-cellular fluid were collected from the hippocampus and striatum at 5-min increments before, during, and after training. These…

A study on fear memory retrieval and REM sleep in maternal separation and isolation stressed rats.

PubMed

Sampath, Dayalan; Sabitha, K R; Hegde, Preethi; Jayakrishnan, H R; Kutty, Bindu M; Chattarji, Sumantra; Rangarajan, Govindan; Laxmi, T R

2014-10-15

As rapid brain development occurs during the neonatal period, environmental manipulation during this period may have a significant impact on sleep and memory functions. Moreover, rapid eye movement (REM) sleep plays an important role in integrating new information with the previously stored emotional experience. Hence, the impact of early maternal separation and isolation stress (MS) during the stress hyporesponsive period (SHRP) on fear memory retention and sleep in rats were studied. The neonatal rats were subjected to maternal separation and isolation stress during postnatal days 5-7 (6h daily/3d). Polysomnographic recordings and differential fear conditioning was carried out in two different sets of rats aged 2 months. The neuronal replay during REM sleep was analyzed using different parameters. MS rats showed increased time in REM stage and total sleep period also increased. MS rats showed fear generalization with increased fear memory retention than normal control (NC). The detailed analysis of the local field potentials across different time periods of REM sleep showed increased theta oscillations in the hippocampus, amygdala and cortical circuits. Our findings suggest that stress during SHRP has sensitized the hippocampus-amygdala-cortical loops which could be due to increased release of corticosterone that generally occurs during REM sleep. These rats when subjected to fear conditioning exhibit increased fear memory and increased fear generalization. The development of helplessness, anxiety and sleep changes in human patients, thus, could be related to the reduced thermal, tactile and social stimulation during SHRP on brain plasticity and fear memory functions. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.

PubMed

Yadav, Rajesh S; Chandravanshi, Lalit P; Shukla, Rajendra K; Sankhwar, Madhu L; Ansari, Reyaz W; Shukla, Pradeep K; Pant, Aditya B; Khanna, Vinay K

2011-12-01

Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. Copyright © 2011 Elsevier Inc. All rights reserved.

Juvenile Taiep rats have shorter dendritic trees in the dorsal field of the hippocampus without spatial learning disabilities.

PubMed

Silva-Gómez, Adriana B; Bravo-Duran, Dolores A; Eguibar, Jose R; Cortes, Carmen

2018-06-01

Myelin mutant taiep rats show a progressive demyelination in the central nervous system due to an abnormal accumulation of microtubules in the cytoplasm and the processes on their oligodendrocytes. Demyelination is associated with electrophysiological alterations and the mutant had a progressive astrocytosis. The illness is associated with change in cytokine levels and in the expression of different nitric oxide synthase and concomitantly lipoperoxidation in several areas of the brain. However, until now there has been no detailed anatomical analysis of neurons in this mutant. The aim of this study was to analyze the dendritic morphology in the hippocampus using Golgi-Cox staining and spatial memory through Morris water maze test in young adult (3 months old) taiep rats and compare them with normal Sprague-Dawley. Our results showed that taiep rats have altered dendritic tree morphology in pyramidal neurons in the CA1 field of the hippocampus, but not in the CA3 region. These morphological changes did not produce a concomitant deficit in spatial memory acquisition or recall at this early stage of the disease. Our results suggest that impairment of dendritic morphology in the CA1 field of the hippocampus is a landmark of the pathology of this progressive multiple sclerosis model. © 2018 Wiley Periodicals, Inc.

Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B.

PubMed

Kuga, Gabriel Keine; Muñoz, Vitor Rosetto; Gaspar, Rafael Calais; Nakandakari, Susana Castelo Branco Ramos; da Silva, Adelino Sanchez Ramos; Botezelli, José Diego; Leme, José Alexandre Curiacos de Almeida; Gomes, Ricardo José; de Moura, Leandro Pereira; Cintra, Dennys Esper; Ropelle, Eduardo Rochete; Pauli, José Rodrigo

2018-04-01

The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promotes synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer's Disease (AD). The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies. In this context, our study aims to investigate the age-related changes in PTP1B content, insulin signaling, β-amyloid content, and Tau phosphorylation in the hippocampus of middle-aged rats. Young (3 months) and middle-aged (17 months) Wistar rats were submitted to Morris-water maze (MWM) test, insulin tolerance test, and molecular analysis in the hippocampus. Aging resulted in increased body weight, and insulin resistance and decreases learning process in MWM. Interestingly, the middle-aged rats have higher levels of PTP-1B, lower phosphorylation of IRS-1, Akt, GSK3β, mTOR, and TrkB. Also, the aging process increased Tau phosphorylation and β-amyloid content in the hippocampus region. In summary, this study provides new evidence that aging-related PTP1B increasing, contributing to insulin resistance and the onset of the AD. Copyright © 2018 Elsevier Inc. All rights reserved.

THE ROLE OF THE HIPPOCAMPUS IN OBJECT DISCRIMINATION BASED ON VISUAL FEATURES.

PubMed

Levcik, David; Nekovarova, Tereza; Antosova, Eliska; Stuchlik, Ales; Klement, Daniel

2018-06-07

The role of rodent hippocampus has been intensively studied in different cognitive tasks. However, its role in discrimination of objects remains controversial due to conflicting findings. We tested whether the number and type of features available for the identification of objects might affect the strategy (hippocampal-independent vs. hippocampal-dependent) that rats adopt to solve object discrimination tasks. We trained rats to discriminate 2D visual objects presented on a computer screen. The objects were defined either by their shape only or by multiple-features (a combination of filling pattern and brightness in addition to the shape). Our data showed that objects displayed as simple geometric shapes are not discriminated by trained rats after their hippocampi had been bilaterally inactivated by the GABA A -agonist muscimol. On the other hand, objects containing a specific combination of non-geometric features in addition to the shape are discriminated even without the hippocampus. Our results suggest that the involvement of the hippocampus in visual object discrimination depends on the abundance of object's features. Copyright © 2018. Published by Elsevier Inc.

Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

PubMed Central

Wang, Jun-Ying; Chen, Renbo; Feng, Xiu-Mei; Yan, Yaxia; Lippe, Irmgard Th.

2016-01-01

To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia. PMID:27833763

COGNITIVE IMPAIRMENT AND MORPHOLOGICAL CHANGES IN THE DORSAL HIPPOCAMPUS OF VERY OLD FEMALE RATS

PubMed Central

Morel, Gustavo R.; Andersen, Tomás; Pardo, Joaquín; Zuccolilli, Gustavo O.; Cambiaggi, Vanina L.; Hereñú, Claudia B.; Goya, Rodolfo G.

2015-01-01

The hippocampus, a medial temporal lobe structure necessary for the formation of spatial memory, is particularly affected by both normal and pathologic aging. In previous studies, we observed a significant age-related increase in dopaminergic neuron loss in the hypothalamus and the substantia nigra of female rats, which becomes more conspicuous at extreme ages. Here, we extend our studies by assessing spatial memory 4–6 months old (young), 26 months old (old) and 29–32 months old (senile) Sprague–Dawley female rats as well as the age-related histopathological changes in their dorsal hippocampus. Age changes in spatial memory performance were assessed with a modified version of the Barnes maze test. We employed two probe trials (PT), one and five days after training, respectively, in order to evaluate learning ability as well as short-term and longer-term spatial memory retention. A set of relevant hippocampal cell markers was also quantitated in the animals by means of an unbiased stereological approach. The results revealed that old rats perform better than senile rats in acquisition trials and young rats perform better than both aging groups. However, during short-term PT both aging groups showed a preserved spatial memory while in longer-term PT, spatial memory showed deterioration in both aged groups. Morphological analysis showed a marked decrease (94–97%) in doublecortin neuron number in the dentate gyrus in both aged groups and a reduction in glial fibrillary acidic protein-positive cell number in the stratum radiatum of aging rats. Astroglial process length and branching complexity decreased in the aged rats. We conclude that while target-seeking activity and learning ability decrease in aged females, spatial memory only declines in the longer-term tests. The reduction in neuroblast number and astroglial arborescence complexity in the dorsal hippocampus are likely to play a role in the cognitive deficits of aging rats. PMID:26141841

Extremely weak magnetic field exposure may inhibit hippocampal neurogenesis of Sprague Dawley rats

NASA Astrophysics Data System (ADS)

Zhang, B.; Tian, L.; Cai, Y.; Xu, H.; Pan, Y.

2016-12-01

Hippocampal neurogenesis occurs throughout life in mammals brains and can be influenced by animals' age as well as environmental factors. Lines of evidences have shown that the magnetic field is an important physics environmental factor influencing many animals' growth and development, and extremely weak magnetic field exposures have been proved having serious adverse effects on the metabolism and behaviors in some animals, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we experimentally examined the extremely weak magnetic field effects on neurogenesis of the dentate gyrus (DG) of hippocampus of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, an extremely weak magnetic field (≤ 0.5μT) and the geomagnetic fields (strength 31-58μT) as controls. Thirty-two SD rats (3-weeks old) were used in this study. New cell survival in hippocampus was assessed at 0, 14, 28, and 42 days after a 7-day intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU). Meanwhile, the amounts of immature neurons and mature neurons which are both related to hippocampal neurogenesis, as documented by labeling with doublecortin (DCX) and neuron (NeuN), respectively, were also analyzed at 0, 14, 28, and 42 days. Compared with geomagnetic field exposure groups, numbers of BrdU-, DCX-positive cells of DG of hippocampus in tested rats reduces monotonously and more rapidly after 14 days, and NeuN-positive cells significantly decreases after 28days when exposed in the extremely weak magnetic field condition. Our data suggest that the exposure to an extremely weak magnetic field may suppress the neurogenesis in DG of SD rats.

Hippocampal-dependent Pavlovian conditioning in adult rats exposed to binge-like doses of ethanol as neonates.

PubMed

Lindquist, Derick H

2013-04-01

Binge-like postnatal ethanol exposure produces significant damage throughout the brain in rats, including the cerebellum and hippocampus. In the current study, cue- and context-mediated Pavlovian conditioning were assessed in adult rats exposed to moderately low (3E; 3g/kg/day) or high (5E; 5g/kg/day) doses of ethanol across postnatal days 4-9. Ethanol-exposed and control groups were presented with 8 sessions of trace eyeblink conditioning followed by another 8 sessions of delay eyeblink conditioning, with an altered context presented over the last two sessions. Both forms of conditioning rely on the brainstem and cerebellum, while the more difficult trace conditioning also requires the hippocampus. The hippocampus is also needed to gate or modulate expression of the eyeblink conditioned response (CR) based on contextual cues. Results indicate that the ethanol-exposed rats were not significantly impaired in trace EBC relative to control subjects. In terms of CR topography, peak amplitude was significantly reduced by both doses of alcohol, whereas onset latency but not peak latency was significantly lengthened in the 5E rats across the latter half of delay EBC in the original training context. Neither dosage resulted in significant impairment in the contextual gating of the behavioral response, as revealed by similar decreases in CR production across all four treatment groups following introduction of the novel context. Results suggest ethanol-induced brainstem-cerebellar damage can account for the present results, independent of the putative disruption in hippocampal development and function proposed to occur following postnatal ethanol exposure. Copyright © 2013 Elsevier B.V. All rights reserved.

Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus.

PubMed

Foffani, Guglielmo; Uzcategui, Yoryani G; Gal, Beatriz; Menendez de la Prida, Liset

2007-09-20

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.

Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus.

PubMed

Takeda, Atsushi; Itagaki, Kosuke; Ando, Masaki; Oku, Naoto

2012-03-01

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus. Copyright © 2011 Wiley Periodicals, Inc.

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus.

PubMed

Rao, Raghavendra; Nashawaty, Motaz; Fatima, Saher; Ennis, Kathleen; Tkac, Ivan

2018-05-01

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo 1 H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs. Copyright © 2018 John Wiley & Sons, Ltd.

Voxelized Computational Model for Convection-Enhanced Delivery in the Rat Ventral Hippocampus: Comparison with In Vivo MR Experimental Studies

PubMed Central

Kim, Jung Hwan; Astary, Garrett W.; Kantorovich, Svetlana; Mareci, Thomas H.; Carney, Paul R.; Sarntinoranont, Malisa

2012-01-01

Convection-enhanced delivery (CED) is a promising local delivery technique for overcoming the blood–brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, therapeutics are infused directly into brain tissue and the drug agent is spread through the extracellular space, considered to be highly tortuous porous media. In this study, 3D computational models developed using magnetic resonance (MR) diffusion tensor imaging data sets were used to predict CED transport in the rat ventral hippocampus using a voxelized modeling previously developed by our group. Predicted albumin tracer distributions were compared with MR-measured distributions from in vivo CED in the ventral hippocampus up to 10 μL of Gd-DTPA albumin tracer infusion. Predicted and measured tissue distribution volumes and distribution patterns after 5 and 10 μL infusions were found to be comparable. Tracers were found to occupy the underlying landmark structures with preferential transport found in regions with less fluid resistance such as the molecular layer of the dentate gyrus. Also, tracer spread was bounded by high fluid resistance layers such as the granular cell layer and pyramidal cell layer of dentate gyrus. Leakage of tracers into adjacent CSF spaces was observed towards the end of infusions. PMID:22532321

Cognition Enhancing and Neuromodulatory Propensity of Bacopa monniera Extract Against Scopolamine Induced Cognitive Impairments in Rat Hippocampus.

PubMed

Pandareesh, M D; Anand, T; Khanum, Farhath

2016-05-01

Cognition-enhancing activity of Bacopa monniera extract (BME) was evaluated against scopolamine-induced amnesic rats by novel object recognition test (NOR), elevated plus maze (EPM) and Morris water maze (MWM) tests. Scopolamine (2 mg/kg body wt, i.p.) was used to induce amnesia in rats. Piracetam (200 mg/kg body wt, i.p.) was used as positive control. BME at three different dosages (i.e., 10, 20 and 40 mg/kg body wt.) improved the impairment induced by scopolamine by increasing the discrimination index of NOR and by decreasing the transfer latency of EPM and escape latency of MWM tests. Our results further elucidate that BME administration has normalized the neurotransmitters (acetylcholine, glutamate, 5-hydroxytryptamine, dopamine, 3,4 dihydroxyphenylacetic acid, norepinephrine) levels that were altered by scopolamine administration in hippocampus of rat brain. BME administration also ameliorated scopolamine effect by down-regulating AChE and up-regulating BDNF, muscarinic M1 receptor and CREB expression in brain hippocampus confirms the potent neuroprotective role and these results are in corroboration with the earlier in vitro studies. BME administration showed significant protection against scopolamine-induced toxicity by restoring the levels of antioxidant and lipid peroxidation. These results indicate that, cognition-enhancing and neuromodulatory propensity of BME is through modulating the expression of AChE, BDNF, MUS-1, CREB and also by altering the levels of neurotransmitters in hippocampus of rat brain.

The Effects of Lycopene and Insulin on Histological Changes and the Expression Level of Bcl-2 Family Genes in the Hippocampus of Streptozotocin-Induced Diabetic Rats.

PubMed

Soleymaninejad, Masoume; Joursaraei, Seyed Gholamali; Feizi, Farideh; Jafari Anarkooli, Iraj

2017-01-01

The aim of this study was to evaluate the effects of antioxidants lycopene and insulin on histological changes and expression of Bcl-2 family genes in the hippocampus of streptozotocin-induced type 1 diabetic rats. Forty-eight Wistar rats were divided into six groups of control (C), control treated with lycopene (CL), diabetic (D), diabetic treated with insulin (DI), diabetic treated with lycopene (DL), and diabetic treated with insulin and lycopene (DIL). Diabetes was induced by an injection of streptozotocin (60 mg/kg, IP), lycopene (4 mg/kg/day) was given to the lycopene treated groups as gavages, and insulin (Sc, 1-2 U/kg/day) was injected to the groups treated with insulin. The number of hippocampus neurons undergoing cell death in group D had significant differences with groups C and DIL ( p < 0.001). Furthermore, insulin and lycopene alone or together reduced the expression of Bax , but increased Bcl-2 and Bcl-x L levels in DI, DL, and DIL rats, especially when compared to group D ( p < 0.001). The ratios of Bax/Bcl-2 and Bax/Bcl-xL in DI, DL, and DIL rats were also reduced ( p < 0.001). Our results indicate that treatment with insulin and/or lycopene contribute to the prevention of cell death by reducing the expression of proapoptotic genes and increasing the expression of antiapoptotic genes in the hippocampus.

Ethanol intake and sup 3 H-serotonin uptake I: A study in Fawn-Hooded rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daoust, M.; Compagnon, P.; Legrand, E.

1991-01-01

Ethanol intake and synaptosomal {sup 3}H-serotonin uptake were studied in male Fawn-Hooded and Sprague-Dawley rats. Fawn-Hooded rats consumed more alcohol and more water than Sprague-Dawley rats. Plasma alcohol levels of Sprague-Dawley rats were not detectable but were about 5 mg/dl in Fawn-Hooded rats. Ethanol intake increased the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex, but not in thalamus. In Fawn-Hooded rats, serotonin uptake (Vmax) was higher than in Sprague-Dawley rats cortex. Ethanol intake reduced the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex. In cortex, the carrier affinity for serotonin was increased inmore » alcoholized Fawn-Hooded rats. These results indicate that synaptosomal {sup 3}H-serotonin uptake is affected by ethanol intake. In Fawn-Hooded rats, high ethanol consumption is associated with high serotonin uptake. In rats presenting high serotonin uptake, alcoholization reduces {sup 3}H-serotonin internalization in synaptosomes, indicating a specific sensitivity to alcohol intake of serotonin uptake system.« less

Acetylation of histones in neocortex and hippocampus of rats exposed to different modes of hypobaric hypoxia: Implications for brain hypoxic injury and tolerance.

PubMed

Samoilov, Mikhail; Churilova, Anna; Gluschenko, Tatjana; Vetrovoy, Oleg; Dyuzhikova, Natalia; Rybnikova, Elena

2016-03-01

Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180mm Hg, 3h) and neuroprotective preconditioning mode (three episodes of 360mm Hg for 2h spaced at 24h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II-III, V) and hippocampus (CA1, CA3) by 3-24h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24h, whereas acetylation of H3K24 was intense but transient, peaked at 3h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance. Copyright © 2015 Elsevier GmbH. All rights reserved.

Spatial problem-solving in a wheel-shaped maze: quantitative and qualitative analyses of the behavioural changes following damage to the hippocampus in the rat.

PubMed

Buhot, M C; Chapuis, N; Scardigli, P; Herrmann, T

1991-07-01

The behaviour of sham-operated rats and rats with damage to the dorsal hippocampus was compared in a complex spatial problem-solving task using a 'hub-spoke-rim' wheel type maze. Compared to the classical Olton 8-arm radial maze and Morris water maze, this apparatus presents the animal with a series of possible alternative routes both direct and indirect to the goal (food). The task included 3 main stages: exploration, feeding and testing, as do the classic problem-solving tasks. During exploration, hippocampal rats were found to be more active than sham rats. Nevertheless, they displayed habituation and a relatively efficient circumnavigation, though, in both cases, different from those of sham rats. During test trials, hippocampal rats were characterized as being less accurate, making more errors than sham rats. Nevertheless, both groups increased their accuracy of first choices over trials. The qualitative analyses of test trial performance indicated that hippocampal rats were less accurate in terms of the initial error's deviation from the goal, and less efficient in terms of corrective behaviour than sham rats which used either the periphery or the spokes to attain economically the goal. Surprisingly, hippocampal rats were not limited to a taxon type orientation but learned to use the periphery, a tendency which developed over time. Seemingly, for sham rats, the problem-solving process took the form of updating information during transit. For hippocampal rats, the use of periphery reflected both an ability to discriminate its usefulness in reaching the goal via a taxis type behaviour, and some sparing of ability to generalize the closeness and the location of the goal. These results, especially the strategic correction patterns, are discussed in the light of Sutherland and Rudy's 'configurational association theory'.

Indomethacin can downregulate the levels of inflammatory mediators in the hippocampus of rats submitted to pilocarpine-induced status epilepticus

PubMed Central

Vieira, Michele Juliane; Perosa, Sandra Regina; Argañaraz, Gustavo Adolfo; Silva, José Antônio; Cavalheiro, Esper Abrão; da Graça Naffah-Mazzacoratti, Maria

2014-01-01

OBJECTIVE: Refractory status epilepticus is one of the most life-threatening neurological emergencies and is characterized by high morbidity and mortality. Additionally, the use of anti-inflammatory drugs during this period is very controversial. Thus, this study has been designed to analyze the effect of a low dose of indomethacin (a COX inhibitor) on the expression of inflammatory molecules. METHOD: The hippocampus of rats submitted to pilocarpine-induced long-lasting status epilepticus was analyzed to determine the expression of inflammatory molecules with RT-PCR and immunohistochemistry. RESULTS: Compared with controls, reduced levels of the kinin B2 receptors IL1β and TNFα were found in the hippocampus of rats submitted to long-lasting status epilepticus and treated with indomethacin. CONCLUSIONS: These data show that low doses of indomethacin could be employed to minimize inflammation during long-lasting status epilepticus. PMID:25318094

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.

PubMed

Ewing, Samuel G; Grace, Anthony A

2013-02-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. Copyright © 2012 Elsevier B.V. All rights reserved.

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia

PubMed Central

Ewing, Samuel G.; Grace, Anthony A.

2012-01-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia, but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. PMID:23269227

Cholinergic dysfunctions and enhanced oxidative stress in the neurobehavioral toxicity of lambda-cyhalothrin in developing rats.

PubMed

Ansari, Reyaz W; Shukla, Rajendra K; Yadav, Rajesh S; Seth, Kavita; Pant, Aditya B; Singh, Dhirendra; Agrawal, Ashok K; Islam, Fakhrul; Khanna, Vinay K

2012-11-01

This study is focused on understanding the mechanism of neurobehavioral toxicity of lambda-cyhalothrin, a new generation type II synthetic pyrethroid in developing rats following their exposure from post-lactational day (PLD)22 to PLD49 and investigate whether neurobehavioral alterations are transient or persistent. Post-lactational exposure to lambda-cyhalothrin (1.0 or 3.0 mg/kg body weight, p.o.) affected grip strength and learning activity in rats on PLD50 and the persistent impairment of grip strength and learning was observed at 15 days after withdrawal of exposure on PLD65. A decrease in the binding of muscarinic-cholinergic receptors in frontocortical, hippocampal, and cerebellar membranes associated with decreased expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus was observed following exposure to lambda-cyhalothrin on PLD50 and PLD65. Exposure to lambda-cyhalothrin was also found to increase the expression of growth-associated protein-43 in hippocampus of rats on PLD50 and PLD65 as compared to controls. A significant increase in lipid peroxidation and protein carbonyl levels and decreased levels of reduced glutathione and activity of superoxide dismutase, catalase, and glutathione peroxidase in brain regions of lambda-cyhalothrin exposed rats were distinctly observed indicating increased oxidative stress. Inhibition of ChAT and AChE activity may cause down-regulation of muscarinic-cholinergic receptors consequently impairing learning activity in developing rats exposed to lambda-cyhalothrin. The data further indicate that long-term exposure to lambda-cyhalothrin at low doses may be detrimental and changes in selected behavioral and neurochemical end points may persist if exposure to lambda-cyhalothrin continues.

Chronic traumatic stress impairs memory in mice: Potential roles of acetylcholine, neuroinflammation and corticotropin releasing factor expression in the hippocampus.

PubMed

Bhakta, Ami; Gavini, Kartheek; Yang, Euitaek; Lyman-Henley, Lani; Parameshwaran, Kodeeswaran

2017-09-29

Chronic stress in humans can result in multiple adverse psychiatric and neurobiological outcomes, including memory deficits. These adverse outcomes can be more severe if each episode of stress is very traumatic. When compared to acute or short term stress relatively little is known about the effects of chronic traumatic stress on memory and molecular changes in hippocampus, a brain area involved in memory processing. Here we studied the effects of chronic traumatic stress in mice by exposing them to adult Long Evan rats for 28 consecutive days and subsequently analyzing behavioral outcomes and the changes in the hippocampus. Results show that stressed mice developed memory deficits when assayed with radial arm maze tasks. However, chronic traumatic stress did not induce anxiety, locomotor hyperactivity or anhedonia. In the hippocampus of stressed mice interleukin-1β protein expression was increased along with decreased corticotropin releasing hormone (CRH) gene expression. Furthermore, there was a reduction in acetylcholine levels in the hippocampus of stressed mice. There were no changes in brain derived neurotrophic factor (BDNF) or nerve growth factor (NGF) levels in the hippocampus of stressed mice. Gene expression of immediate early genes (Zif268, Arc, C-Fos) as well as glucocorticoid and mineralocorticoid receptors were also not affected by chronic stress. These data demonstrate that chronic traumatic stress followed by a recovery period might lead to development of resilience resulting in the development of selected, most vulnerable behavioral alterations and molecular changes in the hippocampus. Copyright © 2017 Elsevier B.V. All rights reserved.

[The effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in rats exposed to lead].

PubMed

Feng, Chang; Fan, Guang-qin; Wu, Feng-yun; Lin, Fen; Li, Yan-shu; Chen, Ying

2012-07-01

To study the effects of methionine and choline on the expression levels of CaMKII and CREB mRNA and proteins in hippocampus of rats exposed to lead. Male SD rats were divided into five groups. (1) control group, (2) group exposed to lead+2 by drinking water with 0.40 g/L lead acetate, (3) group exposed to methionine and choline (1:1, 400 mg/kg), (4) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 100 mg/kg), (5) group exposed to 0.40 g/L lead acetate plus methionine and choline (1:1, 400 mg/kg). In 8 weeks after exposure, all rats were killed. Then CREB mRNA and CaMK II mRNA expression levels in hippocampus were detected by real-time PCR, CREB and CaMK II protein expression levels in hippocampus were measured by western blot assay. The expression levels (0.743 ± 0.185 and 0.729 ± 0.199) of CaMKII mRNA and CREB mRNA in the hippocampus of lead group were significantly lower than those (0.950 ± 0.238 and 0.901 ± 0.232) of control group (P < 0.05), also the expression levels (0.271 ± 0.045 and 0.212 ± 0.058) of CREB protein and pCREB protein in the hippocampus of lead group were significantly lower than those (0.319 ± 0.058 and 0.506 ± 0.125) of control group (P < 0.05). The expression levels (1.014 ± 0.210 and 1.126 ± 0.379) of CaMKII mRNA and the expression levels (1.029 ± 0.335 and 0.932 ± 0.251) of CREB mRNA in the hippocampus of 2 groups exposed to lead acetate plus methionine and choline were significantly higher than those of lead group (P < 0.05). The expression levels (0.407 ± 0.951 and 0.563 ± 0.178) of CREB protein and pCREB protein in the hippocampus of group exposed to lead acetate plus 400 mg/kg methionine and choline were significantly higher than those of lead group (P < 0.05). Methionine and choline could decrease the inhibition effects of lead on the expression of CaMKII and CREB mRNA or CREB and pCREB proteins in the hippocampus of rats.

Enhanced susceptibility to seizures modulated by high interleukin-1β levels during early life malnutrition.

PubMed

Simão, Fabrício; Habekost Oliveira, Victória; Lahorgue Nunes, Magda

2016-10-01

Early malnutrition in life has permanent consequences on brain development and has been suggested to influence seizure susceptibility. Despite malnutrition is not a direct cause of seizures, we hypothesize that malnutrition may modulate inflammatory response and result in cerebral vulnerability to seizures. In this study, we provide evidence that malnutrition may increase susceptibility to seizures in the postnatal period by interleukin-1β (IL-1β) in the hippocampus. Malnourished rats were maintained on a nutritional deprivation regimen from postnatal day 1 (P1) to P10. From P7 to P10, the threshold to seizures induced by flurothyl was used as an index of seizure susceptibility. ELISA and western blot was performed to evaluate levels of IL-1β, IL-1R1, PSD-95 and synapsin. The role of inflammation in the changes of seizure threshold was studied with inhibitors of IL-1β and IL-1R1. A significant decrease in body weight and seizure threshold was observed in postnatal malnourished rats. Early malnutrition modulates inflammation by high levels of IL-1β in hippocampus and in serum. Furthermore, our malnutrition paradigm induced an increase in corticosterone levels. Injection of IL-1β and IL-1R1 inhibitors before seizure induction augments seizure threshold in malnourished rats similar to nourished group. Malnutrition did not change PSD-95 and synapsin expression in the hippocampus. We suggest that malnutrition-induced inflammation might contribute to seizure susceptibility in the postnatal period. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1150-1159, 2016. © 2016 Wiley Periodicals, Inc.

Cognitive-enhancing and antioxidant activities of the aqueous extract from Markhamia tomentosa (Benth.) K. Schum. stem bark in a rat model of scopolamine.

PubMed

Ionita, Radu; Postu, Paula Alexandra; Beppe, Galba Jean; Mihasan, Marius; Petre, Brindusa Alina; Hancianu, Monica; Cioanca, Oana; Hritcu, Lucian

2017-03-28

Plants of the genus Markhamia have been traditionally used by different tribes in various parts of West African countries, including Cameroun. Markhamia tomentosa (Benth.) K. Schum. (Bignoniaceae) is used as an antimalarial, anti-inflammatory, analgesic, antioxidant and anti-Alzheimer agent. The current study was undertaken in order to investigate its anti-amnesic and antioxidant potential on scopolamine-induced cognitive impairment and to determine its possible mechanism of action. Rats were pretreated with the aqueous extract (50 and 200 mg/kg, p.o.), for 10 days, and received a single injection of scopolamine (0.7 mg/kg, i.p.) before training in Y-maze and radial arm-maze tests. The biochemical parameters in the rat hippocampus were also assessed to explore oxidative status. Statistical analyses were performed using two-way ANOVA followed by Tukey's post hoc test. F values for which p < 0.05 were regarded as statistically significant. In the scopolamine-treated rats, the aqueous extract improved memory in behavioral tests and decreased the oxidative stress in the rat hippocampus. Also, the aqueous extract exhibited anti-acetylcholinesterase activity. These results suggest that the aqueous extract ameliorates scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

[Effect of high frequency electrotherapy on caspase-3 and ultra microstructure of hippocampus in rats following cerebral ischemia/reperfusion].

PubMed

Fan, Yongmei; Wang, Rumi; Zhang, Changjie; Peng, Wenna; Yin, Jing; Hu, Zhiping

2017-01-28

To investigate the effect of high frequency electrotherapy (HFE) on rat hippocampus after cerebral ischemia/reperfusion (I/R).
 Methods: A rat model of cerebral I/R injury was established. The rats were randomly divided into a sham group, an I/R group and an HFE group. The HFE group received thearapy daily for different sessions for 1, 3, 7 d. Neuronal deficit score,neuron ultra microstructure in the hippocampus and caspase-3 protein expression were measured on 1 st, 3 th and 7th d.
 Results: Compared with the I/R group, the HFE group showed the decreased neurological deficit scores, with significant differences between the 2 groups (P<0.05). The injury in HFE group was reduced compared with that in the I/R group based on the electron microscope test, with significant difference. Caspase-3 protein in brain tissue in the HFE group also downregulated compared with that in the I/R group (P<0.05).
 Conclusion: High frequency electrotherapy can improve neural function, suppress caspase-3 expression and apoptosis in nerve cells and improve the ultra microstructure of neurons, displaying a protective effect on cerebral I/R injury in rats.

Defiant: (DMRs: easy, fast, identification and ANnoTation) identifies differentially Methylated regions from iron-deficient rat hippocampus.

PubMed

Condon, David E; Tran, Phu V; Lien, Yu-Chin; Schug, Jonathan; Georgieff, Michael K; Simmons, Rebecca A; Won, Kyoung-Jae

2018-02-05

Identification of differentially methylated regions (DMRs) is the initial step towards the study of DNA methylation-mediated gene regulation. Previous approaches to call DMRs suffer from false prediction, use extreme resources, and/or require library installation and input conversion. We developed a new approach called Defiant to identify DMRs. Employing Weighted Welch Expansion (WWE), Defiant showed superior performance to other predictors in the series of benchmarking tests on artificial and real data. Defiant was subsequently used to investigate DNA methylation changes in iron-deficient rat hippocampus. Defiant identified DMRs close to genes associated with neuronal development and plasticity, which were not identified by its competitor. Importantly, Defiant runs between 5 to 479 times faster than currently available software packages. Also, Defiant accepts 10 different input formats widely used for DNA methylation data. Defiant effectively identifies DMRs for whole-genome bisulfite sequencing (WGBS), reduced-representation bisulfite sequencing (RRBS), Tet-assisted bisulfite sequencing (TAB-seq), and HpaII tiny fragment enrichment by ligation-mediated PCR-tag (HELP) assays.

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

PubMed

Ma, Jingyi; Leung, L Stan

2018-02-15

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABA A receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors. Copyright © 2017 Elsevier B.V. All rights reserved.

Ketamine potentiates oxidative stress and influences behavior and inflammation in response to lipolysaccharide (LPS) exposure in early life.

PubMed

Réus, Gislaine Z; Simões, Lutiana R; Colpo, Gabriela D; Scaini, Giselli; Oses, Jean P; Generoso, Jaqueline S; Prossin, Alan R; Kaddurah-Daouk, Rima; Quevedo, João; Barichello, Tatiana

2017-06-14

Immune activation (IA) during the early neonatal period is a risk factor for the development of schizophrenia. Lipopolysaccharide (LPS) injected in neonates lead to behavioral and brain changes that persist to adult life. We investigated oxidative stress, levels of cytokines, and the locomotor activity of IA in a schizophrenia animal model in which neonatal male Wistar rats were administered with an injection of LPS (50μg/kg) on postnatal day 3 and different doses of ketamine (5, 15 and 25mg/kg) for 7days during adulthood. Rats LPS-induced did not have locomotor activity alterations. Locomotor activity was elevated in neonatally saline-injected in the higher dose ketamine-treated animals. Carbonyl protein in the prefrontal cortex (PFC), hippocampus and striatum were increased in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Lipid damage occurred in the PFC, striatum and hippocampus in the LPS- and saline-induced in the ketamine (15 and 25mg/kg) -treated animals. In the hippocampus the superoxide dismutase (SOD) was decreased in the LPS- and saline-induced in the ketamine-treated with the dose of 25mg/kg. In the PFC SOD was reduced in the LPS-induced in the ketamine (25mg/kg)-treated animals. Catalase in the PFC and hippocampus was reduced in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Pro- and anti-inflammatory cytokines were lower in the brains of LPS-induced in the higher dose ketamine-treated rats. IA influences the locomotor activity and cytokine levels induced by ketamine, and it has a negative effect in potentiating the oxidative stress by higher doses of ketamine in the brain. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model.

PubMed

Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A

2016-06-15

While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2015 Elsevier B.V. All rights reserved.

Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-κB pathway.

PubMed

Zhang, Xiaobao; Yan, Fang; Feng, Jiying; Qian, Haitao; Cheng, Zhi; Yang, Qianqian; Wu, Yong; Zhao, Zhibin; Li, Aimin; Xiao, Hang

2018-01-01

Dexmedetomidine (DEX) is known to provide neuroprotective effect in the central nervous system. However, the detailed mechanism remains far more elusive. This study was designed to investigate the relevant mechanisms of DEX's neuroprotective effect. Sprague-Dawley (SD) rats were injected with dexmedetomidine and/or Lipopolysaccharide (LPS) intraperitoneally, and inflammatory cytokines in serum and in the hippocampus were measured by enzyme linked immunosorbent assay (ELISA). NF-κB in the brain tissue extracts was analyzed with western-blot. Then, we investigated whether NF-κB inhibitor prevents the elevation of inflammatory cytokines in rats injected with LPS. Our results indicated that compared with the control group, the rats exposed to LPS showed significant cognitive dysfunction. When compared to controls, the levels of TNF-α and IL-6 in the serum and hippocampus homogenate were increased in rats treated with LPS. DEX pretreatment inhibited the rats' TNF-α, IL-6 and NF-κB levels induced by LPS. In response to LPS, PDTC pretreatment restrains the production of proinflammatory cytokines (TNF-α and IL-6). Rats treated with PDTC and DEX alongside LPS exhibited less TNF-α and IL-6 than the LPS treated group. In combination, PDTC and DEX showed addictive effects. Our data suggest that DEX exerts a neuroprotective effect through NF-κB in part after LPS-induced cognitive dysfunction.

Blockade of AT1 Receptors Protects the Blood–Brain Barrier and Improves Cognition in Dahl Salt-Sensitive Hypertensive Rats

PubMed Central

Pelisch, Nicolas; Hosomi, Naohisa; Ueno, Masaki; Nakano, Daisuke; Hitomi, Hirofumi; Mogi, Masaki; Shimada, Kenji; Kobori, Hiroyuki; Horiuchi, Masatsugu; Sakamoto, Haruhiko; Matsumoto, Masayasu; Kohno, Masakazu; Nishiyama, Akira

2011-01-01

BACKGROUND The present study tested the hypothesis that inappropriate activation of the brain renin–angiotensin system (RAS) contributes to the pathogenesis of blood–brain barrier (BBB) disruption and cognitive impairment during development of salt-dependent hypertension. Effects of an angiotensin II (AngII) type-1 receptor blocker (ARB), at a dose that did not reduce blood pressure, were also examined. METHODS Dahl salt-sensitive (DSS) rats at 6 weeks of age were assigned to three groups: low-salt diet (DSS/L; 0.3% NaCl), high-salt diet (DSS/H; 8% NaCl), and high-salt diet treated with ARB, olmesartan at 1 mg/kg. RESULTS DSS/H rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive functions, which were associated with increased brain AngII levels, as well as decreased mRNA levels of tight junctions (TJs) and collagen-IV in the hippocampus. In DSS/H rats, olmesartan treatment, at a dose that did not alter blood pressure, restored the cognitive decline, and ameliorated leakage from brain microvessels. Olmesartan also decreased brain AngII levels and restored mRNA expression of TJs and collagen-IV in DSS/H rats. CONCLUSIONS These results suggest that during development of salt-dependent hypertension, activation of the brain RAS contributes to BBB disruption and cognitive impairment. Treatment with an ARB could elicit neuroprotective effects in cognitive disorders by preventing BBB permeability, which is independent of blood pressure changes. PMID:21164491

Pretreatment with minocycline restores neurogenesis in the subventricular zone and subgranular zone of the hippocampus after ketamine exposure in neonatal rats.

PubMed

Lu, Yang; Giri, P K; Lei, Shan; Zheng, Juan; Li, Weisong; Wang, Ning; Chen, Xinlin; Lu, Haixia; Zuo, Zhiyi; Liu, Yong; Zhang, Pengbo

2017-06-03

Ketamine is commonly used for anesthesia in pediatric patients. Recent studies indicated that ketamine exposure in the developing brain can induce neuroapoptosis and disturb normal neurogenesis, which will result in long-lasting cognitive impairment. Minocycline exerts neuroprotection against a wide range of toxic insults in neurodegenerative disease models. In the present study, we investigated whether the disturbed neurogenesis and behavioral deficits after ketamine neonatal exposure could be alleviated by minocycline. Postnatal day (PND)7 Sprague-Dawley rat pups randomly received either normal saline, ketamine, or minocycline 30min prior to ketamine administration, respectively. The rats were decapitated at PND14 for the detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. The protein expression of p-Akt, p-GSK-3β in the SVZ and SGZ at 12h after anesthesia, PND10 and PND14 were assessed by western blotting analysis. At PND 42-47, spatial learning and memory abilities were measured by the Morris water maze in all groups. Our data showed that ketamine exposure in neonatal rats resulted in neurogenetic damage and persistent cognitive deficits, and that pretreatment with minocycline eliminated the brain development damage and improved the behavioral function in adult rats. Moreover, the protection of minocycline is associated with the PI3K/Akt signaling pathway. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Age-Related Impairments in Object-Place Associations Are Not Due to Hippocampal Dysfunction

PubMed Central

Hernandez, Abigail R.; Maurer, Andrew P.; Reasor, Jordan E.; Turner, Sean M.; Barthle, Sarah E.; Johnson, Sarah A.; Burke, Sara N.

2016-01-01

Age-associated cognitive decline can reduce an individual’s quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object-place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly. PMID:26413723

Fornix and retrosplenial contribution to a hippocampo-thalamic circuit underlying conditional learning.

PubMed

Dumont, Julie R; Petrides, Michael; Sziklas, Viviane

2010-05-01

Rats with combined bilateral lesions of the retrosplenial cortex and the fornix or rats with unilateral lesions to the anterior thalamus and the hippocampus, made in opposite hemispheres (disconnection preparation), and combined with unilateral damage of the retrosplenial cortex in either hemisphere, were tested on a spatial-visual conditional learning task in which they learned arbitrary associations between stimuli and the scene in which they were embedded. All experimental groups were impaired in comparison with normal animals. The more severe deficits occurred when (1) both the fornix and the retrosplenial cortex were damaged bilaterally thus depriving the hippocampus both from subcortical interactions via the fornix and retrosplenial-mediated interactions and (2) when, in the crossed lesion preparation, the unilateral retrosplenial lesion was made in the hemisphere with the intact hippocampus, again because this lesion would be maximally disconnecting the hippocampus from functional interaction with the anterior thalamic nucleus and retrosplenial-mediated input.

Age-related memory decline is associated with vascular and microglial degeneration in aged rats.

PubMed

Zhang, Rong; Kadar, Tamar; Sirimanne, Ernest; MacGibbon, Alastair; Guan, Jian

2012-12-01

The hippocampus processes memory is an early target of aging-related biological and structural lesions, leading to memory decline. With absent neurodegeneration in the hippocampus, which identified in rodent model of normal aging the pathology underlying age-related memory impairment is not complete. The effective glial-vascular networks are the key for maintaining neuronal functions. The changes of glial cells and cerebral capillaries with age may contribute to memory decline. Thus we examined age associated changes in neurons, glial phenotypes and microvasculature in the hippocampus of aged rats with memory decline. Young adult (6 months) and aged (35 months) male rats (Fisher/Norway-Brown) were used. To evaluate memory, four days of acquisition phase of Morris water maze tasks were carried out in both age groups and followed by a probe trial 2 h after the acquisition. The brains were then collected for analysis using immunochemistry. The aged rats showed a delayed latency (p<0.001) and longer swimming path (p<0.001) to locate a hidden platform. They also spent less time in and made delayed and fewer entries into the correct quadrant during the probe trial. Without seen neuronal degeneration, the aged rats with memory impairments have displayed dopamine depletion, profound vascular and microglial degeneration with reduced vascular endothelial growth factor and elevated GFAP expression in the hippocampus. The data indicate the memory decline with age is associated with neuronal dysfunction, possibly due to impaired glial-vascular-neuronal networks, but not neuronal degeneration. Glial and vascular degeneration found in aged rats may represent early event of aging pathology prior to neuronal degeneration. Copyright © 2012 Elsevier B.V. All rights reserved.

Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants.

PubMed

Scaini, Giselli; Santos, Patricia M; Benedet, Joana; Rochi, Natália; Gomes, Lara M; Borges, Lislaine S; Rezin, Gislaine T; Pezente, Daiana P; Quevedo, João; Streck, Emilio L

2010-05-31

Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Hippocampus lipid peroxidation induced by residual oil fly ash intranasal instillation versus habituation to the open field.

PubMed

Zanchi, Ana Claudia; Saiki, Mitiko; Saldiva, Paulo Hilário Nascimento; Barros, Helena Maria Tannhauser; Rhoden, Claudia Ramos

2010-01-01

Epidemiological studies have demonstrated the adverse effects of particulate matter (PM) inhalation on the respiratory and cardiovascular systems. It has been reported that air pollution may affect the central nervous system and decrease cognitive function. In rats, residual oil fly ash (ROFA) instillation causes decreased motor activity and increased lipid peroxidation in the striatum and the cerebellum. Our objective was to determine whether chronic instillation of particles induces changes in learning and memory in rats and whether oxidants in the hippocampus may contribute to these adverse effects. Forty-five-day-old male Wistar rats were exposed to ROFA by intranasal instillation and were treated with N-acetylcysteine (NAC) at 150 mg/kg i.p. for 30 days. Control groups were exposed to ROFA, NAC, or neither. On days 1, 8, and 30 of the protocol, rats were submitted to the open field test to evaluate habituation. After the last open field session, the rats were killed by decapitation. The hippocampus was used to determine lipid peroxidation (LP) by the thiobarbituric acid-reactive substances test. ROFA instillation induced an increase in LP in the hippocampus compared to all treatment groups (p = .012). NAC treatment blocked these changes. All of the treatment groups presented a decrease in the frequency of peripheral walking (p = .001), rearing (p = .001), and exploration (p = .001) over time. Our study demonstrates that exposure to particles for 30 days and/or NAC treatment do not modify habituation to an open field, a simple form of learning and memory in rats, and that oxidative damage induced by ROFA does not modulate these processes.

Alterations in the endocannabinoid system in the rat valproic acid model of autism.

PubMed

Kerr, D M; Downey, L; Conboy, M; Finn, D P; Roche, M

2013-07-15

The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801.

PubMed

Liu, Yong; Tang, Yamei; Pu, Weidan; Zhang, Xianghui; Zhao, Jingping

2011-08-01

To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and γ-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, Bid), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (P<0.05), and the GABA concentration and Glu utilization rate in the mPFC also decreased (P<0.05). Compared with the chronic medication model group, the DA concentration of the mPFC in the SZ developmental group decreased (P<0.05), and the DOPAC concentration and the utility rate of DA in the hippocampus also decreased (P<0.01, P<0.05, respectively). The activities of DA, Glu and GABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats.

Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability.

PubMed

Wiegand, Jean-Paul L; Gray, Daniel T; Schimanski, Lesley A; Lipa, Peter; Barnes, C A; Cowen, Stephen L

2016-05-18

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (∼70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n = 5) and young (n = 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced "vocabulary" of available representational states. The hippocampus is a structure that is critical for the formation of episodic memories. Sharp-wave ripple events generated in the hippocampus have been implicated in memory consolidation processes critical to memory stabilization. We examine here whether these ripple oscillations are altered over the course of the life span, which could contribute to hippocampus-dependent memory deficits that occur during aging. This experiment used young and aged memory-impaired rats to examine age-related changes in ripple architecture, ripple-triggered spike variance, and spike-phase coherence. We found that there are, indeed, significant changes in characteristics of ripples in older animals that could impact consolidation processes and memory stabilization in the aged brain. Copyright © 2016 the authors 0270-6474/16/365650-11$15.00/0.

Long-Term Memory for Place Learning Is Facilitated by Expression of cAMP Response Element-Binding Protein in the Dorsal Hippocampus

ERIC Educational Resources Information Center

Brightwell, Jennifer J.; Smith, Clayton A.; Neve, Rachael L.; Colombo, Paul J.

2007-01-01

Extensive research has shown that the hippocampus is necessary for consolidation of long-term spatial memory in rodents. We reported previously that rats using a place strategy to solve a cross maze task showed sustained phosphorylation of hippocampus cyclic AMP response element-binding protein (CREB), a transcription factor implicated in…

Neuro-overprotection? A functional evaluation of clomethiazole-induced neuroprotection following hypoxic-ischemic injury.

PubMed

Gilby, K L; Kelly, M E; McIntyre, D C; Robertson, H A

2005-01-01

Hypoxic-ischemic (H-I) injury produces extensive damage to the hippocampus of young rats. We have recently shown that administration of 125 mg kg-1 clomethiazole (CMZ), a GABA(A)-agonist, provides complete histological protection against H-I injury if administered 3 h post-H-I (Brain Res 1035 (2005) 194). However, whether that histological protection translates into lasting functional preservation is unclear. To determine whether hippocampal-based circuits remain functionally intact in CMZ-protected H-I rats, we administered 125 mg kg-1 (high dose [CMZ-HD]) or 65 mg kg-1 (low dose [CMZ-LD]) CMZ, 3 h post-H-I, and examined numerous kindling parameters in the dorsal hippocampus 60 days following H-I. Kindling parameters included afterdischarge (AD) thresholds (ADTs), AD durations and kindling rates. Additional groups assessed included vehicle-injected H-I (VIH), hypoxic, ligated and naive rats. VIH, CMZ-HD, CMZ-LD and hypoxic rats all exhibited significantly faster kindling rates than naive rats. Thus, a previous traumatic event, even hypoxia alone, facilitated subsequent seizure propagation. Still, a significantly slower kindling rate was evident in CMZ-HD rats than in hypoxic, VIH or CMZ-LD rats. Moreover, while longer pre-kindling AD durations were observed in the damaged hippocampus of VIH compared with naive rats, this was not true for either CMZ-treated groups, hypoxic or ligated rats. Collectively, these findings suggest CMZ can suppress the epileptogenic effects of H-I. Surprisingly, however, both groups of CMZ-treated rats exhibited a four to nine times greater ADT than any other group and this effect was most profound in the CMZ-protected hippocampus. Thus, CMZ administration protected local neurons against terminal insult and left network excitability relatively normal with respect to seizure offset mechanisms but also caused profound elevation of local ADTs, which suggests a local hypoexcitability/increased inhibition. Finally, this study demonstrates, for the first time, that the kindling model can serve as a sensitive measure of function-related neuroprotective efficacy in animal models of ischemia.

Progesterone receptor isoforms expression pattern in the rat brain during the estrous cycle.

PubMed

Guerra-Araiza, C; Cerbón, M A; Morimoto, S; Camacho-Arroyo, I

2000-03-24

Progesterone receptor (PR) isoforms expression was determined in the hypothalamus, the preoptic area, the hippocampus and the frontal cerebral cortex of the rat at 12:00 h on each day of the estrous cycle by using reverse transcription coupled to polymerase chain reaction. Rats under a 14:10 h light-dark cycle, with lights on at 06:00 h were used. We found that PR-B isoform was predominant in the hypothalamus, the preoptic area and the frontal cerebral cortex. Both PR isoforms were similarly expressed in the hippocampus. The highest PR-B expression was found on proestrus day in the hypothalamus; on metestrus in the preoptic area; and on diestrus in the frontal cortex. We observed no changes in PR isoforms expression in the hippocampus during the estrous cycle. These results indicate that PR isoforms expression is differentially regulated during the estrous cycle in distinct brain regions and that PR-B may be involved in progesterone actions upon the hypothalamus, the preoptic area and the frontal cortex of the rat.

A Study on Neuroprotective Effects of Curcumin on the Diabetic Rat Brain.

PubMed

Zhang, L; Kong, X-J; Wang, Z-Q; Xu, F-S; Zhu, Y-T

2016-01-01

The present study was aimed to study the neuroprotective therapeutic effect of curcumin on the male albino rat brain. Subarachnoid hemorrhage leads to severe mortality rate and morbidity, and oxidative stress is a crucial factor in subarachnoid hemorrhage. Therefore, we investigated the effect of curcumin on oxidative stress and glutamate and glutamate transporter-1 on a subarachnoid hemorrhage-induced male albino rats. The curcumin commonly used for the treatment and saline used for the control. Curcumin (10 mg/kg bwt) dissolved in saline and administered orally to the rats for one week. Glutamate, glutamate transporter-1, malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione reductase and lactate dehydrogenase (LDH) activities were determined. Glutamate level was lower in the curcumin-treated rats compared to their respective controls. Glutamate transporter-1 did not alter in the curcumin-treated rats compared to their controls. Glutamate transporter-1 protein expression is significantly reduced in the curcumin-treated rats. MDA levels decreased 18 and 29 % in the hippocampus and the cortex region respectively. SOD (17% and 32%), and catalase (19% and 24%) activities were increased in the curcumin-treated hippocampus and the cortex region respectively. Glutathione reductase (13% and 19%) and LDH (21% and 30%) activities were increased in the treated hippocampus and the cortex region respectively. The mRNA expression of NK-kB and TLR4 was significantly reduced following curcumin treatment. Taking all these data together, the curcumin found to be effective against oxidative stress and glutamate neurotoxicity in the male albino rats.

The effects of 30 mT electromagnetic fields on hippocampus cells of rats

PubMed Central

Teimori, Farzaneh; Khaki, Amir A.; Rajabzadeh, Asghar; Roshangar, Leila

2016-01-01

Background: Despite the use of electromagnetic waves in the treatment of some acute and chronic diseases, application of these waves in everyday life has created several problems for humans, especially the nerve system. In this study, the effects of 30mT electromagnetic fields (EMFs) on the hippocampus is investigated. Methods: Twenty-four 5-month Wistar rats weighing 150–200 g were divided into two groups. The experimental group rats were under the influence of an EMF at an intensity of 3 mT for approximately 4 hours a day (from 8 AM to 12 PM) during 10 weeks. After the hippocampus was removed, thin slides were prepared for transmission electron microscope (TEM) to study the ultrastructural tissue. Cell death detection POD kits were used to determine the apoptosis rate. Results: The results of the TEM showed that, in the hippocampus of the experimental group, in comparison to the control group, there was a substantial shift; even intracellular organelles such as the mitochondria were morphologically abnormal and uncertain. The number of apoptotic cells in the exposed group compared to the control group showed significant changes. Conclusions: Similar to numerous studies that have reported the effects of EMFs on nerves system, it was also confirmed in this lecture. Hence, the hippocampus which is important in regulating emotions, behavior, motivation, and memory functions, may be impaired by the negative impacts of EMFs. PMID:27453795

Independent Neuronal Representation of Facial and Vocal Identity in the Monkey Hippocampus and Inferotemporal Cortex.

PubMed

Sliwa, Julia; Planté, Aurélie; Duhamel, Jean-René; Wirth, Sylvia

2016-03-01

Social interactions make up to a large extent the prime material of episodic memories. We therefore asked how social signals are coded by neurons in the hippocampus. Human hippocampus is home to neurons representing familiar individuals in an abstract and invariant manner ( Quian Quiroga et al. 2009). In contradistinction, activity of rat hippocampal cells is only weakly altered by the presence of other rats ( von Heimendahl et al. 2012; Zynyuk et al. 2012). We probed the activity of monkey hippocampal neurons to faces and voices of familiar and unfamiliar individuals (monkeys and humans). Thirty-one percent of neurons recorded without prescreening responded to faces or to voices. Yet responses to faces were more informative about individuals than responses to voices and neuronal responses to facial and vocal identities were not correlated, indicating that in our sample identity information was not conveyed in an invariant manner like in human neurons. Overall, responses displayed by monkey hippocampal neurons were similar to the ones of neurons recorded simultaneously in inferotemporal cortex, whose role in face perception is established. These results demonstrate that the monkey hippocampus participates in the read-out of social information contrary to the rat hippocampus, but possibly lack an explicit conceptual coding of as found in humans. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Serum extravasation and cytoskeletal alterations following traumatic brain injury in rats. Comparison of lateral fluid percussion and cortical impact models.

PubMed

Hicks, R R; Baldwin, S A; Scheff, S W

1997-01-01

Disruption of the blood-brain barrier (BBB) and neuronal cytoskeletal damage were evaluated in two commonly used rat models of traumatic brain injury. Adult rats received a lateral cortical impact (CI) or lateral fluid percussion (FP) injury of mild or moderate severity or a sham procedure. Six hours after trauma, the brains were removed and analyzed with immunocytochemical techniques for alterations in the serum protein, IgG, and the cytoskeletal protein, microtubule-associated protein 2 (MAP2). Both models induced profound alterations in these proteins in the ipsilateral cortex and hippocampus compared to sham-injured controls. Following an injury of moderate severity, the CI injury resulted in greater IgG extravasation in the cortex and hippocampus than the FP injury. Conversely, after a mild injury, IgG extravasation in the hippocampus was greater for FP than CI. All of the animals in the CI group and most of the FP group showed a loss of MAP2 in the hippocampus. The specific subregions within the cortex and hippocampus that were affected by the injury varied between models, despite having identical impact sites. These data demonstrate that there are both similarities and differences between a CI and FP injury on vascular and neuronal cystoskeletal integrity, which should be considered when utilizing these animal models to study selected features of human head injury.

[L-glutamate-activated conductivity in the membrane of isolated pyramidal neurons of the rat hippocampus].

PubMed

Kiksin, N I; Tsyndrenko, A Ia

1985-01-01

Isolated pyramidal neurons from rat hippocampus were investigated under conditions of intracellular perfusion and voltage clamp using the method of rapid application of extracellular solution. It was found that the L-glutamate-activated current was carried by sodium and potassium ions with PK+/PNa+ ratio about 0.6. The dose-response relationship demonstrated one to one interaction between L-glutamate and membrane receptor with Kd value about 1.1 mmol/l.

Ingested d-Aspartate Facilitates the Functional Connectivity and Modifies Dendritic Spine Morphology in Rat Hippocampus.

PubMed

Kitamura, Akihiko; Hojo, Yasushi; Ikeda, Muneki; Karakawa, Sachise; Kuwahara, Tomomi; Kim, Jonghyuk; Soma, Mika; Kawato, Suguru; Tsurugizawa, Tomokazu

2018-05-30

d-Aspartate (d-Asp), the stereoisomer of l-aspartate, has a role in memory function in rodents. However, the mechanism of the effect of d-Asp has not been fully understood. In this study, we hypothesized that ingested d-Asp directly reaches the hippocampal tissues via the blood circulation and modifies the functional connectivity between hippocampus and other regions through spinogenesis in hippocampal CA1 neurons. The spinogenesis induced by the application of d-Asp was investigated using rat acute hippocampal slices. The density of CA1 spines was increased following 21 and 100 μM d-Asp application. The nongenomic spine increase pathway involved LIM kinase. In parallel to the acute slice study, brain activation was investigated in awake rats using functional MRI following the intragastric administration of 5 mM d-Asp. Furthermore, the concentration of d-Asp in the blood serum and hippocampus was significantly increased 15 min after intragastric administration of d-Asp. A functional connectivity by awake rat fMRI demonstrated increased slow-frequency synchronization in the hippocampus and other regions, including the somatosensory cortex, striatum, and the nucleus accumbens, 10-20 min after the start of d-Asp administration. These results suggest that ingested d-Asp reaches the brain through the blood circulation and modulates hippocampal neural networks through the modulation of spines.

Proteomic changes in female rat hippocampus following exposure to a terrified sound stress.

PubMed

Yang, Juan; Hu, Lili; Song, Tusheng; Liu, Yong; Wu, Qiuhua; Zhao, Lingyu; Liu, Liying; Zhao, Xiaoge; Zhang, Dianzeng; Huang, Chen

2014-06-01

Stress plays a profound role in the onset of affective disorders, including an elevation in risk factors for depression and anxiety. Women are twice as vulnerable to stress as men because of greater sensitivity to a substance produced during times of anxiety. To better define the abnormal proteins implicated in cognitive deficits and other stress-induced dysfunction, female rats were exposed to terrified sound stress, and two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) were utilized to determine the differential protein expression in the hippocampus in sound-stressed female rats compared with controls. Quantitative differences were found in 44 protein spots which were differentially expressed between the stressed and control groups (fold change of >2; p < 0.01). Eighteen protein spots were downregulated, and 26 protein spots were upregulated in the stressed group. The seven most differentially expressed proteins were identified and validated as follows: dihydropyrimidinase-related protein 2 (DRP-2), creatine kinase B type, dynamin-1 protein, alpha-internexin, glial fibrillary acidic protein beta, gamma-enolase, and peptidyl-prolyl cis-trans isomerase A. Changes in protein levels were detected in the hippocampus of female rats subjected to terrified sound stress. The findings herein may open new opportunities for further investigations on the modulation induced in the hippocampus by stress at the molecular level, especially with respect to females stress.

Correlation between oxytocin neuronal sensitivity and oxytocin receptor binding: An electrophysiological and autoradiographical study comparing rat and guinea pig hippocampus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raggenbass, M.; Tribollet, E.; Dubois-Dauphin, M.

1989-01-01

In transverse hippocampal slices from rat and guinea pig brains, the authors obtained unitary extracellular recordings from nonpyramidal neurones located in or near the stratum pyramidale in the CA1 field and in the transition region between the CA1 and the subiculum. In rats, these neurones responded to oxytocin at 50-1,000 nM by a reversible increase in firing rate. The oxytocin-induced excitation was suppressed by a synthetic structural analogue that acts as a potent, selective antioxytocic on peripheral receptors. Nonpyramidal neurones were also excited by carbachol at 0.5-10 {mu}M. The effect of this compound was postsynaptic and was blocked by themore » muscarinic antagonist atropine. In guinea pigs, by contrast, nonpyramidal neurones were unaffected by oxytocin, although they were excited by carbachol. Light microscopic autoradiography, carried out using a radioiodinated selective antioxytocic as a ligand, revealed labeling in the subiculum and in the CA1 area of the hippocampus of rats, whereas no oxytocin-binding sites were detected in the hippocampus of guinea pigs. The results indicate (i) that a hippocampal action of oxytocin is species-dependent and (ii) that a positive correlation exists between neuronal responsiveness to oxytocin and the presence in the hippocampus of high-affinity binding sites for this peptide.« less

Activity-based anorexia during adolescence disrupts normal development of the CA1 pyramidal cells in the ventral hippocampus of female rats.

PubMed

Chowdhury, Tara G; Ríos, Mariel B; Chan, Thomas E; Cassataro, Daniela S; Barbarich-Marsteller, Nicole C; Aoki, Chiye

2014-12-01

Anorexia nervosa (AN) is a psychiatric illness characterized by restricted eating and irrational fears of gaining weight. There is no accepted pharmacological treatment for AN, and AN has the highest mortality rate among psychiatric illnesses. Anorexia nervosa most commonly affects females during adolescence, suggesting an effect of sex and hormones on vulnerability to the disease. Activity-based anorexia (ABA) is a rodent model of AN that shares symptoms with AN, including over-exercise, elevation of stress hormones, and genetic links to anxiety traits. We previously reported that ABA in adolescent female rats results in increased apical dendritic branching in CA1 pyramidal cells of the ventral hippocampus at postnatal day 44 (P44). To examine the long-term effects of adolescent ABA (P44) in female rats, we compared the apical branching in the ventral hippocampal CA1 after recovery from ABA (P51) and after a relapse of ABA (P55) with age-matched controls. To examine the age-dependence of the hippocampal plasticity, we examined the effect of ABA during adulthood (P67). We found that while ABA at P44 resulted in increased branching of ventral hippocampal pyramidal cells, relapse of ABA at P55 resulted in decreased branching. ABA induced during adulthood did not have an effect on dendritic branching, suggesting an age-dependence of the vulnerability to structural plasticity. Cells from control animals were found to exhibit a dramatic increase in branching, more than doubling from P44 to P51, followed by pruning from P51 to P55. The proportion of mature spines on dendrites from the P44-ABA animals is similar to that on dendrites from P55-CON animals. These results suggest that the experience of ABA may cause precocious anatomical development of the ventral hippocampus. Importantly, we found that adolescence is a period of continued development of the hippocampus, and increased vulnerability to mental disorders during adolescence may be due to insults during this developmentally critical period. © 2014 Wiley Periodicals, Inc.

Magnetic resonance spectroscopic analysis of neurometabolite changes in the developing rat brain at 7T.

PubMed

Ramu, Jaivijay; Konak, Tetyana; Liachenko, Serguei

2016-11-15

We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippocampus and anterior cingulate cortex of the developing rat brain from postnatal days 14-70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e. when the portion of the data could be fit to horizontal line) was estimated and was interpreted as the time when the brain has reached maturity with respect to that metabolite. N-acetyl-aspartate and myo-inositol increased within the observed period. Gluthathione did not vary significantly, while taurine decreased initially and then stabilized. Phosphocreatine and total creatine had a tendency to increase towards the end of the experiment. Some differences between our data and the published literature were observed in the concentrations and dynamics of phosphocreatine, myo-inositol, and GABA in the hippocampus and creatine, GABA, glutamine, choline and N-acetyl-aspartate in the cortex. Such differences may be attributed to experimental conditions, analysis approaches and animal species. The latter is supported by differences between in-house rat colony and rats from Charles River Labs. Spectroscopy provides a valuable tool for non-invasive brain neurochemical profiling for use in developmental neurobiology research. Special attention needs to be paid to important sources of variation like animal strain and commercial source. Published by Elsevier B.V.

The antidepressant fluoxetine normalizes the nuclear glucocorticoid receptor evoked by psychosocial stress

NASA Astrophysics Data System (ADS)

Mitić, M.; Simić, I.; Djordjević, J.; Radojčić, M. B.; Adžić, M.

2011-12-01

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and stress disorders. Glucocorticoids, key regulators of the stress response, exert diverse effects on cellular processes in the hippocampus. Beside non-genomic pathways, glucocorticoid effects are mediated through activation of the glucocorticoid receptor (GR), a ligand activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. We analysed the GR protein levels both in the cytoplasmic and nuclear compartments of the hippocampus of Wistar rats exposed to chronic psychosocial isolation stress upon chronic fluoxetine (FLU) treatment. Under chronic stress, corticosterone levels (CORT) were decreased compared to the control, and treatment with FLU did not change its level in the stressed rats. At the molecular level, FLU normalized the level of nuclear GR protein in the hippocampus of the stressed rats. Discrepancy between normalization of nuclear GR in the hippocampus and lack of normalization of HPA axis activity judged by CORT, suggests that other brain structures such as the amygdale and prefrontal cortex that also regulate HPA axis activity, seem not to be normalized by the FLU treatment used in our study.

PEGylated carbon nanotubes impair retrieval of contextual fear memory and alter oxidative stress parameters in the rat hippocampus.

PubMed

Dal Bosco, Lidiane; Weber, Gisele E B; Parfitt, Gustavo M; Paese, Karina; Gonçalves, Carla O F; Serodre, Tiago M; Furtado, Clascídia A; Santos, Adelina P; Monserrat, José M; Barros, Daniela M

2015-01-01

Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions.

PEGylated Carbon Nanotubes Impair Retrieval of Contextual Fear Memory and Alter Oxidative Stress Parameters in the Rat Hippocampus

PubMed Central

Dal Bosco, Lidiane; Weber, Gisele E. B.; Parfitt, Gustavo M.; Paese, Karina; Gonçalves, Carla O. F.; Serodre, Tiago M.; Furtado, Clascídia A.; Santos, Adelina P.; Monserrat, José M.; Barros, Daniela M.

2015-01-01

Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions. PMID:25738149

COMPENSATORY CHANGES IN THE HIPPOCAMPUS FOLLOWING INTRADENTATE INFUSION OF COLCHICINE

EPA Science Inventory

Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits compensatory behavioral, neurochemical and neuroanatomical changes. olchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antag...

Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease

PubMed Central

Zhang, Li-Da; Ma, Li; Zhang, Li; Dai, Jian-Guo; Chang, Li-Gong; Huang, Pei-Lin; Tian, Xiao-Qiang

2015-01-01

Background: Hyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway. Methods: AD rats were induced by injecting β-amyloid 25–35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg−1·d−1), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues. Results: Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761. Conclusions: Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons. PMID:26608991

The role of the medial caudate nucleus, but not the hippocampus, in a matching-to sample task for a motor response.

PubMed

Kesner, Raymond P; Gilbert, Paul E

2006-04-01

A delayed-match-to-sample task was used to assess memory for motor responses in rats with control, hippocampus, or medial caudate nucleus (MCN) lesions. All testing was conducted on a cheeseboard maze in complete darkness using an infrared camera. A start box was positioned in the centre of the maze facing a randomly determined direction on each trial. On the sample phase, a phosphorescent object was randomly positioned to cover a baited food well in one of five equally spaced positions around the circumference of the maze forming a 180-degree arc 60 cm from the box. The rat had to displace the object to receive food and return to the start box. The box was then rotated to face a different direction. An identical baited phosphorescent object was placed in the same position relative to the start box. A second identical object was positioned to cover a different unbaited well. On the choice phase, the rat must remember the motor response made on the sample phase and make the same motor response on the choice phase to receive a reward. Hippocampus lesioned and control rats improved as a function of increased angle separation used to separate the correct object from the foil (45, 90, 135, and 180 degrees) and matched the performance of controls. However, rats with MCN lesions were impaired across all separations. Results suggest that the MCN, but not the hippocampus, supports working memory and/or a process aimed at reducing interference for motor response selection based on vector angle information.

Aminoguanidine alleviated MMA-induced impairment of cognitive ability in rats by downregulating oxidative stress and inflammatory reaction.

PubMed

Li, Qiliang; Song, Wenqi; Tian, Ze; Wang, Peichang

2017-03-01

Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many "treated" patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of methamphetamine exposure during pregnancy and lactation on hippocampal doublecortin expression, learning and memory of rat offspring.

PubMed

Jalayeri-Darbandi, Zahra; Rajabzadeh, Aliakbar; Hosseini, Mahmoud; Beheshti, Farimah; Ebrahimzadeh-Bideskan, Alireza

2018-06-01

The aim of this study was to evaluate the effect of methamphetamine (MA) exposure during pregnancy and lactation on doublecortin (DCX) expression in the hippocampus of rat offspring and also on learning/memory. Thirty-five pregnant Wistar rats were randomly divided into seven groups of 5 rats each: three experimental groups, each receiving 5 mg/kg body weight (BW) intraperitoneal (i.p.) injections of MA during pregnancy or/and lactation; three sham groups, each receiving saline injections; one control group, receiving no injection. After the interventions, two male pups (1 and 22 days old) were randomly selected from each mother, sacrificed and their brains subjected to DCX immunohistochemistry. One additional male pup from each mother was randomly selected and maintained for 60 days for testing in the Morris water maze and passive avoidance tests. MA administration during pregnancy was found to have significantly decreased the number of DCX-positive cells in the CA1, CA3 and DG regions of the hippocampus in the 1-day pups (P ≤ 0.05) and to have significantly decreased the number of DCX-positive cells in only two regions of the hippocampus, the CA1 and DG regions, in 22-day old pups. In comparison, exposure to MA during lactation was only associated with a significant decrease in the number of DCX-positive cells in the DG. Exposure to MA during pregnancy had significant impact on the intensity of DCX expression in the hippocampus of 1- and 22-day pups (P ≤ 0.05). There was no significant difference in memory/learning among the study groups. Our results indicate the administration of MA during pregnancy had a greater effect that during the lactation period on DCX expression in the hippocampus of rat offspring.

[On the mechanism of noopept action: decrease in activity of stress-induced kinases and increase in expression of neutrophines].

PubMed

Ostrovskaia, R U; Vakhitova, Iu V; Salimgareeva, M Kh; Iamidanov, R S; Sadovnikov, S V; Kapitsa, I G; Seredenin, S B

2010-12-01

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

PubMed

Bray, Brenna; Scholl, Jamie L; Tu, Wenyu; Watt, Michael J; Renner, Kenneth J; Forster, Gina L

2016-08-01

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal. Copyright © 2016 Elsevier B.V. All rights reserved.

Short-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-I.

PubMed

Witty, Christine F; Gardella, Layne P; Perez, Maria C; Daniel, Jill M

2013-02-01

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. Our current goal was to determine whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.

Thymoquinone recovers learning function in a rat model of Alzheimer’s disease

PubMed Central

Poorgholam, Parvin; Yaghmaei, Parichehreh; Hajebrahimi, Zahra

2018-01-01

Objective: Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of amyloid beta in the hippocampus. In recent decades, herbal medicine has been widely used to treat many neurodegenerative disorders,as in comparison to conventional drugs, herbal remedies exert minimal side effects. Here, the effects of thymoquinone, as the main active component of Nigella sativa, on passive avoidance memory in rat model of Alzheimer’s disease, were evaluated. Materials and Methods: Hippocampal injection of amyloid beta (Aβ) was used to induce Alzheimer’s disease in male Wistar rats, followed by intra peritoneal administrations of 5 and 10 mg/kg thymoquinone on a daily basis for 4 weeks. Animals were subjected to fear learning behavior in passive avoidance test and histopathological analysis of the hippocampus was done. Shuttle box test was used to evaluate the condition studying memory. Thioflavin-S and Hematoxylin and Eosine staining were done to confirm Aβ plaque formation and to evaluate the effect of thymoquinone on the pyramidal cells in the hippocampal CA1 region. Results: Amyloid beta caused cognitive dysfunction reflected by increasing initial and step-through latency along with plaque formation and degeneration of pyramidal cells in the hippocampus. Thymoquinone administration ameliorated this effect by significant reductions in plaque formation in CA1 region of the hippocampus and increased latency time. It also increased the number of surviving neurons in the hippocampus. Conclusion: It seems that thymoquinone improved learning function in a rat model of Alzheimer’s disease. Thus, thymoquinone could be possibly used as an anti-neurodegenerative agent for protecting hippocampal neurons against neurotoxic effects of Aβ in patients with Alzheimer’s disease. PMID:29881705

An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia.

PubMed

Chen, Li; Perez, Stephanie M; Lodge, Daniel J

2014-09-01

Schizophrenia is a disease typically associated with an adolescent onset. Although there have been a considerable number of imaging studies investigating the transition to psychosis in prodromal patients, there are relatively few preclinical studies examining potential mechanisms that may contribute to adolescent onset. We have previously demonstrated, in the methylazoxymethanol acetate (MAM) rodent model of schizophrenia, that an enhanced activity within the ventral hippocampus may underlie the dopamine system hyperfunction, suggested to contribute to positive symptoms in patients. Here we demonstrate that the aberrant regulation of dopamine system function, in MAM-treated rats, is present prior to puberty. Furthermore, we now report that while the afferent regulation of ventral tegmental area dopamine neurons (from the hippocampus and pedunculopontine tegmental area) appears intact in preadolescent rats, the behavioral response to alterations in dopamine system function appears to be attenuated in preadolescent rats. Thus, we posit that the pathological alterations underlying psychosis may be present prior to symptom onset and that the "normal" development of the postsynaptic side of the dopamine system may underlie the transition to psychosis. © 2014 Wiley Periodicals, Inc.

[Foshouningshen decoction improves sleeping via the serotonergic system in a rat model of insomnia].

PubMed

Huang, Jie-Cong; Xie, Wei; Deng, Ning; Liang, Wen-Lin; Hu, Dong-Rong; Hong, Yu; Zhou, Yang

2017-08-20

To evaluate the sedative and hypnotic effects of Foshouningshen decoction (FSNSD) and study its effects on expressions of 5-hydroxy tryptamine (5-HT) and 5-HT1A receptor (5-HT 1A R) in the hippocampus in a rat model of insomnia. Male KM mice were divided into control group, estazolam (0.4 mg/kg daily) group, and low-, moderate-, and high-dose FSNSD groups (daily dose of 12, 24, and 48 g/kg, respectively). After corresponding treatments for 1 week, the mice underwent sleep-inducing test with subthreshold and threshold doses of sodium pentobarbital. Forty-eight male SD rats were randomized into control group, insomnia model group, estazolam group (0.2 mg/kg daily), and low-, moderate-, and high-dose FSNSD groups (with daily dose of 6, 12, and 24 g/kg, respectively). Rat models of insomnia were established by intraperitoneal injection of 4-cholro-dl-phenylalanine (PCPA) at the daily dose of 350 mg/kg for 3 days, after which the rats received corresponding treatments via gavage for 1 week. The performance of the rats in open field test was recorded and the hippocampal expression of 5-HT was detected using ELISA; the expressions of 5-HT 1A R protein and mRNA in the hippocampus were detected using immunohistochemistry and real-time PCR, respectively. In the sleep-inducing test with a subthreshold dose of sodium pentobarbital, the mice treated with high-dose FSNSD showed a significantly higher rate of sleep onset than the control mice (P<0.05); in the test with a threshold dose of sodium pentobarbital, treatment with moderate- and high-dose FSNSD resulted in significantly prolonged sleeping time (P<0.01) and shortened sleep latency (P<0.05) in the mice. The rats in insomnia model group showed increased total distance in open field test (P<0.05) with significantly decreased content of 5-HT (P<0.01) and expressions of 5-HT 1A R protein and mRNA in the hippocampus (P<0.01). Treatment of the rats with estazolam or high-dose FSNSD obviously decreased the total distance in open field test (P<0.05) and increased the content of 5-HT (P<0.05) and expressions of 5-HT 1A R (P<0.01) in the hippocampus of rats with insomnia. FSNSD can produce therapeutic effects on insomnia possibly by increasing 5-HT content and expressions of 5-HT 1A R in the hippocampus.

Comparison of the neuropsychological mechanisms of 2,6-diisopropylphenol and N-methyl-D-aspartate receptor antagonist against electroconvulsive therapy-induced learning and memory impairment in depressed rats.

PubMed

Liu, Gang; Liu, Chao; Zhang, Xue-Ning

2015-09-01

The present study aimed to examine the neurophysiological mechanisms of the 2,6-diisopropylphenol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning and memory impairment, induced by electroconvulsive therapy (ECT). A total of 48 adult depressed rats without olfactory bulbs were randomly divided into six experimental groups: i) saline; ii) 10 mg/kg MK‑801; iii) 10 mg/kg MK‑801 and a course of ECT; iv) 200 mg/kg 2,6‑diisopropylphenol; v) 200 mg/kg 2,6‑diisopropylphenol and a course of ECT; and vi) saline and a course of ECT. The learning and memory abilities of the rats were assessed using a Morris water maze 1 day after a course of ECT. The hippocampus was removed 1 day after assessment using the Morris water maze assessment. The content of glutamate in the hippocampus was detected using high‑performance liquid chromatography. The expression levels of p‑AT8Ser202 and GSK‑3β1H8 in the hippocampus were determined using immunohistochemical staining and western blot analysis. The results demonstrated that the 2,6‑diisopropylphenol NMDA receptor antagonist, MK‑801 and ECT induced learning and memory impairment in the depressed rats. The glutamate content was significantly upregulated by ECT, reduced by 2,6‑diisopropylphenol, and was unaffected by the NMDA receptor antagonist in the hippocampus of the depressed rats. Tau protein hyperphosphorylation in the hippocampus was upregulated by ECT, but was reduced by 2,6‑diisopropylphenol and the MK‑801 NMDA receptor antagonist. It was also demonstrated that 2,6‑diisopropylphenol prevented learning and memory impairment and reduced the hyperphosphorylation of the Tau protein, which was induced by eECT. GSK‑3β was found to be the key protein involved in this signaling pathway. The ECT reduced the learning and memory impairment, caused by hyperphosphorylation of the Tau protein, in the depressed rats by upregulating the glutamate content.

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Pranay; Yadav, Rajesh S.; Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenicmore » exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected by curcumin • Functional and structural changes in mitochondria by arsenic protected by curcumin.« less

Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats.

PubMed

Demeter, Kornél; Török, Bibiána; Fodor, Anna; Varga, János; Ferenczi, Szilamér; Kovács, Krisztina J; Eszik, Ildikó; Szegedi, Viktor; Zelena, Dóra

2016-03-01

Schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested that schizophrenia might have an epigenetic component. We aimed to clarify if epigenetic changes contribute to schizophrenia-like behavior of this strain. Behavioral (locomotion by telemetry, cognition by novel object recognition, social recognition and social avoidance test, attention by pre-pulse inhibition) and epigenetic differences were compared between wild type and di/di animals. DNA methyltransferase1 (DNMT1), DNMT3a, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmed schizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model of schizophrenia. Its schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of many schizophrenia-related substances leading to development of schizophrenia-like symptoms. Our studies confirmed that not a single gene, rather fine changes in an array of molecules are responsible for the majority of schizophrenia cases. Copyright © 2015 Elsevier B.V. All rights reserved.

Hippocampal and prefrontal cortex contributions to learning and memory: analysis of lesion and aging effects on maze learning in rats.

PubMed

Winocur, G; Moscovitch, M

1990-08-01

Young adult rats with bilateral lesions to the hippocampus or prefrontal cortex, young operated controls, and normal old rats were tested on two complex mazes in the Hebb-Williams series. Approximately half the animals were previously trained on one of the mazes; the remainder received no previous training. The trained hippocampal rats showed sparing of memory for the general skill of maze learning but poor recall of the specific maze on which they had been previously trained. The opposite pattern was observed in trained prefrontal rats. In contrast, the aged rats' memory for maze-specific and maze-general information was impaired. The results confirmed the importance of the hippocampus for recalling highly specific information and pointed to a possible role for the frontal lobes in learning and remembering nonspecific skill-related information. The generalized deficit of the aged rats indicates that both types of memory were compromised and offers further evidence of frontal lobe and hippocampal dysfunction in normal aging.

The different effects of lithium and tamoxifen on memory formation and the levels of neurotrophic factors in the brain of male and female rats.

PubMed

Valvassori, Samira S; Borges, Cenita P; Varela, Roger B; Bavaresco, Daniela V; Bianchini, Guilherme; Mariot, Edemilson; Arent, Camila O; Resende, Wilson R; Budni, Josiane; Quevedo, João

2017-09-01

Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats. Copyright © 2017. Published by Elsevier Inc.

Clonidine preconditioning improved cerebral ischemia-induced learning and memory deficits in rats via ERK1/2-CREB/ NF-κB-NR2B pathway.

PubMed

Li, Yanli; Yu, Min; Zhao, Bo; Wang, Yan; Zha, Yunhong; Li, Zicheng; Yu, Lingling; Yan, Lingling; Chen, Zhangao; Zhang, Wenjuan; Zeng, Xiaoli; He, Zhi

2018-01-05

Clonidine, a classical α-2 adrenergic agonists, has been shown to antagonize brain damage caused by hypoxia, cerebral ischemia and excitotoxicity and reduce cerebral infarction volume in recent studies. We herein investigate the regulatory effect and possible underlying mechanism of clonidine on learning and memory in rats with cerebral ischemia. The cerebral ischemia rat model was established by right middle cerebral artery occlusion for 2h and reperfusion for 28 days. Drugs were administrated to the rats for consecutive 7 days intraperitoneally and once again on the day of surgery. The learning and memory in rats was assayed by Morris water maze. Moreover, protein expression levels of NMDAR2B (NR2B)/ phosphor - NR2B, ERK1/2/phosphor- ERK1/2, CREB/phosphor-CREB and NF-κB/phosphor-NF-κB in the cortex and hippocampus of the rats were assayed by western blotting. Our results demonstrated that clonidine treatment significantly abrogated the negative effect induced by cerebral ischemia on the learning and memory in the rats. In the Western blotting assay, clonidine treatment led to significant up-regulation of the expression level of NR2B and Phospho-NR2B in the hippocampus of the rats when compared with the cerebral ischemia group. Furthermore, clonidine also significantly decreased the protein expression levels of ERK1/2, Phospho-ERK1/2, CREB, Phospho-CREB and Phospho-NF-κB in the hippocampus of the rats when compared with the cerebral ischemia group. In conclusion, clonidine could improve the learning and memory ability of rats with cerebral ischemia, and NR2B, ERK1/2, CREB, NF-κB were involved in this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats.

PubMed

Zhu, Xianlin; Ye, Gang; Wang, Zaiping; Luo, Jie; Hao, Xuechao

2017-02-03

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats' depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect

PubMed Central

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy. PMID:26309534

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect.

PubMed

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy.

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats.

PubMed

Ji, Jinzhao; Maren, Stephen

2008-12-12

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.

Differences in Monoamine Oxidase Activity in the Brain of Wistar and August Rats with High and Low Locomotor Activity: A Cytochemical Study.

PubMed

Sergutina, A V; Rakhmanova, V I

2016-06-01

Monoamine oxidase activity was quantitatively assessed by cytochemical method in brain structures (layers III and V of the sensorimotor cortex, caudate nucleus, nucleus accumbens, hippocampal CA3 field) of rats of August line and Wistar population with high and low locomotor activity in the open fi eld test. Monoamine oxidase activity (substrate tryptamine) predominated in the nucleus accumbens of Wistar rats with high motor activity in comparison with rats with low locomotor activity. In August rats, enzyme activity (substrates tryptamine and serotonin) predominated in the hippocampus of animals with high motor activity. Comparison of August rats with low locomotor activity and Wistar rats with high motor activity (i.e. animals demonstrating maximum differences in motor function) revealed significantly higher activity of the enzyme (substrates tryptamine and serotonin) in the hippocampus of Wistar rats. The study demonstrates clear-cut morphochemical specificity of monoaminergic metabolism based on the differences in the cytochemical parameter "monoamine oxidase activity", in the studied brain structures, responsible for the formation and realization of goal-directed behavior in Wistar and August rats.

Early Activation of Ventral Hippocampus and Subiculum during Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy

PubMed Central

Toyoda, Izumi; Bower, Mark R.; Leyva, Fernando

2013-01-01

Temporal lobe epilepsy is the most common form of epilepsy in adults. The pilocarpine-treated rat model is used frequently to investigate temporal lobe epilepsy. The validity of the pilocarpine model has been challenged based largely on concerns that seizures might initiate in different brain regions in rats than in patients. The present study used 32 recording electrodes per rat to evaluate spontaneous seizures in various brain regions including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. Compared with published results from patients, seizures in rats tended to be shorter, spread faster and more extensively, generate behavioral manifestations more quickly, and produce generalized convulsions more frequently. Similarities to patients included electrographic waveform patterns at seizure onset, variability in sites of earliest seizure activity within individuals, and variability in patterns of seizure spread. Like patients, the earliest seizure activity in rats was recorded most frequently within the hippocampal formation. The ventral hippocampus and ventral subiculum displayed the earliest seizure activity. Amygdala, olfactory cortex, and septum occasionally displayed early seizure latencies, but not above chance levels. Substantia nigra and dorsomedial thalamus demonstrated consistently late seizure onsets, suggesting their unlikely involvement in seizure initiation. The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine-treated rats that support the model's validity. PMID:23825415

Effects of the Methanolic Extract of Vitellaria paradoxa Stem Bark Against Scopolamine-Induced Cognitive Dysfunction and Oxidative Stress in the Rat Hippocampus.

PubMed

Foyet, Harquin Simplice; Asongalem, Acha Emmanuel; Oben, Eyong Kenneth; Cioanca, Oana; Hancianu, Monica; Hritcu, Lucian

2016-10-01

Vitellaria paradoxa C.F. Gaertn (Sapotaceae) is a perennial three which naturally grows in the northern part of Cameroon. It has been traditionally used in the Cameroonian folk medicine for treating inflammation and pain. In the present study, we evaluate the possible anti-amnesic and antioxidative effects of the methanolic extract of V. paradoxa stem bark in an Alzheimer's disease (AD) rat model of scopolamine. Rats received a single injection of scopolamine (1.5 mg/kg) before behavioral testing and were treated with the methanolic extract (25 and 50 mg/kg), daily, for eight continuous days. Also, the antioxidant activity in the hippocampus was assessed using the total content of reduced glutathione and malondialdehyde levels. The scopolamine-treated rats exhibited the following: decrease of exploratory time and discrimination index within the novel object recognition test, decrease of spontaneous alternations percentage within Y-maze task, and increase of working memory errors, reference memory errors, and time taken to consume all five baits within radial arm-maze task. Administration of the methanolic extract significantly improved these parameters, suggesting positive effects on memory formation processes and antioxidant potential. Our results suggest that the methanolic extract ameliorates scopolamine-induced memory impairment by attenuation of the oxidative stress in the rat hippocampus.

Effect of electroacupuncture on the expression of mTOR and eIF4E in hippocampus of rats with vascular dementia.

PubMed

Zhu, Yanzhen; Zeng, Yanjun; Wang, Xuan; Ye, Xiaobao

2013-07-01

Clinically, electroacupuncture is proved to be an effective therapy for vascular dementia; however, their mechanisms remain uncertain. The aim of the current study was to investigate the mechanism of electroacupuncture therapy for vascular dementia. One month after a vascular dementia animal model was established by bilateral occlusion of common carotid arteries, electroacupuncture treatment was given at "Baihui" (DU20), "Dazhui" (DU14), and "Shenshu" (BL23). Morris water maze was used to assess the learning and memory ability of rats. Western blot assay was performed to detect the expression of mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E) in hippocampus of rats. Morris water maze test showed that electroacupuncture improved the learning ability of vascular dementia rats. Western blot assay revealed that the expression level of mTOR and eIF4E in the electroacupuncture group and sham-operated group was higher than that in the vascular dementia group (P < 0.05). In conclusion, the decreasing expression of mTOR and eIF4E plays important roles in the pathogenesis of vascular dementia. Electroacupuncture improves learning and memory ability by up-regulating expression of mTOR and eIF4E in the hippocampus of vascular dementia rats.

Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity

PubMed Central

Piroli, Gerardo G.; Lawrence, Robert C.; Wrighten, Shayna A.; Green, Adrienne J.; Wilson, Steven P.; Sakai, Randall R.; Kelly, Sandra J.; Wilson, Marlene A.; Mott, David D.; Reagan, Lawrence P.

2015-01-01

Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS–treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS–treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control. PMID:26216852

Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats.

PubMed

Jalkanen, Aaro J; Puttonen, Katja A; Venäläinen, Jarkko I; Sinervä, Veijo; Mannila, Anne; Ruotsalainen, Sirja; Jarho, Elina M; Wallén, Erik A A; Männistö, Pekka T

2007-02-01

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-month-old) and old (8- to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP(3)) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP(3) concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.

Bidirectional global spontaneous network activity precedes the canonical unidirectional circuit organization in the developing hippocampus.

PubMed

Shi, Yulin; Ikrar, Taruna; Olivas, Nicholas D; Xu, Xiangmin

2014-06-15

Spontaneous network activity is believed to sculpt developing neural circuits. Spontaneous giant depolarizing potentials (GDPs) were first identified with single-cell recordings from rat CA3 pyramidal neurons, but here we identify and characterize a large-scale spontaneous network activity we term global network activation (GNA) in the developing mouse hippocampal slices, which is measured macroscopically by fast voltage-sensitive dye imaging. The initiation and propagation of GNA in the mouse is largely GABA-independent and dominated by glutamatergic transmission via AMPA receptors. Despite the fact that signal propagation in the adult hippocampus is strongly unidirectional through the canonical trisynaptic circuit (dentate gyrus [DG] to CA3 to CA1), spontaneous GNA in the developing hippocampus originates in distal CA3 and propagates both forward to CA1 and backward to DG. Photostimulation-evoked GNA also shows prominent backward propagation in the developing hippocampus from CA3 to DG. Mouse GNA is strongly correlated to electrophysiological recordings of highly localized single-cell and local field potential events. Photostimulation mapping of neural circuitry demonstrates that the enhancement of local circuit connections to excitatory pyramidal neurons occurs over the same time course as GNA and reveals the underlying pathways accounting for GNA backward propagation from CA3 to DG. The disappearance of GNA coincides with a transition to the adult-like unidirectional circuit organization at about 2 weeks of age. Taken together, our findings strongly suggest a critical link between GNA activity and maturation of functional circuit connections in the developing hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Gene expression changes in the ventral hippocampus and medial prefrontal cortex of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking.

PubMed

McClintick, Jeanette N; McBride, William J; Bell, Richard L; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J

2018-05-01

Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including decreased hippocampal and prefrontal cortex volume and deficits in memory. We used RNA sequencing to assess the effects of adolescent binge drinking on gene expression in these regions. Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-h sessions/day during the dark/cycle, 5 days/week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session). Ethanol significantly altered the expression of 416 of 11,727 genes expressed in the ventral hippocampus. Genes and pathways involved in neurogenesis, long-term potentiation, and axonal guidance were decreased, which could relate to the impaired memory function found in subjects with adolescent alcohol binge-like exposure. The decreased expression of myelin and cholesterol genes and apparent decrease in oligodendrocytes in P rats could result in decreased myelination. In the medial prefrontal cortex, 638 of 11,579 genes were altered; genes in cellular stress and inflammatory pathways were increased, as were genes involved in oxidative phosphorylation. Overall, the results of this study suggest that adolescent binge-like alcohol drinking may alter the development of the ventral hippocampus and medial prefrontal cortex and produce long-term consequences on learning and memory, and on control of impulsive behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury.

PubMed

Cope, Elise C; Morris, Deborah R; Gower-Winter, Shannon D; Brownstein, Naomi C; Levenson, Cathy W

2016-05-01

There is great deal of debate about the possible role of adult-born hippocampal cells in the prevention of depression and related mood disorders. We first showed that zinc supplementation prevents the development of the depression-like behavior anhedonia associated with an animal model of traumatic brain injury (TBI). This work then examined the effect of zinc supplementation on the proliferation of new cells in the hippocampus that have the potential to participate in neurogenesis. Rats were fed a zinc adequate (ZA, 30ppm) or zinc supplemented (ZS, 180ppm) diet for 4wk followed by TBI using controlled cortical impact. Stereological counts of EdU-positive cells showed that TBI doubled the density of proliferating cells 24h post-injury (p<0.05), and supplemental zinc significantly increased this by an additional 2-fold (p<0.0001). While the survival of these proliferating cells decreased at the same rate in ZA and in ZS rats after injury, the total density of newly born cells was approximately 60% higher in supplemented rats 1wk after TBI. Furthermore, chronic zinc supplementation resulted in significant increases in the density of new doublecortin-positive neurons one week post-TBI that were maintained for 4wk after injury (p<0.01). While the effect of zinc supplementation on neuronal precursor cells in the hippocampus was robust, use of targeted irradiation to eliminate these cells after zinc supplementation and TBI revealed that these cells are not the sole mechanism through which zinc acts to prevent depression associated with brain injury, and suggest that other zinc dependent mechanisms are needed for the anti-depressant effect of zinc in this model of TBI. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiepileptic effect of fisetin in iron-induced experimental model of traumatic epilepsy in rats in the light of electrophysiological, biochemical, and behavioral observations.

PubMed

Das, Jharana; Singh, Rameshwar; Sharma, Deepak

2017-05-01

Traumatic epilepsy is defined by episodes of recurring seizures secondary to severe brain injury. Though drugs are found effective to control seizures, their long-term use have been observed to increase reactive oxygen species in animals. Flavonoid fisetin, a natural bioactive phytonutrient reported to exert anticonvulsive effect in experimental seizure models. But, trauma-induced seizures could not be prevented by anticonvulsants was reported in some clinical studies. To study the effect of fisetin on epileptiform electrographic activity in iron-induced traumatic epilepsy and also the probable reason behind the effect in rats. Fisetin pretreatment (20 mg/kg body wt., p.o.) of rats for 12 weeks were chosen followed by injecting iron (5 µl, 100 mM) stereotaxically to generate iron-induced epilepsy. Experimental design include electrophysiological study (electroencephalograph in correlation with multiple unit activity (MUA) in the cortex and CA1 subfield of the hippocampus; spectral analysis of seizure and seizure-associated behavioral study (Morris water maze for spatial learning, open-field test for anxiety) and biochemical study (lipid peroxidation, Na + ,K + -ATPase activity) in both the cortex and the hippocampus. Fisetin pretreatment was found to prevent the development of iron-induced electrical seizure and decrease the corresponding MUA in the cortex (*P˂0.05) as well as in the hippocampus (***P˂0.001). Fisetin pretreatment decreased the lipid peroxides (*P˂0.05) and retained the Na + ,K + -ATPase activity (*P˂0.05) which was found altered in the epileptic animals and also found to attenuate the seizure-associated cognitive dysfunctions. This study demonstrated the antiepileptic action of fisetin in iron-induced model of epileptic rats by inhibiting oxidative stress.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

Environmental Enrichment Alters Neurotrophin Levels After Fetal Alcohol Exposure in Rats

PubMed Central

Parks, Elizabeth A.; McMechan, Andrew P.; Hannigan, John H.; Berman, Robert F.

2014-01-01

Background Prenatal alcohol exposure causes abnormal brain development, leading to behavioral deficits, some of which can be ameliorated by environmental enrichment. As both environmental enrichment and prenatal alcohol exposure can individually alter neurotrophin expression, we studied the interaction of prenatal alcohol and postweaning environmental enrichment on brain neurotrophin levels in rats. Methods Pregnant rats received alcohol by gavage, 0, 4, or 6 g / kg / d (Zero, Low, or High groups), or no treatment (Naïve group), on gestational days 8 to 20. After weaning on postnatal day 21, offspring were housed for 6 weeks in Isolated, Social, or Enriched conditions. Levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were then measured in frontal cortex, occipital cortex, hippocampus, and cerebellar vermis. Results Prenatal alcohol exposure increased NGF levels in frontal cortex (High-dose group) and cerebellar vermis (High- and Low-dose groups); increased BDNF in frontal cortex, occipital cortex and hippocampus (Low-dose groups), and increased NT-3 in hippocampus and cerebellar vermis (High-dose). Environmental enrichment resulted in lower NGF, BDNF, and NT-3 levels in occipital cortex and lower NGF in frontal cortex. The only significant interaction between prenatal alcohol treatment and environment was in cerebellar vermis where NT-3 levels were higher for enriched animals after prenatal alcohol exposure, but not for animals housed under Isolated or Social conditions. Conclusions Both prenatal alcohol exposure and postweaning housing conditions alter brain neurotrophin levels, but the effects appear to be largely independent. Although environmental enrichment can improve functional outcomes, these results do not provide strong support for the hypothesis that rearing in a complex environment ameliorates prenatal alcohol effects on brain neurotrophin levels in rats. PMID:18652597

Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups.

PubMed

Lee, Sung-Min; Kim, Bo-Kyun; Kim, Tae-Woon; Ji, Eun-Sang; Choi, Hyun-Hee

2016-06-01

Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2'-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits.

The effect of ovariectomy on learning and memory and relationship to changes in brain volume and neuronal density.

PubMed

Su, Jian; Sripanidkulchai, Kittisak; Hu, Ying; Wyss, J Michael; Sripanidkulchai, Bungorn

2012-10-01

The loss of sex hormones in postmenopausal women has been suggested to be involved in cognitive degenerative diseases, such as Alzheimer's disease. In the present study, ovariectomized (OVX) and control rats were tested for 4 months in a Morris water maze (MWM) task to track their memory status. Thereafter, postmortem frozen brain sections were analyzed to determine if changes in brain area volumes and neuronal density were related to changes in cognitive ability. A modified artificial-land-mark-based method was used to assure the fidelity of the three dimensions (3D) reconstructed structures. Volumetric areas of the hippocampus, cortex, caudate putamen (cpu), and cerebellum were estimated from the reconstructions, and neuron densities of CA1 and CA3 subregions of the hippocampus were measured in an adjacent second series of Nissl-stained sections. Compared to the control rats, OVX rats displayed memory impairments, beginning in the second month after the ovariectomy (p < .05). Assessments at the end of the study demonstrated that OVX (compared to control) rats displayed reduced brain volume in the hippocampus and neocortex and in the brain as a whole. In contrast, when compared to controls, the volumes of cpu and cerebellum of OVX rats increased slightly. CA3 neuron density of OVX (compared to controls) rats was significantly lower, but the CA1 neuron density was significantly higher. In conclusion, ovariectomy impaired spatial memory and led to morphological changes in cognitive centers of rat brain. The results demonstrate that the 3D reconstructed method is useful for the study of brain morphological abnormality in rats.

Galanin inhibits acetylcholine release in the ventral hippocampus of the rat: histochemical, autoradiographic, in vivo, and in vitro studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisone, G.; Wu, C.F.; Consolo, S.

1987-10-01

A high density of galanin binding sites was found by using /sup 125/I-labeled galanin, iodinated by chloramine-T, followed by autoradiography in the ventral, but not in the dorsal, hippocampus of the rat. Lesions of the fimbria and of the septum caused disappearance of a major population of these binding sites, suggesting that a large proportion of them is localized on cholinergic nerve terminals of septal afferents. As a functional correlate to these putative galanin receptor sites, it was shown, both in vivo and in vitro, that galanin, in a concentration-dependent manner, inhibited the evoked release of acetylcholine in the ventral,more » but not in the dorsal, hippocampus. Intracerebroventricularly applied galanin fully inhibited the scopolamine stimulated release of acetylcholine in the ventral, but not in the dorsal, hippocampus, as measured by the microdialysis technique. In vitro, galanin inhibited the 25 mM K/sup +/-evoked release of (/sup 3/H)acetylcholine from slices of the ventral hippocampus, with an IC/sub 50/ value of approx. = 50 nM. These results are discussed with respect to the colocalization of galanin- and choline acetyltransferase-like immunoreactivity in septal somata projecting to the hippocampus.« less

Hippocampus and Retrograde Amnesia in the Rat Model: A Modest Proposal for the Situation of Systems Consolidation

PubMed Central

Sutherland, Robert J.; Sparks, Fraser; Lehmann, Hugo

2010-01-01

The properties of retrograde amnesia after damage to the hippocampus have been explicated with some success using a rat model of human medial temporal lobe amnesia. We review the results of this experimental work with rats focusing on several areas of consensus in this growing literature. We evaluate the theoretically significant hypothesis that hippocampal retrograde amnesia normally exhibits a temporal gradient, affecting recent, but sparing remote memories. Surprisingly, the evidence does not provide much support for the idea that there is a lengthy process of systems consolidation following a learning episode. Instead, recent and remote memories tend to be equally affected. The extent of damage to the hippocampus is a significant factor in this work since it is likely that spared hippocampal tissue can support at least partial memory retrieval. With extensive hippocampal damage gradients are flat or, in the case of memory tasks with flavour/odour retrieval cues, the retrograde amnesia covers a period of about 1 – 3 days. There is consistent evidence that at the time of learning the hippocampus interferes with or overshadows memory acquisition by other systems. This contributes to the breadth and severity of retrograde amnesia relative to anterograde amnesia in the rat. The fact that multiple, distributed learning episodes can overcome this overshadowing is consistent with a parallel dual-store theory or a Distributed Reinstatement Theory in which each learning episode triggers a short period of memory replay that provides a brief hippocampal-dependent systems consolidation. PMID:20430043

Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS-BDNF-TrkB Pathway.

PubMed

Song, Xiaoyu; Zhou, Biao; Zhang, Pingping; Lei, Di; Wang, Yubin; Yao, Guodong; Hayashi, Toshihiko; Xia, Mingyu; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

2016-07-01

Silibinin, a flavonoid derived from the herb milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver disease. In the present study, the effect of silibinin on lipopolysaccharide (LPS)-induced neuroinflammatory impairment in rats is investigated. Injection of LPS into lateral ventricle caused learning and memory impairment. Rats were treated with silibinin to see the effect in comparison with resveratrol as a positive control. Y-maze and Morris water maze tests showed that silibinin significantly attenuated memory damage caused by LPS treatment. At the molecular analysis, the levels of IL-1β and of IL-4 in the hippocampus were decreased and enhanced, respectively, by the treatment with silibinin. NF-κB expression was attenuated by silibinin treatment. Furthermore, generation of total reactive oxygen species (ROS) in the hippocampus was elevated in silibinin-treated groups, and so were the expressions of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). At the same time, LPS-induced reduction of neurons in hippocampus was reversed by silibinin. In conclusion, silibinin ameliorated the impairment of learning and memory of LPS-injection rats, possibly due to the activation of ROS-BDNF-TrkB pathway in the hippocampus as well as the suppression of inflammatory response. This study gives an insight on the beneficial consequences of ROS in central nervous system. Silibinin might be a potential candidate drug for neurodegenerative diseases.

Maternal administration of melatonin prevents spatial learning and memory deficits induced by developmental ethanol and lead co-exposure.

PubMed

Soleimani, Elham; Goudarzi, Iran; Abrari, Kataneh; Lashkarbolouki, Taghi

2017-05-01

Melatonin is a radical scavenger with the ability to remove reactive oxidant species. There is report that co-exposure to lead and ethanol during developmental stages induces learning and memory deficits and oxidative stress. Here, we studied the effect of melatonin, with strong antioxidant properties, on memory deficits induced by lead and ethanol co-exposure and oxidative stress in hippocampus. Pregnant rats in lead and ethanol co-exposure group received lead acetate of 0.2% in distilled drinking water and ethanol (4g/kg) by oral gavages once daily from the 5th day of gestation until weaning. Rats received 10mg/kg melatonin by oral gavages. On postnatal days (PD) 30, rats trained with six trials per day for 6 consecutive days in the water maze. On day 37, a probe test was done and oxidative stress markers in the hippocampus were evaluated. Results demonstrated lead and ethanol co-exposed rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency in probe trial test and had significantly higher malondialdehyde (MDA) levels, significantly lower superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities in the hippocampus. Melatonin treatment could improve memory deficits, antioxidants activity and reduced MDA levels in the hippocampus. We conclude, co-exposure to lead and ethanol impair memory and melatonin can prevent from it by oxidative stress modulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Grape seed extract has superior beneficial effects than vitamin E on oxidative stress and apoptosis in the hippocampus of streptozotocin induced diabetic rats.

PubMed

Yonguc, Goksin Nilufer; Dodurga, Yavuz; Adiguzel, Esat; Gundogdu, Gulsah; Kucukatay, Vural; Ozbal, Seda; Yilmaz, Ismail; Cankurt, Ulker; Yilmaz, Yusuf; Akdogan, Ilgaz

2015-01-25

We aimed to investigate the effects of grape seed extract (GSE) and vitamin E (Vit E) on oxidative stress and apoptosis in the hippocampus of streptozotocin-induced diabetic rats. In Control, Diabetic, and Diabetic treated with GSE (Diabetic+GSE) and vitamin E (Diabetic+Vit E) groups, oxidative stress index (OSI), TUNEL staining and Bcl-2, Bcl-XL, Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were evaluated. OSI was significantly increased in the plasma and hippocampus of the Diabetic compared to Control group and decreased in Diabetic+GSE and Diabetic+Vit E groups compared to Diabetic. TUNEL positive neurons significantly increased in the hippocampus of the Diabetic group compared to Control and decreased in Diabetic+GSE (more prominently) and Diabetic+Vit E groups compared to Diabetic. In the hippocampus of the Diabetic group, Bcl-2 and Bcl-XL gene expressions were significantly decreased; Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB gene expressions were significantly increased compared to Control. In Diabetic+GSE and Diabetic+Vit E groups, Bcl-2 gene expressions were significantly increased; Bcl-XL gene expressions did not differ compared to the Diabetic group. The expression of Bax, caspase-3, -9, and -8, Cyt-c, TNF-α, and NF-κB genes in the Diabetic+GSE group and the expression of caspase-3 and -9, TNF-α, and NF-κB genes in the Diabetic+Vit E group were significantly decreased compared to Diabetic. In conclusion, GSE (more prominently) and vitamin E decreased oxidative stress and neuronal apoptosis occurring in the hippocampus of diabetic rats. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of genistein and swimming exercise on spatial memory and expression of microRNA 132, BDNF, and IGF-1 genes in the hippocampus of ovariectomized rats.

PubMed

Habibi, Parisa; Babri, Shirin; Ahmadiasl, Nasser; Yousefi, Hadi

2017-08-01

The aim of the present study was to investigate the effects of genistein and exercise on the spatial memory and expression of microRNA-132, BDNF, and IGF-1 in the hippocampus of ovariectomized rats. Sixty animals were divided into six groups of control, sham, ovariectomy (OVX), ovariectomized with 8 weeks of genistein administration (OVX.G), with 8 weeks of swimming training (OVX.E), and with 8 weeks of both of them (OVX.G.E). The effect of genistein and/or exercise was evaluated by measuring microRNA-132, BDNF, and IGF-1 expression levels in the hippocampus tissue. Grafts were analyzed using Real-time polymerase chain reaction for microRNA-132, BDNF, IGF-1, and spatial memory via a Morris water maze (MWM). Our findings showed that ovariectomy decreased the expression of microRNA-132, BDNF, and IGF-1 in the hippocampus ( P <0.05) in comparison with the sham group as well as performance in the water maze ( P <0.05). Also according to results ovariectomized groups that were treated with genistein/exercise or both of them showed significant difference in expression of microRNA-132, BDNF, and IGF-1 in the hippocampus ( P <0.05) and decreased latency in MWM ( P <0.05) compared with the OVX group but combination treatment was more effective in the OVX.G.E group in comparison with OVX.E and OVX.G groups. Overall our results emphasized that combination treatment with genistein and exercise could improve microRNA-132, BDNF, and IGF-1 expression in the hippocampus as well as the spatial memory of ovariectomized rats. These effects may have beneficial impacts on the menopausal period.

Oxytocin Modulates Expression of Neuron and Glial Markers in the Rat Hippocampus.

PubMed

Havránek, T; Lešťanová, Z; Mravec, B; Štrbák, V; Bakoš, J; Bačová, Z

2017-01-01

Neuropeptides including oxytocin belong to the group of factors that may play a role in the control of neuronal cell survival, proliferation and differentiation. The aim of the present study was to investigate potential contribution of oxytocin to neuronal differentiation by measuring gene and protein expression of specific neuron and glial markers in the brain. Neonatal and adult oxytocin administration was used to reveal developmental and/or acute effects of oxytocin in Wistar rats. Gene and protein expression of neuron-specific enolase (NSE) in the hippocampus was increased in 21-day and 2-month old rats in response to neonatal oxytocin administration. Neonatal oxytocin treatment induced a significant increase of gene and protein expression of the marker of astrocytes - glial fibrillary acid protein (GFAP). Oxytocin treatment resulted in a decrease of oligodendrocyte marker mRNA - 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) - in 21-day and 2-month old rats, while no change of CD68 mRNA, marker of microglia, was observed. Central oxytocin administration in adult rats induced a significant increase of gene expression of NSE and CNPase. The present study provides the first data revealing the effect of oxytocin on the expression of neuron and glial markers in the brain. It may be suggested that the oxytocin system is involved in the regulation of development of neuronal precursor cells in the brain.

Differential DNA damage in response to the neonatal and adult excitotoxic hippocampal lesion in rats.

PubMed

Khaing, Z Z; Weickert, C S; Weinberger, D R; Lipska, B K

2000-12-01

We examined the developmental profile of excitotoxin-induced nuclear DNA fragmentation using the transferase dUTP nick-end labelling (TUNEL) technique, as a marker of DNA damage and cell death in rats with neonatal and adult excitotoxic lesions of the ventral hippocampus. We hypothesized that infusion of neurotoxin may result in a differential pattern of cell death in neonatally and adult lesioned rats, both in the infusion site and in remote brain regions presumably involved in mediating behavioural changes observed in these animals. Brains of rats lesioned at 7 days of age and in adulthood were collected at several survival times 1-21 days after the lesion. In the lesioned neonates 1-3 days postlesion, marked increases in TUNEL-positive cells occurred in the ventral hippocampus, the site of neurotoxin infusion, and in a wide surrounding area. Adult lesioned brains showed more positive cells than controls only at the infusion site. In the lesioned neonates, TUNEL-labelled cells were also present in the striatum and nucleus accumbens 1 day postlesion but not at later survival times. Our findings indicate that cell death in remote regions is more prominent in immature than adult brains, that it may lead to distinct alterations in development of these brain regions, and thus may be responsible for functional differences between neonatally and adult lesioned rats.

Omega-3 fatty acid supplementation decreases DNA damage in brain of rats subjected to a chemically induced chronic model of Tyrosinemia type II.

PubMed

Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Rebelo, Joyce; Damiani, Adriani P; Pereira, Maiara; Andrade, Vanessa M; Gava, Fernanda F; Valvassori, Samira S; Schuck, Patricia F; Ferreira, Gustavo C; Streck, Emilio L

2017-08-01

Tyrosinemia type II is an inborn error of metabolism caused by a mutation in a gene encoding the enzyme tyrosine aminotransferase leading to an accumulation of tyrosine in the body, and is associated with neurologic and development difficulties in numerous patients. Because the accumulation of tyrosine promotes oxidative stress and DNA damage, the main aim of this study was to investigate the possible antioxidant and neuroprotective effects of omega-3 treatment in a chemically-induced model of Tyrosinemia type II in hippocampus, striatum and cerebral cortex of rats. Our results showed chronic administration of L-tyrosine increased the frequency and the index of DNA damage, as well as the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the hippocampus, striatum and cerebral cortex. Moreover, omega-3 fatty acid treatment totally prevented increased DNA damage in the striatum and hippocampus, and partially prevented in the cerebral cortex, whereas the increase in 8-OHdG levels was totally prevented by omega-3 fatty acid treatment in hippocampus, striatum and cerebral cortex. In conclusion, the present study demonstrated that the main accumulating metabolite in Tyrosinemia type II induce DNA damage in hippocampus, striatum and cerebral cortex, possibly mediated by free radical production, and the supplementation with omega-3 fatty acids was able to prevent this damage, suggesting that could be involved in the prevention of oxidative damage to DNA in this disease. Thus, omega-3 fatty acids supplementation to Tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the curren t treatment of this disease.

Prenatal Nutritional Deficiency Reprogrammed Postnatal Gene Expression in Mammal Brains: Implications for Schizophrenia

PubMed Central

Xu, Jiawei; He, Guang; Zhu, Jingde; Zhou, Xinyao; St Clair, David; Wang, Teng; Xiang, Yuqian; Zhao, Qingzhu; Xing, Qinghe; Liu, Yun; Wang, Lei; Li, Qiaoli

2015-01-01

Background: Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia. Methods: The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure. Results: In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10–9 and 5.36×10–9, respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring. Conclusions: Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia. PMID:25522397

Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction.

PubMed

Kim, Chi Hun; Romberg, Carola; Hvoslef-Eide, Martha; Oomen, Charlotte A; Mar, Adam C; Heath, Christopher J; Berthiaume, Andrée-Anne; Bussey, Timothy J; Saksida, Lisa M

2015-11-01

The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

PubMed

Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

2017-03-15

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of Combined Stress on Morphological Changes and Expression of NO Synthases in Rat Ventral Hippocampus.

PubMed

Smirnov, A V; Tyurenkov, I N; Shmidt, M V; Ekova, M R; Mednikov, D S; Borodin, D D

2015-11-01

Adult rats were subjected to 7-day combined stress with stochastic changes of stressors of different modalities (noise, vibration, pulsating bright light) along with mobility restriction and elevated temperature in the chamber during stress exposures (daily 30-min sessions). Circulatory disorders, inhibition of endothelial NO-synthase expression in endothelial cells of the microcirculatory bed, perivascular edema, pronounced degenerative changes, and enhanced expression of inducible NO synthase in CA3 pyramidal neurons in the ventral hippocampus of stressed 12-month-old rats were observed. These findings can attest to the involvement NOdependent mechanisms and different contribution of NO synthase isoforms into the formation of hippocampal neuronal damage.

Strain-dependent effects of long-term treatment with melatonin on kainic acid-induced status epilepticus, oxidative stress and the expression of heat shock proteins.

PubMed

Atanasova, Milena; Petkova, Zlatina; Pechlivanova, Daniela; Dragomirova, Petya; Blazhev, Alexander; Tchekalarova, Jana

2013-10-01

Oxidative stress is implicated in the pathogenesis of both hypertension and epileptogenesis, therefore it could be used as a tool for studying co-morbidity of hypertension and epilepsy. Clinical data suggest that melatonin is a potent antioxidant that is effective in the adjunctive therapy of hypertension and neurodegenerative diseases. The present study aimed to explore and compare the efficacy of chronic pretreatment with melatonin infused via subcutaneous osmotic mini-pumps for 14 days (10 mg/kg per day) on kainic acid (KA)-induced status epilepticus, oxidative stress and expression of heat shock protein (HSP) 72 in spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. SHRs showed higher lipid peroxidation (LP) in the frontal cortex and hippocampus and decreased cytosolic superoxide dismutase (SOD/CuZn) production in the frontal cortex compared to Wistar rats. Status epilepticus (SE) induced by KA (12 mg/kg, i.p.) was accompanied by increased LP and expression of HSP 72 in the hippocampus of the two strains and increased SOD/CuZn production in the frontal cortex of SHRs. Melatonin failed to suppress seizure incidence and intensity though the latency for seizure onset was significantly increased in SHRs. Melatonin attenuated the KA-induced increase in the level of LP in the hippocampus both in SHRs and Wistar rats. However, an increased activity in SOD/CuZn and mitochondrial SOD Mn as well as reduced expression of HSP 72 in the hippocampus was observed only in Wistar rats pretreated with melatonin. Taken together, the observed strain differences in the efficacy of chronic melatonin exposure before SE suggest a lack of a direct link between the seizure activity and the markers of oxidative stress and neurotoxicity. © 2013.

Physical training improves non-spatial memory, locomotor skills and the blood brain barrier in diabetic rats.

PubMed

de Senna, Priscylla Nunes; Xavier, Léder Leal; Bagatini, Pamela Brambilla; Saur, Lisiani; Galland, Fabiana; Zanotto, Caroline; Bernardi, Caren; Nardin, Patrícia; Gonçalves, Carlos Alberto; Achaval, Matilde

2015-08-27

Type 1 diabetes mellitus (T1DM) progressively affects cognitive domains, increases blood-brain barrier (BBB) permeability and promotes neurovascular impairment in specific brain areas. Physical exercise, on the other hand, has beneficial effects on brain functions, improving learning and memory. This study investigated the effects of treadmill training on cognitive and motor behavior, and on the expression of proteins related to BBB integrity, such as claudin-5 and aquaporin-4 (AQP4) in the hippocampus and striatum in diabetic rats. For this study, 60 Wistar rats were divided into four groups (n=15 per group): non-trained control (NTC), trained control (TC), non-trained diabetic (NTD), trained diabetic (TD). After diabetic induction of 30 days by streptozotocin injection, the exercise groups were submitted to 5 weeks of running training. After that, all groups were assessed in a novel object-recognition task (NOR) and the rotarod test. Additionally, claudin-5 and AQP4 levels were measured using biochemical assays. The results showed that exercise enhanced NOR task performance and rotarod ability in the TC and TD animals. Diabetes produced a decrease in claudin-5 expression in the hippocampus and striatum and reduced AQP4 in the hippocampus. Exercise preserved the claudin-5 content in the striatum of TD rats, but not in the hippocampus. The reduction of AQP4 levels produced by diabetes was not reversed by exercise. We conclude that exercise improves short-term memory retention, enhances motor performance in diabetic rats and affects important structural components of the striatal BBB. The results obtained could enhance the knowledge regarding the neurochemical benefits of exercise in diabetes. Copyright © 2015 Elsevier B.V. All rights reserved.

Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats.

PubMed

Monserrat Hernández-Hernández, Elizabeth; Serrano-García, Carolina; Antonio Vázquez-Roque, Rubén; Díaz, Alfonso; Monroy, Elibeth; Rodríguez-Moreno, Antonio; Florán, Benjamin; Flores, Gonzalo

2016-05-01

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1- and CA3-dorsal hippocampus (DH) as well as CA1-ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18-month-old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi-Cox stain procedure, followed by Sholl analysis on 20-month-old rats. In all resveratrol-treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease. © 2016 Wiley Periodicals, Inc.

Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T.

PubMed

Hemanth Kumar, B S; Mishra, Sushanta Kumar; Rana, Poonam; Singh, Sadhana; Khushu, Subash

2012-06-15

Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy ((1)H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. (1)H MRS was performed in both control and CMS rats (n=10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA+NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using (1)H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression. Copyright © 2012 Elsevier B.V. All rights reserved.

Altered GABAergic and glutamatergic activity within the rat hippocampus and amygdala in rats subjected to repeated corticosterone administration but not restraint stress.

PubMed

Lussier, A L; Romay-Tallón, R; Caruncho, H J; Kalynchuk, L E

2013-02-12

We investigated the effect of two well characterized preclinical animal models of depression - repeated injections of corticosterone (CORT) and repeated restraint stress - on markers of GABAergic and glutamatergic activity in the hippocampus and amygdala. Stress is an identified risk factor for the onset of major depression, but the neurobiological mechanisms by which stress may produce depressogenic effects are not clear. Rats received one of the following four treatments for 21 consecutive days: daily single CORT injections (40mg/kg), daily single vehicle injections, daily 6h of restraint stress, or daily handling. After the 21-day stress period, all rats were sacrificed and hippocampal and amygdalar tissue was collected and prepared for Western blot analyses. We examined the effect of CORT and restraint stress on glutamate decarboxylase (GAD)-65 and GAD67, as well as the α1, α2, α3, and β2-3 GABA(A) receptor subunits, and the vesicular glutamate transporter (VGLUT)-2. We found that CORT significantly decreased GAD65 and the α2 receptor subunit and increased VGLUT2 within the hippocampus. We also found that CORT decreased GAD67 and the α2 receptor subunit in the amygdala. However, restraint stress had no significant effect on protein expression in either the hippocampus or the amygdala. These findings parallel our previous results showing that repeated CORT injections, but not restraint stress, increase depression-like behavior in rats, and suggest that the depressogenic effects of CORT may be related to alterations in GABAergic and glutamatergic neurotransmission in stress-sensitive regions of the brain. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Peony glycosides reverse the effects of corticosterone on behavior and brain BDNF expression in rats.

PubMed

Mao, Qing-Qiu; Huang, Zhen; Ip, Siu-Po; Xian, Yan-Fang; Che, Chun-Tao

2012-02-01

Repeated injections of corticosterone (CORT) induce the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depressive-like behavior. This study aimed to examine the antidepressant-like effect and the possible mechanisms of total glycosides of peony (TGP) in the CORT-induced depression model in rats. The results showed that the 3-week CORT injections induced the significant increase in serum CORT levels in rats. Repeated CORT injections also caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Moreover, it was found that brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex were significantly decreased in CORT-treated rats. Treatment of the rats with TGP significantly suppressed the depression-like behavior and increased brain BDNF levels in CORT-treated rats. The results suggest that TGP produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex. Copyright © 2011 Elsevier B.V. All rights reserved.

Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward.

PubMed

Newman, Lori A; Scavuzzo, Claire J; Gold, Paul E; Korol, Donna L

2017-01-01

Recent evidence suggests that astrocytes convert glucose to lactate, which is released from the astrocytes and supports learning and memory. This report takes a multiple memory perspective to test the role of astrocytes in cognition using real-time lactate measurements during learning and memory. Extracellular lactate levels in the hippocampus or striatum were determined with lactate biosensors while rats were learning place (hippocampus-sensitive) or response (striatum-sensitive) versions of T-mazes. In the first experiment, rats were trained on the place and response tasks to locate a food reward. Extracellular lactate levels in the hippocampus increased beyond those of feeding controls during place training but not during response training. However, striatal lactate levels did not increase beyond those of controls when rats were trained on either the place or the response version of the maze. Because food ingestion itself increased blood glucose and brain lactate levels, the contribution of feeding may have confounded the brain lactate measures. Therefore, we conducted a second similar experiment using water as the reward. A very different pattern of lactate responses to training emerged when water was used as the task reward. First, provision of water itself did not result in large increases in either brain or blood lactate levels. Moreover, extracellular lactate levels increased in the striatum during response but not place learning, whereas extracellular lactate levels in the hippocampus did not differ across tasks. The findings from the two experiments suggest that the relative engagement of the hippocampus and striatum dissociates not only by task but also by reward type. The divergent lactate responses of the hippocampus and striatum in place and response tasks under different reward conditions may reflect ethological constraints tied to foraging for food and water. Copyright © 2016 Elsevier Inc. All rights reserved.

Oxidative stress in a model of toxic demyelination in rat brain: the effect of piracetam and vinpocetine.

PubMed

Abdel-Salam, Omar M E; Khadrawy, Yasser A; Salem, Neveen A; Sleem, Amany A

2011-06-01

We studied the role of oxidative stress and the effect of vinpocetine (1.5, 3 or 6 mg/kg) and piracetam (150 or 300 mg/kg) in acute demyelination of the rat brain following intracerebral injection of ethidium bromide (10 μl of 0.1%). ethidium bromide caused (1) increased malondialdehyde (MDA) in cortex, hippocampus and striatum; (2) decreased total antioxidant capacity (TAC) in cortex, hippocampus and striatum; (3) decreased reduced glutathione (GSH) in cortex and hippocampus (4); increased serum nitric oxide and (5) increased striatal (but not cortical or hippocampal) acetylcholinesterase (AChE) activity. MDA decreased in striatum and cortex by the lower doses of vinpocetine or piracetam but increased in cortex and hippocampus and in cortex, hypothalamus and striatum by the higher dose of vinpocetine or piracetam, respectively along with decreased TAC. GSH increased by the higher dose of piracetam and by vinpocetine which also decreased serum nitric oxide. Vinpocetine and piracetam displayed variable effects on regional AChE activity.

Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus.

PubMed

Calhoun, Michael E; Fletcher, Bonnie R; Yi, Stella; Zentko, Diana C; Gallagher, Michela; Rapp, Peter R

2008-08-01

Age-related impairments in hippocampus-dependent learning and memory tasks are not associated with a loss of hippocampal neurons, but may be related to alterations in synaptic integrity. Here we used stereological techniques to estimate spine number in hippocampal subfields using immunostaining for the spine-associated protein, spinophilin, as a marker. Quantification of the immunoreactive profiles was performed using the optical disector/fractionator technique. Aging was associated with a modest increase in spine number in the molecular layer of the dentate gyrus and CA1 stratum lacunosum-moleculare. By comparison, spinophilin protein levels in the hippocampus, measured by Western blot analysis, failed to differ as a function of age. Neither the morphological nor the protein level data were correlated with spatial learning ability across individual aged rats. The results extend current evidence on synaptic integrity in the aged brain, indicating that a substantial loss of dendritic spines and spinophilin protein in the hippocampus are unlikely to contribute to age-related impairment in spatial learning.

Oxidative stress induces the decline of brain EPO expression in aging rats.

PubMed

Li, Xu; Chen, Yubao; Shao, Siying; Tang, Qing; Chen, Weihai; Chen, Yi; Xu, Xiaoyu

2016-10-01

Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2months) were simulated by subcutaneously injecting with d-gal at doses of 50mg·kg(-1), 150mg·kg(-1) and 250mg·kg(-1) daily for 8weeks while the control group received vehicle only. These groups were all compared with the aging rats (24months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of β-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2α (HIF-2α) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150mg·kg(-1) and 250mg·kg(-1) (p<0.05). Also, the amount of β-galactosidase and the MDA level in the hippocampus were significantly increased but the SOD activity was significantly decreased (p<0.05, 0.01 and 0.01, respectively). Similar to aging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2αin the brain of d-gal-treated rats were significantly decreased (p<0.05) at 150mg·kg(-1) and 250mg·kg(-1). Interestingly, negative correlations were found between EPOR (r=-0.699, p<0.01), EPO (r=-0.701, p<0.01) and the MDA level. These results indicated that aging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2α stability. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats

PubMed Central

LIU, GUANGYI; WANG, TAO; WANG, TINGING; SONG, JINMING; ZHOU, ZHEN

2013-01-01

Neuron apoptosis is known to mediate a change of ethology following cerebral ischemia-reperfusion injury in rats. Additionally, Bcl-2, Bax and caspase-3 proteins may exert a significant effect on neuron injury. The aim of this study was to investigate the role, mechanism of action and clinical significance of these proteins in neuron apoptosis and functional impairment following cerebral ischemia-reperfusion injury in rats. Sixty male healthy adult Wistar rats were randomly assigned into control (n=6), sham operation (n=6) and experimental (n=48) groups. The model of rat cerebral ischemia-reperfusion injury was set up according to the method of Zea-Longa. Eight subsets of 6 rats-subset were designed according to time points (at 3, 6, 12, 24 and 48 h and at 3, 7 and 14 days). Nerve functional injury was evaluated and graded using nerve function score, balance, coordination function detection and measurement of forelimb placing. The neurons expressing caspase-3, Bax and Bcl-2 in the cortical area, CA3, CA1, stratum lucidum (Slu) and molecular layer of the dentate gyrus (MoDG) of the hippocampus were detected using immunohistochemistry or the TUNEL method. The expression of caspase-3, Bax and Bcl-2 genes was detected by the reverse transcriptase polymerase chain reaction (RT-PCR). The results indicated that, compared to the sham operation group, the score of nerve function and balance beam walking were distinctly higher (P<0.01) and the percentage of rat foreleg touching the angle or margin of the table was significantly lower in the experimental rat group (P<0.01) at 3 h following reperfusion. The expression of TUNEL-positive neurons was high in the cortical area and the CA3 region of the hippocampus (P<0.01), caspase-3 was at peak value in the cortical area and the CA1 region of the hippocampus (P<0.01), Bax was increased in the cortical area and the Slu of the hippocampus (P<0.01) and Bcl-2 was low in the cortical area and the MoDG of the hippocampus (P<0.01) in the experimental group at 48 h following reperfusion. In conclusion, cerebral ischemia/reperfusion injury may cause neurological impairment and lead to a change of ethology, and neuron apoptosis may be associated with the activation of caspase-3 and Bax and the downregulation of Bcl-2. PMID:24649043

Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats.

PubMed

Liu, Guangyi; Wang, Tao; Wang, Tinging; Song, Jinming; Zhou, Zhen

2013-11-01

Neuron apoptosis is known to mediate a change of ethology following cerebral ischemia-reperfusion injury in rats. Additionally, Bcl-2, Bax and caspase-3 proteins may exert a significant effect on neuron injury. The aim of this study was to investigate the role, mechanism of action and clinical significance of these proteins in neuron apoptosis and functional impairment following cerebral ischemia-reperfusion injury in rats. Sixty male healthy adult Wistar rats were randomly assigned into control (n=6), sham operation (n=6) and experimental (n=48) groups. The model of rat cerebral ischemia-reperfusion injury was set up according to the method of Zea-Longa. Eight subsets of 6 rats-subset were designed according to time points (at 3, 6, 12, 24 and 48 h and at 3, 7 and 14 days). Nerve functional injury was evaluated and graded using nerve function score, balance, coordination function detection and measurement of forelimb placing. The neurons expressing caspase-3, Bax and Bcl-2 in the cortical area, CA3, CA1, stratum lucidum (Slu) and molecular layer of the dentate gyrus (MoDG) of the hippocampus were detected using immunohistochemistry or the TUNEL method. The expression of caspase-3, Bax and Bcl-2 genes was detected by the reverse transcriptase polymerase chain reaction (RT-PCR). The results indicated that, compared to the sham operation group, the score of nerve function and balance beam walking were distinctly higher (P<0.01) and the percentage of rat foreleg touching the angle or margin of the table was significantly lower in the experimental rat group (P<0.01) at 3 h following reperfusion. The expression of TUNEL-positive neurons was high in the cortical area and the CA3 region of the hippocampus (P<0.01), caspase-3 was at peak value in the cortical area and the CA1 region of the hippocampus (P<0.01), Bax was increased in the cortical area and the Slu of the hippocampus (P<0.01) and Bcl-2 was low in the cortical area and the MoDG of the hippocampus (P<0.01) in the experimental group at 48 h following reperfusion. In conclusion, cerebral ischemia/reperfusion injury may cause neurological impairment and lead to a change of ethology, and neuron apoptosis may be associated with the activation of caspase-3 and Bax and the downregulation of Bcl-2.

Biochemical and histological studies on adverse effects of mobile phone radiation on rat's brain.

PubMed

Hussein, Shaymaa; El-Saba, Abdel-Aleem; Galal, Mona K

2016-12-01

With the rapid development of electronic technologies, the public concern about the potential health hazards induced by radiofrequency (RF) radiation has been grown. To investigate the effect of 1800MHz RF radiation emitted from mobile phone on the rat's brain, the present study was performed. Forty male rats were randomly divided into two equal groups; control and exposed group. The later one exposed to 1800MHz emitted from mobile phone with an SAR value of 0.6W/kg for two hours/day for three months. The brain tissues were collected at the end of the experimental period and separated into hippocampus and cerebellum for subsequent biochemical, histological, immunohistochemical and electron microscopic investigations. The rats that were exposed to RF- radiation had a significant elevation in MDA content and a significant reduction in antioxidant parameters (glutathione, super oxide dismutase and glutathione peroxidase) in both regions. Degenerative changes were observed in the hippocampus pyramidal cells, dark cells and cerebellar Purkinje cells with vascular congestion. In addition a significant DNA fragmentation and over expression of cyclooxygenase-2 apoptotic gene was detected. Those results suggested that, direct chronic exposure to mobile phone caused severe biochemical and histopathological changes in the brain. Copyright © 2016 Elsevier B.V. All rights reserved.

Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy.

PubMed

Han, Chun-Lei; Ge, Ming; Liu, Yun-Peng; Zhao, Xue-Min; Wang, Kai-Liang; Chen, Ning; Hu, Wei; Zhang, Jian-Guo; Li, Liang; Meng, Fan-Gang

2018-05-23

Temporal lobe epilepsy (TLE) is one of the most common types of intractable epilepsy, characterized by hippocampal neuron damage and hippocampal sclerosis. Long noncoding RNAs (lncRNAs) have been increasingly recognized as posttranscriptional regulators. However, their expression levels and functions in TLE remain largely unknown. In the present study, TLE rat model is used to explore the expression profiles of lncRNAs in the hippocampus of epileptic rats using microarray analysis. Our results demonstrate that H19 is the most pronouncedly differentiated lncRNA, significantly upregulated in the latent period of TLE. Moreover, the in vivo studies using gain- and loss-of-function approaches reveal that the overexpression of H19 aggravates SE-induced neuron apoptosis in the hippocampus, while inhibition of H19 protects the rats from SE-induced cellular injury. Finally, we show that H19 might function as a competing endogenous RNA to sponge microRNA let-7b in the regulation of cellular apoptosis. Overall, our study reveals a novel lncRNA H19-mediated mechanism in seizure-induced neural damage and provides a new target in developing lncRNA-based strategies to reduce seizure-induced brain injury.

High postnatal susceptibility of hippocampal cytoskeleton in response to ethanol exposure during pregnancy and lactation.

PubMed

Reis, Karina Pires; Heimfarth, Luana; Pierozan, Paula; Ferreira, Fernanda; Loureiro, Samanta Oliveira; Fernandes, Carolina Gonçalves; Carvalho, Rônan Vivian; Pessoa-Pureur, Regina

2015-11-01

Ethanol exposure to offspring during pregnancy and lactation leads to developmental disorders, including central nervous system dysfunction. In the present work, we have studied the effect of chronic ethanol exposure during pregnancy and lactation on the phosphorylating system associated with the astrocytic and neuronal intermediate filament (IF) proteins: glial fibrillary acidic protein (GFAP), and neurofilament (NF) subunits of low, medium, and high molecular weight (NFL, NFM, and NFH, respectively) in 9- and 21-day-old pups. Female rats were fed with 20% ethanol in their drinking water during pregnancy and lactation. The homeostasis of the IF phosphorylation was not altered in the cerebral cortex, cerebellum, or hippocampus of 9-day-old pups. However, GFAP, NFL, and NFM were hyperphosphorylated in the hippocampus of 21-day-old pups. PKA had been activated in the hippocampus, and Ser55 in the N-terminal region of NFL was hyperphosphorylated. In addition, JNK/MAPK was activated and KSP repeats in the C-terminal region of NFM were hyperphosphorylated in the hippocampus of 21-day-old pups. Decreased NFH immunocontent but an unaltered total NFH/phosphoNFH ratio suggested altered stoichiometry of NFs in the hippocampus of ethanol-exposed 21-day-old pups. In contrast to the high susceptibility of hippocampal cytoskeleton in developing rats, the homeostasis of the cytoskeleton of ethanol-fed adult females was not altered. Disruption of the cytoskeletal homeostasis in neural cells supports the view that regions of the brain are differentially vulnerable to alcohol insult during pregnancy and lactation, suggesting that modulation of JNK/MAPK and PKA signaling cascades target the hippocampal cytoskeleton in a window of vulnerability in 21-day-old pups. Our findings are relevant, since disruption of the cytoskeleton in immature hippocampus could contribute to later hippocampal damage associated with ethanol toxicity. Copyright © 2015 Elsevier Inc. All rights reserved.

Anthocyanins Reversed D-Galactose-Induced Oxidative Stress and Neuroinflammation Mediated Cognitive Impairment in Adult Rats.

PubMed

Rehman, Shafiq Ur; Shah, Shahid Ali; Ali, Tahir; Chung, Jong Il; Kim, Myeong Ok

2017-01-01

Aging is a major factor involved in neurological impairments, decreased anti-oxidant activities, and enhanced neuroinflammation. D-galactose (D-gal) has been considered an artificial aging model which induces oxidative stress and inflammatory response resulting in memory and synaptic dysfunction. Dietary supplementation exerts valuable effects against oxidative stress and neuroinflammation. Polyphenolic flavonoids, such as anthocyanins, have been reported as an anti-inflammatory and anti-oxidant agents against various neurodegenerative diseases. Recently, our group reported anthocyanin neuroprotection of the developing rat brain against ethanol-induced oxidative stress and neurodegenaration and ethanol-induced neuronal apoptosis via GABA B1 receptor intracellular signaling in prenatal rat hippocampus. Here, we examined the protective effect of anthocyanin neuroprotection against D-gal-induced oxidative and inflammatory response in the hippocampus and cortex regions and explore the potential mechanism of its action. Our results indicated that anthocyanins treatment significantly improved behavioral performance of D-gal-treated rats in Morris water maze and Y-maze tests. One of the potential mechanisms of this action was decreased expression of the receptor for advance glycation end product, reduced level of reactive oxygen species (ROS) and lipid peroxidation as well as markers of the Alzheimer's disease. Furthermore, the results also indicated that anthocyanins inhibited activated astrocytes and neuroinflammation via suppression of various inflammatory markers including p-NF- K B, inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α) in the hippocampus and cortex regions of D-gal-treated rats brain. Moreover, anthocyanins abrogated neuroapoptosis via C-jun N-terminal kinase (p-JNK) suppression and improved deregulated synaptic proteins including synaptophysin, synaptosomal-associated protein (SNAP)-23, SNAP-25, and phosphorylated CREB. This data suggests that anthocyanins could be a safe and promising anti-oxidant and anti-neuroinflammatory agent for age-related neurodegenerative diseases such as Alzheimer's disease.

Standardised extract of Bacopa monniera (CDRI-08) improves contextual fear memory by differentially regulating the activity of histone acetylation and protein phosphatases (PP1α, PP2A) in hippocampus.

PubMed

Preethi, Jayakumar; Singh, Hemant K; Venkataraman, Jois Shreyas; Rajan, Koilmani Emmanuvel

2014-05-01

Contextual fear conditioning is a paradigm for investigating cellular mechanisms involved in hippocampus-dependent memory. Earlier, we showed that standardised extract of Bacopa monniera (CDRI-08) improves hippocampus-dependent learning in postnatal rats by elevating the level of serotonin (5-hydroxytryptamine, 5-HT), activate 5-HT3A receptors, and cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein. In this study, we have further examined the molecular mechanism of CDRI-08 in hippocampus-dependent memory and compared to the histone deacetylase (HDACs) inhibitor sodium butyrate (NaB). To assess the hippocampus-dependent memory, wistar rat pups were subjected to contextual fear conditioning (CFC) following daily (postnatal days 15-29) administration of vehicle solution (0.5 % gum acacia + 0.9 % saline)/CDRI-08 (80 mg/kg, p.o.)/NaB (1.2 g/kg in PBS, i.p.). CDRI-08/NaB treated group showed enhanced freezing behavior compared to control group when re-exposed to the same context. Administration of CDRI-08/NaB resulted in activation of extracellular signal-regulated kinase ERK/CREB signaling cascade and up-regulation of p300, Ac-H3 and Ac-H4 levels, and down-regulation of HDACs (1, 2) and protein phosphatases (PP1α, PP2A) in hippocampus following CFC. This would subsequently result in an increased brain-derived neurotrophic factor (Bdnf) (exon IV) mRNA in hippocampus. Altogether, our results indicate that CDRI-08 enhances hippocampus-dependent contextual memory by differentially regulating histone acetylation and protein phosphatases in hippocampus.

Replay of Episodic Memories in the Rat.

PubMed

Panoz-Brown, Danielle; Iyer, Vishakh; Carey, Lawrence M; Sluka, Christina M; Rajic, Gabriela; Kestenman, Jesse; Gentry, Meredith; Brotheridge, Sydney; Somekh, Isaac; Corbin, Hannah E; Tucker, Kjersten G; Almeida, Bianca; Hex, Severine B; Garcia, Krysten D; Hohmann, Andrea G; Crystal, Jonathon D

2018-05-21

Vivid episodic memories in people have been characterized as the replay of multiple unique events in sequential order [1-3]. The hippocampus plays a critical role in episodic memories in both people and rodents [2, 4-6]. Although rats remember multiple unique episodes [7, 8], it is currently unknown if animals "replay" episodic memories. Therefore, we developed an animal model of episodic memory replay. Here, we show that rats can remember a trial-unique stream of multiple episodes and the order in which these events occurred by engaging hippocampal-dependent episodic memory replay. We document that rats rely on episodic memory replay to remember the order of events rather than relying on non-episodic memories. Replay of episodic memories survives a long retention-interval challenge and interference from the memory of other events, which documents that replay is part of long-term episodic memory. The chemogenetic activating drug clozapine N-oxide (CNO), but not vehicle, reversibly impairs episodic memory replay in rats previously injected bilaterally in the hippocampus with a recombinant viral vector containing an inhibitory designer receptor exclusively activated by a designer drug (DREADD; AAV8-hSyn-hM4Di-mCherry). By contrast, two non-episodic memory assessments are unaffected by CNO, showing selectivity of this hippocampal-dependent impairment. Our approach provides an animal model of episodic memory replay, a process by which the rat searches its representations in episodic memory in sequential order to find information. Our findings using rats suggest that the ability to replay a stream of episodic memories is quite old in the evolutionary timescale. Copyright © 2018 Elsevier Ltd. All rights reserved.

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

PubMed Central

Ramírez-López, María Teresa; Vázquez, Mariam; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosario Noemi; Alén, Francisco; Antón, María; Decara, Juan; Arco, Rocío; Orio, Laura; Suárez, Juan; Lutz, Beat; Gómez de Heras, Raquel; Bindila, Laura

2017-01-01

Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight. PMID:28346523

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner.

PubMed

Ramírez-López, María Teresa; Vázquez, Mariam; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosario Noemi; Alén, Francisco; Antón, María; Decara, Juan; Arco, Rocío; Orio, Laura; Suárez, Juan; Lutz, Beat; Gómez de Heras, Raquel; Bindila, Laura; Rodríguez de Fonseca, Fernando

2017-01-01

Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight.

Classical Conditioning of Hippocampal Theta Patterns in the Rat.

DTIC Science & Technology

1976-08-01

associated with changes in performance of learned tasks , 1,4,5, 8,9 there have been very few studies of neurona l plasticity of the hippocampus It self...rapid development of a conditioned hippocampal theta response to a visual sti mulus demonstrates tha t there is considerable neurona l plasticity in the

Adult neurogenesis and its anatomical context in the hippocampus of three mole-rat species

PubMed Central

Amrein, Irmgard; Becker, Anton S.; Engler, Stefanie; Huang, Shih-hui; Müller, Julian; Slomianka, Lutz; Oosthuizen, Maria K.

2014-01-01

African mole-rats (family Bathyergidae) are small to medium sized, long-lived, and strictly subterranean rodents that became valuable animal models as a result of their longevity and diversity in social organization. The formation and integration of new hippocampal neurons in adult mammals (adult hippocampal neurogenesis, AHN) correlates negatively with age and positively with habitat complexity. Here we present quantitative data on AHN in wild-derived mole-rats of 1 year and older, and briefly describe its anatomical context including markers of neuronal function (calbindin and parvalbumin). Solitary Cape mole-rats (Georychus capensis), social highveld mole-rats (Cryptomys hottentotus pretoriae), and eusocial naked mole-rats (Heterocephalus glaber) were assessed. Compared to other rodents, the hippocampal formation in mole-rats is small, but shows a distinct cytoarchitecture in the dentate gyrus and CA1. Distributions of the calcium-binding proteins differ from those seen in rodents; e.g., calbindin in CA3 of naked mole-rats distributes similar to the pattern seen in early primate development, and calbindin staining extends into the stratum lacunosum-moleculare of Cape mole-rats. Proliferating cells and young neurons are found in low numbers in the hippocampus of all three mole-rat species. Resident granule cell numbers are low as well. Proliferating cells expressed as a percentage of resident granule cells are in the range of other rodents, while the percentage of young neurons is lower than that observed in surface dwelling rodents. Between mole-rat species, we observed no difference in the percentage of proliferating cells. The percentages of young neurons are high in social highveld and naked mole-rats, and low in solitary Cape mole-rats. The findings support that proliferation is regulated independently of average life expectancy and habitat. Instead, neuronal differentiation reflects species-specific demands, which appear lower in subterranean rodents. PMID:24904308

Resistance of neurofilaments to degradation, and lack of neuronal death and mossy fiber sprouting after kainic acid-induced status epilepticus in the developing rat hippocampus.

PubMed

Lopez-Picon, Francisco; Puustinen, Niina; Kukko-Lukjanov, Tiina-Kaisa; Holopainen, Irma E

2004-12-01

Neurofilament (NF) proteins, the major constituent of intermediate filaments in neurons, have an important role in cellular stability and plasticity. We have now studied the short-term (hours) and long-term (up to 1 week) effects of kainic acid (KA)-induced status epilepticus (SE) on the reactivity of NF proteins, and mossy fiber (MF) sprouting and neuronal death up to 4 weeks in 9-day-old rats. In Western blotting, the expression of the phosphorylation-independent epitopes of NF-L, NF-M, and NF-H rapidly but transiently increased after the treatment, whereas the phosphorylated NF-M remained elevated for 7 days. However, the treatment did not change the immunoreactivity of NF proteins, and no neuronal death or mossy fiber sprouting was detected at any time point. Our findings indicate seizure-induced reactivity of NF proteins but their resistance to degradation, which could be of importance in neuronal survival and may also prevent MF sprouting in the developing hippocampus.

Glazed clay pottery and lead exposure in Mexico: Current experimental evidence.

PubMed

Diaz-Ruiz, Araceli; Tristán-López, Luis Antonio; Medrano-Gómez, Karen Itzel; Torres-Domínguez, Juan Alejandro; Ríos, Camilo; Montes, Sergio

2017-11-01

Lead exposure remains a significant environmental problem; lead is neurotoxic, especially in developing humans. In Mexico, lead in human blood is still a concern. Historically, much of the lead exposure is attributed to the use of handcrafted clay pottery for cooking, storing and serving food. However, experimental cause-and-effect demonstration is lacking. The present study explores this issue with a prospective experimental approach. We used handcrafted clay containers to prepare and store lemonade, which was supplied as drinking water to pregnant rats throughout the gestational period. We found that clay pots, jars, and mugs leached on average 200 µg/l lead, and exposure to the lemonade resulted in 2.5 µg/dl of lead in the pregnant rats' blood. Neonates also showed increased lead content in the hippocampus and cerebellum. Caspase-3 activity was found to be statistically increased in the hippocampus in prenatally exposed neonates, suggesting increased apoptosis in that brain region. Glazed ceramics are still an important source of lead exposure in Mexico, and our results confirm that pregnancy is a vulnerable period for brain development.

Supplemental choline during the periweaning period protects against trace conditioning impairments attributable to post-training ethanol exposure in adolescent rats.

PubMed

Hunt, Pamela S

2012-08-01

Supplemental choline during early stages of development can result in long-lasting improvements to memory function. In addition, pre- or postnatal choline has been shown to be protective against some of the adverse effects of early alcohol exposure. The present experiment examined whether supplemental choline given to rats would protect against the effects of posttraining alcohol administration on trace fear conditioning. Posttraining alcohol exposure in adolescent rats results in poor performance in this hippocampus-dependent task, although delay conditioning is unaffected. Here, rats were given an s.c. injection of either saline or choline chloride daily on postnatal days (PD) 15-26. On PD 30 subjects were trained in a trace fear conditioning procedure. For the next 3 days animals were administered 2.5 g/kg ethanol or water control, and conditional stimulus (CS)-elicited freezing was measured on PD 34. Results indicated that posttraining alcohol disrupted the expression of trace conditioning and that supplemental choline on PD 15-26 was protective against this effect. That is, choline-treated animals subsequently given posttraining ethanol performed as well as animals not given ethanol. These results indicate that supplemental choline given during the periweaning period protects against ethanol-induced impairments in a hippocampus-dependent learning task. Findings contribute to the growing literature showing improvements in learning and memory in subjects given extra dietary choline during critical periods of brain development.

Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation.

PubMed

Carbone, K M; Duchala, C S; Griffin, J W; Kincaid, A L; Narayan, O

1987-11-01

Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.

SUPPLEMENTAL CHOLINE DURING THE PERIWEANING PERIOD PROTECTS AGAINST TRACE CONDITIONING IMPAIRMENTS DUE TO POST-TRAINING ETHANOL EXPOSURE IN ADOLESCENT RATS

PubMed Central

Hunt, Pamela S.

2012-01-01

Supplemental choline during early stages of development can result in long-lasting improvements to memory function. In addition, pre- or postnatal choline has been shown to be protective against some of the adverse effects of early alcohol exposure. The present experiment examined whether supplemental choline given to rats would protect against the effects of post-training alcohol administration on trace fear conditioning. Post-training alcohol exposure in adolescent rats results in poor performance in this hippocampus-dependent task, although delay conditioning is unaffected. Here, rats were given an s.c. injection of either saline or choline chloride daily on postnatal days (PD) 15-26. On PD 30 subjects were trained in a trace fear conditioning procedure. For the next three days animals were administered 2.5 g/kg ethanol or water control, and CS-elicited freezing was measured on PD 34. Results indicated that post-training alcohol disrupted the expression of trace conditioning and that supplemental choline on PD 15-26 was protective against this effect. That is, choline-treated animals subsequently given post-training ethanol performed as well as animals not given ethanol. These results indicate that supplemental choline given during the periweaning period protects against ethanol-induced impairments in a hippocampus-dependent learning task. Findings contribute to the growing literature showing improvements in learning and memory in subjects given extra dietary choline during critical periods of brain development. PMID:22687150

Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

PubMed

Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

2003-10-10

The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

An immunohistochemical study of APG-2 protein in the rat hippocampus after transient forebrain ischemia.

PubMed

Lee, Mun-Yong; Choi, Yun-Sik; Choi, Jeong-Sun; Min, Do Sik; Chun, Myung-Hoon; Kim, Ok Nyu; Lee, Sang Bok; Kim, Seong Yun

2002-01-11

The cellular localization and spatiotemporal expression pattern of APG-2 protein, a member of the heat shock protein 110 family, were investigated in the rat hippocampus after transient forebrain ischemia. The spatiotemporal patterns of immunoreactivity of both APG-2 and glial fibrillary acidic protein were very similar, indicating that reactive astrocytes express APG-2, which was confirmed by double immunofluorescence histochemistry. Colocalization of APG-2 and a neuronal marker NeuN in the neurons of the CA2 and CA3 subfields was also confirmed.

Temporary inhibition of dorsal or ventral hippocampus by muscimol: distinct effects on measures of innate anxiety on the elevated plus maze, but similar disruption of contextual fear conditioning.

PubMed

Zhang, Wei-Ning; Bast, Tobias; Xu, Yan; Feldon, Joram

2014-04-01

Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of infrared laser irradiation on amino acid neurotransmitters in an epileptic animal model induced by pilocarpine.

PubMed

Radwan, Nasr Mahmoud; El Hay Ahmed, Nawal Abd; Ibrahim, Khayria Mansour; Khedr, Mona Emam; Aziz, Mona A; Khadrawy, Yasser Ashry

2009-06-01

The aim of the present study was to investigate the effect of daily laser irradiation on the levels of amino acid neurotransmitters in the cortex and hippocampus in an epileptic animal model induced by pilocarpine. It has been claimed that at specific wavelengths and energy densities, laser irradiation is a novel and useful tool for the treatment of peripheral and central nervous system injuries and disorders. Adult male albino rats were divided into three groups: control rats, pilocarpinized rats (epileptic animal model), and pilocarpinized rats treated daily with laser irradiation (90 mW at 830 nm) for 7 d. The following parameters were assayed in cortex and hippocampus: amino acid neurotransmitters (excitatory: glutamic acid and aspartate; and inhibitory: gamma-aminobutyric acid [GABA], glycine, and taurine) by high-performance liquid chromatography (HPLC), glucose content, and the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), using a spectrophotometer. Significant increases in the concentrations of glutamic acid, glutamine, glycine, and taurine were recorded in the cortices of pilocarpinized rats, and they returned to initial levels after laser treatment. In the hippocampus, a moderate increase in aspartate accompanied by a significant increase in glycine were observed in the epileptic animal model, and these dropped to near-control values after laser treatment. In addition, a significant increase in cortical AST activity and a significant decrease in ALT activity and glucose content were obtained in the pilocarpinized animals and pilocarpinized rats treated with laser irradiation. In the hippocampus, significant decreases in the activity of AST and ALT and glucose content were recorded in the epileptic animals and in the epileptic animals treated with laser irradiation. Based on the results obtained in this study, it may be suggested that nearinfrared laser irradiation may reverse the neurochemical changes in amino acid neurotransmitters induced by pilocarpine.

Paternal stress prior to conception alters DNA methylation and behaviour of developing rat offspring.

PubMed

Mychasiuk, R; Harker, A; Ilnytskyy, S; Gibb, R

2013-06-25

Although there has been an abundance of research focused on offspring outcomes associated with maternal experiences, there has been limited examination of the relationship between paternal experiences and offspring brain development. As spermatogenesis is a continuous process, experiences that have the ability to alter epigenetic regulation in fathers may actually change developmental trajectories of offspring. The purpose of this study was to examine the effects of paternal stress prior to conception on behaviour and the epigenome of both male and female developing rat offspring. Male Long-Evans rats were stressed for 27 consecutive days and then mated with control female rats. Early behaviour was tested in offspring using the negative geotaxis task and the open field. At P21 offspring were sacrificed and global DNA methylation levels in the hippocampus and frontal cortex were analysed. Paternal stress prior to conception altered behaviour of all offspring on the negative geotaxis task, delaying acquisition of the task. In addition, male offspring demonstrated a reduction in stress reactivity in the open field paradigm spending more time than expected in the centre of the open field. Paternal stress also altered DNA methylation patterns in offspring at P21, global methylation was reduced in the frontal cortex of female offspring, but increased in the hippocampus of both male and female offspring. The results from this study clearly demonstrate that paternal stress during spermatogenesis can influence offspring behaviour and DNA methylation patterns, and these affects occur in a sex-dependent manner. Development takes place in the centre of a complex interaction between maternal, paternal, and environmental influences, which combine to produce the various phenotypes and individual differences that we perceive. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Prenatal Stress Impairs Spatial Learning and Memory Associated with Lower mRNA Level of the CAMKII and CREB in the Adult Female Rat Hippocampus.

PubMed

Sun, Hongli; Wu, Haibin; Liu, Jianping; Wen, Jun; Zhu, Zhongliang; Li, Hui

2017-05-01

Prenatal stress (PS) results in various behavioral and emotional alterations observed in later life. In particular, PS impairs spatial learning and memory processes but the underlying mechanism involved in this pathogenesis still remains unknown. Here, we reported that PS lowered the body weight in offspring rats, particularly in female rats, and impaired spatial learning and memory of female offspring rats in the Morris water maze. Correspondingly, the decreased CaMKII and CREB mRNA in the hippocampus were detected in prenatally stressed female offspring, which partially explained the effect of PS on the spatial learning and memory. Our findings suggested that CaMKII and CREB may be involved in spatial learning and memory processes in the prenatally stressed adult female offspring.

Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study.

PubMed

Nilsen, Linn H; Melø, Torun M; Saether, Oddbjørn; Witter, Menno P; Sonnewald, Ursula

2012-11-01

We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats.

PubMed

Abdel-Moneim, Adel; Yousef, Ahmed I; Abd El-Twab, Sanaa M; Abdel Reheim, Eman S; Ashour, Mohamed B

2017-08-01

The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

PubMed

Cohen, Joshua L; Glover, Matthew E; Pugh, Phyllis C; Fant, Andrew D; Simmons, Rebecca K; Akil, Huda; Kerman, Ilan A; Clinton, Sarah M

2015-01-01

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

High sucrose consumption induces memory impairment in rats associated with electrophysiological modifications but not with metabolic changes in the hippocampus.

PubMed

Lemos, C; Rial, D; Gonçalves, F Q; Pires, J; Silva, H B; Matheus, F C; da Silva, A C; Marques, J M; Rodrigues, R J; Jarak, I; Prediger, R D; Reis, F; Carvalho, R A; Pereira, F C; Cunha, R A

2016-02-19

High sugar consumption is a risk factor for metabolic disturbances leading to memory impairment. Thus, rats subject to high sucrose intake (HSu) develop a metabolic syndrome and display memory deficits. We now investigated if these HSu-induced memory deficits were associated with metabolic and electrophysiological alterations in the hippocampus. Male Wistar rats were submitted for 9 weeks to a sucrose-rich diet (35% sucrose solution) and subsequently to a battery of behavioral tests; after sacrifice, their hippocampi were collected for ex vivo high-resolution magic angle spinning (HRMAS) metabolic characterization and electrophysiological extracellular recordings in slices. HSu rats displayed a decreased memory performance (object displacement and novel object recognition tasks) and helpless behavior (forced swimming test), without altered locomotion (open field). HRMAS analysis indicated a similar hippocampal metabolic profile of HSu and control rats. HSu rats also displayed no change of synaptic transmission and plasticity (long-term potentiation) in hippocampal Schaffer fibers-CA1 pyramid synapses, but had decreased amplitude of long-term depression in the temporoammonic (TA) pathway. Furthermore, HSu rats had an increased density of inhibitory adenosine A1 receptors (A1R), that translated into a greater potency of A1R in Schaffer fiber synapses, but not in the TA pathway, whereas the endogenous activation of A1R in HSu rats was preserved in the TA pathway but abolished in Schaffer fiber synapses. These results suggest that HSu triggers a hippocampal-dependent memory impairment that is not associated with altered hippocampal metabolism but is probably related to modified synaptic plasticity in hippocampal TA synapses. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Middle-aged, but not young, rats develop cognitive impairment and cortical neurodegeneration following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion.

PubMed

Ferreira, Emilene D Fiuza; Romanini, Cássia V; Mori, Marco A; de Oliveira, Rúbia M Weffort; Milani, Humberto

2011-10-01

Permanent, stepwise occlusion of the vertebral arteries (VAs) and internal carotid arteries (ICAs) following the sequence VA→ICA→ICA, with an interstage interval (ISI, →) of 7 days, has been investigated as a four-vessel occlusion (4-VO)/ICA model of chronic cerebral hypoperfusion. This model has the advantage of not causing retinal damage. In young rats, however, 4-VO/ICA with an ISI of 7 days fails to cause behavioral sequelae. We hypothesized that such a long ISI would allow the brain to efficiently compensate for cerebral hypoperfusion, preventing the occurrence of cognitive impairment and neurodegeneration. The present study evaluated whether brain neurodegeneration and learning/memory deficits can be expressed by reducing the length of the ISI and whether aging influences the outcome. Young, male Wistar rats were subjected to 4-VO/ICA with different ISIs (5, 4, 3 or 2 days). An ISI of 4 days was used in middle-aged rats. Ninety days after 4-VO/ICA, the rats were tested for learning/memory impairment in a modified radial maze and then examined for neurodegeneration of the hippocampus and cerebral cortex. Regardless of the ISI, young rats were not cognitively impaired, although hippocampal damage was evident. Learning/memory deficits and hippocampal and cortical neurodegeneration occurred in middle-aged rats. The data indicate that 4-VO/ICA has no impact on the capacity of young rats to learn the radial maze task, despite 51% hippocampal cell death. Such resistance is lost in middle-aged animals, for which the most extensive neurodegeneration observed in both the hippocampus and cerebral cortex may be responsible. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

A response strategy predicts acquisition of schedule-induced polydipsia in rats.

PubMed

Gregory, James Gardner; Hawken, Emily R; Banasikowski, Tomek J; Dumont, Eric C; Beninger, Richard J

2015-08-03

Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phenotypic learning traits representative of neural circuitry that underlies SIP and hypothesized that rats that are response-learners will be more susceptible in developing compulsive water drinking. Using the Y-maze, the rats were characterized as either place- or response-learners. They were exposed to the SIP protocol for a period of 21days. Subsequent histological staining for FosB/ΔFosB examined neuronal activation associated with SIP in several brain regions. The rats with a preference for a response-learning strategy were more likely to develop SIP than the rats using a place-learning strategy. Furthermore amphetamine sensitization, observed to increase SIP, also shifted learning strategy to a response-learning strategy. No differences were observed in FosB/ΔFosB expression between SIP and non-SIP rats in the dorsolateral striatum (DLS) and CA1 region of the hippocampus. However, SIP rats had greater FosB/ΔFosB expression in prefrontal cortex regions. The rats that develop SIP have a preference for response-learning strategies and increased neuronal activation in frontal cortical regions associated with habit formation and compulsion. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats.

PubMed

Itoh, Tetsuji; Tokumura, Miwa; Abe, Kohji

2004-09-13

The brain cAMP regulating system and its downstream elements play a pivotal role in the therapeutic effects of antidepressants. We previously reported the increase in activities of phosphodiesterase 4, a major phosphodiesterase isozyme hydrolyzing cAMP, in the frontal cortex and hippocampus of learned helplessness rats, an animal model for depression. The present study was undertaken to examine the combination of effects of rolipram, a phosphodiesterase 4 inhibitor, with imipramine, a typical tricyclic antidepressant, on depressive behavior in learned helplessness rats. Concurrently, cAMP-response element (CRE)-binding activity and brain-derived neurotrophic factor (BDNF) levels related to the therapeutic effects of antidepressants were determined. Repeated administration of imipramine (1.25-10 mg/kg, i.p.) or rolipram (1.25 mg/kg, i.p.) reduced the number of escape failures in learned helplessness rats. Imipramine could not completely ameliorate the escape behavior to a level similar to that of non-stressed rats even at 10 mg/kg. However, repeated coadministration of rolipram with imipramine (1.25 and 2.5 mg/kg, respectively) almost completely eliminated the escape failures in learned helplessness rats. The reduction of CRE-binding activities and BDNF levels in the frontal cortex or hippocampus in learned helplessness rats were ameliorated by treatment with imipramine or rolipram alone. CRE-binding activities and/or BDNF levels of the frontal cortex and hippocampus were significantly increased by treatment with a combination of rolipram and imipramine compared to those in imipramine-treated rats. These results indicated that coadministration of phosphodiesterase type 4 inhibitors with antidepressants may be more effective for depression therapy and suggest that elevation of the cAMP signal transduction pathway is involved in the antidepressive effects.

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus.

PubMed

Vasconcelos, Andrea Rodrigues; Kinoshita, Paula Fernanda; Yshii, Lidia Mitiko; Marques Orellana, Ana Maria; Böhmer, Ana Elisa; de Sá Lima, Larissa; Alves, Rosana; Andreotti, Diana Zukas; Marcourakis, Tania; Scavone, Cristoforo; Kawamoto, Elisa Mitiko

2015-05-01

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in α2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS. Copyright © 2015 Elsevier Inc. All rights reserved.

The interplay of BDNF-TrkB with NMDA receptor in propofol-induced cognition dysfunction : Mechanism for the effects of propofol on cognitive function.

PubMed

Zhou, Junfei; Wang, Fang; Zhang, Jun; Li, Jianfeng; Ma, Li; Dong, Tieli; Zhuang, Zhigang

2018-04-05

The aim of the present study was to verify whether propofol impaired learning and memory through the interplay of N-methyl-D-aspartate (NMDA) receptor with brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. 120 Sprague-Dawley (SD) rats were randomly assigned into eight groups. Experimental drugs including saline, intralipid, propofol, N-methyl-D-aspartate (NMDA), 7,8-dihydroxyflavone (7,8-DHF), K252a and MK-801. Spatial learning and memory of rats were tested by the Morris water maze (MWM) test. The mRNA and protein expression were determined by immunohistochemistry, RT-PCR and western blot. Finally, hippocampus cells proliferation and apoptosis were examined by PCNA immunohistochemistry and TUNEL respectively. The memory and learning was diminished in the propofol exposure group, however, the impaired memory and learning of rats were improved with the addition of NMDA and 7,8-DHF, while the improvement of memory and learning of rats were reversed with the addition of K252a and MK-801. In addition, the mRNA and protein expression levels and hippocampus cells proliferation were the same trend with the results of the MWM test, while apoptosis in hippocampus was reversed. The propofol can impair memory and learning of rats and induce cognition dysfunction through the interplay of NMDA receptor and BDNF-TrkB-CREB signaling pathway.

[Coenzyme Q10 enhances the expression of Bcl-2 and inhibits the expressions of Bax and GSK-3β in the hippocampus of rats exposed to ischemia/reperfusion injury].

PubMed

Tian, Shuang; Wang, Di; Li, Xiaodong; Tang, Jianjie; Han, Guang; Dai, Yongyi

2013-07-01

To investigate the effects of coenzyme Q10 pretreatment on the expressions of Bcl-2, Bax and glycogen synthase kinase-3β (GSK-3β) in rats suffering from ischemia/reperfusion injury. Thirty-six adult male SD rats were randomly assigned into 3 groups: sham-operated group (sham), ischemia/reperfusion group (I/R) and coenzyme Q10 preconditioning group (Q10). Focal cerebral ischemia/reperfusion models were established in experimental rats by blocking middle cerebral artery with suture. Histological changes of hippocampal neurons were observed by HE staining. The expressions of Bcl-2, Bax and GSK-3β were detected by immunohistochemistry and Western blotting. Immunohistochemistry showed that the percentage of Bcl-2 positive cells increased in the hippocampus, while the percentages of Bax and GSK-3β positive cells decreased in Q10 group compared with I/R group. Western blotting revealed that the expression level of Bcl-2 was higher and the expression levels of Bax and GSK-3β were lower in Q10 group than in I/R group. There were significant differences between the two groups (P<0.05). Coenzyme Q10 promoted the expression of Bcl-2 and suppressed the expressions of Bax and GSK-3β in the hippocampus of rats exposed to cerebral ischemia/reperfusion.

Protective Effects of a Rhodiola Crenulata Extract and Salidroside on Hippocampal Neurogenesis against Streptozotocin-Induced Neural Injury in the Rat

PubMed Central

Qu, Ze-qiang; Zhou, Yan; Zeng, Yuan-shan; Lin, Yu-kun; Li, Yan; Zhong, Zhi-qiang; Chan, Wood Yee

2012-01-01

Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre-incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS. PMID:22235318

MICROINJECTION OF DYNORPHIN INTO THE HIPPOCAMPUS IMPAIRS SPATIAL LEARNING IN RATS

EPA Science Inventory

The effect of hippocampal dynorphin administration on learning and memory was examined in spatial and nonspatial tasks. ilateral infusion of dynorphin A(1-8)(DYN; 10 or 20 ug in one ul) into the dorsal hippocampus resulted in dose-related impairment of spatial working memory in a...

Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model.

PubMed

Ponce-Lopez, Teresa; Liy-Salmeron, Gustavo; Hong, Enrique; Meneses, Alfredo

2011-12-02

Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3β (p-GSK3β) and total GSK3β levels were determined, and importantly GSK3β regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3β levels, while total GSK3β did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3β levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3β levels in neither the hippocampus nor PFC. Total GSK3β levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3β levels, a kinase key of signaling cascade of insulin receptor. 2011 Elsevier B.V. All rights reserved.

[Effect of Corydalis Rhizoma and L-tetrahydropalmatine on dopamine system of hippocampus and striatum in morphine-induced conditioned place preference rats].

PubMed

Yu, Shou-Yang; Bai, Wei-Feng; Tu, Ping; Qiu, Cheng-Kai; Yang, Pei-Run; Luo, Su-Yuan

2016-10-01

To investigate the effects of Corydalis Rhizoma and L-tetrahydropalma-tine (L-THP) on the levels of dopamine neurotransmitter (DA), dopamine transporter (DAT) and the second dopamine receptor (D2R) in learning and memory-related brain areas, hippocampus and striatum, the DA, DAT and D2R were detected in conditioned place preference (CPP) rats suffered from morphine. And comparation the degree of similarity and consistency of the pharmacological effects was also studied. The rats were trained in black compartments and white ones (drug-paired compartment) with the increasing doses of morphine for 10 days (hypodermically injected from 10 mg•kg⁻¹ to 100 mg•kg⁻¹). Models of CPP were validated in those psychological dependence rats after 48 h training. The dopamine contents were detected as soon as the materials of hippocampus and striatum are harvested from rats of NS control group and model group. The DAT and D2R levels are measured by Western blot. The high, medium and low dose group of Corydalis Rhizoma are given Corydalis Rhizoma 2, 1, 0.5 g•kg⁻¹ water extraction liquid respectively (which contains L-THP were 0.274, 0.137 and 0.137 mg respectively), and the high, medium and low dose group of L-THP were given L-THP 3.76, 1.88, 0.94 mg•kg⁻¹ lavage treatment respectively, NS treatment group were lavaged normal saline for 6 days and they were killed after test of CPP, again tested DA levels and expression of DAT and D2R similar to the front of materials. The reduction effects of CPP were observed in the groups of both Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) subjected to medicine for 6 days (P<0.01). Compared with the NS treatment group and the model group, the higher values including in the contents of neurotransmitter dopamine were detected of hippocampus and striatum (P<0.01, P<0.05), the DAT and D2R protein expression of Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) increased in hippocampus and striatum (P<0.01). Learning and memory-related brain regions hippocampus and striatum was another neuroanatomical sites of action in the treatment of mental dependence of fumarate and L-THP, its mechanism was related to lowering its elevated DA neurotransmitter levels, and increasing the expression of DAT and D2R. Corydalis Rhizoma could be play 14-times roles in effect of L-THP. The similar effects were observed on the neurotransmitter dopamine, DAT and D2R in learning and memory-related brain areas, hippocampus and striatum of the morphine- dependent rats. Copyright© by the Chinese Pharmaceutical Association.

Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors.

PubMed

Huo, Tao-guang; Li, Wei-kai; Zhang, Ying-hua; Yuan, Jie; Gao, Lan-yue; Yuan, Yuan; Yang, Hui-lei; Jiang, Hong; Sun, Gui-fan

2015-01-01

Realgar is a type of mineral drug containing arsenic. The nervous system toxicity of realgar has received extensive attention. However, the underlying mechanisms of realgar-induced neurotoxicity have not been clearly elucidated. To explore the mechanisms that contribute to realgar-induced neurotoxicity, weanling rats were exposed to realgar (0, 0.3, 0.9, 2.7 g/kg) for 6 weeks, and cognitive ability was tested using the Morris water maze (MWM) test and object recognition task (ORT). The levels of arsenic in the blood and hippocampus were monitored. The ultrastructures of hippocampal neurons were observed. The levels of glutamate (Glu) and glutamine (Gln) in the hippocampus and hippocampal CA1 region; the activities of glutamine synthetase (GS) and phosphate-activated glutaminase (PAG); the mRNA and protein expression of glutamate transporter 1 (GLT-1), glutamate/aspartate transporter (GLAST), and N-methyl-D-aspartate (NMDA) receptors; and the level of intracellular Ca(2+) were also investigated. The results indicate that the rats developed deficiencies in cognitive ability after a 6-week exposure to realgar. The arsenic contained in realgar and the arsenic metabolites passed through the blood-brain barrier (BBB) and accumulated in the hippocampus, which resulted in the excessive accumulation of Glu in the extracellular space. The excessive accumulation of Glu in the extracellular space induced excitotoxicity, which was shown by enhanced GS and PAG activities, inhibition of GLT-1 mRNA and protein expression, alterations in NMDA receptor mRNA and protein expression, disturbance of intracellular Ca(2+) homeostasis, and ultrastructural changes in hippocampal neurons. In conclusion, the findings from our study indicate that exposure to realgar induces excitotoxicity and that the mechanism by which this occurs may be associated with disturbances in Glu metabolism and transportation and alterations in NMDA receptor expression.

CHOLINE SUPPLEMENTATION AND DNA METHYLATION IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX OF RATS EXPOSED TO ALCOHOL DURING DEVELOPMENT

PubMed Central

Otero, Nicha K. H.; Thomas, Jennifer D.; Saski, Christopher A.; Xia, Xiaoxia; Kelly, Sandra J.

2012-01-01

Background Some of the most frequent deficits seen in children with FASD and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and prefrontal cortex (PFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol's teratogenic effects and this effect may be mediated through choline' effects on DNA methylation. Methods Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2–10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a non-treated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal day 2 to 20. On postnatal day 21, the brains of the subjects were removed and assayed for global DNA methylation patterning as measured by chemiluminescence using the cpGlobal assay in both the hippocampal region and PFC. Results Alcohol exposure caused hypermethylation in the hippocampus and PFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain. Conclusions This study is the first to show changes in global DNA methylation of the hippocampal region and PFC after neonatal alcohol exposure. Choline supplementation impacts global DNA methylation in these two brain regions in alcohol-exposed and control animals in a differential manner. The current findings suggest that both alcohol and choline have substantial impact on the epigenome in the prefrontal cortex and hippocampus and future studies will be needed to describe which gene families are impacted in such a way that function of the nervous system is changed. PMID:22509990

Memory modulates journey-dependent coding in the rat hippocampus

PubMed Central

Ferbinteanu, J.; Shirvalkar, P.; Shapiro, M. L.

2011-01-01

Neurons in the rat hippocampus signal current location by firing in restricted areas called place fields. During goal-directed tasks in mazes, place fields can also encode past and future positions through journey-dependent activity, which could guide hippocampus-dependent behavior and underlie other temporally extended memories, such as autobiographical recollections. The relevance of journey-dependent activity for hippocampal-dependent memory, however, is not well understood. To further investigate the relationship between hippocampal journey-dependent activity and memory we compared neural firing in rats performing two mnemonically distinct but behaviorally identical tasks in the plus maze: a hippocampus-dependent spatial navigation task, and a hippocampus-independent cue response task. While place, prospective, and retrospective coding reflected temporally extended behavioral episodes in both tasks, memory strategy altered coding differently before and after the choice point. Before the choice point, when discriminative selection of memory strategy was critical, a switch between the tasks elicited a change in a field’s coding category, so that a field that signaled current location in one task coded pending journeys in the other task. After the choice point, however, when memory strategy became irrelevant, the fields preserved coding categories across tasks, so that the same field consistently signaled either current location or the recent journeys. Additionally, on the start arm firing rates were affected at comparable levels by task and journey, while on the goal arm firing rates predominantly encoded journey. The data demonstrate a direct link between journey-dependent coding and memory, and suggest that episodes are encoded by both population and firing rate coding. PMID:21697365

Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory.

PubMed

Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V; Ronzoni, Giacomo; Demougin, Philippe; Peter, Fabian; Atsak, Piray; Coolen, Marcel W; Papassotiropoulos, Andreas; McGaugh, James L; de Quervain, Dominique J-F; Roozendaal, Benno

2017-08-22

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkm ζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.

Ethylene glycol ethers induce apoptosis and disturb glucose metabolism in the rat brain.

PubMed

Pomierny, Bartosz; Krzyżanowska, Weronika; Niedzielska, Ewa; Broniowska, Żaneta; Budziszewska, Bogusława

2016-02-01

Ethylene glycol ethers (EGEs) are compounds widely used in industry and household products, but their potential, adverse effect on brain is poorly understood, so far. The aim of the present study was to determine whether 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE), and 2-ethoxyethanol (EE) induces apoptotic process in the rat hippocampus and frontal cortex, and whether their adverse effect on the brain cells can result from disturbances in the glucose metabolism. Experiments were conducted on 40 rats, exposed to BE, PHE, EE, saline or sunflower oil for 4 weeks. Markers of apoptosis and glucose metabolism were determined in frontal cortex and hippocampus by western blot, ELISA, and fluorescent-based assays. BE and PHE, but not EE, increased expression of the active form of caspase-3 in the examined brain regions. BE and PHE increased caspase-9 level in the cortex and PHE also in the hippocampus. BE and PHE increased the level of pro-apoptotic proteins (Bax, Bak) and/or reduced the concentration of anti-apoptotic proteins (Bcl-2, Bcl-xL); whereas, the effect of BE was observed mainly in the cortex and that of PHE in the hippocampus. It has also been found that PHE increased brain glucose level, and both BE and PHE elevated pyruvate and lactate concentration. It can be concluded that chronic treatment with BE and PHE induced mitochondrial pathway of apoptosis, and disturbed glucose metabolism in the rat brain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Monosodium glutamate neurotoxicity increases beta amyloid in the rat hippocampus: a potential role for cyclic AMP protein kinase.

PubMed

Dief, Abeer E; Kamha, Eman S; Baraka, Azza M; Elshorbagy, Amany K

2014-05-01

Glutamate excitotoxicity and cyclic AMP-activated protein kinase (AMPK) are both recognized as important mediators in neurodegenerative disorders including Alzheimer's disease (AD). To investigate whether oral or subcutaneous monosodium glutamate (MSG) neurotoxicity mimics some features of AD and whether these can be reversed by the AMPK activator Pioglitazone. Male Wistar rats aged 5 weeks were administered oral or subcutaneous MSG for 10 days with or without daily oral Pioglitazone. Two additional groups given only saline orally or subcutaneously acted as controls. At age 10 weeks the rats were subjected to neurobehavioral testing, then sacrificed for measurement of AMPK, β-amyloid and Fas ligand in the hippocampus. Oral and subcutaneous MSG both induced a lowering of hippocampal AMPK by 43% and 31% respectively (P<0.05 for both) and >2-fold increase in hippocampal Fas ligand, a mediator of apoptosis (P<0.001 for both). MSG treatment also induced a significant increase in β-amyloid in the hippocampus by >4-fold and >5-fold in the oral and subcutaneous groups. This was associated with increased latency before crossing to the white half in the black-white alley and before the first rear in the holeboard test, suggesting increased anxiety. Pioglitazone decreased hippocampal β-amyloid accumulation and Fas ligand, but did not ameliorate the neurobehavioural deficits induced by MSG. MSG treatment enhances β-amyloid accumulation in the rat hippocampus. Our results suggest a role for AMPK reduction in mediating the neurotoxic effects of glutamate, including β-amyloid accumulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Proteomic changes during adult stage in pre-optic, hypothalamus, hippocampus and pituitary regions of female rat brain following neonatal exposure to estradiol-17β.

PubMed

Govindaraj, Vijayakumar; Shridharan, Radhika Nagamangalam; Rao, Addicam Jagannadha

2018-05-16

Although neonatal exposure to estrogen or estrogenic compounds results in irreversible changes in the brain function and reproductive abnormalities during adulthood but the underlying mechanisms are still largely unknown. The present study has attempted to compare the protein profiles of sexually dimorphic brain regions of adult female rats which were exposed to estradiol- 17β during neonatal period. The total proteins extracted from pre-optic area (POA), hypothalamus, hippocampus and pituitary of control and neonatally E2 treated female rats was subjected to 2D-SDS-PAGE and differentially expressed proteins were identified by MALDI TOF/TOF-MS. Our results revealed that a total of 21 protein spots which were identified as differentially expressed in all the four regions analyzed; the differential expression was further validated by RT-PCR and western blotting. The differentially expressed proteins such as 14-3-3 zeta/delta (POA), LMNA (hippocampus), Axin2 (hypothalamus), Syntaxin-7 (hippocampus), prolactin and somatotropin (pituitary) which have very important functions in the process of neuronal differentiation, migration, axon outgrowth, formation of dendritic spine density and synaptic plasticity and memory have not been previously reported in association with neonatal estrogen exposure. The affected brain functions are very important for the establishment of sex specific brain morphology and behavior. Our results suggest that the differentially expressed proteins may play an important role in irreversible changes in the brain function as well as reproductive abnormalities observed in the female rats during adulthood. Copyright © 2018 Elsevier Inc. All rights reserved.

[Effect of limb ischemic preconditioning on the expression of p38 MAPK and HSP 70 in CA3 and DG regions of the hippocampus of rats].

PubMed

Sun, Xiao-Cai; Li, Wen-Bin; Zhao, Li; Jia, Hui-Xian; Wang, Fang; Zhang, Min; Li, Shu-Qin

2013-01-01

To observe the expression of p38 MAPK and HSP 70 in CA3 and dentate gyrus (DG) regions of the hippocampus of rats induced by limb ischemic preconditioning (LIP). Ninety-six rats were randomly divided into sham and LIP groups. And the animals in the LIP group were further divided into LIP 6 h, LIP 12 h, LIP 1 d, LIP 2 d, LIP 3 d, LIP 4 d and LIP 5 d subgroups according to the time of reperfusion after LIP. Immunohistochemical staining and Western blot were used to observe the expression of p38 MAPK and HSP 70 in CA3 and DG regions of the hippocampus. The results of the immunohistochemical staining and Western blot were consistent, which indicated that there were fluctuation in the p-p38 MAPK and HSP 70 expression in CA3 and DG regions after LIP compared with those of the sham group. The expression of p-p38 MAPK began to be up-regulated 1d after LIP and reached its peak at 3 d and lasted for 4 d after LIP. However, the expression of HSP 70 was significantly up-regulated 2 d after LIP compared to the sham group, reached its peak at 3 d and lasted until the 4 d after LIP. LIP up-regulates the expression of p38 MAPK and HSP 70 in the CA3 and DG regions of the hippocampus of rats.

MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain

PubMed Central

Perrine, Shane A.; Ghoddoussi, Farhad; Michaels, Mark S.; Hyde, Elisabeth M.; Kuhn, Donald M.; Galloway, Matthew P.

2010-01-01

In animals, repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) reduces markers of serotonergic activity and studies show similar serotonergic deficits in human MDMA users. Using proton magnetic resonance spectroscopy (1H-MRS) at 11.7 Tesla, we measured the metabolic neurochemical profile in intact, discrete tissue punches taken from prefrontal cortex, anterior striatum, and hippocampus of rats administered MDMA (5 mg/kg IP, 4× q 2 h) or saline and euthanized 7 days after the last injection. Monoamine content was measured with HPLC in contralateral punches from striatum and hippocampus to compare the MDMA-induced loss of 5HT innervation with constituents in the 1H-MRS profile. When assessed 7 days after the last MDMA injection, levels of hippocampal and striatal serotonin (5HT) were significantly reduced, consistent with published animal studies. N-acetylaspartate (NAA) levels were significantly increased in prefrontal cortex and not affected in anterior striatum or hippocampus; myo-inositol (INS) levels were increased in prefrontal cortex and hippocampus but not anterior striatum. Glutamate levels were increased in prefrontal cortex and decreased in hippocampus, while GABA levels were decreased only in hippocampus. The data suggest that NAA may not reliably reflect MDMA-induced 5HT neurotoxicity. However, the collective pattern of changes in 5HT, INS, glutamate and GABA is consistent with persistent hippocampal neuroadaptations caused by MDMA. PMID:20800616

Matrix Metalloproteinase 9 Displays a Particular Time Response to Acute Stress: Variation in Its Levels and Activity Distribution in Rat Hippocampus.

PubMed

Aguayo, Felipe I; Pacheco, Aníbal A; García-Rojo, Gonzalo J; Pizarro-Bauerle, Javier A; Doberti, Ana V; Tejos, Macarena; García-Pérez, María A; Rojas, Paulina S; Fiedler, Jenny L

2018-05-16

A single stress exposure facilitates memory formation through neuroplastic processes that reshape excitatory synapses in the hippocampus, probably requiring changes in extracellular matrix components. We tested the hypothesis that matrix metalloproteinase 9 (MMP-9), an enzyme that degrades components of extracellular matrix and synaptic proteins such as β-dystroglycan (β-DG 43 ), changes their activity and distribution in rat hippocampus during the acute stress response. After 2.5 h of restraint stress, we found (i) increased MMP-9 levels and potential activity in whole hippocampal extracts, accompanied by β-DG 43 cleavage, and (ii) a significant enhancement of MMP-9 immunoreactivity in dendritic fields such as stratum radiatum and the molecular layer of hippocampus. After 24 h of stress, we found that (i) MMP-9 net activity rises at somatic field, i.e., stratum pyramidale and granule cell layers, and also at synaptic field, mainly stratum radiatum and the molecular layer of hippocampus, and (ii) hippocampal synaptoneurosome fractions are enriched with MMP-9, without variation of its potential enzymatic activity, in accordance with the constant level of cleaved β-DG 43 . These findings indicate that stress triggers a peculiar timing response in the MMP-9 levels, net activity, and subcellular distribution in the hippocampus, suggesting its involvement in the processing of substrates during the stress response.

MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain.

PubMed

Perrine, Shane A; Ghoddoussi, Farhad; Michaels, Mark S; Hyde, Elisabeth M; Kuhn, Donald M; Galloway, Matthew P

2010-12-01

In animals, repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) reduces markers of serotonergic activity and studies show similar serotonergic deficits in human MDMA users. Using proton-magnetic resonance spectroscopy ((1)H-MRS) at 11.7Tesla, we measured the metabolic neurochemical profile in intact, discrete tissue punches taken from prefrontal cortex, anterior striatum, and hippocampus of rats administered MDMA (5mg/kg IP, 4× q 2h) or saline and euthanized 7 days after the last injection. Monoamine content was measured with HPLC in contralateral punches from striatum and hippocampus to compare the MDMA-induced loss of 5HT innervation with constituents in the (1)H-MRS profile. When assessed 7 days after the last MDMA injection, levels of hippocampal and striatal serotonin (5HT) were significantly reduced, consistent with published animal studies. N-Acetylaspartate (NAA) levels were significantly increased in prefrontal cortex and not affected in anterior striatum or hippocampus; myo-inositol (INS) levels were increased in prefrontal cortex and hippocampus but not anterior striatum. Glutamate levels were increased in prefrontal cortex and decreased in hippocampus, while GABA levels were decreased only in hippocampus. The data suggest that NAA may not reliably reflect MDMA-induced 5HT neurotoxicity. However, the collective pattern of changes in 5HT, INS, glutamate and GABA is consistent with persistent hippocampal neuroadaptations caused by MDMA. Copyright © 2010 Elsevier Inc. All rights reserved.

Alpha lipoic acid (ALA) modulates expression of apoptosis associated proteins in hippocampus of rats exposed during postnatal period to sodium arsenite (NaAsO2).

PubMed

Dixit, Shilpi; Dhar, Pushpa; Mehra, Raj D

2015-01-01

The present study focused on the role of exogenous alpha lipoic acid (ALA) in amelioration of inorganic arsenic ( iAs ) induced effects on apoptosis and apoptosis associated proteins in developing rat hippocampus. NaAsO 2 (1.5/2.0 mg/kg bw) alone or along with ALA (70 mg/kg bw) was administered to rat pups (experimental groups) by intraperitoneal (i.p.) route from postnatal day (PND) 4-15. Controls received no treatment/distilled water/ALA. On PND 16, the animals were perfusion fixed and the brains were processed for paraffin embedding (CV and TUNEL staining) and cryopreservation (immunohistochemistry). The fresh brain tissue was used for Western blotting. Significant increase was observed in TUNEL positive cells and Bax (pro-apoptotic protein) expression in hippocampal sub-regions of iAs alone treated groups, whereas Bcl-2 expression was intensified in animals receiving ALA with iAs . Densitometric analysis (Western blots) revealed optimal restoration of Bax and Bcl-2 ratio in animals receiving ALA with iAs , thereby suggesting the protective role of ALA in iAs induced developmental neurotoxicity.

Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats.

PubMed

Li, Jay-Shake; Chao, Yuen-Shin

2008-02-01

Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.

The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus

PubMed Central

Wang, Nan; Yu, Hai-Ying; Shen, Xiao-Feng; Gao, Zhi-Qin; Yang, Chun; Yang, Jian-Jun

2015-01-01

Objectives. Active inflammatory responses play an important role in the pathogenesis of depression. We hypothesized that the rapid antidepressant effect of ketamine is associated with the down-regulation of pro-inflammatory mediators. Methods. Forty-eight rats were equally randomized into six groups (a control and five chronic unpredictable mild stress (CUMS) groups) and given either saline or 10 mg/kg ketamine, respectively. The forced swimming test was performed, and the hippocampus was subsequently harvested for the determination of levels of interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α), indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), and tryptophan (TRP). Results. CUMS induced depression-like behaviours and up-regulated the hippocampal levels of IL-1β, IL-6, TNF-α, IDO, and the KYN/TRP ratio, which were attenuated by a sub-anaesthetic dose of ketamine. Conclusion. CUMS-induced depression-like behaviours are associated with a reduction in hippocampal inflammatory mediators, whereas ketamine’s antidepressant effect is associated with a down-regulation of pro-inflammatory cytokines in the rat hippocampus. PMID:26220286

Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress.

PubMed

Campbell, Adam M; Park, Collin R; Zoladz, Phillip R; Muñoz, Carmen; Fleshner, Monika; Diamond, David M

2008-02-01

Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of predator stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-stress training, as well as in rats which had only a single day of training. Tianeptine blocked stress effects on memory without altering the stress-induced increase in corticosterone levels. Propranolol, a beta-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of stress on cognitive functions of the hippocampus.

The role of α-synuclein and tau hyperphosphorylation-mediated autophagy and apoptosis in lead-induced learning and memory injury.

PubMed

Zhang, Jianbin; Cai, Tongjian; Zhao, Fang; Yao, Ting; Chen, Yaoming; Liu, Xinqin; Luo, Wenjing; Chen, Jingyuan

2012-01-01

Lead (Pb) is a well-known heavy metal in nature. Pb can cause pathophysiological changes in several organ systems including central nervous system. Especially, Pb can affect intelligence development and the ability of learning and memory of children. However, the toxic effects and mechanisms of Pb on learning and memory are still unclear. To clarify the mechanisms of Pb-induced neurotoxicity in hippocampus, and its effect on learning and memory, we chose Sprague-Dawley rats (SD-rats) as experimental subjects. We used Morris water maze to verify the ability of learning and memory after Pb treatment. We used immunohistofluorescence and Western blotting to detect the level of tau phosphorylation, accumulation of α-synuclein, autophagy and related signaling molecules in hippocampus. We demonstrated that Pb can cause abnormally hyperphosphorylation of tau and accumulation of α-synuclein, and these can induce hippocampal injury and the ability of learning and memory damage. To provide the new insight into the underlying mechanisms, we showed that Grp78, ATF4, caspase-3, autophagy-related proteins were induced and highly expressed following Pb-exposure. But mTOR signaling pathway was suppressed in Pb-exposed groups. Our results showed that Pb could cause hyperphosphorylation of tau and accumulation of α-synuclein, which could induce ER stress and suppress mTOR signal pathway. These can enhance type II program death (autophgy) and type I program death (apoptosis) in hippocampus, and impair the ability of learning and memory of rats. This is the first evidence showing the novel role of autophagy in the neurotoxicity of Pb.

Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder.

PubMed

Hlavacova, Natasa; Wes, Paul D; Ondrejcakova, Maria; Flynn, Marianne E; Poundstone, Patricia K; Babic, Stanislav; Murck, Harald; Jezova, Daniela

2012-03-01

The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 μg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

Contextual Fear Memories Formed in the Absence of the Dorsal Hippocampus Decay Across Time

PubMed Central

Zelikowsky, Moriel; Bissiere, Stephanie; Fanselow, Michael S.

2012-01-01

Mammals suffering damage to the hippocampus display a dramatic loss of explicit, recently formed memories (retrograde amnesia). In contrast, deficits in the ability to form new memories following hippocampal damage (anterograde amnesia) can be overcome with sufficient training. By combining contextual fear conditioning with lesions of the dorsal hippocampus in rats, we discovered that while animals can form long-term contextual fear memories in the absence of the hippocampus, these memories decay with time, lacking the permanence that is a hallmark characteristic of normal fear memories. These findings indicate that while it is initially possible to acquire explicit memories when the hippocampus is compromised, these memories cannot transfer from a recent to remote state. This suggests that memories formed outside the hippocampus may nevertheless require the hippocampus to undergo systems consolidation, which has important clinical implications for the treatment of memory disorders. PMID:22399761

Effects of unpredictable chronic stress on behavior and brain-derived neurotrophic factor expression in CA3 subfield and dentate gyrus of the hippocampus in different aged rats.

PubMed

Li, Ying; Ji, Yong-juan; Jiang, Hong; Liu, De-xiang; Zhang, Qian; Fan, Shu-jian; Pan, Fang

2009-07-05

Brain-derived neurotrophic factor (BDNF) is a stress-responsive intercellular messenger modifying hypothalamic-pituitary-adrenal (HPA) axis activity. The interaction between stress and age in BDNF expression is currently not fully understood. This study was conducted to observe unpredictable stress effect on behavior and BDNF expression in CA3 subfield (CA3) and dentate gyrus of hippocampus in different aged rats. Forty-eight Wistar rats of two different ages (2 months and 15 months) were randomly assigned to six groups: two control groups and four stress groups. The rats in the stress group received three weeks of unpredictable mild stress. The depression state and the stress level of the animals were determined by sucrose preference test and observation of exploratory behavior in an open field (OF) test. The expressions of BDNF in CA3 and dentate gyrus of the hippocampus were measured using immunohistochemistry. Age and stress had different effects on the behavior of different aged animals (age: F = 6.173, P < 0.05, stress: F = 6.056, P < 0.05). Stress was the main factor affecting sucrose preference (F = 123.608, P < 0.05). Decreased sucrose preference and suppressed behavior emerged directly following stress, lasting to at least the eighth day after stress in young animals (P < 0.05). The older stress rats showed a lower sucrose preference than young stress rats (P < 0.05). Older control rats behaved differently from the younger control animals in the OF test, spending more time in the central square (P < 0.05), exhibiting fewer vertical movements (P < 0.05) and less grooming (P < 0.05). Following exposure to stress, older-aged rats showed no obvious changes in vertical movement and grooming. This indicates that aged rats were in an unexcited state before the stress period, and responded less to stressful stimuli than younger rats. There was significantly lower BDNF expression in the CA3 and dentate gyrus regions of the hippocampus following stress in both age groups (P < 0.05), a reduction that was still present at the eighth day after stress (P < 0.05). Stress and age were the main factors affecting the expression of BDNF (F = 9.408, P < 0.05; F = 106.303, P < 0.05). The aged stress group showed lower BDNF expression compared to the young stressed group at every testing time point. Stress has age-dependent effects on behavioral responses and hippocampal BDNF expression in rats.

Developmental trajectory of contextual learning and 24-h acetylcholine release in the hippocampus

PubMed Central

Takase, Kenkichi; Sakimoto, Yuya; Kimura, Fukuko; Mitsushima, Dai

2014-01-01

To determine the developmental trajectory of hippocampal function in rats, we examined 24-h changes in extracellular acetylcholine (ACh) levels and contextual learning performance. Extracellular ACh significantly correlated with spontaneous behavior, exhibiting a 24-h rhythm in juvenile (4-week-old), pubertal (6-week-old), and adult (9- to 12-week-old) rats. Although juveniles of both sexes exhibited low ACh levels, adult males had higher ACh levels than adult females. Moreover, juveniles exhibited much more spontaneous activity than adults when they showed equivalent ACh levels. Similarly, juveniles of both sexes exhibited relatively low contextual learning performance. Because contextual learning performance was significantly increased only in males, adult males exhibited better performance than adult females. We also observed a developmental relationship between contextual learning and ACh levels. Scopolamine pretreatment blocked contextual learning and interrupted the correlation. Since long-term scopolamine treatment after weaning impaired contextual learning in juveniles, the cholinergic input may participate in the development of hippocampus. PMID:24435246

Aging modifies daily variation of antioxidant enzymes and oxidative status in the hippocampus.

PubMed

Lacoste, María Gabriela; Ponce, Ivana Tamara; Golini, Rebeca Laura; Delgado, Silvia Marcela; Anzulovich, Ana Cecilia

2017-02-01

Aging is a complex and multifactorial biological process that leads to the progressive deterioration of physiological systems, including the circadian system. In addition, oxidative stress has been associated with the aging of the normal brain and the development of late-onset neurodegenerative diseases. Even though, functional weakening of circadian rhythms and antioxidant function has been observed during aging, the mechanisms by which the circadian system signaling and oxidative stress are interrelated have not yet been elucidated. The objectives of this study were to evaluate the consequences of aging on the temporal organization of the antioxidant defense system and oxidative status as well as to analyze the endogenous clock activity, in the hippocampus of aged rats. Young adults (3-month-old) or older (22-month-old) male Holtzman rats were maintained under constant darkness conditions, during 15days before the sacrifice. Levels of catalase (CAT) and glutathione peroxidase (GPx) mRNA and activity, reduced glutathione (GSH), lipoperoxidation (LPO) and BMAL1 protein were analyzed in hippocampus samples isolated every 4h during a 24-h period. Locomotor activity was recorded during 20days before the experiment. Our results show that aging modifies temporal patterns of CAT and GPx expression and activity in the hippocampus in a different way. On the one hand, it abolishes the oscillating CAT expression and specific enzymatic activity while, on the other, it increases the mesor of circadian GPx activity rhythm (p<0.01). Additionally, we observed increased GSH (p<0.05) and reduced LPO (p<0.01) levels in the hippocampus of aged rats. Moreover, the nocturnal locomotor activity was reduced in the older animals in comparison to the young adult rats (p<0.01). Interestingly, the 22month-old animals became arrhythmic and showed a marked fragmentation as well as a significant decline in daily locomotor activity when they were maintained under constant darkness conditions (p<0.05). Aging also abolished circadian rhythms of the core clock BMAL1 protein. The loss of temporal organization of the antioxidant enzymes activity, the oxidative status and the cellular clock machinery could result in a temporally altered antioxidant defense system in the aging brain. Learning about how aging affects the circadian system and the expression of genes involved in the antioxidant defense system could contribute to the design of new strategies to improve the quality of life of older people and also to promote a healthy aging. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in endocannabinoid and N-acylethanolamine levels in rat brain structures following cocaine self-administration and extinction training.

PubMed

Bystrowska, Beata; Smaga, Irena; Frankowska, Małgorzata; Filip, Małgorzata

2014-04-03

Preclinical investigations have demonstrated that drugs of abuse alter the levels of lipid-based signalling molecules, including endocannabinoids (eCBs) and N-acylethanolamines (NAEs), in the rodent brain. In addition, several drugs targeting eCBs and/or NAEs are implicated in reward and/or seeking behaviours related to the stimulation of dopamine systems in the brain. In our study, the brain levels of eCBs (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and NAEs (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) were analyzed via an LC-MS/MS method in selected brain structures of rats during cocaine self-administration and after extinction training according to the "yoked" control procedure. Repeated (14days) cocaine (0.5mg/kg/infusion) self-administration and yoked drug delivery resulted in a significant decrease (ca. 52%) in AEA levels in the cerebellum, whereas levels of 2-AG increased in the frontal cortex, the hippocampus and the cerebellum and decreased in the hippocampus and the dorsal striatum. In addition, we detected increases (>150%) in the levels of OEA and PEA in the limbic areas in both cocaine treated groups, as well as an increase in the tissue levels of OEA in the dorsal striatum in only the yoked cocaine group and increases in the tissue levels of PEA in the dorsal striatum (both cocaine groups) and the nucleus accumbens (yoked cocaine group only). Compared to the yoked saline control group, extinction training (10days) resulted in a potent reduction in AEA levels in the frontal cortex, the hippocampus and the nucleus accumbens and in 2-AG levels in the hippocampus, the dorsal striatum and the cerebellum. The decreases in the limbic and subcortical areas were more apparent for rats that self-administered cocaine. Following extinction, there was a region-specific change in the levels of NAEs in rats previously injected with cocaine; a potent increase (ca. 100%) in the levels of OEA and PEA was detected in the prefrontal cortex and the hippocampus, whilst a drop was noted in the striatal areas versus yoked saline yoked animals. Our findings support the previous pharmacological evidence that the eCB system and NAEs are involved in reinforcement and extinction of positively reinforced behaviours and that these lipid-derived molecules may represent promising targets for the development of new treatments for drug addiction. Copyright © 2014 Elsevier Inc. All rights reserved.

Impact of Adolescent Sucrose Access on Cognitive Control, Recognition Memory, and Parvalbumin Immunoreactivity

ERIC Educational Resources Information Center

Reichelt, Amy C.; Killcross, Simon; Hambly, Luke D.; Morris, Margaret J.; Westbrook, R. Fred

2015-01-01

In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral…

ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress.

PubMed

Bai, Yin-Yin; Ruan, Chun-Sheng; Yang, Chun-Rui; Li, Jia-Yi; Kang, Zhi-Long; Zhou, Li; Liu, Dennis; Zeng, Yue-Qing; Wang, Ting-Hua; Tian, Chang-Fu; Liao, Hong; Bobrovskaya, Larisa; Zhou, Xin-Fu

2016-11-01

Chronic exposure to stressful environment is a key risk factor contributing to the development of depression. However, the mechanisms involved in this process are still unclear. Brain-derived neurotropic factor (BDNF) has long been investigated for its positive role in regulation of mood, although the role of its precursor, proBDNF, in regulation of mood is not known. In this study, using an unpredictable chronic mild stress (UCMS) paradigm we found that the protein levels of proBDNF were increased in the neocortex and hippocampus of stressed mice and this UCMS-induced upregulation of proBDNF was abolished by chronic administration of fluoxetine. We then established a rat model of UCMS and found that the expression of proBDNF/p75 NTR /sortilin was upregulated, whereas the expression of mature BDNF and TrkB was downregulated in both neocortex and hippocampus of chronically stressed rats. Finally, we found that the injection of anti-proBDNF antibody via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) approaches into the UCMS rats significantly reversed the stress-induced depression-like behavior and restored the exploratory activity and spine growth. Although intramuscular injection of AAV-proBDNF did not exacerbate the UCMS-elicited rat mood-related behavioral or pathological abnormalities, i.c.v. injection of AAV-proBDNF increased the depression-like behavior in naive rats. Our findings suggest that proBDNF plays a role in the development of chronic stress-induced mood disturbances in rodents. Central (i.c.v.) or peripheral (i.p.) inhibition of proBDNF by injecting specific anti-proBDNF antibodies may provide a novel therapeutic approach for the treatment of stress-related mood disorders.

PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats.

PubMed

Zhong, Yu; Chen, Jing; Li, Li; Qin, Yi; Wei, Yi; Pan, Shining; Jiang, Yage; Chen, Jialin; Xie, Yubo

2018-04-20

Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway. Copyright © 2018. Published by Elsevier B.V.

Behavioral profiling as a translational approach in an animal model of posttraumatic stress disorder.

PubMed

Ardi, Ziv; Albrecht, Anne; Richter-Levin, Alon; Saha, Rinki; Richter-Levin, Gal

2016-04-01

Diagnosis of psychiatric disorders in humans is based on comparing individuals to the normal population. However, many animal models analyze averaged group effects, thus compromising their translational power. This discrepancy is particularly relevant in posttraumatic stress disorder (PTSD), where only a minority develop the disorder following a traumatic experience. In our PTSD rat model, we utilize a novel behavioral profiling approach that allows the classification of affected and unaffected individuals in a trauma-exposed population. Rats were exposed to underwater trauma (UWT) and four weeks later their individual performances in the open field and elevated plus maze were compared to those of the control group, allowing the identification of affected and resilient UWT-exposed rats. Behavioral profiling revealed that only a subset of the UWT-exposed rats developed long-lasting behavioral symptoms. The proportion of affected rats was further enhanced by pre-exposure to juvenile stress, a well-described risk factor of PTSD. For a biochemical proof of concept we analyzed the expression levels of the GABAA receptor subunits α1 and α2 in the ventral, dorsal hippocampus and basolateral amygdala. Increased expression, mainly of α1, was observed in ventral but not dorsal hippocampus of exposed animals, which would traditionally be interpreted as being associated with the exposure-resultant psychopathology. However, behavioral profiling revealed that this increased expression was confined to exposed-unaffected individuals, suggesting a resilience-associated expression regulation. The results provide evidence for the importance of employing behavioral profiling in animal models of PTSD, in order to better understand the neural basis of stress vulnerability and resilience. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term aerobic exercise increases redox-active iron through nitric oxide in rat hippocampus.

PubMed

Chen, Qian; Xiao, De-Sheng

2014-01-30

Adult hippocampus is highly vulnerable to iron-induced oxidative stress. Aerobic exercise has been proposed to reduce oxidative stress but the findings in the hippocampus are conflicting. This study aimed to observe the changes of redox-active iron and concomitant regulation of cellular iron homeostasis in the hippocampus by aerobic exercise, and possible regulatory effect of nitric oxide (NO). A randomized controlled study was designed in the rats with swimming exercise treatment (for 3 months) and/or an unselective inhibitor of NO synthase (NOS) (L-NAME) treatment. The results from the bleomycin-detectable iron assay showed additional redox-active iron in the hippocampus by exercise treatment. The results from nonheme iron content assay, combined with the redox-active iron content, showed increased storage iron content by exercise treatment. NOx (nitrate plus nitrite) assay showed increased NOx content by exercise treatment. The results from the Western blot assay showed decreased ferroportin expression, no changes of TfR1 and DMT1 expressions, increased IRP1 and IRP2 expression, increased expressions of eNOS and nNOS rather than iNOS. In these effects of exercise treatment, the increased redox-active iron content, storage iron content, IRP1 and IRP2 expressions were completely reversed by L-NAME treatment, and decreased ferroportin expression was in part reversed by L-NAME. L-NAME treatment completely inhibited increased NOx and both eNOS and nNOS expression in the hippocampus. Our findings suggest that aerobic exercise could increase the redox-active iron in the hippocampus, indicating an increase in the capacity to generate hydroxyl radicals through the Fenton reactions, and aerobic exercise-induced iron accumulation in the hippocampus might mainly result from the role of the endogenous NO. Copyright © 2013 Elsevier Inc. All rights reserved.

Lanthanum chloride impairs spatial memory through ERK/MSK1 signaling pathway of hippocampus in rats.

PubMed

Liu, Huiying; Yang, Jinghua; Liu, Qiufang; Jin, Cuihong; Wu, Shengwen; Lu, Xiaobo; Zheng, Linlin; Xi, Qi; Cai, Yuan

2014-12-01

Rare earth elements (REEs) are used in many fields for their diverse physical and chemical properties. Surveys have shown that REEs can impair learning and memory in children and cause neurobehavioral defects in animals. However, the mechanism underlying these impairments has not yet been completely elucidated. Lanthanum (La) is often selected to study the effects of REEs. The aim of this study was to investigate the spatial memory impairments induced by lanthanum chloride (LaCl3) and the probable underlying mechanism. Wistar rats were exposed to LaCl3 in drinking water at 0 % (control, 0 mM), 0.25 % (18 mM), 0.50 % (36 mM), and 1.00 % (72 mM) from birth to 2 months after weaning. LaCl3 considerably impaired the spatial learning and memory of rats in the Morris water maze test, damaged the synaptic ultrastructure and downregulated the expression of p-MEK1/2, p-ERK1/2, p-MSK1, p-CREB, c-FOS and BDNF in the hippocampus. These results indicate that LaCl3 exposure impairs the spatial learning and memory of rats, which may be attributed to disruption of the synaptic ultrastructure and inhibition of the ERK/MSK1 signaling pathway in the hippocampus.

Lactuca capensis reverses memory deficits in Aβ1-42-induced an animal model of Alzheimer's disease.

PubMed

Postu, Paula Alexandra; Noumedem, Jaures A K; Cioanca, Oana; Hancianu, Monica; Mihasan, Marius; Ciorpac, Mitica; Gorgan, Dragos Lucian; Petre, Brindusa Alina; Hritcu, Lucian

2018-01-01

We investigated the neuropharmacological effects of the methanolic extract from Lactuca capensis Thunb. leaves (100 and 200 mg/kg) for 21 days on memory impairment in an Alzheimer's disease (AD) rat model produced by direct intraventricular delivery of amyloid-β1-42 (Aβ1-42). Behavioural assays such as Y-maze and radial arm maze test were used for assessing memory performance. Aβ1-42 decreased cognitive performance in the behavioural tests which were ameliorated by pre-treatment with the methanolic extract. Acetylcholinesterase activity and oxidant-antioxidant balance in the rat hippocampus were abnormally altered by Aβ1-42 treatment while these deficits were recovered by pre-treatment with the methanolic extract. In addition, rats were given Aβ1-42 exhibited in the hippocampus decreased brain-derived neurotrophic factor (BDNF) mRNA copy number and increased IL-1β mRNA copy number which was reversed by the methanolic extract administration. These findings suggest that the methanolic extract could be a potent neuropharmacological agent against dementia via modulating cholinergic activity, increasing of BDNF levels and promoting antioxidant action in the rat hippocampus. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Edible Bird's Nest Prevents Menopause-Related Memory and Cognitive Decline in Rats via Increased Hippocampal Sirtuin-1 Expression

PubMed Central

He, Peiyuan; Qi, Jiemen; Tang, Shiying; Song, Chengjun; Ismail, Maznah

2017-01-01

Menopause causes cognitive and memory dysfunction due to impaired neuronal plasticity in the hippocampus. Sirtuin-1 (SIRT1) downregulation in the hippocampus is implicated in the underlying molecular mechanism. Edible bird's nest (EBN) is traditionally used to improve general wellbeing, and in this study, we evaluated its effects on SIRT1 expression in the hippocampus and implications on ovariectomy-induced memory and cognitive decline in rats. Ovariectomized female Sprague-Dawley rats were fed with normal pellet alone or normal pellet + EBN (6, 3, or 1.5%), compared with estrogen therapy (0.2 mg/kg/day). After 12 weeks of intervention, Morris water maze (four-day trial and one probe trial) was conducted, and serum estrogen levels, toxicity markers (alanine transaminase, alkaline phosphatase, urea, and creatinine), and hippocampal SIRT1 immunohistochemistry were estimated after sacrifice. The results indicated that EBN and estrogen enhanced spatial learning and memory and increased serum estrogen and hippocampal SIRT1 expression. In addition, the EBN groups did not show as much toxicity to the liver as the estrogen group. The data suggested that EBN treatment for 12 weeks could improve cognition and memory in ovariectomized female rats and may be an effective alternative to estrogen therapy for menopause-induced aging-related memory loss. PMID:29104731

Impairment of the glymphatic system after diabetes.

PubMed

Jiang, Quan; Zhang, Li; Ding, Guangliang; Davoodi-Bojd, Esmaeil; Li, Qingjiang; Li, Lian; Sadry, Neema; Nedergaard, Maiken; Chopp, Michael; Zhang, Zhenggang

2017-04-01

The glymphatic system has recently been shown to clear brain extracellular solutes and abnormalities in glymphatic clearance system may contribute to both initiation and progression of neurological diseases. Despite that diabetes is known as a risk factor for vascular diseases, little is known how diabetes affects the glymphatic system. The current study is the first investigation of the effect of diabetes on the glymphatic system and the link between alteration of glymphatic clearance and cognitive impairment in Type-2 diabetes mellitus rats. MRI analysis revealed that clearance of cerebrospinal fluid contrast agent Gd-DTPA from the interstitial space was slowed by a factor of three in the hippocampus of Type-2 diabetes mellitus rats compared to the non-DM rats and confirmed by florescence imaging analysis. Cognitive deficits detected by behavioral tests were highly and inversely correlated to the retention of Gd-DTPA contrast and fluorescent tracer in the hippocampus of Type-2 diabetes mellitus rats. Type-2 diabetes mellitus suppresses clearance of interstitial fluid in the hippocampus and hypothalamus, suggesting that an impairment of the glymphatic system contributes to Type-2 diabetes mellitus-induced cognitive deficits. Whole brain MRI provides a sensitive, non-invasive tool to quantitatively evaluate cerebrospinal fluid and interstitial fluid exchange in Type-2 diabetes mellitus and possibly in other neurological disorders, with potential clinical application.

Impairment of the glymphatic system after diabetes

PubMed Central

Zhang, Li; Ding, Guangliang; Davoodi-Bojd, Esmaeil; Li, Qingjiang; Li, Lian; Sadry, Neema; Nedergaard, Maiken; Chopp, Michael; Zhang, Zhenggang

2016-01-01

The glymphatic system has recently been shown to clear brain extracellular solutes and abnormalities in glymphatic clearance system may contribute to both initiation and progression of neurological diseases. Despite that diabetes is known as a risk factor for vascular diseases, little is known how diabetes affects the glymphatic system. The current study is the first investigation of the effect of diabetes on the glymphatic system and the link between alteration of glymphatic clearance and cognitive impairment in Type-2 diabetes mellitus rats. MRI analysis revealed that clearance of cerebrospinal fluid contrast agent Gd-DTPA from the interstitial space was slowed by a factor of three in the hippocampus of Type-2 diabetes mellitus rats compared to the non-DM rats and confirmed by florescence imaging analysis. Cognitive deficits detected by behavioral tests were highly and inversely correlated to the retention of Gd-DTPA contrast and fluorescent tracer in the hippocampus of Type-2 diabetes mellitus rats. Type-2 diabetes mellitus suppresses clearance of interstitial fluid in the hippocampus and hypothalamus, suggesting that an impairment of the glymphatic system contributes to Type-2 diabetes mellitus-induced cognitive deficits. Whole brain MRI provides a sensitive, non-invasive tool to quantitatively evaluate cerebrospinal fluid and interstitial fluid exchange in Type-2 diabetes mellitus and possibly in other neurological disorders, with potential clinical application. PMID:27306755

Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline.

PubMed

Arakawa, Shiho; Shirayama, Yukihiko; Fujita, Yuko; Ishima, Tamaki; Horio, Mao; Muneoka, Katsumasa; Iyo, Masaomi; Hashimoto, Kenji

2012-01-01

Previous studies have indicated that minocycline might function as an antidepressant drug. The aim of this study was to evaluate the antidepressant-like effects of minocycline, which is known to suppress activated microglia, using learned helplessness (LH) rats (an animal model of depression). Infusion of minocycline into the cerebral ventricle of LH rats induced antidepressant-like effects. However, infusion of minocycline into the cerebral ventricle of naïve rats did not produce locomotor activation in the open field tests, suggesting that the antidepressant-like effects of minocycline were not attributed to the enhanced locomotion. LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats induced significant increases in the levels of dopamine and its metabolites in the amygdala when compared with untreated LH rats. Taken together, minocycline may be a therapeutic drug for the treatment of depression. Copyright © 2011 Elsevier Inc. All rights reserved.

Gladiolus dalenii lyophilisate reverses scopolamine-induced amnesia and reduces oxidative stress in rat brain.

PubMed

Ngoupaye, Gwladys Temkou; Pahaye, David Bougolla; Ngondi, Judith; Moto, Fleur Clarisse Okomolo; Bum, Elisabeth Ngo

2017-07-01

Learning and memory are the most important executive functions performed by the human brain, the loss of which is a prominent feature in dementia. Gladiolus dalenii is traditionally used to treat a number of illnesses such as epilepsy and schizophrenia in Cameroon. This study aims to investigate the anti-amnesia effect of Gladiolus dalenii in scopolamine-induced amnesia in rats and its possible antioxidant properties in this model. Morris water maze, novel object location and recognition tasks were used to assess spatial and working memory. Male rats were treated for 12 days with saline, G. dalenii or Tacrine. Experimental animals were co-treated with scopolamine once daily from day 9 to 12. Acetylcholinesterase activity was measured in the prefrontal cortex and hippocampus. Malondialdehyde and glutathione levels were measured in the hippocampus. G. dalenii reversed memory impairment induced by scopolamine in the Morris water maze, novel object location and recognition tasks. It decreased acetylcholinesterase activity in the hippocampus and prefrontal cortex. It also decreased the level of malondialdehyde and increased the level of glutathione in the hippocampus. The results of this study show that G. dalenii ameliorates the cognitive impairment induced by scopolamine, through inhibition of oxidative stress and enhancement of cholinergic neurotransmission. It can therefore be useful for treatment of conditions associated with memory dysfunction as seen in dementia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The effects of intracranial administration of hallucinogens on operant behavior in the rat. I. Lysergic acid diethylamide.

PubMed

Mokler, D J; Stoudt, K W; Sherman, L C; Rech, R H

1986-10-01

Lysergic acid diethylamide (LSD) was infused in one microliter volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, LSD (8.6 to 86 micrograms) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 micrograms for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 micrograms. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency.

PubMed

Kim, Hyun-Bum; Kwon, Byeong-Jae; Cho, Hyun-Ji; Kim, Ji-Won; Chon, Jeong-Woo; Do, Moon-Ho; Park, Sang-Yong; Kim, Sun-Yeou; Maeng, Sung-Ho; Park, Yoo-Kyoung; Park, Ji-Ho

2015-03-01

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Immunological cross-reactivity of cultured rat hippocampal neurons with goldfish brain proteins synthesized during memory consolidation.

PubMed

Schmidt, R; Löffler, F; Müller, H W; Seifert, W

1986-10-29

Ependymins are goldfish brain glycoproteins exhibiting a specifically enhanced rate of synthesis when the animals adopt a new pattern of swimming behavior. With specific antisera against ependymins it has become possible to look for ependymin-like immunoreactivity in other animal species, both qualitatively by immunofluorescence staining and quantitatively by radioimmunoassay. Ependymin-like immunoreactivity was detected not only in other fish but also in rat brain. In the rat radioimmunoassay measurements were highest for the hippocampal formation and for cultured neurons derived from the embryonic hippocampus. Immunofluorescence staining was performed on various cell culture systems derived from rat brain, in order to establish which cell type contains the antigen. Only neuronal cell populations reacted with the anti-ependymin antisera. Cells derived from embryonic rat brain hippocampus which resembled pyramidal neurons stained particularly bright for ependymin-like immunoreactivity. The antigenic material was distributed throughout the cytoplasm including the neuronal extensions. Various neuron-specific antisera have been used to counterstain the cells containing ependymin-like immunoreactivity.

Theta Oscillations During Active Sleep Synchronize The Developing Rubro-Hippocampal Sensorimotor Network

PubMed Central

Rio-Bermudez, Carlos Del; Kim, Jangjin; Sokoloff, Greta; Blumberg, Mark S.

2017-01-01

Summary Neuronal oscillations comprise a fundamental mechanism by which distant neural structures establish and express functional connectivity. Long-range functional connectivity between the hippocampus and other forebrain structures is enabled by theta oscillations. Here we show for the first time that the infant rat red nucleus (RN)—a brainstem sensorimotor structure— exhibits theta (4-7 Hz) oscillations restricted primarily to periods of active (REM) sleep. At postnatal day (P) 8, theta is expressed as brief bursts immediately following myoclonic twitches; by P12, theta oscillations are expressed continuously across bouts of active sleep. Simultaneous recordings from the hippocampus and RN at P12 show that theta oscillations in both structures are coherent, co-modulated, and mutually interactive during active sleep. Critically, at P12, inactivation of the medial septum eliminates theta in both structures. The developmental emergence of theta-dependent functional coupling between the hippocampus and RN parallels that between the hippocampus and prefrontal cortex. Accordingly, disruptions in the early expression of theta could underlie the cognitive and sensorimotor deficits associated with neurodevelopmental disorders such as autism and schizophrenia. PMID:28479324

Supplementation with complex milk lipids during brain development promotes neuroplasticity without altering myelination or vascular density

PubMed Central

Guillermo, Rosamond B.; Yang, Panzao; Vickers, Mark H.; McJarrow, Paul; Guan, Jian

2015-01-01

Background Supplementation with complex milk lipids (CML) during postnatal brain development has been shown to improve spatial reference learning in rats. Objective The current study examined histo-biological changes in the brain following CML supplementation and their relationship to the observed improvements in memory. Design The study used the brain tissues from the rats (male Wistar, 80 days of age) after supplementing with either CML or vehicle during postnatal day 10–80. Immunohistochemical staining of synaptophysin, glutamate receptor-1, myelin basic protein, isolectin B-4, and glial fibrillary acidic protein was performed. The average area and the density of the staining and the numbers of astrocytes and capillaries were assessed and analysed. Results Compared with control rats, CML supplementation increased the average area of synaptophysin staining and the number of GFAP astrocytes in the CA3 sub-region of the hippocampus (p<0.01), but not in the CA4 sub-region. The supplementation also led to an increase in dopamine output in the striatum that was related to nigral dopamine expression (p<0.05), but did not alter glutamate receptors, myelination or vascular density. Conclusion CML supplementation may enhance neuroplasticity in the CA3 sub-regions of the hippocampus. The brain regions-specific increase of astrocyte may indicate a supporting role for GFAP in synaptic plasticity. CML supplementation did not associate with postnatal white matter development or vascular remodelling. PMID:25818888

A high calorie diet causes memory loss, metabolic syndrome and oxidative stress into hippocampus and temporal cortex of rats.

PubMed

Treviño, Samuel; Aguilar-Alonso, Patrícia; Flores Hernandez, Jose Angel; Brambila, Eduardo; Guevara, Jorge; Flores, Gonzalo; Lopez-Lopez, Gustavo; Muñoz-Arenas, Guadalupe; Morales-Medina, Julio Cesar; Toxqui, Veronica; Venegas, Berenice; Diaz, Alfonso

2015-09-01

A high calorie intake can induce the appearance of the metabolic syndrome (MS), which is a serious public health problem because it affects glucose levels and triglycerides in the blood. Recently, it has been suggested that MS can cause complications in the brain, since chronic hyperglycemia and insulin resistance are risk factors for triggering neuronal death by inducing a state of oxidative stress and inflammatory response that affect cognitive processes. This process, however, is not clear. In this study, we evaluated the effect of the consumption of a high-calorie diet (HCD) on both neurodegeneration and spatial memory impairment in rats. Our results demonstrated that HCD (90 day consumption) induces an alteration of the main energy metabolism markers, indicating the development of MS in rats. Moreover, an impairment of spatial memory was observed. Subsequently, the brains of these animals showed activation of an inflammatory response (increase in reactive astrocytes and interleukin1-β as well as tumor necrosis factor-α) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus. Altogether, these results suggest that a HCD promotes the development of MS and contributes to the development of a neurodegenerative process and cognitive failure. In this regard, it is important to understand the relationship between MS and neuronal damage in order to prevent the onset of neurodegenerative disorders. © 2015 Wiley Periodicals, Inc.

Chronic Swimming Exercise Ameliorates Low-Soybean-Oil Diet-Induced Spatial Memory Impairment by Enhancing BDNF-Mediated Synaptic Potentiation in Developing Spontaneously Hypertensive Rats.

PubMed

Cheng, Mei; Cong, Jiyan; Wu, Yulong; Xie, Jiacun; Wang, Siyuan; Zhao, Yue; Zang, Xiaoying

2018-05-01

Exercise and low-fat diets are common lifestyle modifications used for the treatment of hypertension besides drug therapy. However, unrestrained low-fat diets may result in deficiencies of low-unsaturated fatty acids and carry contingent risks of delaying neurodevelopment. While aerobic exercise shows positive neuroprotective effects, it is still unclear whether exercise could alleviate the impairment of neurodevelopment that may be induced by certain low-fat diets. In this research, developing spontaneously hypertensive rats (SHR) were treated with chronic swimming exercise and/or a low-soybean-oil diet for 6 weeks. We found that performance in the Morris water maze was reduced and long-term potentiation in the hippocampus was suppressed by the diet, while a combination treatment of exercise and diet alleviated the impairment induced by the specific low-fat diet. Moreover, the combination treatment effectively increased the expression of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartic acid receptor (NMDAR), which were both down-regulated by the low-soybean-oil diet in the hippocampus of developing SHR. These findings suggest that chronic swimming exercise can ameliorate the low-soybean-oil diet-induced learning and memory impairment in developing SHR through the up-regulation of BDNF and NMDAR expression.

Intrahippocampal Muscimol Shifts Learning Strategy in Gonadally Intact Young Adult Female Rats

ERIC Educational Resources Information Center

McElroy, Molly W.; Korol, Donna L.

2005-01-01

Learning strategy preferences depend upon circulating estrogen levels, with enhanced hippocampus-sensitive place learning coinciding with elevated estrogen levels. The effects of estrogen on strategy may be mediated by fluctuations in GABAergic function, given that inhibitory tone in the hippocampus is low when estrogen is high. We investigated…

Kindling-Induced Changes in Plasticity of the Rat Amygdala and Hippocampus

ERIC Educational Resources Information Center

Schubert, Manja; Siegmund, Herbert; Pape, Hans-Christian; Albrecht, Doris

2005-01-01

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar…

Elevated expression of pleiotrophin in pilocarpine-induced seizures of immature rats and in pentylenetetrazole-induced hippocampal astrocytes in vitro.

PubMed

Zhang, Shuqin; Liang, Feng; Wang, Bing; Le, Yuan; Wang, Hua

2014-03-01

Pleiotrophin (PTN) is a secreted extracellular matrix (ECM)-associated cytokine that has emerged as an important neuromodulator with multiple neuronal functions. In the present study, we detected and compared the dynamic expression of PTN in the hippocampus and adjacent cortex of immature rats with pilocarpine-induced epilepsy. Moreover, we also confirmed the results by examining PTN expression in hippocampal astrocytes cultured in the presence of pentylenetetrazole (PTZ). Immunohistochemistry showed faint immunostaining of PTN in the control hippocampus and adjacent cortex. Notably, PTN immunoreactivity began to increase in relatively small cells in the hippocampus and adjacent cortex at 2h and 3 weeks after seizures, and the labeling intensity reached the maximum level in the hippocampus and adjacent cortex at 8 weeks after seizures. Furthermore, we also found that PTZ treatment significantly reduced astrocytic viability in a dose-dependent manner and time-dependently increased expression levels of PTN in hippocampal astrocytes. In conclusion, our data suggest that increased expression of PTN in the brain tissues may be involved in epileptogenesis. Copyright © 2013 Elsevier GmbH. All rights reserved.

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats.

PubMed

Zhao, Baisong; Pan, Yongying; Xu, Haiping; Song, Xingrong

2017-12-01

Hyperbaric oxygen (HBO) therapy is proven to attenuate neuropathic pain in rodents. The goal of the present study was to determine the potential involvement of the Kindlin-1/Wnt-10a signaling pathway during astrocyte activation and inflammation in a rodent model of neuropathic pain. Rats were assigned into sham operation, chronic constriction injury (CCI), and CCI + HBO treatment groups. Neuropathic pain developed in rats following CCI of the sciatic nerve. Rats in the CCI + HBO group received HBO treatment for five consecutive days beginning on postoperative day 1. The mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) tests were performed to determine mechanical and heat hypersensitivity of animals, respectively. Kindlin-1, Wnt-10a and β-catenin protein expression was examined by immunohistochemistry and Western blot analysis. Expression of tumor necrosis factor (TNF)-α was also determined by ELISA. Our findings demonstrated that HBO treatment significantly suppressed mechanical and thermal hypersensitivity in the CCI neuropathic pain model in rats. HBO therapy significantly reversed the up-regulation of Kindlin-1 in dorsal root ganglia (DRG), spinal cord, and hippocampus of CCI rats. CCI-induced astrocyte activation and increased levels of TNF-α were efficiently reversed by HBO (P < 0.05 vs. CCI). HBO also reversed Wnt-10a up-regulation induced by CCI in the DRG, spinal cord, and hippocampus (P < 0.05 vs. CCI). Our findings demonstrate that HBO attenuated CCI-induced rat neuropathic pain and inflammatory responses, possibly through regulation of the Kindlin-1/Wnt-10a signaling pathway.

Kainic acid-mediated increase of preprotachykinin-A messenger RNA expression in the rat hippocampus and a region-selective attenuation by dexamethasone.

PubMed

Brené, S; Lindefors, N; Ballarin, M; Persson, H

1992-10-01

The hippocampus contains the highest number of glucocorticoid-sensitive neurons in the rat brain and excessive exposure to glucocorticoids can cause damage to hippocampal neurons and impair the capacity of the hippocampus to survive neuronal insults. In this study in situ hybridization combined with quantitative image analysis was used to study preprotachykinin-A mRNA levels after administration of a toxic dose of kainic acid in animals pretreated with glucocorticoids. Kainic acid was injected into dorsal hippocampus CA3 region in animals pretreated with the synthetic glucocorticoid receptor agonist dexamethasone and in control animals. Preprotachykinin-A mRNA was not detected in the hippocampus of untreated animals or in animals analysed 30 min after a kainic acid injection. However, 4 h after injection of kainic acid, the level of preprotachykinin-A mRNA increased to 20-times above the detection limit both in the dentate gyrus and the CA3 region of the hippocampus. Treatment of kainic acid-injected animals with dexamethasone 30 min before and 2 h after the injection attenuated the increase in the granule cells of the dentate gyrus by 50%. In contrast, dexamethasone pretreatment had no significant effect on the kainic acid-induced increase of preprotachykinin-A mRNA in pyramidal cells in regions CA3 or CA1. These results show that an excitatory stimulus within the hippocampus causes a substantial increase in the level of preprotachykinin-A mRNA in hippocampal granule and pyramidal cells and suggest that in granule cells of the dentate gyrus this increase can be modulated by glucocorticoids.

Effectiveness of memantine on depression-like behavior, memory deficits and brain mRNA levels of BDNF and TrkB in rats subjected to repeated unpredictable stress.

PubMed

Amidfar, Meysam; Kim, Yong-Ku; Wiborg, Ove

2018-06-01

Previous clinical and preclinical studies have indicated that the N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, has neuroprotective properties as well as antidepressant effects. The present study was designed to examine behavioral and molecular effects of memantine administration in rats subjected to the repeated unpredictable stress (RUS) paradigm. Rats were split into four groups at random including control+saline, control+memantine, stressed+saline and stressed+memantine. After 10days of exposure to the RUS paradigm, rats were administered memantine (20mg/kg) intraperitoneally (ip) for 14days. Depression-like behavior and memory performance were assessed by measuring immobility time in the forced swim test and passive avoidance test, respectively. The mRNA levels of BDNF and TrkB in the prefrontal cortex and hippocampus were measured by real-time quantitative PCR. Our results demonstrated that the RUS paradigm caused depression-like behavior and impairment of memory retrieval in rats. We did not find significant changes in BDNF or TrkB mRNA levels in hippocampus, but mRNA levels of TrkB in the prefrontal cortex showed a significant downregulation. Administration of memantine reversed depression-like behavior and memory impairment and significantly increased BDNF and TrkB mRNA levels in both prefrontal cortex and hippocampus of stress exposed rats. Our study supports the hypothesis that drugs with antagonistic properties on the NMDA receptor, such as memantine, might be efficient in treatment of major depression. Our results also suggest that upregulated mRNA levels of BDNF and TrkB in the brain might be essential for antidepressant-like activity of memantine in stress exposed rats. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

The cyclooxygenase-2 inhibitor parecoxib inhibits surgery-induced proinflammatory cytokine expression in the hippocampus in aged rats.

PubMed

Peng, Mian; Wang, Yan-Lin; Wang, Fei-Fei; Chen, Chang; Wang, Cheng-Yao

2012-11-01

Neuroinflammatory response triggered by surgery has been increasingly reported to be associated with postoperative cognitive dysfunction. Proinflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), play a pivotal role in mediating surgery-induced neuroinflammation. The role of cyclooxygenase-2 (COX-2), a critical regulator in inflammatory response, in surgery-induced neuroinflammation is still unknown. The aim of the study was to investigate the changes of COX-2 expression and prostaglandin E2 (PGE2) production in the hippocampus in aged rats following partial hepatectomy. The effects of selective COX-2 inhibitor (parecoxib) on hippocampal proinflammatory cytokine expression were also evaluated. Aged rats were randomly divided into three groups: control (n = 10), surgery (n = 30), and parecoxib (n = 30). Control animals received sterile saline to control for the effects of injection stress. Rats in the surgery group received partial hepatectomy under isoflurane anesthesia and sterile saline injection. Rats in the parecoxib group received surgery and anesthesia similar to surgery group rats, and parecoxib treatment. On postanesthetic days 1, 3, and 7, animals were euthanized to assess levels of hippocampal COX-2 expression, PGE2 production, and cytokines IL-1β and TNF-α expression. The effects of parecoxib on proinflammatory cytokine expression were also assessed. Partial hepatectomy significantly increased COX-2 expression, PGE2 production, and proinflammatory cytokine expression in the hippocampus in aged rats on postoperative days 1 and 3. Parecoxib inhibited hippocampal IL-1β and TNF-α expression through downregulation of the COX-2/PGE2 pathway. COX-2 may play a critical role in surgery-induced neuroinflammation. The COX-2 inhibitor may be a promising candidate for treatment of neuroinflammation caused by surgical trauma. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Aβ-Induced Rats

PubMed Central

Thorajak, Piyaporn; Pannangrong, Wanassanun; Umka Welbat, Jariya; Chaijaroonkhanarak, Wunnee; Sripanidkulchai, Kittisak; Sripanidkulchai, Bungorn

2017-01-01

Alzheimer’s disease (AD) has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-β (Aβ). It has been claimed that aged garlic extract (AGE) has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Aβ-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg) daily for 65 days. At day 56, they were injected with 1 μL of aggregated Aβ (1–42) into each lateral ventricle, bilaterally. After six days of Aβ injection, the rats’ working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2), and glutamate decarboxylase (GAD) in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Aβ-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Aβ-induced rats. PMID:28671572

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization

PubMed Central

Fonken, Laura K.; Kitt, Meagan M.; Gaudet, Andrew D.; Barrientos, Ruth M.; Watkins, Linda R.; Maier, Steven F.

2016-01-01

Aged animals exhibit diminished circadian rhythms, and both aging and circadian disruption sensitize neuroinflammatory responses. Microglia –the innate immune cell of the CNS – possess endogenous timekeeping mechanisms that regulate immune responses. Here, we explored whether aging is associated with disrupted diurnal rhythms in microglia and neuroinflammatory processes. First, hippocampal microglia isolated from young rats (4 mos. F344XBN) rhythmically expressed circadian clock genes, whereas microglia isolated from the hippocampus of aged rats (25 mos.) had aberrant Per1 and Per2 rhythms. Unstimulated microglia from young rats exhibited robust rhythms of TNFα and IL-1β mRNA expression, whereas those from aged rats had flattened and tonically-elevated cytokine expression. Similarly, microglial activation markers were diurnally regulated in the hippocampus of young but not aged rats and diurnal differences in responsiveness to both ex vivo and in vivo inflammatory challenges were abolished in aged rats. Corticosterone is an entraining signal for extra-SCN circadian rhythms. Here, corticosterone stimulation elicited similar Per1 induction in aged and young microglia. Overall, these results indicate that aging dysregulates circadian regulation of neuroinflammatory functions. PMID:27568094

Effects of repeated exposure to white noise on central cholinergic activity in the rat.

PubMed

Lai, H

1988-03-01

Acute (45 min) exposure to noise has been shown to decrease sodium-dependent high-affinity choline uptake activity in the frontal cortex and hippocampus of the rat. In the present experiment, the effects of repeated noise exposure on choline uptake in these two brain regions were studied. Rats were exposed to 100-dB white noise in ten 45-min sessions. Tolerance developed to the effects of noise on choline uptake. In addition, the effects were found to be classically conditionable to cues in the exposure environment. These data may have important implications in understanding the health hazard of noise exposure in both the public and occupational environments.

Novelty and fear conditioning induced gene expression in high and low states of anxiety.

PubMed

Donley, Melanie P; Rosen, Jeffrey B

2017-09-01

Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety-like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety-like states do not respond uniformly to novelty during high and low states of anxiety. © 2017 Donley and Rosen; Published by Cold Spring Harbor Laboratory Press.

The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats.

PubMed

Willeman, Mari N; Mennenga, Sarah E; Siniard, Ashley L; Corneveaux, Jason J; De Both, Matt; Hewitt, Lauren T; Tsang, Candy W S; Caselli, Jason; Braden, B Blair; Bimonte-Nelson, Heather A; Huentelman, Matthew J

2018-01-01

Enzastaurin is a Protein Kinase C-β selective inhibitor that was developed to treat cancers. Protein Kinase C-β is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-β. Due to Enzastaurin's mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (Illumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-ß inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.

Neural Stem Cell or Human Induced Pluripotent Stem Cell-derived GABA-ergic Progenitor Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy

PubMed Central

Upadhya, Dinesh; Hattiangady, Bharathi; Shetty, Geetha A.; Zanirati, Gabriele; Kodali, Maheedhar; Shetty, Ashok K.

2016-01-01

Grafting of neural stem cells (NSCs) or GABA-ergic progenitor cells (GPCs) into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts >30% of temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). On the other hand, GPCs could be generated from the medial and lateral ganglionic eminences of the embryonic brain and from hESCs and hiPSCs. To provide comprehensive methodologies involved in testing the efficacy of transplantation of NSCs and GPCs in a rat model of chronic TLE, NSCs derived from the rat medial ganglionic eminence (MGE) and MGE-like GPCs derived from hiPSCs are taken as examples in this unit. The topics comprise description of the required materials, reagents and equipment, methods for obtaining rat MGE-NSCs and hiPSC-derived MGE-like GPCs in culture, generation of chronically epileptic rats, intrahippocampal grafting procedure, post-grafting evaluation of the effects of grafts on spontaneous recurrent seizures and cognitive and mood impairments, analyses of the yield and the fate of graft-derived cells, and the effects of grafts on the host hippocampus. PMID:27532817

Object location and object recognition memory impairments, motivation deficits and depression in a model of Gulf War illness.

PubMed

Hattiangady, Bharathi; Mishra, Vikas; Kodali, Maheedhar; Shuai, Bing; Rao, Xiolan; Shetty, Ashok K

2014-01-01

Memory and mood deficits are the enduring brain-related symptoms in Gulf War illness (GWI). Both animal model and epidemiological investigations have indicated that these impairments in a majority of GW veterans are linked to exposures to chemicals such as pyridostigmine bromide (PB, an antinerve gas drug), permethrin (PM, an insecticide) and DEET (a mosquito repellant) encountered during the Persian Gulf War-1. Our previous study in a rat model has shown that combined exposures to low doses of GWI-related (GWIR) chemicals PB, PM, and DEET with or without 5-min of restraint stress (a mild stress paradigm) causes hippocampus-dependent spatial memory dysfunction in a water maze test (WMT) and increased depressive-like behavior in a forced swim test (FST). In this study, using a larger cohort of rats exposed to GWIR-chemicals and stress, we investigated whether the memory deficiency identified earlier in a WMT is reproducible with an alternative and stress free hippocampus-dependent memory test such as the object location test (OLT). We also ascertained the possible co-existence of hippocampus-independent memory dysfunction using a novel object recognition test (NORT), and alterations in mood function with additional tests for motivation and depression. Our results provide new evidence that exposure to low doses of GWIR-chemicals and mild stress for 4 weeks causes deficits in hippocampus-dependent object location memory and perirhinal cortex-dependent novel object recognition memory. An open field test performed prior to other behavioral analyses revealed that memory impairments were not associated with increased anxiety or deficits in general motor ability. However, behavioral tests for mood function such as a voluntary physical exercise paradigm and a novelty suppressed feeding test (NSFT) demonstrated decreased motivation levels and depression. Thus, exposure to GWIR-chemicals and stress causes both hippocampus-dependent and hippocampus-independent memory impairments as well as mood dysfunction in a rat model.

The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

PubMed

Réus, Gislaine Z; Becker, Indianara R T; Scaini, Giselli; Petronilho, Fabricia; Oses, Jean P; Kaddurah-Daouk, Rima; Ceretta, Luciane B; Zugno, Alexandra I; Dal-Pizzol, Felipe; Quevedo, João; Barichello, Tatiana

2018-02-02

Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

The influence of propofol anesthesia exposure on nonaversive memory retrieval and expression of molecules involved in memory process in the dorsal hippocampus in peripubertal rats.

PubMed

Pavković, Željko; Milanović, Desanka; Ruždijić, Sabera; Kanazir, Selma; Pešić, Vesna

2018-06-01

The effects of anesthetic drugs on postoperative cognitive function in children are not well defined and have not been experimentally addressed. The present study aimed to examine the influence of propofol anesthesia exposure on nonaversive hippocampus-dependent learning and biochemical changes involved in memory process in the dorsal hippocampus, in peripubertal rats as the rodent model of periadolescence. The intersession spatial habituation and the novel object recognition tasks were used to assess spatial and nonspatial, nonaversive hippocampus-dependent learning. The exposure to anesthesia was performed after comparably long acquisition phases in both tasks. Behavioral testing lasted for 2 consecutive days (24-hour retention period). Changes in the expression of molecules involved in memory retrieval/reconsolidation were examined in the dorsal hippocampus by Western blot and immunohistochemistry, at the time of behavioral testing. Exposure to propofol anesthesia resulted in inappropriate assessment of spatial novelty at the beginning of the test session and affected continuation of acquisition in the spatial habituation test. The treatment did not affect recognition of the novel object at the beginning of the test session but it attenuated overall preference to novelty, reflecting retrieval of a weak memory. The expression of phosphorylated extracellular signal-regulated kinase 2 (involved in memory retrieval) was decreased while the level of phosphorylated Ca 2+ /calmodulin-dependent protein kinase IIα and early growth response protein 1 (involved in memory reconsolidation) was increased in the dorsal hippocampus. The level of Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B (neuronal activity indicator) was increased in the dorsal dentate gyrus. Enhanced exploratory activity was still evident in the propofol anesthesia exposure (PAE) group 48 hour after the treatment in both tasks. In peripubertal rats, propofol anesthesia exposure affects memory retrieval and acquisition of new learning in the spatial and nonspatial, nonaversive learning tasks 24 hour after the treatment, along with the expression of molecules that participate in memory retrieval/reconsolidation in the dorsal hippocampus. These results may have clinical implications, favoring control of basic cognitive functions in older children after the propofol exposure. © 2018 John Wiley & Sons Ltd.

A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

PubMed Central

Grosse, Jocelyn; Krummenacher, Claude; Sandi, Carmen

2013-01-01

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions. PMID:23418609

Perinatal supplementation with omega-3 polyunsaturated fatty acids improves sevoflurane-induced neurodegeneration and memory impairment in neonatal rats.

PubMed

Lei, Xi; Zhang, Wenting; Liu, Tengyuan; Xiao, Hongyan; Liang, Weimin; Xia, Weiliang; Zhang, Jun

2013-01-01

To investigate if perinatal Omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation can improve sevoflurane-induced neurotoxicity and cognitive impairment in neonatal rats. Female Sprague-Dawley rats (n = 3 each group) were treated with or without an n-3 PUFAs (fish oil) enriched diet from the second day of pregnancy to 14 days after parturition. The offspring rats (P7) were treated with six hours sevoflurane administration (one group without sevoflurane/prenatal n-3 PUFAs supplement as control). The 5-bromodeoxyuridine (Brdu) was injected intraperitoneally during and after sevoflurane anesthesia to assess dentate gyrus (DG) progenitor proliferation. Brain tissues were harvested and subjected to Western blot and immunohistochemistry respectively. Morris water maze spatial reference memory, fear conditioning, and Morris water maze memory consolidation were tested at P35, P63 and P70 (n = 9), respectively. Six hours 3% sevoflurane administration increased the cleaved caspase-3 in the thalamus, parietal cortex but not hippocampus of neonatal rat brain. Sevoflurane anesthesia also decreased the neuronal precursor proliferation of DG in rat hippocampus. However, perinatal n-3 PUFAs supplement could decrease the cleaved caspase-3 in the cerebral cortex of neonatal rats, and mitigate the decrease in neuronal proliferation in their hippocampus. In neurobehavioral studies, compared with control and n-3 PUFAs supplement groups, we did not find significant spatial cognitive deficit and early long-term memory impairment in sevoflurane anesthetized neonatal rats at their adulthood. However, sevoflurane could impair the immediate fear response and working memory and short-term memory. And n-3 PUFAs could improve neurocognitive function in later life after neonatal sevoflurane exposure. Our study demonstrated that neonatal exposure to prolonged sevoflurane could impair the immediate fear response, working memory and short-term memory of rats at their adulthood, which may through inducing neuronal apoptosis and decreasing neurogenesis. However, these sevoflurane-induced unfavorable neuronal effects can be mitigated by perinatal n-3 PUFAs supplementation.

The mitochondrial toxin, 3-nitropropionic acid, induces extracellular Zn2+ accumulation in rat hippocampus slices.

PubMed

Wei, Guo; Hough, Christopher J; Sarvey, John M

2004-11-11

3-nitropropionic acid (3-NPA), a suicide inhibitor of succinate dehydrogenase (SDH; complex II), has been used to provide useful experimental models of Huntington's disease (HD) and "chemical hypoxia" in rodents. The trace ion Zn2+ has been shown to cause neurodegeneration. Employing real-time Newport Green fluorescence imaging of extracellular Zn2+, we found that 3-NPA (10-100 microM) caused a concentration-dependent increase in the concentration of extracellular Zn2+ ([Zn2+]o) in acute rat hippocampus slices. This increase in [Zn2+]o was abolished by 10 mM CaEDTA. The increase of [Zn2+]o was also accompanied by a rapid increase of cytoplasmic-free Zn2+ concentration ([Zn2+]i). The induction of Zn2+ release by 3-MPA in hippocampus slices points to a potential mechanism by which 3-NPA might induce neurodegeneration.

Diet-induced effects on neuronal and glial elements in the middle-aged rat hippocampus

PubMed Central

Freeman, Linnea R.; Haley-Zitlin, Vivian; Stevens, Cheryl; Granholm, Ann-Charlotte

2014-01-01

Consumption of a high-fat and/or high-cholesterol diet can have detrimental effects on the brain. In the present study, dietary treatment with saturated fats, trans fats, or cholesterol to middle-aged Fischer 344 rats resulted in alterations to serum triglyceride and cholesterol levels, organ weights, and hippocampal morphology. Previously, we demonstrated that a 10% hydrogenated coconut oil and 2% cholesterol diet resulted in worse performance on the 12-day water radial arm maze, increased cholesterol and triglyceride levels, and decreased dendritic microtubule associated protein 2 (MAP2) staining in the hippocampus. The diets administered herein were used to examine components from the previous diet and further examine their effects on hippocampal morphology. Specifically, neuronal morphology, dendritic integrity, fatty acid metabolism, microgliosis, and blood vessel structure in the hippocampus and/or adjacent structures were explored. Our results indicate alterations to peripheral and neural systems following each of the diets. PMID:21535919

Thyroid hormone improves insulin signaling and reduces the activation of neurodegenerative pathway in the hippocampus of diabetic adult male rats.

PubMed

Prieto-Almeida, Fernanda; Panveloski-Costa, Ana Carolina; Crunfli, Fernanda; da Silva Teixeira, Silvania; Nunes, Maria Tereza; Torrão, Andréada Silva

2018-01-01

Diabetes mellitus (DM) and impairments of glucose metabolism and insulin resistance in the brain have been suggested as a likely etiology of Alzheimer's disease (AD). Studies have shown that thyroid hormones (THs) improve insulin sensitivity in DM rats and act as mediators of the plasticity of the nervous system altering behavior and cognitive function. Based on these findings, this study aimed to evaluate the effects of diabetes and triiodothyronine (T3) treatment upon proteins associated with DM and AD in the central nervous system. Euglycemic and Diabetic (alloxan-induced) male Wistar rats were daily treated with T3 (1.5μg/100g body weight) or vehicle (saline) for a 4-week period and subdivided into the following groups: euglycemic treated with saline (Control=C); diabetic treated with saline (Diabetic=D); euglycemic treated with T3 (T3); diabetic treated with T3 (DT3). The expression of insulin signaling, neurodegenerative and neuron survival markers was evaluated in the hippocampus by immunoblotting, ELISA, and RT-PCR. T3 treatment decreased glycemia, restored the insulin signaling and reduced the activation of glycogen synthase kinase 3 (GSK3) and tau proteins content in the hippocampus of diabetic rats. The present data provide evidence that T3 treatment of diabetic rats is able to improve insulin sensitivity and reduce the activation of the neurodegenerative pathway in the brain, which might provide neuroprotection in this experimental model. Copyright © 2017 Elsevier Inc. All rights reserved.

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy.

PubMed

Ouedraogo, David W; Lenck-Santini, Pierre-Pascal; Marti, Geoffrey; Robbe, David; Crépel, Valérie; Epsztein, Jérôme

2016-01-01

The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus-neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities. Yet, whether the gating of physiological SWO by dentate granule cells (DGCs) is altered in TLE has remained unexplored. We combined intracellular recordings of membrane potential (V m) of DGCs and local field potential recordings of the SWO in parietal cortex in anesthetized rats early during epileptogenesis [post-status epilepticus (SE) rats]. As expected, in control rats, the V m of DGCs weakly and rarely oscillated in the SWO frequency range. In contrast, in post-SE rats, the V m of DGCs displayed strong and long-lasting SWO. In these cells, clear UP and DOWN states, in phase with the neocortical SWO, led to a bimodal V m distribution. In post-SE rats, the firing of DGCs was increased and more temporally modulated by the neocortical SWO. We conclude that UP/DOWN state dynamics dominate the V m of DGCs and firing early during epileptogenesis. This abnormally strong neocortical influence on the dynamics of DGCs may profoundly modify the hippocampus-neocortex dialogue during sleep and associated cognitive functions.

Chronic ethanol exposure during adolescence through early adulthood in female rats induces emotional and memory deficits associated with morphological and molecular alterations in hippocampus.

PubMed

Oliveira, Ana Ca; Pereira, Maria Cs; Santana, Luana N da Silva; Fernandes, Rafael M; Teixeira, Francisco B; Oliveira, Gedeão B; Fernandes, Luanna Mp; Fontes-Júnior, Enéas A; Prediger, Rui D; Crespo-López, Maria E; Gomes-Leal, Walace; Lima, Rafael R; Maia, Cristiane do Socorro Ferraz

2015-06-01

There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus. © The Author(s) 2015.

Proteomic Analysis of Rat Hippocampus under Simulated Microgravity

NASA Astrophysics Data System (ADS)

Wang, Yun; Li, Yujuan; Zhang, Yongqian; Liu, Yahui; Deng, Yulin

It has been found that microgravity may lead to impairments in cognitive functions performed by CNS. However, the exact mechanism of effects of microgravity on the learning and memory function in animal nervous system is not elucidated yet. Brain function is mainly mediated by membrane proteins and their dysfunction causes degeneration of the learning and memory. To induce simulated microgravity, the rat tail suspension model was established. Comparative O (18) labeling quantitative proteomic strategy was applied to detect the differentially expressed proteins in rat brain hippocampus. The proteins in membrane fraction from rat hippocampus were digested by trypsin and then the peptides were separated by off-gel for the first dimension with 24 wells device encompassing the pH range of 3 - 10. An off-gel fraction was subjected into LC-ESI-QTOF in triplicate. Preliminary results showed that nearly 77% of the peptides identified were specific to one fraction. 676 proteins were identified among which 108 proteins were found differentially expressed under simulated microgravity. Using the KOBAS server, many enriched pathways, such as metabolic pathway, synaptic vesicle cycle, endocytosis, calcium signaling pathway, and SNAREs pathway were identified. Furthermore, it has been found that neurotransmitter released by Ca (2+) -triggered synaptic vesicles fusion may play key role in neural function. Rab 3A might inhibit the membrane fusion and neurotransmitter release. The protein alteration of the synaptic vesicle cycle may further explain the effects of microgravity on learning and memory function in rats. Key words: Microgravity; proteomics; synaptic vesicle; O (18) ({}) -labeling

Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity.

PubMed

Grillo, Claudia A; Piroli, Gerardo G; Lawrence, Robert C; Wrighten, Shayna A; Green, Adrienne J; Wilson, Steven P; Sakai, Randall R; Kelly, Sandra J; Wilson, Marlene A; Mott, David D; Reagan, Lawrence P

2015-11-01

Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS-treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS-treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Stimulus-dependent changes of extracellular glucose in the rat hippocampus determined by in vivo microdialysis.

PubMed

Rex, A; Bert, B; Fink, H; Voigt, J-P

2009-10-19

Neuronal activity is tightly coupled with brain energy metabolism; and glucose is an important energy substrate for neurons. The present in vivo microdialysis study was aimed at investigating changes in extracellular glucose concentrations in the rat ventral hippocampus due to exposure to the elevated plus maze. Determination of basal hippocampal glucose and lactate/pyruvate ratio in male Wistar rats was conducted in the home cage using in vivo microdialysis. Rats were exposed to the elevated plus maze, a rodent model of anxiety-related behaviour, or to unspecific stress induced by white noise (95dB) as a control condition. Basal hippocampal levels of glucose, as determined by zero-net-flux, and the basal lactate/pyruvate ratio were 1.49+/-0.05mmol/l and 13.8+/-1.1, respectively. In rats without manipulation, glucose levels remained constant throughout the experiment (120min). By contrast, exposure to the elevated plus maze led to a temporary decline in hippocampal glucose (-33.2+/-4.4%) which returned to baseline level in the home cage. White noise caused only a non-significant decrease in extracellular glucose level (-9.3+/-3.5%). In all groups, the lactate/pyruvate ratio remained unchanged by the experimental procedures. Our microdialysis study demonstrates that exposure to the elevated plus maze induces a transient decrease in extracellular hippocampal glucose concentration. In contrast, an unspecific stimulus did not change hippocampal glucose. The latter suggests that only specific behavioural stimuli increase hippocampal glucose utilization in the ventral hippocampus.

Melatonin reverses the decreases in hippocampal protein serine/threonine kinases observed in an animal model of autism.

PubMed

Tian, Yun; Yabuki, Yasushi; Moriguchi, Shigeki; Fukunaga, Kohji; Mao, Pei-Jiang; Hong, Ling-Juan; Lu, Ying-Mei; Wang, Rui; Ahmed, Muhammad Masood; Liao, Mei-Hua; Huang, Ji-Yun; Zhang, Rui-Ting; Zhou, Tian-Yi; Long, Sen; Han, Feng

2014-01-01

Lower global cognitive function scores are a common symptom of autism spectrum disorders (ASDs). This study investigates the effects of melatonin on hippocampal serine/threonine kinase signaling in an experimental ASD model. We found that chronic melatonin (1.0 or 5.0 mg/kg/day, 28 days) treatment significantly rescued valproic acid (VPA, 600 mg/kg)-induced decreases in CaMKII (Thr286), NMDAR1 (Ser896), and PKA (Thr197) phosphorylation in the hippocampus without affecting total protein levels. Compared with control rats, the immunostaining of pyramidal neurons in the hippocampus revealed a decrease in immunolabeling intensity for phospho-CaMKII (Thr286) in the hippocampus of VPA-treated rats, which was ameliorated by chronic melatonin treatment. Consistent with the elevation of CaMKII/PKA/PKC phosphorylation observed in melatonin-treated rat, long-term potentiation (LTP) was enhanced after chronic melatonin (5.0 mg/kg) treatment, as reflected by extracellular field potential slopes that increased from 56 to 60 min (133.4 ± 3.9% of the baseline, P < 0.01 versus VPA-treated rats) following high-frequency stimulation (HFS) in hippocampal slices. Accordingly, melatonin treatment also significantly improved social behavioral deficits at postnatal day 50 in VPA-treated rats. Taken together, the increased phosphorylation of CaMKII/PKA/PKC signaling might contribute to the beneficial effects of melatonin on autism symptoms. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of Ethanol on the Expression Level of Various BDNF mRNA Isoforms and Their Encoded Protein in the Hippocampus of Adult and Embryonic Rats

PubMed Central

Shojaei, Shahla; Ghavami, Saeid; Panjehshahin, Mohammad Reza; Owji, Ali Akbar

2015-01-01

We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low (0.25 g/kg body weight (BW)/day) dose of Eth produced an increase in the expression of BDNF exons I, III and IV and a decrease in that of the exon IX in embryos, but failed to affect BDNF transcript and pro-BDNF protein expression in adults. However, co-administration of Eth 0.25 g/kg·BW/day and Rsv led to increased expression of BDNF exons I, III and IV and to a small but significant increase in the level of pro-BDNF protein in maternal rats. A high (2.5 g/kg·BW/day) dose of Eth increased the expression of BDNF exons III and IV in embryos, but it decreased the expression of exon IX containing BDNF mRNAs in the maternal rats. While the high dose of Eth alone reduced the level of pro-BDNF in adults, it failed to change the levels of pro-BDNF in embryos. Eth differentially affects the expression pattern of BDNF transcripts and levels of pro-BDNF in the hippocampus of both adult and embryonic rats. PMID:26703578

Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory

PubMed Central

Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V.; Ronzoni, Giacomo; Demougin, Philippe; Peter, Fabian; Atsak, Piray; Coolen, Marcel W.; Papassotiropoulos, Andreas; McGaugh, James L.; de Quervain, Dominique J.-F.; Roozendaal, Benno

2017-01-01

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock–context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory. PMID:28790188

The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus.

PubMed

Valle-Dorado, María Guadalupe; Santana-Gómez, César Emmanuel; Orozco-Suárez, Sandra Adela; Rocha, Luisa

2015-05-01

Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p < 0.001) and neuronal damage in dentate gyrus, CA1 and CA3. In contrast to SS-SE group, rats from the CG-SE group showed increased latency to the establishment of the status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus.

PubMed

Marquet-de Rougé, Perrine; Clamagirand, Christine; Facchinetti, Patricia; Rose, Christiane; Sargueil, Françoise; Guihenneuc-Jouyaux, Chantal; Cynober, Luc; Moinard, Christophe; Allinquant, Bernadette

2013-10-01

The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.

Housing conditions modulate escitalopram effects on antidepressive-like behaviour and brain neurochemistry.

PubMed

Bjørnebekk, Astrid; Mathé, Aleksander A; Gruber, Susanne H M; Brené, Stefan

2008-12-01

Despite limited understanding of the pathophysiology of depression and the underlying mechanisms mediating antidepressant effects, there are several efficient treatments. The anhedonia symptoms of depression are characterized by decreased motivation and drive and imply possible malfunctioning of the mesolimbic dopamine system, whereas cognitive deficits might reflect decreased plasticity in hippocampus. In female Flinders Sensitive Line (FSL) rats, a model of depression, we compared the effects of three long-term antidepressant treatments: voluntary running, escitalopram and the combination of both on antidepressant-like behaviour in the Porsolt swim test (PST), and on regulation of mRNA for dopamine and neuropeptides in striatal dopamine pathways and brain-derived neurotrophic factor (BDNF) in hippocampus. Escitalopram diet attenuated running behaviour in FSL rats but not in non-depressed controls rats. In the PST the running group had increased climbing activity (noradrenergic/dopaminergic response), whereas the combination of escitalopram and running-wheel access increased swimming (serotonergic response). Running elevated mRNA for dynorphin in caudate putamen and BDNF in hippocampus. The combined treatment down-regulated D1 receptor and enkephalin mRNA in accumbens. Escitalopram alone did not affect behaviour or mRNA levels. We demonstrate a novel behavioural effect of escitalopram, i.e. attenuation of running in 'depressed' rats. The antidepressant-like effect of escitalopram was dependent on the presence of a running wheel, but not actual running indicating that the environment influenced the antidepressant effect of escitalopram. Different patterns of mRNA changes in hippocampus and brain reward pathways and responses in the PST by running and escitalopram suggest that antidepressant-like responses by running and escitalopram are achieved by different mechanisms.

Protein Drug Targets of Lavandula angustifolia on treatment of Rat Alzheimer's Disease

PubMed Central

Zali, Hakimeh; Zamanian-Azodi, Mona; Rezaei Tavirani, Mostafa; Akbar-zadeh Baghban, Alireza

2015-01-01

Different treatment strategies of Alzheimer's disease (AD) are being studied for treating or slowing the progression of AD. Many pharmaceutically important regulation systems operate through proteins as drug targets. Here, we investigate the drug target proteins in beta-amyloid (Aβ) injected rat hippocampus treated with Lavandula angustifolia (LA) by proteomics techniques. The reported study showed that lavender extract (LE) improves the spatial performance in AD animal model by diminishing Aβ production in histopathology of hippocampus, so in this study neuroprotective proteins expressed in Aβ injected rats treated with LE were scrutinized. Rats were divided into three groups including normal, Aβ injected, and Aβ injected that was treated with LE. Protein expression profiles of hippocampus tissue were determined by two-dimensional electrophoresis (2DE) method and dysregulated proteins such as Snca, NF-L, Hspa5, Prdx2, Apoa1, and Atp5a1were identified by MALDI-TOF/TOF. KEGG pathway and gene ontology (GO) categories were used by searching DAVID Bioinformatics Resources. All detected protein spots were used to determine predictedinteractions with other proteins in STRING online database. Different isoforms of important protein, Snca that exhibited neuroprotective effects by anti-apoptotic properties were expressed. NF-L involved in the maintenance of neuronal caliber. Hspa5 likewise Prdx2 displays as anti-apoptotic protein that Prdx2 also involved in the neurotrophic effects. Apoa1 has anti-inflammatory activity and Atp5a1, produces ATP from ADP. To sum up, these proteins as potential drug targets were expressed in hippocampus in response to effective components in LA may have therapeutic properties for the treatment of AD and other neurodegenerative diseases. PMID:25561935

Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels

PubMed Central

Dastgerdi, Azadehalsadat Hosseini; Radahmadi, Maryam; Pourshanazari, Ali Asghar; Dastgerdi, Hajaralsadat Hosseini

2017-01-01

Background: Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Materials and Methods: Forty male rats were randomly allocated to five different groups (n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results: Results revealed that chronic stress had a significantly (P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly (P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly (P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly (P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. Conclusions: It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain. PMID:29387668

Ulinastatin alleviates neurological deficiencies evoked by transient cerebral ischemia via improving autophagy, Nrf-2-ARE and apoptosis signals in hippocampus.

PubMed

Jiang, Xiao-Ming; Hu, Jing-Hai; Wang, Lu-Lu; Ma, Chi; Wang, Xu; Liu, Xiao-Liang

2018-05-10

Ulinastatin [or called as urinary trypsin inhibitor (UTI)] plays a role in regulating neurological deficits evoked by transient cerebral ischemia. However, the underlying mechanisms still need to be determined. The present study was to examine the effects of UTI on autophagy, Nrf2-ARE and apoptosis signal pathway in the hippocampus in the process of neurological functions after cerebral ischemia using a rat model of cardiac arrest (CA). CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Western Blot analysis was employed to determine the expression of representative autophagy (namely, Atg5, LC3, Beclin 1), p62 protein (a maker of autophagic flux), and Nrf2-ARE pathways. Neuronal apoptosis was assessed by determining expression levels of Caspase-3 and Caspase-9, and by examining terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL). The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. Our results show that CA amplified autophagy and apoptotic Caspase-3/Caspase-9, and downregulated Nrf2-ARE pathway in the hippocampus CA1 region. Systemic administration of UTI attenuated autophagy and apoptosis, and largely restored Nrf2-ARE signal pathway following cerebral ischemia and thereby alleviated neurological deficits with increasing survival of CA rats. Our data suggest that UTI improves the worsened protein expression of autophagy and apoptosis, and restores Nrf2-ARE signals in the hippocampus and this is linked to inhibition of neurological deficiencies in transient cerebral ischemia. UTI plays a beneficial role in modulating neurological deficits induced by transient cerebral ischemia via central autophagy, apoptosis and Nrf2-ARE mechanisms.

Combination of PPT with LiCl Treatment Prevented Bilateral Ovariectomy-Induced Hippocampal-Dependent Cognition Deficit in Rats.

PubMed

Qu, Na; Zhou, Xiang-Yu; Han, Li; Wang, Lei; Xu, Jia-Xin; Zhang, Teng; Chu, Jiang; Chen, Qiao; Wang, Jian-Zhi; Zhang, Qi; Tian, Qing

2016-03-01

Estrogen deprivation is a high risk of cognitive dysfunction in neurodegenerative diseases, and the early used estrogen replacement has been proved effective in many studies. Because of the adverse actions, selective estrogen receptor modulating has been raised to substitute for estrogen replacement. In this study, we observed in hippocampus of bilaterally ovariectomized rats that the level of estrogen receptor α (ERα) was decreased in nuclei with activated glycogen synthase kinase-3β (GSK-3β) in cytoplasm at 8 weeks after operation. The level of nuclear ERα is important for its transcriptional property, and the inhibition of GSK-3β benefits to ERα nuclear translocation. Then, we used 4,4k,4a-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) (1 mg/kg/day), an agonist of ERα, combined with LiCl (40 mg/kg/day), an inhibitor of GSK-3β, to treat the ovariectomized rats. After the combination treatment of these two drugs (PPT + LiCl), the improved learning and memory abilities of ovariectomized rats in Morris water maze, increased dendritic spines in CA1 region, and decreased tau phosphorylation at Ser-396 in hippocampus were observed. Furthermore, PPT + LiCl treatment significantly increased ERα level in the nuclear fraction of hippocampus, and in the cytoplasmic fraction, the total level of GSK-3β was declined after treatment with its increased phosphorylation at Ser-9 (inactivation form). This study suggested that PPT + LiCl treatment could inhibit the activation of cytoplasmic GSK-3β and promote the nuclear translocation of ERα, and ERα together with GSK-3β maybe the targets to preserve hippocampus-dependent cognitive ability after long-term ovariectomy.

Selection of nutrients for prevention or amelioration of lead-induced learning and memory impairment in rats.

PubMed

Fan, Guangqin; Feng, Chang; Li, Yu; Wang, Chunhong; Yan, Ji; Li, Wei; Feng, Jiangao; Shi, Xianglin; Bi, Yongyi

2009-06-01

We carried out animal experiments based on the orthogonal design L(8)(2(7)) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc. The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment. Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l(-1)) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus. Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO. In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.

Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels.

PubMed

Dastgerdi, Azadehalsadat Hosseini; Radahmadi, Maryam; Pourshanazari, Ali Asghar; Dastgerdi, Hajaralsadat Hosseini

2017-01-01

Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Forty male rats were randomly allocated to five different groups ( n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results revealed that chronic stress had a significantly ( P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly ( P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly ( P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly ( P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain.

Uncaria rhynchophylla upregulates the expression of MIF and cyclophilin A in kainic acid-induced epilepsy rats: A proteomic analysis.

PubMed

Lo, Wan-Yu; Tsai, Fuu-Jen; Liu, Chung-Hsiang; Tang, Nou-Ying; Su, Shan-Yu; Lin, Shinn-Zong; Chen, Chun-Chung; Shyu, Woei-Cherng; Hsieh, Ching-Liang

2010-01-01

Uncaria rhynchophylla (Miq) Jack (UR) is a traditional Chinese herb and is used for the treatment of convulsive disorders, including epilepsy. Our previous study has shown that UR, as well as its major component rhynchophylline (RH), has an anticonvulsive effect and this effect is closely related to its scavenging activities of oxygen free radicals. The purpose of the present study was to investigate the effect of (UR) on the expression of proteins using a proteomics analysis in Sprague-Dawley (SD) rats with kainic acid (KA)-induced epileptic seizures. We profiled the differentially expressed proteins on two-dimensional electrophoresis (2-DE) maps derived from the frontal cortex and hippocampus of rat brain tissue 24 hours after KA-induced epileptic seizures. The results indicated that macrophage migration inhibitory factor (MIF) and cyclophilin A were under expressed in frontal cortex by an average of 0.19- and 0.23-fold, respectively. In the frontal cortex, MIF and cyclophilin A were significantly decreased in the KA group and these decreases were confirmed by the Western blots. However, in the hippocampus, only cyclophilin A was significantly decreased in the KA group. In addition, in real-time quantitative PCR (Q-PCR), MIF and cyclophilin A gene expressions were also significantly under expressed in the frontal cortex, and only the cyclophilin A gene was also significantly under expressed in the hippocampus in the KA group. These under expressions of MIF and cyclophilin A could be overcome by the treatment of UR and RH. In conclusion, the under expressions of MIF and cyclophilin A in the frontal cortex and hippocampus in KA-treated rats, which were overcome by both UR and UH treatment, suggesting that both MIF and cyclophilin A at least partly participate in the anticonvulsive effect of UR.

Modulation of oxidative stress, inflammation, autophagy and expression of Nrf2 in hippocampus and frontal cortex of rats fed with açaí-enriched diets.

PubMed

Poulose, Shibu M; Bielinski, Donna F; Carey, Amanda; Schauss, Alexander G; Shukitt-Hale, Barbara

2017-06-01

Açaí (Euterpe spp.), an exotic palm fruit, has recently emerged as a promising source of natural antioxidants with wide pharmacological and nutritional value. In this study, two different species of açaí pulp extracts, naturally grown in two distinct regions of the Amazon, namely, Euterpe oleracea Mart. (habitat: Brazilian floodplains of the Amazon) and Euterpe precatoria Mart. (habitat: Bolivian Amazon), were studied for their effects on brain health and cognition. Neurochemical analyses were performed in critical brain regions associated with memory and cognition of 19-month-old açaí-fed rats, in whom the cognitive benefits of açaí had been established. Results indicated significant reductions (P< 0.05) in prooxidant NADPH-oxidoreductase-2 (NOX2) and proinflammatory transcription factor NF-κB in açaí-fed rats. Measurement of Nrf2 expression, a transcription factor for antioxidant enzymes, and a possible link between oxidative stress, neuroinflammation and autophagy mechanisms, indicated significant overexpression (P<0.005) in the hippocampus and frontal cortex of the açaí-fed rats. Furthermore, significant activation of endogenous antioxidant enzymes GST and SOD were also observed in the açaí-fed animals when compared to control. Analysis of autophagy markers such as p62, phospho-mTOR, beclin1 and MAP1B-LC3 revealed differential expression in frontal cortex and hippocampus, mostly indicating an upregulation in the açaí-fed rats. In general, results were more profound for EP than EO in hippocampus as well as frontal cortex. Therefore, an açaí-enriched diet could possibly modulate Nrf2, which is known to modulate the intracellular redox status, thereby regulating the ubiquitin-proteosomal pathway, ultimately affecting cognitive function in the aging brain.

Effects of a normolipidic diet containing trans fatty acids during perinatal period on the growth, hippocampus fatty acid profile, and memory of young rats according to sex.

PubMed

de Souza, Amanda Santos; Rocha, Mônica Santos; Tavares do Carmo, Maria das Graças

2012-04-01

To investigate whether dietary trans fatty acids (TFAs) are incorporated in the hippocampus and its effects on the growth and aversive and spatial memories of young rats. Wistar rat offspring whose mothers were fed with normolipidic diets containing soybean oil (soy group) or hydrogenated vegetable oil (trans group) during gestation and lactation were used. Male and female pups received the same diets as their mothers until the end of behavioral testing. The composition of fatty acids in the total lipids of the diets and hippocampus was quantified by gas chromatography. The results were evaluated by Student's t test or analysis of variance followed by the Bonferroni correction. The trans male and female body weights were higher during lactation and after weaning, with trans males having the lower body weight of the two. There was incorporation of 0.11% and 0.17% of TFAs in the hippocampi of male and female rats, respectively. During passive avoidance test, there was no significant difference. In the water maze test, there was no significant difference between male groups in the training and retention phases, except on day 4, when there was a significant decrease in latency in trans males. Trans females were worse on day 2 only and showed an improvement in spatial memory during the probe trial. The TFAs were incorporated in small amounts in the hippocampus and did not affect aversive memory. However, spatial memory was modified in young rats fed with a diet rich in TFAs. These findings suggested that, in addition to the TFA content of the diet provided, it is important to consider the provision of essential fatty acids and the ω-6/ω-3 ratio. Copyright © 2012 Elsevier Inc. All rights reserved.

Increased expression of CRF and CRF-receptors in dorsal striatum, hippocampus, and prefrontal cortex after the development of nicotine sensitization in rats.

PubMed

Carboni, Lucia; Romoli, Benedetto; Bate, Simon T; Romualdi, Patrizia; Zoli, Michele

2018-05-29

Nicotine addiction supports tobacco smoking, a main preventable cause of disease and death in Western countries. It develops through long-term neuroadaptations in the brain reward circuit by modulating intracellular pathways and regulating gene expression. This study assesses the regional expression of the transcripts of the CRF transmission in a nicotine sensitization model, since it is hypothesised that the molecular neuroadaptations that mediate the development of sensitization contribute to the development of addiction. Rats received intraperitoneal nicotine administrations (0.4 mg/kg) once daily for either 1 day or over 5 days. Locomotor activity was assessed to evaluate the development of sensitization. The mRNA expression of CRF and CRF1 and CRF2 receptors was measured by qPCR in the ventral mesencephalon, ventral striatum, dorsal striatum (DS), prefrontal cortex (PFCx), and hippocampus (Hip). Acute nicotine administration increased locomotor activity in rats. In the sub-chronic group, locomotor activity progressively increased and reached a clear sensitization. Significant effects of sensitization on CRF mRNA levels were detected in the DS (increasing effect). Significantly higher CRF1 and CRF2 receptor levels after sensitization were detected in the Hip. Additionally, CRF2 receptor levels were augmented by sensitization in the PFCx, and treatment and time-induced increases were detected in the DS. Nicotine treatment effects were observed on CRF1R levels in the DS. This study suggests that the CRF transmission, in addition to its role in increasing withdrawal-related anxiety, may be involved in the development of nicotine-habituated behaviours through reduced control of impulses and the aberrant memory plasticity characterising addiction. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of thyroxine on munc-18 and syntaxin-1 expression in dorsal hippocampus of adult-onset hypothyroid rats

PubMed Central

Zhu, Y.; Ning, D.; Wang, F.; Liu, C.; Xu, Y.; Jia, X.; Zhu, D.

2012-01-01

Adult-onset hypothyroidism induces a variety of impairments on hippocampus- dependent neurocognitive functioningin which many synaptic proteins in hippocampus neurons are involved. Here, we observed the effect of adult-onset hypothyroidism on the expression of syntaxin-1 and munc-18 in the dorsal hippocampus and whether the altered proteins could be restored by levothyroxine (T4) treatment. All rats were separated into 4 groups randomly: hypothyroid group, 5 µg T4 /100 g body weight (BW) treated group, 20 µg T4/100 g BW treated group and control group. The radioimmunoassay kits were applied to assay the levels of serum T3 and T4, and the levels of syntaxin-1 and munc-18 in hippocampus were assessed by immunohistochemistry and Western blot. Both analysis corroborated that syntaxin-1 in the hypothyroid group was significantly higher. Munc-18 was lower in four layers of CA3 and dentate gyrus by immunohistochemistry. After two weeks of treatment with 5 µg T4/100 g BW for hypothyroidism, syntaxin-1 levels were completely restored, whereas the recovery of munc-18 only located in two of the four impaired layers. Twenty µg T4/100 g BW treatment normalized munc-18 levels. These data suggested that adult-onset hypothyroidism induced increment of syntaxin-1 and decrement of munc-18 in the dorsal hippocampus, which could be restored by T4 treatment. Larger dosage of T4 caused more effective restorations. PMID:22688303

Radiation Damage to Nervous System: Designing Optimal Models for Realistic Neuron Morphology in Hippocampus

NASA Astrophysics Data System (ADS)

Batmunkh, Munkhbaatar; Bugay, Alexander; Bayarchimeg, Lkhagvaa; Lkhagva, Oidov

2018-02-01

The present study is focused on the development of optimal models of neuron morphology for Monte Carlo microdosimetry simulations of initial radiation-induced events of heavy charged particles in the specific types of cells of the hippocampus, which is the most radiation-sensitive structure of the central nervous system. The neuron geometry and particles track structures were simulated by the Geant4/Geant4-DNA Monte Carlo toolkits. The calculations were made for beams of protons and heavy ions with different energies and doses corresponding to real fluxes of galactic cosmic rays. A simple compartmental model and a complex model with realistic morphology extracted from experimental data were constructed and compared. We estimated the distribution of the energy deposition events and the production of reactive chemical species within the developed models of CA3/CA1 pyramidal neurons and DG granule cells of the rat hippocampus under exposure to different particles with the same dose. Similar distributions of the energy deposition events and concentration of some oxidative radical species were obtained in both the simplified and realistic neuron models.

Silicon chip with capacitors and transistors for interfacing organotypic brain slice of rat hippocampus.

PubMed

Hutzler, Michael; Fromherz, Peter

2004-04-01

Probing projections between brain areas and their modulation by synaptic potentiation requires dense arrays of contacts for noninvasive electrical stimulation and recording. Semiconductor technology is able to provide planar arrays with high spatial resolution to be used with planar neuronal structures such as organotypic brain slices. To address basic methodical issues we developed a silicon chip with simple arrays of insulated capacitors and field-effect transistors for stimulation of neuronal activity and recording of evoked field potentials. Brain slices from rat hippocampus were cultured on that substrate. We achieved local stimulation of the CA3 region by applying defined voltage pulses to the chip capacitors. Recording of resulting local field potentials in the CA1 region was accomplished with transistors. The relationship between stimulation and recording was rationalized by a sheet conductor model. By combining a row of capacitors with a row of transistors we determined a simple stimulus-response matrix from CA3 to CA1. Possible contributions of inhomogeneities of synaptic projection, of tissue structure and of neuroelectronic interfacing were considered. The study provides the basis for a development of semiconductor chips with high spatial resolution that are required for long-term studies of topographic mapping.

Place Cell Networks in Pre-weanling Rats Show Associative Memory Properties from the Onset of Exploratory Behavior.

PubMed

Muessig, L; Hauser, J; Wills, T J; Cacucci, F

2016-08-01

Place cells are hippocampal pyramidal cells that are active when an animal visits a restricted area of the environment, and collectively their activity constitutes a neural representation of space. Place cell populations in the adult rat hippocampus display fundamental properties consistent with an associative memory network: the ability to 1) generate new and distinct spatial firing patterns when encountering novel spatial contexts or changes in sensory input ("remapping") and 2) reinstate previously stored firing patterns when encountering a familiar context, including on the basis of an incomplete/degraded set of sensory cues ("pattern completion"). To date, it is unknown when these spatial memory responses emerge during brain development. Here, we show that, from the age of first exploration (postnatal day 16) onwards, place cell populations already exhibit these key features: they generate new representations upon exposure to a novel context and can reactivate familiar representations on the basis of an incomplete set of sensory cues. These results demonstrate that, as early as exploratory behaviors emerge, and despite the absence of an adult-like grid cell network, the developing hippocampus processes incoming sensory information as an associative memory network. © The Author 2016. Published by Oxford University Press.

Perirhinal Cortex Lesions Produce Retrograde Amnesia for Spatial Information in Rats: Consolidation or Retrieval?

ERIC Educational Resources Information Center

Ramos, Juan M. J.

2008-01-01

Several lines of evidence in humans and experimental animals suggest that the hippocampus is critical for the formation and retrieval of spatial memory. However, although the hippocampus is reciprocally connected to adjacent cortices within the medial temporal lobe and they, in turn, are connected to the neocortex, little is known regarding the…

Anterior Thalamic Lesions Alter Both Hippocampal-Dependent Behavior and Hippocampal Acetylcholine Release in the Rat

ERIC Educational Resources Information Center

Savage, Lisa M.; Hall, Joseph M.; Vetreno, Ryan P.

2011-01-01

The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo…

Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

ERIC Educational Resources Information Center

Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

2011-01-01

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT RAT HIPPOCAMPUS BUT DOES NOT IMPAIR SPATIAL LEARNING.

EPA Science Inventory

It has long been heralded that the mature brain does not generate new neurons, it only loses them as a function of injury, disease and age. An exciting recent finding in neuroscience has been that the dentate granule cell layer of the hippocampus has the distinctive property of ...

Prefrontal Cortex and Hippocampus Subserve Different Components of Working Memory in Rats

ERIC Educational Resources Information Center

Yoon, Taejib; Okada, Jeffrey; Jung, Min W.; Kim, Jeansok J.

2008-01-01

Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working…

[Development of long-term post-tetanic potentiation and changes in S-100 protein contents in hippocampal slices of rats in different functional states].

PubMed

Baĭdo, A I; Shiriaeva, N V; Khichenko, V I; Liuboslavskaia, P N; Starostina, M V

1992-06-01

Male rats of the strains with low (LE) high excitability (HE) of the nervous system have been used in this study. Half of the animals of each strain were neurotized in accordance with the Hecht's scheme. In the hippocampal slices of the non-neurotized LE rats there was a significant increase of the populational spike amplitude during development of LTP as compared with the opposite group of the animals. The LTP formation in the LE strain of rats caused a decrease in the S-100 protein content in the water-soluble, and an increase in the membrane-bound fraction of the protein. Similar results we have observed with the non-inbred Wistar rats but not with the HE strain of the animals. The levels of the water-soluble S-100 protein fraction were also higher in the hippocampuses and entorenal cortices, but not in the cerebellae of the LE strain, as compared with the HE strain of the rats. No differences have been found in the membrane-bound fraction of S-100 protein.

Micro Electrochemical pH Sensor Applicable for Real-Time Ratiometric Monitoring of pH Values in Rat Brains.

PubMed

Zhou, Jie; Zhang, Limin; Tian, Yang

2016-02-16

To develop in vivo monitoring meter for pH measurements is still the bottleneck for understanding the role of pH plays in the brain diseases. In this work, a selective and sensitive electrochemical pH meter was developed for real-time ratiometric monitoring of pH in different regions of rat brains upon ischemia. First, 1,2-naphthoquinone (1,2-NQ) was employed and optimized as a selective pH recognition element to establish a 2H(+)/2e(-) approach over a wide range of pH from 5.8 to 8.0. The pH meter demonstrated remarkable selectivity toward pH detection against metal ions, amino acids, reactive oxygen species, and other biological species in the brain. Meanwhile, an inner reference, 6-(ferrocenyl)hexanethiol (FcHT), was selected as a built-in correction to avoid the environmental effect through coimmobilization with 1,2-NQ. In addition, three-dimensional gold nanoleaves were electrodeposited onto the electrode surface to amplify the signal by ∼4.0-fold and the measurement was achieved down to 0.07 pH. Finally, combined with the microelectrode technique, the microelectrochemical pH meter was directly implanted into brain regions including the striatum, hippocampus, and cortex and successfully applied in real-time monitoring of pH values in these regions of brain followed by global cerebral ischemia. The results demonstrated that pH values were estimated to 7.21 ± 0.05, 7.13 ± 0.09, and 7.27 ± 0.06 in the striatum, hippocampus, and cortex in the rat brains, respectively, in normal conditions. However, pH decreased to 6.75 ± 0.07 and 6.52 ± 0.03 in the striatum and hippocampus, upon global cerebral ischemia, while a negligible pH change was obtained in the cortex.

POST-PUBERTAL DECREASE IN HIPPOCAMPAL DENDRITIC SPINES OF FEMALE RATS

PubMed Central

Yildirim, Murat; Mapp, Oni M.; Janssen, William G.M.; Yin, Weiling; Morrison, John H.; Gore, Andrea C.

2011-01-01

Hippocampal dendritic spine and synapse numbers in female rats vary across the estrous cycle and following experimental manipulation of hormone levels in adulthood. Based on behavioral studies demonstrating that learning patterns are altered following puberty, we hypothesized that dendritic spine number in rat hippocampal CA1 region would change post-pubertally. Female Sprague-Dawley rats were divided into prepubertal (postnatal day (P) 22), peripubertal (P35) and post-pubertal (P49) groups, with the progression of puberty evaluated by vaginal opening, and estrous cyclicity subsequently assessed by daily vaginal smears. Spinophilin immunoreactivity in dendritic spines was used as an index of spinogenesis in area CA1 stratum radiatum (CA1sr) of hippocampus. First, electron microscopy analyses confirmed the presence of spinophilin specifically in dendritic spines of CA1sr, supporting spinophilin as a reliable marker of hippocampal spines in young female rats. Second, stereologic analysis was performed to assess the total number of spinophilin-immunoreactive puncta (i.e. spines) and CA1sr volume in developing rats. Our results indicated that the number of spinophilin-immunoreactive spines in CA1sr was decreased 46% in the post-pubertal group compared to the two younger groups, whereas the volume of the hippocampus underwent an overall increase during this same developmental time frame. Third, to determine a potential role of estradiol in this process, an additional group of rats was ovariectomized (OVX) prepubertally at P22, then treated with estradiol or vehicle at P35, and spinophilin quantified as above in rats perfused on P49. No difference in spinophilin puncta number was found in OVX rats between the two hormone groups, suggesting that this developmental decrease is independent of peripheral estradiol. These changes in spine density coincident with puberty may be related to altered hippocampal plasticity and synaptic consolidation at this phase of maturity. PMID:18096161

Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats

PubMed Central

Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A.; Viveros, Maria-Paz

2015-01-01

Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect. PMID:26382238

Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane.

PubMed

Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Taoro-González, Lucas; Malaguarnera, Michele; Agustí, Ana; Llansola, Marta; Felipo, Vicente

2016-02-16

Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement. We analyzed the following in control and hyperammonemic rats, treated or not with sulforaphane: (1) microglia and astrocytes activation by immunohistochemistry, (2) markers of pro-inflammatory (M1) (IL-1β, IL-6) and anti-inflammatory (M2) microglia (Arg1, YM-1) by Western blot, (3) membrane expression of GABA, AMPA, and NMDA receptors using the BS3 cross-linker, and (4) spatial learning using the radial maze. The results reported show that hyperammonemia induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6. This is associated with altered membrane expression of AMPA, NMDA, and GABA receptors which would be responsible for altered neurotransmission and impairment of spatial learning in the radial maze. Treatment with sulforaphane promotes microglia differentiation from pro-inflammatory M1 to anti-inflammatory M2 phenotype and reduces activation of astrocytes in hyperammonemic rats. This reduces neuroinflammation, normalizes membrane expression of glutamate and GABA receptors, and restores spatial learning in hyperammonemic rats. Hyperammonemia-induced neuroinflammation impairs glutamatergic and GABAergic neurotransmission by altering membrane expression of glutamate and GABA receptors, resulting in impaired spatial learning. Sulforaphane reverses all these effects. Treatment with sulforaphane could be useful to improve cognitive function in cirrhotic patients with minimal or clinical hepatic encephalopathy.

LONG-LASTING NEUROSTRUCTURAL CONSEQUENCES IN THE RAT HIPPOCAMPUS BY DEVELOPMENTAL EXPOSURE TO A MIXTURE OF POLYCHLORINATED BIPHENYLS (PCBS).

EPA Science Inventory

The objective of the study was to assess the effects of developmental exposure to a commercial mixture of PCBs (Aroclor 1254) on neuronal dendritic morphology of hippocampal CA1 pyramidal neurons in postnatal day (PND) 22 and PND 60 male Long-Evans rats. Rat pups were born to mot...

Idiothetic input into object-place configuration as the contribution to memory of the monkey and human hippocampus: a review.

PubMed

Gaffan, D

1998-11-01

Memory for object-place configurations appears to be a common function of the hippocampus in the human and monkey brain. The nature of the spatial information which enters into these object-configural memories in the primate, and the location of the memories themselves, have remained obscure, however. In the rat, much evidence indicates that the hippocampus processes idiothetic spatial information, an estimate of the animal's current environmental location derived from path integration. I propose that in primates the hippocampus provides idiothetic information about the environmental location of body parts, and that the main function of this information in the primate brain is to become configured with object-identity information provided by temporal lobe cortex outside the hippocampus.

Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress.

PubMed

Gemmel, Mary; Hazlett, Mariah; Bögi, Eszter; De Lacalle, Sonsoles; Hill, Lesley A; Kokras, Nikolaos; Hammond, Geoffrey L; Dalla, Christina; Charlier, Thierry D; Pawluski, Jodi L

2017-10-01

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Nerve Growth Factor Peptide Retards Seizure Development and Inhibits Neuronal Sprouting in a Rat Model of Epilepsy

NASA Astrophysics Data System (ADS)

Rashid, Kashif; van der Zee, Catharina E. E. M.; Ross, Gregory M.; Chapman, C. Andrew; Stanisz, Jolanta; Riopelle, Richard J.; Racine, Ronald J.; Fahnestock, Margaret

1995-10-01

Kindling, an animal model of epilepsy wherein seizures are induced by subcortical electrical stimulation, results in the upregulation of neurotrophin mRNA and protein in the adult rat forebrain and causes mossy fiber sprouting in the hippocampus. Intraventricular infusion of a synthetic peptide mimic of a nerve growth factor domain that interferes with the binding of neurotrophins to their receptors resulted in significant retardation of kindling and inhibition of mossy fiber sprouting. These findings suggest a critical role for neurotrophins in both kindling and kindling-induced synaptic reorganization.

Hippocampus and serum metabolomic studies to explore the regulation of Chaihu-Shu-Gan-San on metabolic network disturbances of rats exposed to chronic variable stress.

PubMed

Su, Zhi-heng; Jia, Hong-mei; Zhang, Hong-wu; Feng, Yu-Fei; An, Lei; Zou, Zhong-mei

2014-03-04

Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine formula, has been effectively used for the treatment of depression. However, studies of its anti-depressive mechanism are challenging, due to the complex pathophysiology of depression, and complexity of CSGS with multiple constituents acting on different receptors. In the present work, metabolomic studies of biochemical changes in the hippocampus and serum of chronic variable stress (CVS)-induced depression rats after treatment with CSGS were performed using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Partial least squares-discriminate analysis indicated that the metabolic perturbation induced by CVS was reduced by treatment with CSGS. A total of twenty-six metabolites (16 from the hippocampus and 10 from serum) were considered as potential biomarkers involved in the development of depression. Among them, 11 were first reported to have potential relevance in the pathogenesis of depression, and 25 may correlate to the regulation of CSGS treatment on depression. The results combined with a previous study indicated that CSGS mediated synergistically abnormalities of the metabolic network, composed of energy metabolism, synthesis of neurotransmitters, tryptophan, phospholipids, fatty acid and bile acid metabolism, bone loss and liver detoxification, which may be helpful for understanding its mechanism of action. Furthermore, the extracellular signal-regulated kinase (ERK) signal pathway, involved in the neuronal protective mechanism of depression related to energy metabolism, was investigated by western blot analysis. The results showed that CSGS reversed disruptions of BDNF, ERK1/2 and pERK1/2 in CVS rats, which provides the first evidence that the ERK signal system may be one of the targets related to the antidepressant action of CSGS.

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

PubMed Central

García-Rojo, Gonzalo; Fresno, Cristóbal; Vilches, Natalia; Díaz-Véliz, Gabriela; Mora, Sergio; Aguayo, Felipe; Pacheco, Aníbal; Parra-Fiedler, Nicolás; Parra, Claudio S.; Rojas, Paulina S.; Tejos, Macarena; Aliaga, Esteban

2017-01-01

Abstract Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity. PMID:27927737

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus.

PubMed

García-Rojo, Gonzalo; Fresno, Cristóbal; Vilches, Natalia; Díaz-Véliz, Gabriela; Mora, Sergio; Aguayo, Felipe; Pacheco, Aníbal; Parra-Fiedler, Nicolás; Parra, Claudio S; Rojas, Paulina S; Tejos, Macarena; Aliaga, Esteban; Fiedler, Jenny L

2017-04-01

Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Sign-trackers have elevated myo-inositol in the nucleus accumbens and ventral hippocampus following Pavlovian conditioned approach.

PubMed

Fitzpatrick, Christopher J; Perrine, Shane A; Ghoddoussi, Farhad; Galloway, Matthew P; Morrow, Jonathan D

2016-01-04

Pavlovian conditioned approach (PCA) is a behavioral procedure that can be used to assess individual differences in the addiction vulnerability of drug-naïve rats and identify addiction vulnerability factors. Using proton magnetic resonance spectroscopy ( 1 H-MRS) ex vivo, we simultaneously analyzed concentrations of multiple neurochemicals throughout the mesocorticolimbic system two weeks after PCA training in order to identify potential vulnerability factors to addiction in drug naïve rats for future investigations. Levels of myo-inositol (Ins), a 1 H-MRS-detectable marker of glial activity/proliferation, were increased in the nucleus accumbens (NAc) and ventral hippocampus (vHPC), but not dorsal hippocampus or medial prefrontal cortex, of sign-trackers compared to goal-trackers or intermediate responders. In addition, Ins levels positively correlated with PCA behavior in the NAc and vHPC. Because the sign-tracker phenotype is associated with increased drug-seeking behavior, these results observed in drug-naïve rats suggest that alterations in glial activity/proliferation within these regions may represent an addiction vulnerability factor. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus.

PubMed

Hundahl, Christian Ansgar; Fahrenkrug, Jan; Hannibal, Jens

2014-09-01

Cytoglobin (Cygb), a novel oxygen-binding protein, is expressed in the majority of tissues and has been proposed to function in nitric oxide (NO) metabolism in the vasculature and to have cytoprotective properties. However, the overall functions of Cygb remain elusive. Cygb is also expressed in a subpopulation of brain neurons. Recently, it has been shown that stress upregulates Cygb expression in the brain and the majority of neuronal nitric oxide synthase (nNOS)-positive neurons, an enzyme that produces NO, co-express Cygb. However, there are more neurons expressing Cygb than nNOS, thus a large number of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic structure being an important target in a number of neurodegenerative diseases. Using triple immunohistochemistry, it was demonstrated that nearly all the parvalbumin- and heme oxygenase 1-positive neurons co-express Cygb and to a large extent, these neuron populations are distinct from the population of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool in determining the function of Cygb in the brain.

Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats.

PubMed

Shirayama, Yukihiko; Muneoka, Katsumasa; Fukumoto, Makoto; Tadokoro, Shigenori; Fukami, Goro; Hashimoto, Kenji; Iyo, Masaomi

2011-10-01

Patients with depression showed a decrease in plasma and cerebrospinal fluid allopregnanolone (ALLO). But antidepressants increased the contents of ALLO in the rat brain. We examined the antidepressant-like effects of infusion of ALLO into the cerebral ventricle, hippocampus, amygdala, nucleus accumbens, or prefrontal cortex of learned helplessness (LH) rats (an animal model of depression). Of these regions, infusions of ALLO into the cerebral ventricle, the CA3 region of hippocampus, or the central region of amygdala exerted antidepressant-like effects. Infusion of ALLO into the hippocampal CA3 region or the central amygdala did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. It is well documented that ALLO exerts its effects through GABA receptors. Therefore, we examined the antagonistic effects of flumazenil (a GABA receptor antagonist) on the antidepressant-like effects of ALLO. Coinfusion of flumazenil with ALLO into the hippocampal CA3 region, but not into the central amygdala, blocked the antidepressant-like effects of ALLO. However, coinfusion of (+)MK801 (an NMDA receptor antagonist), but not cycloheximide (a protein synthesis inhibitor), blocked the antidepressant-like effects of ALLO in the central amygdala. These results suggest that ALLO exerts antidepressant-like effects in the CA3 region of hippocampus through the GABA system and in the central region of amygdala, dependently on the activation of the glutamatergic mechanisms. Copyright © 2010 Wiley-Liss, Inc.