[Electrophysiological characteristics of hippocampal postnatal early development mediated by AMPA receptors in rats].

PubMed

Chen, Xue-Yi; Zhang, Ai-Feng; Zhao, Wen; Gao, Yu-Dan; Duan, Hong-Mei; Hao, Peng; Yang, Zhao-Yang; Li, Xiao-Guang

2018-04-25

The present study was aimed to investigate the electrophysiological characteristics of hippocampal postnatal early development mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rats. Forty-eight Wistar rats were divided into postnatal 0.5-, 1-, 2- and 3-month groups (n = 12). Spontaneous excitatory postsynaptic currents (sEPSCs) and field excitatory postsynaptic potentials (fEPSPs) mediated by AMPA receptors were recorded to evaluate the changes in the intrinsic membrane properties of hippocampal CA1 pyramidal neurons by using patch-clamp and MED64 planar microelectrode array technique respectively. The results showed that, during the period of postnatal 0.5-3 months, some of the intrinsic membrane properties of hippocampal CA1 pyramidal neurons, such as the membrane capacitance (Cm) and the resting membrane potential (RMP), showed no significant changes, while the membrane input resistance (Rin) and the time constant (τ) of the cells were decreased significantly. The amplitude, frequency and kinetics (both rise and decay times) of sEPSCs were significantly increased during the period of postnatal 0.5-1 month, but they were all decreased during the period of postnatal 1-3 months. In addition, the range of evoked fEPSPs in hippocamal CA1 region was significantly expanded, but the fEPSP amplitudes were decreased significantly during the period of postnatal 0.5-3 months. Furthermore, the evoked fEPSPs could be significantly inhibited by extracellular application of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These results suggest that AMPA receptor may act as a major type of excitatory receptor to regulate synaptic transmission and connections during the early stage of hippocampal postnatal development, which promotes the development and functional maturation of hippocampus in rats.

Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.

PubMed

Suo, Guihai; Shen, Feifei; Sun, Baolan; Song, Honghua; Xu, Meiyu; Wu, Youjia

2018-05-14

EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically.

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.

Neonatal Treatment with a Pegylated Leptin Antagonist Induces Sexually Dimorphic Effects on Neurones and Glial Cells, and on Markers of Synaptic Plasticity in the Developing Rat Hippocampal Formation.

PubMed

López-Gallardo, M; Antón-Fernández, A; Llorente, R; Mela, V; Llorente-Berzal, A; Prada, C; Viveros, M P

2015-08-01

The present study aimed to better understand the role of the neonatal leptin surge, which peaks on postnatal day (PND)9-10, on the development of the hippocampal formation. Accordingly, male and female rats were administered with a pegylated leptin antagonist on PND9 and the expression of neurones, glial cells and diverse markers of synaptic plasticity was then analysed by immunohistochemistry in the hippocampal formation. Antagonism of the actions of leptin at this specific postnatal stage altered the number of glial fibrillary acidic protein positive cells, and also affected type 1 cannabinoid receptors, synaptophysin and brain-derived neurotrophic factor (BDNF), with the latter effect being sexually dimorphic. The results indicate that the physiological leptin surge occurring around PND 9-10 is critical for hippocampal formation development and that the dynamics of leptin activity might be different in males and females. The data obtained also suggest that some but not all the previously reported effects of maternal deprivation on hippocampal formation development (which markedly reduces leptin levels at PND 9-10) might be mediated by leptin deficiency in these animals. © 2015 British Society for Neuroendocrinology.

17β Estradiol increases resilience and improves hippocampal synaptic function in helpless ovariectomized rats

PubMed Central

Bredemann, Teruko M.; McMahon, Lori L.

2014-01-01

Summary Memory impairment is the most commonly reported cognitive symptom associated with major depressive disorder. Decreased hippocampal volume and neurogenesis in depression link hippocampal dysfunction with deficits in memory. Stress decreases hippocampal dendritic spine density and long-term potentiation (LTP) at glutamate synapses, a cellular correlate of learning and memory. However, elevated plasma levels of 17β estradiol (E2) during proestrus increase hippocampal structure and function, directly opposing the negative consequences of stress. In women, significant fluctuations in ovarian hormones likely increase vulnerability of hippocampal circuits to stress, potentially contributing to the greater incidence of depression compared to men. Using the learned helplessness model of depression and ovariectomized female rats, we investigated whether acquisition of helplessness and hippocampal synaptic dysfunction is differentially impacted by the presence or absence of plasma E2. We find that inescapable shock induces a greater incidence of helplessness in vehicle- versus E2-treated OVX rats. In the vehicle-treated group, LTP was absent at CA3-CA1 synapses in slices only from helpless rats, and CA1 spine density was decreased compared to resilient rats. In contrast, significant LTP was observed in slices from E2-treated helpless rats; importantly, spine density was not different between E2-treated helpless and resilient rats, dissociating spine density from the LTP magnitude. We also find that E2 replacement can reverse previously established helpless behavior. Thus, our results show that E2 replacement in OVX rats increases resilience and improves hippocampal plasticity, suggesting that E2 therapy may increase resilience to stress and preserve hippocampal function in women experiencing large fluctuations in plasma estrogen levels. PMID:24636504

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.

Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons.

PubMed

Calvo-Rodríguez, María; de la Fuente, Carmen; García-Durillo, Mónica; García-Rodríguez, Carmen; Villalobos, Carlos; Núñez, Lucía

2017-01-31

Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system recognizing diverse pathogen-derived and tissue damage-related ligands. It has been suggested that TLR signaling contributes to the pathogenesis of age-related, neurodegenerative diseases, including Alzheimer's disease (AD). AD is associated to oligomers of the amyloid β peptide (Aβo) that cause intracellular Ca 2+ dishomeostasis and neuron cell death in rat hippocampal neurons. Here we assessed the interplay between inflammation and Aβo in long-term cultures of rat hippocampal neurons, an in vitro model of neuron aging and/or senescence. Ca 2+ imaging and immunofluorescence against annexin V and TLR4 were applied in short- and long-term cultures of rat hippocampal neurons to test the effects of TLR4-agonist LPS and Aβo on cytosolic [Ca 2+ ] and on apoptosis as well as on expression of TLR4. LPS increases cytosolic [Ca 2+ ] and promotes apoptosis in rat hippocampal neurons in long-term culture considered aged and/or senescent neurons, but not in short-term cultured neurons considered young neurons. TLR4 antagonist CAY10614 prevents both effects. TLR4 expression in rat hippocampal neurons is significantly larger in aged hippocampal cultures. Treatment of aged hippocampal cultures with Aβo increases TLR4 expression and enhances LPS-induced Ca 2+ responses and neuron cell death. Aging and amyloid β oligomers, the neurotoxin involved in Alzheimer's disease, enhance TLR4 expression as well as LPS-induced Ca 2+ responses and neuron cell death in rat hippocampal neurons aged in vitro.

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

SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS INDUCED BY OKADAIC ACID (EXPERIMENTAL STUDY).

PubMed

Chighladze, M; Dashniani, M; Beselia, G; Kruashvili, L; Naneishvili, T

2016-01-01

In the present study, we evaluated and compared effect of intracerebroventricular (ICV) and intrahippocampal bilateral microinjection of okadaic acid (OA) on spatial memory function assessed in one day water maze paradigm and hippocampal structure in rats. Rats were divided in following groups: Control(icv) - rats injected with ICV and aCSF; Control(hipp) - rats injected intrahippocampally with aCSF; OAicv - rats injected with ICV and OA; OAhipp - rats injected intrahippocampally with OA. Nissl staining of hippocampal sections showed that the pyramidal cell loss in OAhipp group is significantly higher than that in the OAicv. The results of behavioral experiments showed that ICV or intrahippocampal bilateral microinjection of OA did not affect learning process and short-term spatial memory but induced impairment in spatial long-term memory assessed in probe test performance 24 h after training. OA-induced spatial memory impairment may be attributed to the hippocampal cell death. Based on these results OA induced memory deficit and hippocampal cell loss in rat may be considered as a potential animal model for preclinical evaluation of antidementic drug activity.

Exposure to social defeat stress in adolescence improves the working memory and anxiety-like behavior of adult female rats with intrauterine growth restriction, independently of hippocampal neurogenesis.

PubMed

Furuta, Miyako; Ninomiya-Baba, Midori; Chiba, Shuichi; Funabashi, Toshiya; Akema, Tatsuo; Kunugi, Hiroshi

2015-04-01

Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015 Elsevier Inc. All rights reserved.

Insulin treatment partially prevents cognitive and hippocampal alterations as well as glucocorticoid dysregulation in early-onset insulin-deficient diabetic rats.

PubMed

Marissal-Arvy, Nathalie; Campas, Marie-Neige; Semont, Audrey; Ducroix-Crepy, Céline; Beauvieux, Marie-Christine; Brossaud, Julie; Corcuff, Jean-Benoit; Helbling, Jean-Christophe; Vancassel, Sylvie; Bouzier-Sore, Anne-Karine; Touyarot, Katia; Ferreira, Guillaume; Barat, Pascal; Moisan, Marie-Pierre

2018-04-17

The diagnosis of Type 1 Diabetes (T1D) in ever younger children led us to question the impact of insulin deficiency or chronic hyperglycemia on cerebral development and memory performances. Here, we sought abnormalities in these traits in a model of streptozotocin-induced diabetes in juvenile rats treated or not by insulin. We made the assumption that such alterations would be related, at least in part, to excessive glucocorticoid exposition in hippocampal neurons. We have compared 3 groups of juvenile rats: controls, untreated diabetics and insulin-treated diabetics. Diabetes was induced by streptozotocin (65 mg/kg IP/day, 2 consecutive days), at postnatal days 21 and 22 and a subcutaneous pellet delivering 2 U of insulin/day was implanted in treated diabetic rats 3 days later. Three weeks after diabetes induction, cognitive performances (Y maze, object location and recognition tests), in vivo brain structure (brain volume and water diffusion by structural magnetic resonance imaging), and hippocampal neurogenesis (immunohistochemical labeling) measurements were undertaken. Corticosterone levels were evaluated in plasma under basal and stress conditions, and within hippocampus together with 11β-dehydrocorticosterone to assess 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. The comparison of the three experimental groups revealed that, compared to controls, untreated diabetic rats showed decreased cognitive performances in Y-maze and object location test (p < 0.05), decreased brain and hippocampal microstructure (p < 0.05), and decreased maturation and survival of hippocampal newborn neurons (p < 0.05). These alterations were associated with increased plasma corticosterone at the baseline nadir of its secretion (p < 0.001) and during the recovery phase following a restraint stress (p < 0.001), as well as increased hippocampal corticosterone levels (p < 0.01) and 11β-HSD1 activity (p < 0.05). As untreated diabetic rats, insulin-treated diabetic rats displayed decreased brain volume and water diffusion (p < 0.05 compared to controls) and intermediate memory performances and hippocampal neurogenesis (p value not significant compared to either controls or untreated diabetics). Moreover, they were similar to controls for basal plasma and hippocampal corticosterone and 11β-HSD1 activity but show increased plasma corticosterone during the recovery phase following a restraint stress similar to untreated diabetics (p < 0.001 compared to controls). Thus, insulin did not completely prevent several hippocampal-dependent behavioral and structural alterations induced by diabetes in juvenile rats which may relate to the higher cognitive difficulties encountered in T1D children compared to non-diabetic controls. Although insulin restored basal corticosterone and 11β-HSD1 activity (in hippocampus and plasma), the negative feedback regulation of corticosterone secretion after stress was still impaired in insulin-treated diabetic rats. Further characterization of insulin control on glucocorticoid regulation and availability within hippocampus is awaited. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of radio-frequency electromagnetic radiations (RF-EMR) on passive avoidance behaviour and hippocampal morphology in Wistar rats.

PubMed

Narayanan, Sareesh Naduvil; Kumar, Raju Suresh; Potu, Bhagath Kumar; Nayak, Satheesha; Bhat, P Gopalakrishna; Mailankot, Maneesh

2010-05-01

The interaction of mobile phone radio-frequency electromagnetic radiation (RF-EMR) with the brain is a serious concern of our society. We evaluated the effect of RF-EMR from mobile phones on passive avoidance behaviour and hippocampal morphology in rats. Healthy male albino Wistar rats were exposed to RF-EMR by giving 50 missed calls (within 1 hour) per day for 4 weeks, keeping a GSM (0.9 GHz/1.8 GHz) mobile phone in vibratory mode (no ring tone) in the cage. After the experimental period, passive avoidance behaviour and hippocampal morphology were studied. Passive avoidance behaviour was significantly affected in mobile phone RF-EMR-exposed rats demonstrated as shorter entrance latency to the dark compartment when compared to the control rats. Marked morphological changes were also observed in the CA(3) region of the hippocampus of the mobile phone-exposed rats in comparison to the control rats. Mobile phone RF-EMR exposure significantly altered the passive avoidance behaviour and hippocampal morphology in rats.

Loss of Hippocampal Neurons after Kainate Treatment Correlates with Behavioral Deficits

PubMed Central

Maia, Gisela H.; Quesado, José L.; Soares, Joana I.; do Carmo, Joana M.; Andrade, Pedro A.; Andrade, José P.; Lukoyanov, Nikolai V.

2014-01-01

Treating rats with kainic acid induces status epilepticus (SE) and leads to the development of behavioral deficits and spontaneous recurrent seizures later in life. However, in a subset of rats, kainic acid treatment does not induce overt behaviorally obvious acute SE. The goal of this study was to compare the neuroanatomical and behavioral changes induced by kainate in rats that developed convulsive SE to those who did not. Adult male Wistar rats were treated with kainic acid and tested behaviorally 5 months later. Rats that had experienced convulsive SE showed impaired performance on the spatial water maze and passive avoidance tasks, and on the context and tone retention tests following fear conditioning. In addition, they exhibited less anxiety-like behaviors than controls on the open-field and elevated plus-maze tests. Histologically, convulsive SE was associated with marked neuron loss in the hippocampal CA3 and CA1 fields, and in the dentate hilus. Rats that had not experienced convulsive SE after kainate treatment showed less severe, but significant impairments on the spatial water maze and passive avoidance tasks. These rats had fewer neurons than control rats in the dentate hilus, but not in the hippocampal CA3 and CA1 fields. Correlational analyses revealed significant relationships between spatial memory indices of rats and neuronal numbers in the dentate hilus and CA3 pyramidal field. These results show that a part of the animals that do not display intense behavioral seizures (convulsive SE) immediately after an epileptogenic treatment, later in life, they may still have noticeable structural and functional changes in the brain. PMID:24409306

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

[Effects of rapamycin on amyloid β-protein induced impairments of working memory and synaptic plasticity in rats].

PubMed

Hao, Ming; Tong, Jia-qing; Zhang, Jun; Wu, Mei-na; Qi, Jin-shun

2016-01-01

The present study investigated the effects of rapamycin on Aβ1-42-induced deficits in working memory and synaptic plasticity. After bilateral hippocampal injection of Aβ1-42 and rapamycinin rats, spontaneous alternation in Y-maze and in vivo hippocampal long-term potentiation (LTP) of rats were recorded. All data were analized by two-way repeated measures analysis of variance (ANOVA). (Hippocampal injection of Aβ1-42 alone impaired working memory of rats; (2) Rapamycin did not affect working memory of rats, but alleviated Aβ1-42-induced working memory deficits, compared with Aβ1-42 alone group; (Aβ1-42 remarkably suppressed in vivo hippocampal LTP of fEPSPs in the CA1 region; (4) Pretreatment with rapamycin prevented Aβ1-42-induced suppression of LTP. These data indicates that rapamycin could protect against Aβ1-42-induced impairments in working memory and synaptic plasticity in rats.

Metyrapone Reveals That Previous Chronic Stress Differentially Impairs Hippocampal-dependent Memory

PubMed Central

CONRAD, CHERYL D.; MAULDIN-JOURDAIN, MELISSA L.; HOBBS, REBECCA J.

2007-01-01

Chronic stress facilitates fear conditioning in rats with hippocampal neuronal atrophy and in rats in which the atrophy is prevented with tianeptine, a serotonin re-uptake enhancer. The purpose of this study was to determine whether the lack of dissociation between fear conditioning performance and hippocampal integrity was masked by the presence of endogenous corticosteroids during training. As in previous studies, rats were stressed by daily restraint (6 h/day for 21 days), trained in the conditioning chamber (day 23), and then assessed for conditioned fear (day 25) at a time when hippocampal dendritic atrophy persists. On the training day, half of the control and stressed rats were injected with metyrapone to reduce corticosterone release. Two hours later, two paired or unpaired presentations of tone and footshock were delivered. Although metyrapone reduced conditioned fear in all rats, only stressed rats showed dissociated fear conditioning (i.e. tone conditioning was reduced while contextual conditioning was eliminated). Chronically stressed rats, regardless of metyrapone treatment displayed more rearing in the open field when tested immediately after the completion of fear conditioning. These data support the hypothesis that increased emotionality and enhanced fear conditioning exhibited by chronically stressed rats may be due to endogenous corticosterone secretion at the time of fear conditioned training. Moreover, these data suggest that chronic stress impairs hippocampal-dependent processes more robustly than hippocampal-independent processes after metyrapone to reduce corticosterone secretion during aversive training. PMID:18301732

Neuroprotective effect of curcumin on hippocampal injury in 6-OHDA-induced Parkinson's disease rat.

PubMed

Yang, Jiaqing; Song, Shilei; Li, Jian; Liang, Tao

2014-06-01

Clinically, Parkinson's disease (PD)-related neuronal lesions commonly occur. The purpose of this study is to investigate potential therapeutic effect of curcumin against hippocampal damage of 6-hydroxydopamine (6-OHDA)-PD rat model. These results showed that curcumin significantly increased the body weight of 6-OHDA-impaired rats (P<0.01), and reversed the anhedonia in rats induced by 6-OHDA impairment (P<0.01). Meanwhile, behavioral manifestations of curcumin-treated PD rats were effectively ameliorated as shown in open field test (P<0.01). In addition, curcumin increased the contents of monoaminergic neurotransmitters (P<0.01), such as dopamine (DA) and norepinephrine (NE), in hippocampal homogenate through high performance liquid chromatography (HPLC) assay. Curcumin effectively alleviated the 6-OHDA-induced hippocampal damage as observed in hematoxylin-eosin (H&E) staining. Furthermore, curcumin obviously up-regulated hippocampal brain derived neurotrophic factor (BDNF), TrkB, phosphatidylinositide 3-kinases (PI3K) protein expressions, respectively as shown in Western blot analysis. These findings demonstrated that curcumin mediated the neuroprotection against 6-OHDA-induced hippocampus neurons in rats, which the underlying mechanism is involved in activating BDNF/TrkB-dependent pathway for promoting neural regeneration of hippocampal tissue. Copyright © 2014 Elsevier GmbH. All rights reserved.

Neonatal allopregnanolone or finasteride administration modifies hippocampal K(+) Cl(-) co-transporter expression during early development in male rats.

PubMed

Mòdol, Laura; Casas, Caty; Llidó, Anna; Navarro, Xavier; Pallarès, Marc; Darbra, Sònia

2014-09-01

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood

PubMed Central

Wong-Goodrich, Sarah J.E.; Tognoni, Christina M.; Mellott, Tiffany J.; Glenn, Melissa J.; Blusztajn, Jan K.; Williams, Christina L.

2011-01-01

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12–17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. PMID:21840511

Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism.

PubMed

Shiraki, Ayako; Saito, Fumiyo; Akane, Hirotoshi; Akahori, Yumi; Imatanaka, Nobuya; Itahashi, Megu; Yoshida, Toshinori; Shibutani, Makoto

2016-01-01

We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. Copyright © 2015 John Wiley & Sons, Ltd.

Effect of prenatal protein malnutrition on long-term potentiation and BDNF protein expression in the rat entorhinal cortex after neocortical and hippocampal tetanization.

PubMed

Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

2008-01-01

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55-60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

Effect of Prenatal Protein Malnutrition on Long-Term Potentiation and BDNF Protein Expression in the Rat Entorhinal Cortex after Neocortical and Hippocampal Tetanization

PubMed Central

Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

2008-01-01

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals. PMID:18604298

Comparison of the force exerted by hippocampal and DRG growth cones.

PubMed

Amin, Ladan; Ercolini, Erika; Ban, Jelena; Torre, Vincent

2013-01-01

Mechanical properties such as force generation are fundamental for neuronal motility, development and regeneration. We used optical tweezers to compare the force exerted by growth cones (GCs) of neurons from the Peripheral Nervous System (PNS), such as Dorsal Root Ganglia (DRG) neurons, and from the Central Nervous System (CNS) such as hippocampal neurons. Developing GCs from dissociated DRG and hippocampal neurons were obtained from P1-P2 and P10-P12 rats. Comparing their morphology, we observed that the area of GCs of hippocampal neurons was 8-10 µm(2) and did not vary between P1-P2 and P10-P12 rats, but GCs of DRG neurons were larger and their area increased from P1-P2 to P10-P12 by 2-4 times. The force exerted by DRG filopodia was in the order of 1-2 pN and never exceeded 5 pN, while hippocampal filopodia exerted a larger force, often in the order of 5 pN. Hippocampal and DRG lamellipodia exerted lateral forces up to 20 pN, but lamellipodia of DRG neurons could exert a vertical force larger than that of hippocampal neurons. Force-velocity relationships (Fv) in both types of neurons had the same qualitative behaviour, consistent with a common autocatalytic model of force generation. These results indicate that molecular mechanisms of force generation of GC from CNS and PNS neurons are similar but the amplitude of generated force is influenced by their cytoskeletal properties.

Comparison of the Force Exerted by Hippocampal and DRG Growth Cones

PubMed Central

Amin, Ladan; Ercolini, Erika; Ban, Jelena; Torre, Vincent

2013-01-01

Mechanical properties such as force generation are fundamental for neuronal motility, development and regeneration. We used optical tweezers to compare the force exerted by growth cones (GCs) of neurons from the Peripheral Nervous System (PNS), such as Dorsal Root Ganglia (DRG) neurons, and from the Central Nervous System (CNS) such as hippocampal neurons. Developing GCs from dissociated DRG and hippocampal neurons were obtained from P1-P2 and P10-P12 rats. Comparing their morphology, we observed that the area of GCs of hippocampal neurons was 8-10 µm2 and did not vary between P1-P2 and P10-P12 rats, but GCs of DRG neurons were larger and their area increased from P1-P2 to P10-P12 by 2-4 times. The force exerted by DRG filopodia was in the order of 1-2 pN and never exceeded 5 pN, while hippocampal filopodia exerted a larger force, often in the order of 5 pN. Hippocampal and DRG lamellipodia exerted lateral forces up to 20 pN, but lamellipodia of DRG neurons could exert a vertical force larger than that of hippocampal neurons. Force-velocity relationships (Fv) in both types of neurons had the same qualitative behaviour, consistent with a common autocatalytic model of force generation. These results indicate that molecular mechanisms of force generation of GC from CNS and PNS neurons are similar but the amplitude of generated force is influenced by their cytoskeletal properties. PMID:23991169

Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

PubMed Central

Lensu, Sanna; Ahtiainen, Juha P.; Johansson, Petra P.; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki

2016-01-01

Key points Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents.Little is known about the effects of high‐intensity interval training (HIT) or of purely anaerobic resistance training on AHN.Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats.We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity.Our results confirm that sustained aerobic exercise is key in improving AHN. Abstract Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high‐intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low‐response trainer (LRT) and high‐response trainer (HRT) adult male rats to various forms of physical exercise for 6–8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin‐positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non‐significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength. Furthermore, RT had no effect on proliferation (Ki67), maturation (doublecortin) or survival (bromodeoxyuridine) of new adult‐born hippocampal neurons in adult male Sprague–Dawley rats. Our results suggest that physical exercise promotes AHN most effectively if the exercise is aerobic and sustained, especially when accompanied by a heightened genetic predisposition for response to physical exercise. PMID:26844666

Effect of Noopept on Dynamics of Intracellular Calcium in Neurons of Cultured Rat Hippocampal Slices.

PubMed

Kolbaev, S N; Aleksandrova, O P; Sharonova, I N; Skrebitsky, V G

2018-01-01

A neuroprotective and nootropic drug Noopept increased the frequency of spontaneous calcium transients in neurons of CA1 radial layer in cultured rat hippocampal slices. In contrast, the drug exerted no significant effect on intracellular calcium concentration and its dynamics in neurons of hippocampal CA1 pyramidal layer.

Hippocampal Morphology in a Rat Model of Depression: The Effects of Physical Activity

PubMed Central

Sierakowiak, Adam; Mattsson, Anna; Gómez-Galán, Marta; Feminía, Teresa; Graae, Lisette; Aski, Sahar Nikkhou; Damberg, Peter; Lindskog, Mia; Brené, Stefan; Åberg, Elin

2015-01-01

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers. PMID:25674191

Hippocampal morphology in a rat model of depression: the effects of physical activity.

PubMed

Sierakowiak, Adam; Mattsson, Anna; Gómez-Galán, Marta; Feminía, Teresa; Graae, Lisette; Aski, Sahar Nikkhou; Damberg, Peter; Lindskog, Mia; Brené, Stefan; Åberg, Elin

2014-01-01

Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers.

Hippocampal 3alpha,5alpha-THP may alter depressive behavior of pregnant and lactating rats.

PubMed

Frye, Cheryl A; Walf, Alicia A

2004-07-01

The 5alpha-reduced metabolite of progesterone (P), 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), may mediate progestins' effects to reduce depressive behavior of female rats in part through actions in the hippocampus. To investigate, forced swim test behavior and plasma and hippocampal progestin levels were assessed in groups of rats expected to differ in their 3alpha,5alpha-THP levels due to endogenous differences (pregnant and postpartum), administration of a 5alpha-reductase inhibitor (finasteride; 50 mg/kg sc), and/or gestational stress [prenatal stress (PNS)], an animal model of depression. Pregnant rats had higher plasma and hippocampal 3alpha,5alpha-THP levels and less depressive behavior (decreased immobility, increased struggling and swimming) in the forced swim test than did postpartum rats. Finasteride, compared to vehicle-administration, reduced plasma and hippocampal 3alpha,5alpha-THP levels and increased depressive behavior (increased immobility, decreased struggling and swimming). PNS was associated with lower hippocampal, but not plasma, 3alpha,5alpha-THP levels and increased swimming compared to that observed in control rats. Together, these data suggest that 3alpha,5alpha-THP in the hippocampus may mediate antidepressive behavior of female rats.

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

Development of the Hippocampal Cognitive Map in Pre-weanling Rats

PubMed Central

Wills, Tom; Cacucci, Francesca; Burgess, Neil; O’Keefe, John

2011-01-01

Orienting in large-scale space depends on the interaction of environmental experience and pre-configured, possibly innate, constructs. Place, head-direction and grid cells in the hippocampal formation provide allocentric representations of space. Here we show how these cognitive representations emerge and develop as rat pups first begin to explore their environment. Directional, locational and rhythmic organization of firing are present during initial exploration, including adult-like directional firing. The stability and precision of place cell firing continues to develop throughout juvenility. Stable grid cell firing appears later but matures rapidly to adult levels. Our results demonstrate the presence of three neuronal representations of space prior to extensive experience, and show how they develop with age. PMID:20558720

Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats.

PubMed

McHugh, Stephen B; Francis, Anna; McAuley, J Devin; Stewart, Amanda L; Baxter, Mark G; Bannerman, David M

2015-08-01

We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50-97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL. (c) 2015 APA, all rights reserved).

Hippocampal Acetylcholine Depletion Has No Effect on Anxiety, Spatial Novelty Preference, or Differential Reward for Low Rates of Responding (DRL) Performance in Rats

PubMed Central

2015-01-01

We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50–97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL. PMID:26214215

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.

The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise.

PubMed

Cai, Ming; Wang, Hong; Li, Jing-Jing; Zhang, Yun-Li; Xin, Lei; Li, Feng; Lou, Shu-Jie

2016-10-01

High fat diet (HFD)-induced obesity has been shown to reduce the levels of neuronal plasticity-related proteins, specifically brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN), in the hippocampus. However, the underlying mechanisms are not fully clear. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating gene expression and protein production by affecting stress signaling pathways and ER functions of protein folding and post-translational modification in peripheral tissues of obese rodent models. Additionally, HFD that is associated with hyperglycemia could induce hippocampal ERS, thus impairing insulin signaling and cognitive health in HFD mice. One goal of this study was to determine whether hyperglycemia and hyperlipidemia could cause hippocampal ERS in HFD-induced obese SD rats, and explore the potential mechanisms of ERS regulating hippocampal BDNF and SYN proteins production. Additionally, although regular aerobic exercise could reduce central inflammation and elevate hippocampal BDNF and SYN levels in obese rats, the regulated mechanisms are poorly understood. Nrf2-HO-1 pathways play roles in anti-ERS, anti-inflammation and anti-apoptosis in peripheral tissues. Therefore, the other goal of this study was to determine whether aerobic exercise could activate Nrf2-HO-1 in hippocampus to alleviate obesity-induced hippocampal ERS, which would lead to increased BDNF and SYN levels. Male SD rats were fed on HFD for 8weeks to establish the obese model. Then, 8weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that HFD-induced obesity caused hyperglycemia and hyperlipidemia, and significantly promoted hippocampal glucose transporter 3 (GLUT3) and fatty acid transport protein 1 (FATP1) protein expression. These results were associated with the activation of hippocampal ERS and ERS-mediated apoptosis. At the same time, we found that excessive hippocampal ERS not only significantly decreased proBDNF-the precursor of mature BDNF, but also attenuated p38/ERK-CREB signaling pathways and activated NLRP3-IL-1β pathways in obese rats. These results were associated with reduced BDNF and SYN protein production. However, these adverse changes were obviously reversed by aerobic exercise intervention through activating the Nrf2-HO-1 pathways. These results suggest that dietary obesity could induce hippocampal ERS in male SD rats, and excessive hippocampal ERS plays a critical role in decreasing the levels of BDNF and SYN. Moreover, aerobic exercise could activate hippocampal Nrf2 and HO-1 to relieve ERS and heighten BDNF and SYN production in obese rats. Copyright © 2016 Elsevier Inc. All rights reserved.

A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats

PubMed Central

Lin, Ching-I; Shen, Chu-Fu; Hsu, Tsui-Han; Lin, Shyh-Hsiang

2017-01-01

We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group (n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high-fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain. PMID:28621759

A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats.

PubMed

Lin, Ching-I; Shen, Chu-Fu; Hsu, Tsui-Han; Lin, Shyh-Hsiang

2017-06-16

We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group ( n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high-fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain.

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

Turmeric extract inhibits apoptosis of hippocampal neurons of trimethyltin-exposed rats.

PubMed

Yuliani, S; Widyarini, S; Mustofa; Partadiredja, G

2017-01-01

The aim of the present study was to reveal the possible antiapoptotic effect of turmeric (Curcuma longa Linn.) on the hippocampal neurons of rats exposed to trimethyltin (TMT). Oxidative damage in the hippocampus can induce the apoptosis of neurons associated with the pathogenesis of dementiaMETHODS. The ethanolic turmeric extract and a citicoline (as positive control) solution were administered to the TMT-exposed rats for 28 days. The body weights of rats were recorded once a week. The hippocampal weights and imumunohistochemical expression of caspase 3 proteins in the CA1 and CA2-CA3 regions of the hippocampi were examined at the end of the experiment. Immunohistochemical analysis showed that the injection of TMT increased the expression of caspase 3 in the CA1 and CA2-CA3 regions of hippocampus. TMT also decreased the body and hippocampal weights. Furthermore, the administration of 200 mg/kg bw dose of turmeric extract decreased the caspase 3 expression in the CA2-CA3 pyramidal neurons but not in the CA1 neurons. It also prevented the decrease of the body and hippocampal weights. We suggest that the 200 mg/kg bw dose of turmeric extract may exert antiapoptotic effect on the hippocampal neurons of the TMT-exposed rats (Tab. 1, Fig. 3, Ref. 49).

Dietary CDP-Choline Supplementation Prevents Memory Impairment Caused by Impoverished Environmental Conditions in Rats

ERIC Educational Resources Information Center

Teather, Lisa A.; Wurtman, Richard J.

2005-01-01

The authors previously showed that dietary cytidine (5')-diphosphocholine (CDP-choline) supplementation could protect against the development of memory deficits in aging rats. In the present study, younger rats exposed to impoverished environmental conditions and manifesting hippocampal-dependent memory impairments similar to those observed in the…

Enhanced oscillatory activity in the hippocampal-prefrontal network is related to short-term memory function after early-life seizures

PubMed Central

Kleen, Jonathan K.; Wu, Edie X.; Holmes, Gregory L.; Scott, Rod C.; Lenck-Santini, Pierre-Pascal

2011-01-01

Neurological insults during development are associated with later impairments in learning and memory. Although remedial training can help restore cognitive function, the neural mechanisms of this recovery in memory systems are largely unknown. To examine this issue we measured electrophysiological oscillatory activity in the hippocampus (both CA3 and CA1) and prefrontal cortex of adult rats that had experienced repeated seizures in the first weeks of life, while they were remedially trained on a delayed-nonmatch-to-sample memory task. Seizure-exposed rats showed initial difficulties learning the task but performed similar to control rats after extra training. Whole-session analyses illustrated enhanced theta power in all three structures while seizure rats learned response tasks prior to the memory task. Whilst performing the memory task, dynamic oscillation patterns revealed that prefrontal cortex theta power was increased among seizure-exposed rats. This enhancement appeared after the first memory training steps using short delays and plateaued at the most difficult steps which included both short and long delays. Further, seizure rats showed enhanced CA1-prefrontal theta coherence in correct trials compared to incorrect trials when long delays were imposed, suggesting increased hippocampal-prefrontal synchrony for the task in this group when memory demand was high. Seizure-exposed rats also showed heightened gamma power and coherence among all three structures during the trials. Our results demonstrate the first evidence of hippocampal-prefrontal enhancements following seizures in early development. Dynamic compensatory changes in this network and interconnected circuits may underpin cognitive rehabilitation following other neurological insults to higher cognitive systems. PMID:22031886

[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.

Hypothyroxinemia induced by maternal mild iodine deficiency impairs hippocampal myelinated growth in lactational rats.

PubMed

Wei, Wei; Wang, Yi; Dong, Jing; Wang, Yuan; Min, Hui; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Xi, Qi; Chen, Jie

2015-11-01

Hypothyroxinemia induced by maternal mild iodine deficiency causes neurological deficits and impairments of brain function in offspring. Hypothyroxinemia is prevalent in developing and developed countries alike. However, the mechanism underlying these deficits remains less well known. Given that the myelin plays an important role in learning and memory function, we hypothesize that hippocampal myelinated growth may be impaired in rat offspring exposed to hypothyroxinemia induced by maternal mild iodine deficiency. To test this hypothesis, the female Wistar rats were used and four experimental groups were prepared: (1) control; (2) maternal mild iodine deficiency diet inducing hypothyroxinemia; (3) hypothyroidism induced by maternal severe iodine deficiency diet; (4) hypothyroidism induced by maternal methimazole water. The rats were fed the diet from 3 months before pregnancy to the end of lactation. Our results showed that the physiological changes occuring in the hippocampal myelin were altered in the mild iodine deficiency group as indicated by the results of immunofluorescence of myelin basic proteins on postnatal day 14 and postnatal day 21. Moreover, hypothyroxinemia reduced the expressions of oligodendrocyte lineage transcription factor 2 and myelin-related proteins in the treatments on postnatal day 14 and postnatal day 21. Our data suggested that hypothyroxinemia induced by maternal mild iodine deficiency may impair myelinated growth of the offspring. © 2014 Wiley Periodicals, Inc.

Clioquinol and vitamin B12 (cobalamin) synergistically rescue the lead-induced impairments of synaptic plasticity in hippocampal dentate gyrus area of the anesthetized rats in vivo.

PubMed

Chen, W-H; Wang, M; Yu, S-S; Su, L; Zhu, D-M; She, J-Q; Cao, X-J; Ruan, D-Y

2007-07-13

Lead (Pb(2+)) exposure in development induces impairments of synaptic plasticity in the hippocampal dentate gyrus (DG) area of the anesthetized rats in vivo. The common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, CQ, clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline), which is a transition metal ion chelator and/or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions. In addition, CQ-associated side effects are believed to be overcome with vitamin B12 (VB12) supplementation. To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb(2+) exposure, we investigated the input/output functions (I/Os), paired-pulse reactions (PPRs) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anesthetized rat in vivo by recording field potentials and measured hippocampal Pb(2+) concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results show: CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anesthetized rats in vivo; VB12 alone partly rescues the lead-induced impairments of LTP; however the co-administration of CQ and VB12 totally rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.

Effects of intermittent hypobaric hypoxia preconditioning on the expression of neuroglobin and Bcl-2 in the rat hippocampal CA1 area following ischemia-reperfusion.

PubMed

Wu, Q; Yu, K X; Ma, Q S; Liu, Y N

2015-09-09

This study was aimed at understanding the effect of intermittent hypobaric hypoxia preconditioning (IHHP) on neuroglobin (NGB) and Bcl-2 expression in the hippocampal CA1 region of rats following global cerebral ischemia-reperfusion. Wistar rats were randomly divided into sham, IHHP control, global cerebral ischemia-reperfusion (IR group), and IHHP+IR groups. The four-vessel occlusion rat model of Pulsinelli was used for the IR groups, in which the common carotid artery was occluded for 8 min before reperfusion. Thionin and immunohistochemical staining were used to observe NGB and Bcl-2 expression in the hippocampal CA1 region. Data was analyzed using the SPSS software. There was a significant increase in the number of surviving cells in the hippocampal CA1 region of the IHHP+IR group (119.5 ± 14) compared to the IR group (41.7 ± 3.8) (P < 0.05). There was a significant increase in the expression of NGB and Bcl-2 in the hippocampal CA1 region of the IHHP+IR group compared to the IR group. By upregulating hippocampal NGB and Bcl-2 expression, IHHP may play a role in neural protection by reducing hippocampal neuronal apoptosis following IR.

The development of spatial behaviour and the hippocampal neural representation of space

PubMed Central

Wills, Thomas J.; Muessig, Laurenz; Cacucci, Francesca

2014-01-01

The role of the hippocampal formation in spatial cognition is thought to be supported by distinct classes of neurons whose firing is tuned to an organism's position and orientation in space. In this article, we review recent research focused on how and when this neural representation of space emerges during development: each class of spatially tuned neurons appears at a different age, and matures at a different rate, but all the main spatial responses tested so far are present by three weeks of age in the rat. We also summarize the development of spatial behaviour in the rat, describing how active exploration of space emerges during the third week of life, the first evidence of learning in formal tests of hippocampus-dependent spatial cognition is observed in the fourth week, whereas fully adult-like spatial cognitive abilities require another few weeks to be achieved. We argue that the development of spatially tuned neurons needs to be considered within the context of the development of spatial behaviour in order to achieve an integrated understanding of the emergence of hippocampal function and spatial cognition. PMID:24366148

[Over-expressed Bax inhibitor 1 (BI-1) inhibits apoptosis of hippocampal neurons via endoplasmic reticulum IRE1-JNK pathway in rats with subarachnoid hemorrhage].

PubMed

Liu, Jiaxin; Zhou, Shuai; Qian, Xiying; Zhang, Yueting; Zhao, Jianhua

2017-10-01

Objective To investigate the protective effect of lentivirus-mediated BI-1 overexpression on hippocampal neurons in rats with subarachnoid hemorrhage (SAH) and the relationship with endoplasmic reticulum IRE1-JNK signaling pathway. Methods The lentivirus solution of BI-1 over-expression was injected into the brain of rats 24 hours before SAH rat model was established by intravascular puncture method. At 24 hours after modeling, the brain water content and neurological score of the rats were measured. The apoptosis of hippocampal neurons was detected by TUNEL assay. Western blotting was used to detect the expressions of BI-1 protein and endoplasmic reticulum stress (ERS) marker proteins GRP78 and IRE1. ERS in hippocampal neurons of the rats with SAH was intervened by IRE1α-specific inhibitor KIRA6, and then the protein expressions of p-IRE1, p-JNK, Bax, Bcl2 and caspase-3 were detected by Western blotting. Results BI-1 over-expression improved neurobehavioral score, decreased brain water content and hippocampal neuron apoptosis rate, and also down-regulated GRP78 and IRE1 protein levels in the rats with SAH. Both the interference of KIRA6 and the over-expression of BI-1 inhibited the expressions of p-IRE1, p-JNK, Bax and caspase-3, and promoted the expression of anti-apoptotic protein Bcl2. Conclusion Over-expression of BI-1 can inhibit the apoptosis of hippocampal neurons in rats with SAH by inhibiting the activation of ERS-mediated IRE1-JNK signaling pathway, thus ultimately attenuating the early brain injury following SAH.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood.

PubMed

Wong-Goodrich, Sarah J E; Tognoni, Christina M; Mellott, Tiffany J; Glenn, Melissa J; Blusztajn, Jan K; Williams, Christina L

2011-09-21

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. Copyright © 2011 Elsevier B.V. All rights reserved.

1H magnetic resonance spectroscopy metabolite profiles of neonatal rat hippocampus and brainstem regions following early postnatal exposure to intermittent hypoxia

NASA Astrophysics Data System (ADS)

Darnall, Robert A.; Chen, Xi; Nemani, Krishnamurthy V.; Sirieix, Chrystelle M.; Gimi, Barjor

2017-03-01

Most premature infants born at less than 30 weeks gestation are exposed to periods of mild intermittent hypoxia (IH) associated with apnea of prematurity and periodic breathing. In adults, IH associated with sleep apnea causes neurochemical and structural alterations in the brain. However, it is unknown whether IH in the premature infant leads to neurodevelopmental impairment. Quantification of biochemical markers that can precisely identify infants at risk of adverse neurodevelopmental outcome is essential. In vivo 1H magnetic resonance spectroscopy (1H MRS) facilitates the quantification of metabolites from distinct regions of the developing brain. We report the changes in metabolite profiles in the brainstem and hippocampal regions of developing rat brains, resulting from exposure to IH. Rat pups were chosen for study because there is rapid postnatal hippocampal development that occurs during the first 4 weeks in the developing rat brain, which corresponds to the first 2-3 postnatal years of development in humans. The brainstem was examined because of our interest in respiratory control disorders in the newborn and because of brainstem gliosis described in infants who succumb to Sudden Infant Death Syndrome (SIDS). Metabolite profiles were compared between hypoxia treated rat pups (n = 9) and normoxic controls (n = 6). Metabolite profiles were acquired using the Point-RESolved spectroscopy (PRESS) MRS sequence and were quantified using the TARQUIN software. There was a significant difference in the concentrations of creatine (p = 0.031), total creatine (creatine + phosphocreatine) (p = 0.028), and total choline (p = 0.001) in the brainstem, and glycine (p = 0.031) in the hippocampal region. The changes are consistent with altered cellular bioenergetics and metabolism associated with hypoxic insult.

Are newborn rat-derived neural stem cells more sensitive to lead neurotoxicity?★

PubMed Central

Chan, Yan Ho; Gao, Mingyong; Wu, Wutian

2013-01-01

Lead ion (Pb2+) has been proven to be a neurotoxin due to its neurotoxicity on mammalian nervous system, especially for the developing brains of juveniles. However, many reported studies involved the negative effects of Pb2+ on adult neural cells of humans or other mammals, only few of which have examined the effects of Pb2+ on neural stem cells. The purpose of this study was to reveal the biological effects of Pb2+ from lead acetate [Pb (CH3COO)2] on viability, proliferation and differentiation of neural stem cells derived from the hippocampus of newborn rats aged 7 days and adult rats aged 90 days, respectively. This study was carried out in three parts. In the first part, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT viability assay) was used to detect the effects of Pb2+ on the cell viability of passage 2 hippocampal neural stem cells after 48-hour exposure to 0–200 μM Pb2+. In the second part, 10 μM bromodeoxyuridine was added into the culture medium of passage 2 hippocampal neural stem cells after 48-hour exposure to 0–200 μM Pb2+, followed by immunocytochemical staining with anti-bromodeoxyuridine to demonstrate the effects of Pb2+ on cell proliferation. In the last part, passage 2 hippocampal neural stem cells were allowed to grow in the differentiation medium with 0–200 μM Pb2+. Immunocytochemical staining with anti-microtubule-associated protein 2 (a neuron marker), anti-glial fibrillary acidic protein (an astrocyte marker), and anti-RIP (an oligodendrocyte marker) was performed to detect the differentiation commitment of affected neural stem cells after 6 days. The data showed that Pb2+ inhibited not only the viability and proliferation of rat hippocampal neural stem cells, but also their neuronal and oligodendrocyte differentiation in vitro. Moreover, increased activity of astrocyte differentiation of hippocampal neural stem cells from both newborn and adult rats was observed after exposure to high concentration of lead ion in vitro. These findings suggest that hippocampal neural stem cells of newborn rats were more sensitive than those from adult rats to Pb2+ cytotoxicity. PMID:25206702

Effects of pharmacological treatments on hippocampal NCAM1 and ERK2 expression in epileptic rats with cognitive dysfunction

PubMed Central

Kong, Qingxia; Min, Xia; Sun, Ran; Gao, Jianying; Liang, Ruqing; Li, Lei; Chu, Xu

2016-01-01

The present study aimed to investigate the effects of various pharmacological agents on the hippocampal expression of neural cell adhesion molecule 1 (NCAM1) and extracellular signal-regulated kinase 2 (ERK2) in epileptic rats with cognitive dysfunction. The experiments were conducted using 120 Wistar rats: 20 controls and 100 with pilocarpine-induced status epilepticus (SE). The SE rats were randomly assigned to 5 groups (n=20/group) that received daily treatments for 1 month with one of the following: (i) saline (no effect on epilepsy); (ii) carbamazepine (an anticonvulsant); (iii) oxcarbazepine (an anticonvulsant); (iv) aniracetam (a nootropic); or (v) donepezil (an acetylcholinesterase inhibitor). Spatial learning and memory were assessed using a Morris Water Maze (MWM). Hippocampal tissue was assessed for NCAM1 and ERK2 messenger RNA (mRNA) expression by reverse transcription polymerase chain reaction, and protein expression by immunochemistry. The results revealed that SE rats had significantly poorer MWM performances compared with controls (P<0.01). Performance in SE rats was improved with donepezil treatment (P<0.01), but declined with carbamazepine (P<0.01). Compared with controls, saline-treated SE rats exhibited increased hippocampal NCAM1 mRNA expression (P<0.01). Among SE rats, NCAM1 mRNA expression was highest in those treated with donepezil, followed by aniracetam-, saline-, oxcarbazepine- and carbamazepine-treated rats. Compared to controls, saline-treated SE rats exhibited decreased hippocampal ERK2 mRNA expression (P<0.01). Among SE rats, ERK2 mRNA expression was highest in those treated with donepezil, followed by aniracetam, saline, oxcarbazepine and carbamazepine. NCAM1 and ERK2 protein expression levels were parallel to those of the mRNA. In saline-treated SE rats, hippocampal ERK2 expression was decreased and NCAM1 expression was increased; thus, these two molecules may be involved in the impairment of spatial memory. Carbamazepine augmented this impairment, whereas donepezil was found to ameliorate the dysfunction associated with epilepsy. In conclusion, ERK2 and NCAM1 have significant roles in impairment of spatial memory in SE rats. Carbamazepine may increase this impairment, while donepezil may decrease this impairment. PMID:27588125

Unilateral lesion of dorsal hippocampus in adult rats impairs contralateral long-term potentiation in vivo and spatial memory in the early postoperative phase.

PubMed

Li, Hongjie; Wu, Xiaoyan; Bai, Yanrui; Huang, Yan; He, Wenting; Dong, Zhifang

2012-05-01

It is well documented that bilateral hippocampal lesions or unilateral hippocampal lesion at birth causes impairment of contralateral LTP and long-term memory. However, effects of unilateral hippocampal lesion in adults on contralateral in vivo LTP and memory are not clear. We here examined the influence of unilateral electrolytic dorsal hippocampal lesion in adult rats on contralateral LTP in vivo and spatial memory during different postoperative phases. We found that acute unilateral hippocampal lesion had no effect on contralateral LTP. However, contralateral LTP was impaired at 1 week after lesion, and was restored to the control level at postoperative week 4. Similarly, spatial memory was also impaired at postoperative week 1, and was restored at postoperative week 4. In addition, the rats at postoperative week 1 showed stronger spatial exploratory behavior in a novel open-field environment. The sham operation had no effects on contralateral LTP, spatial memory and exploration at either postoperative week 1 or week 4. These results suggest that unilateral dorsal hippocampal lesion in adult rats causes transient contralateral LTP impairment and spatial memory deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats

PubMed Central

Glenn, Melissa J.; Gibson, Erin M.; Kirby, Elizabeth D.; Mellott, Tiffany J.; Blusztajn, Jan K.; Williams, Christina L.

2008-01-01

Increased dietary intake of choline early in life improves performance of adult rats on memory tasks and prevents their age-related memory decline. Because neurogenesis in the adult hippocampus also declines with age, we investigated whether prenatal choline availability affects hippocampal neurogenesis in adult Sprague–Dawley rats and modifies their neurogenic response to environmental stimulation. On embryonic days (ED) 12−17, pregnant rats ate a choline-supplemented (SUP-5 g/kg), choline sufficient (SFF-1.1 g/kg), or choline-free (DEF) semisynthetic diet. Adult offspring either remained in standard housing or were given 21 daily visits to explore a maze. On the last ten exploration days, all rats received daily injections of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg). The number of BrdU+ cells was significantly greater in the dentate gyrus in SUP rats compared to SFF or DEF rats. While maze experience increased the number of BrdU+ cells in SFF rats to the level seen in the SUP rats, this enriching experience did not alter cell proliferation in DEF rats. Similar patterns of cell proliferation were obtained with immunohistochemical staining for neuronal marker doublecortin, confirming that diet and exploration affected hippocampal neurogenesis. Moreover, hippocampal levels of the brain-derived neurotrophic factor (BDNF) were increased in SUP rats as compared to SFF and DEF animals. We conclude that prenatal choline intake has enduring effects on adult hippocampal neurogenesis, possibly via up-regulation of BDNF levels, and suggest that these alterations of neurogenesis may contribute to the mechanism of life-long changes in cognitive function governed by the availability of choline during gestation. PMID:17445242

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

PubMed Central

Wong-Goodrich, Sarah J. E.; Mellott, Tiffany J.; Glenn, Melissa J.; Blusztajn, Jan K.; Williams, Christina L.

2008-01-01

Prenatal choline supplementation (SUP) protects adult rats against spatial memory deficits observed after excitotoxin-induced status epilepticus (SE). To examine the mechanism underlying this neuroprotection, we determined the effects of SUP on a variety of hippocampal markers known to change in response to SE and thought to underlie ensuing cognitive deficits. Adult offspring from rat dams that received either a Control or SUP diet on embryonic days 12–17 were administered saline or kainic acid (i.p.) to induce SE and were euthanized 16 days later. SUP markedly attenuated seizure-induced hippocampal neurodegeneration, dentate cell proliferation, hippocampal GFAP mRNA expression levels, prevented the loss of hippocampal GAD65 protein and mRNA expression, and altered growth factor expression patterns. SUP also enhanced pre-seizure hippocampal levels of BDNF, NGF, and IGF-1, which may confer a neuroprotective hippocampal microenvironment that dampens the neuropathological response to and/or helps facilitate recovery from SE to protect cognitive function. PMID:18353663

Contributions from the animal laboratory-- drug and response inhibition.

PubMed

Iwahara, S

1977-01-01

Recent developments in animal psychopharmacology were reviewed with special reference to our 10-year studies in confirming the disinhibitory theory of chlordiazepoxide in frustrative nonreward (rats), spontaneous alternation (rats), discrimination reversal (rats), successive discrimination (rats), go/no-go type descrimination (rats, monkeys), passive and shuttle avoidance (rats) and differential heart rate conditioning (rats). Although anticholinergics have a similar behavioral function, their sites of action seem to be different because of their effect on the hippocampal electrical activity is markedly distinct from that of chlordiazepoxide.

Damage of hippocampal neurons in rats with chronic alcoholism.

PubMed

Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

2014-09-01

Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

Two organizational effects of pubertal testosterone in male rats: transient social memory and a shift away from long-term potentiation following a tetanus in hippocampal CA1.

PubMed

Hebbard, Pamela C; King, Rebecca R; Malsbury, Charles W; Harley, Carolyn W

2003-08-01

The organizational role of pubertal androgen receptor (AR) activation in synaptic plasticity in hippocampal CA1 and in social memory was assessed. Earlier data suggest pubertal testosterone reduces adult hippocampal synaptic plasticity. Four groups were created following gonadectomy at the onset of puberty: rats given testosterone; rats given testosterone but with the AR antagonist flutamide, present during puberty; rats given testosterone at the end of puberty; and rats given cholesterol at the end of puberty. A tetanus normally inducing long-term potentiation (LTP) was used to stimulate CA1 in the urethane-anesthetized adults during the dark phase of their cycle. Social memory was assessed prior to electrophysiology. Social memory for a juvenile rat at 120 min was seen only in rats not exposed to AR activation during puberty. Pubertal AR activation may induce the reduced social memory of male rats. Early CA1 LTP occurred following tetanus in rats with no pubertal testosterone. Short-term potentiation occurred in rats exposed to pubertal testosterone. Unexpectedly, rats with pubertal AR activation developed long-term depression (LTD). The same pattern was seen in normal male rats. Lack of LTP during the dark phase is consistent with other data on circadian modulation of CA1 LTP. No correlations were seen among social memory scores and CA1 plasticity measures. These data argue for two organizational effects of pubertal testosterone: (1) CA1 synaptic plasticity shifts away from potentiation toward depression; (2) social memory is reduced. Enduring effects of pubertal androgen on limbic circuits may contribute to reorganized behaviors in the postpubertal period.

[Effects of Electroacupuncture Intervention on Oxygen Free Radicals and Expression of Apoptosis-related Proteins in Rats with Ischemic Learning and Memory Disorder].

PubMed

Hou, Zhi-tao; Sun, Zhong-ren; Liu, Song-tao; Xiong, Sheng-biao; Liu, Yi-tian; Han, Xiao-xia; Sun, Hong-fang; Han, Yu-sheng; Yin, Hong-na; Xu, Jin-qiao; Li, Dong-dong

2015-12-01

To observe the effect of electroacupuncture (EA) therapy on levels of oxygen free radicals (OFR) and hippocampal apoptosis-related protein expression in ischemic learning-memory disorder rats so as to investigate its mechanisms underlying improvement of ischemic learning-memory impairment. A total of 60 SD rats were randomly divided into sham operation (sham), model, medication, and EA groups, with 15 rats in each group. The learning-memory disorder model was made by occlusion of bilateral carotid arteries. EA (2- 3 Hz, 2 mA) was applied to "Zhi San Zhen" ["Shenting" (GV 24) and bilateral "Benshen" (GB 13)] for 30 min, once a day for 3 weeks. The rats of the medication group were treated by lavage of Aricept (0.03 mg . kg(-1) . d(-1)), once daily for 3 weeks. The rats' learning-memory ability was detected by Morris water maze tests and the state of hippocampal apoptosis cells was observed by light microscope after TUNEL staining and the expression of hippocampal Bcl-2, Bax and Caspase-3 proteins was detected by immunohistochemistry. Serum and hippocampal superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) contents were detected by chemical colorimetric analysis. Compared with the sham group, the escape latencies (place-navigation) after modeling were evidently prolonged, and the times of target-platform crossing in 90 sec (spatial probe test) considerably reduced in the model group (P<0.01), suggesting an impairment of learning-memory ability. After the treatment for 21 d, the increased escape latency and the reduced target-platform crossing time in both EA and medication groups were reversed in comparison with the model group (P<0.01), suggesting an improvement of memory ability, and the effect of the EA group was significantly superior to that of the medication group (P<0.05). Compared with the sham group, the number of apoptotic cells in hippocampal CA 1- CA 3 regions, and the expression levels of hippocampal Bcl-2, Bax and Caspase-3 proteins, and serum and hippocampal MDA contents were significantly increased in the model group (P<0.01), while serum and hippocampal SOD and GSH-Px levels obviously decreased in the model group (P<0.01). After the treatment for 21 days, compared to the model group, the number of the apoptotic cells, the expression levels of hippocampal Bax and Caspase--3 proteins, and the contents of serum and hippocampal MDA were notably decreased in the EA and medication groups (P<0.01), whereas, Bcl-2 protein expression levels, and serum and hippocampal SOD and GSH-Px activity were notably up-regulated in the EA and medication groups (P<0.01). The effects of EA group were obviously superior to those of medication group in increasing hippocampal Bcl-2 immunoactivity, serum SOD and GSH-Px and hippocampal GSH-Px activity and in down-regulating serum MDA level (P<0.01, P<0.05). Electroacupuncture intervention can improve learning-memory ability in ischemic learning-memory disorder rats which may be associated with its effects in reducing blood and hippocampal OFR contents and hippocampal cellular apoptosis.

The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones.

PubMed

Gould, E; Woolley, C S; McEwen, B S

1991-01-01

The hippocampal formation is of considerable interest due to its proposed role in a number of important functions, including learning and memory processes. Manipulations of thyroid, gonadal and adrenal hormones have been shown to influence hippocampal physiology as well as learning and memory. The cellular events which underlie these hormone-induced functional changes are largely unexplored. However, studies suggest that hormonal manipulations during development and in adulthood result in dramatic morphological changes within the hippocampal formation. Because neuronal physiology has been suggested to depend upon neuronal morphology, we have been determining the morphologic sensitivity of hippocampal neurons to thyroid and steroid hormones in an effort to elucidate possible structural mechanisms to account for differences in hippocampal function. In this review, hormone-induced structural changes in the developing and adult hippocampal formation are discussed, with particular emphasis on their functional relevance. Sex differences, as well as the developmental effects of thyroid hormone and glucocorticoids, are described. Moreover, the effects of ovarian steroids, thyroid hormone and glucocorticoids on neuronal morphology in the hippocampal formation of the adult rat are reviewed. These hormone-induced structural changes may account, at least in part, for previously reported hormone-induced changes in hippocampal function.

Gel-Based Hippocampal Proteomic Analysis 2 Weeks following Traumatic Brain Injury to Immature Rats Using Controlled Cortical Impact

PubMed Central

Kochanek, Ashley R.; Kline, Anthony E.; Gao, Wei-Min; Chadha, Mandeep; Lai, Yichen; Clark, Robert S.B.; Dixon, C. Edward; Jenkins, Larry W.

2009-01-01

Traumatic brain injury (TBI) to postnatal day 17 rats has been shown to produce acute changes in hippocampal global protein levels and spatial learning and memory deficits. The purpose of the present study was to analyze global hippocampal protein changes 2 weeks after a moderate ipsilateral controlled cortical impact in postnatal day 17 rats using 2-dimensional difference gel electrophoresis and mass spectrometry. Paired sham and ipsilateral injured hippocampal lysates were independently labeled with different fluorescent cyanine dyes and coseparated within the same immobilized pH gradient strips and slab gel based on isoelectric point and molecular mass. Significant changes in key proteins involved in glial and neuronal stress, oxidative metabolism, calcium uptake and neurotransmitter function were found 2 weeks after injury, and their potential roles in hippocampal plasticity and cognitive dysfunction were discussed. PMID:16943664

Mapping parahippocampal systems for recognition and recency memory in the absence of the rat hippocampus

PubMed Central

Kinnavane, L; Amin, E; Horne, M; Aggleton, J P

2014-01-01

The present study examined immediate-early gene expression in the perirhinal cortex of rats with hippocampal lesions. The goal was to test those models of recognition memory which assume that the perirhinal cortex can function independently of the hippocampus. The c-fos gene was targeted, as its expression in the perirhinal cortex is strongly associated with recognition memory. Four groups of rats were examined. Rats with hippocampal lesions and their surgical controls were given either a recognition memory task (novel vs. familiar objects) or a relative recency task (objects with differing degrees of familiarity). Perirhinal Fos expression in the hippocampal-lesioned groups correlated with both recognition and recency performance. The hippocampal lesions, however, had no apparent effect on overall levels of perirhinal or entorhinal cortex c-fos expression in response to novel objects, with only restricted effects being seen in the recency condition. Network analyses showed that whereas the patterns of parahippocampal interactions were differentially affected by novel or familiar objects, these correlated networks were not altered by hippocampal lesions. Additional analyses in control rats revealed two modes of correlated medial temporal activation. Novel stimuli recruited the pathway from the lateral entorhinal cortex (cortical layer II or III) to hippocampal field CA3, and thence to CA1. Familiar stimuli recruited the direct pathway from the lateral entorhinal cortex (principally layer III) to CA1. The present findings not only reveal the independence from the hippocampus of some perirhinal systems associated with recognition memory, but also show how novel stimuli engage hippocampal subfields in qualitatively different ways from familiar stimuli. PMID:25264133

Age-Related Memory Impairment Associated With Decreased Endogenous Estradiol in the Hippocampus of Female Rats.

PubMed

Chamniansawat, Siriporn; Sawatdiyaphanon, Chattraporn

It is widely known that not only the gonadal estradiol (E2) but also hippocampal E2 plays an essential role in memory process. However, the role of hippocampal E2-enhanced memory mechanism during aging is largely unknown. The aim of the present study was to investigate the effect of age on E2 concentration, the expression level of its receptors, and key steroidogenic enzymes in hippocampus. We also investigated the effect of microglia activation on E2 synthesis in hippocampal neurons. The results showed that serum E2 was higher in 19-month-old (aged) rats, which exhibited spatial memory decline in the Morris water maze (MWM) test when compared to the younger rats. Hence, serum E2 may not be associated with the reduced spatial memory performance in aging. In contrast, the level of E2 and the expressions of its receptors were significantly decreased in hippocampus of aged female rat compared to younger females. Furthermore, the expressions of key hippocampal steroidogenic enzymes, steroidogenic acute regulatory protein (StAR), and cytochrome P450 (P450) also significantly decreased with age, which resulted in lower hippocampal E2 levels. In addition, we found that the microglia of aged brain highly expressed interleukin 6 (IL-6), which directly inhibited E2 synthesis in hippocampal neurons via suppression of P450 synthesis. Taken together, we summarized that the microglia-derived IL-6 inhibited hippocampal E2 synthesis in aged rats which, in turn, contributed to the deficit of spatial memory performance.

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

Effect of agmatine on long-term potentiation in morphine-treated rats.

PubMed

Lu, Wei; Dong, Hua-Jin; Bi, Guo-Hua; Zhao, Yong-Qi; Yang, Zheng; Su, Rui-Bin; Li, Jin

2010-08-01

Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5-10mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor. Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.

Neonatal infection produces significant changes in immune function with no associated learning deficits in juvenile rats.

PubMed

Osborne, Brittany F; Caulfield, Jasmine I; Solomotis, Samantha A; Schwarz, Jaclyn M

2017-10-01

The current experiments examined the impact of early-life immune activation and a subsequent mild immune challenge with lipopolysaccharide (LPS; 25µg/kg) on hippocampal-dependent learning, proinflammatory cytokine expression in the brain, and peripheral immune function in juvenile male and female rats at P24, an age when hippocampal-dependent learning and memory first emerges. Our results indicate that neonatal infection did not produce learning deficits in the hippocampal-dependent context pre-exposure facilitation effect paradigm in juvenile males and females, contrary to what has been observed in adults. Neonatal infection produced an increase in baseline IL-1β expression in the hippocampus (HP) and medial prefrontal cortex (mPFC) of juvenile rats. Furthermore, neonatally infected rats showed exaggerated IL-1β expression in the HP following LPS treatment as juveniles; and juvenile females, but not males, showed exaggerated IL-1β expression in the mPFC following LPS treatment. Neonatal infection attenuated the production of IL-6 expression following LPS treatment in both the brain and the spleen, and neonatal infection decreased the numbers of circulating white blood cells in juvenile males and females, an effect that was further exacerbated by subsequent LPS treatment. Together, our data indicate that the consequences of neonatal infection are detectable even early in juvenile development, though we found no concomitant hippocampal-dependent learning deficits at this young age. These findings underscore the need to consider age and associated on-going neurodevelopmental processes as important factors contributing to the emergence of cognitive and behavioral disorders linked to early-life immune activation. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1221-1236, 2017. © 2017 Wiley Periodicals, Inc.

Early developmental bisphenol-A exposure sex-independently impairs spatial memory by remodeling hippocampal dendritic architecture and synaptic transmission in rats

NASA Astrophysics Data System (ADS)

Liu, Zhi-Hua; Ding, Jin-Jun; Yang, Qian-Qian; Song, Hua-Zeng; Chen, Xiang-Tao; Xu, Yi; Xiao, Gui-Ran; Wang, Hui-Li

2016-08-01

Bisphenol-A (BPA, 4, 4‧-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARβ2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARβ2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment.

Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling

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

Ni, Cheng; Li, Zhengqian; Qian, Min

Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased andmore » peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD. - Highlights: • Isoflurane induces hippocampal calcineurin activation. • Isoflurane induces hippocampal NFAT, especially NFATc4, nuclear import. • Cyclosporine A attenuates isoflurane induced aberrant calcineurin/NFAT signaling. • Cyclosporine A rescues isoflurane induced cognitive impairment. • Calcineurin/NFAT signaling is the upstream mechanism of isoflurane induced synaptic dysfunction and cognitive impairment.« less

Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

PubMed Central

García-Fuster, M. Julia; Parsegian, Aram; Watson, Stanley J.; Akil, Huda; Flagel, Shelly B.

2018-01-01

Rationale Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered “addiction-prone”, whereas bLR rats are “addiction-resilient”, at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to “sign-track”. Objectives We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e. sign- vs. goal-tracking) and hippocampal neurogenesis. Methods bHR and bLR rats were administered cocaine (15 mg/kg) or saline for 7 days during adolescence (postnatal day, PND 33–39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62–75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed towards the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry. Results Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats. Conclusions Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats. PMID:28210781

Blocking GABA-A receptors in the Medial Septum Enhances Hippocampal Acetylcholine Release and Behavior in a Rat Model of Diencephalic Amnesia

PubMed Central

Roland, Jessica J.; Savage, Lisa M.

2009-01-01

Wernicke-Korsakoff syndrome (WKS), a form of diencephalic amnesia caused by thiamine deficiency, results in severe anterograde memory loss. Pyrithiamine-induced thiamine deficiency (PTD), an animal model of WKS, produces cholinergic abnormalities including decreased functional hippocampal acetylcholine (ACh) release and poor spatial memory. Increasing hippocampal ACh levels has increased performance in PTD animals. Intraseptal bicuculline (GABAA antagonist) augments hippocampal ACh release in normal animals and we found it (0.50μg/μl & 0.75μg/μl) also increased in-vivo hippocampal ACh release in PTD animals. However, the 0.75 μg/μl dose produced a greater change in hippocampal ACh release in control animals. The 0.50μg/μl dose of bicuculline was then selected to determine if it could enhance spontaneous alternation performance in PTD animals. This dose of bicuculline significantly increased hippocampal ACh levels above baseline in both PTD and control rats and resulted in complete behavioral recovery in PTD animals, without altering performance in control rats. This suggests that balancing ACh-GABA interactions in the septohippocampal circuit may be an effective therapeutic approach in certain amnestic syndromes. PMID:19463263

Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.

PubMed

Li, Fang; Yan, Chao-Qun; Lin, Li-Ting; Li, Hui; Zeng, Xiang-Hong; Liu, Yi; Du, Si-Qi; Zhu, Wen; Liu, Cun-Zhi

2015-04-28

Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P < 0.05) and tended to decrease the number of astrocytes (P = 0.063). However, there was no significant change in the synaptic bouton number of hippocampal CA1 area in any of the groups (P > 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.

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.

Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats.

PubMed

Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong

2017-05-01

One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT 3 receptor in the development of PTSD, even though 5-HT 3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT 3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT 3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT 3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT 3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT 3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

[A study of complexity and power spectrum of cortical EEG and hippocampal potential in rats under different behavioral states].

PubMed

Feng, Zhou-yan; Zheng, Xiao-xiang

2002-08-01

Objective. To study the complexity and the power spectrum of cortical EEG and hippocampal potential in rats under waking and sleep states. Method. Cortical EEG and hippocampal potential were collected by implanted electrodes in freely moving rats. Algorithmic complexity (Kc), approximate entropy (ApEn), power spectral density (PSD) and gravity frequency of PSD of the potential waves were calculated. Result. The complexity of hippocampal potential was higher than that of cortical EEG under every state. The complexity of cortical EEG was lowest under the state of non rapid eye movement (NREM) sleep. The complexity of hippocampal potential was highest under waking state. The total power of both potentials in 0.5- 30 Hz frequency band showed their highest values under NREM state. Conclusion. The values of Kc and ApEn are closely related to the distributions of PSD. When there are evident peaks in PSD, the complexities of signals will decrease. The complexities may be used to distinguish the difference between cortical EEG and hippocampal potential, or large differences between the same kind of potentials under different behavioral states.

Enhanced sequential reaction time task performance in a rat model of mesial temporal lobe epilepsy with classic hippocampal sclerosis.

PubMed

Will, Johanna L; Eckart, Moritz T; Rosenow, Felix; Bauer, Sebastian; Oertel, Wolfgang H; Schwarting, Rainer K W; Norwood, Braxton A

2013-06-15

The human serial reaction time task (SRTT) has widely been used to study the neural basis of implicit learning. It is well documented, in both human and animal studies, that striatal dopaminergic processes play a major role in this task. However, findings on the role of the hippocampus - which is mainly associated with declarative memory - in implicit learning and performance are less univocal. We used a SRTT to evaluate implicit learning and performance in rats with perforant pathway stimulation-induced hippocampal neuron loss; a clinically-relevant animal model of mesial temporal lobe epilepsy (MTLS-HS). As has been previously reported for the Sprague-Dawley strain, 8h of continuous stimulation in male Wistar rats reliably induced widespread neuron loss in areas CA3 and CA1 with a characteristic sparing of CA2 and the granule cells. Histological analysis revealed that hippocampal volume was reduced by an average of 44%. Despite this severe hippocampal injury, rats showed superior performance in our instrumental SRTT, namely shorter reaction times, and without a loss in accuracy, especially during the second half of our 16-days testing period. These results demonstrate that a hippocampal lesion can improve performance in a rat SRTT, which is probably due to enhanced instrumental performance. In line with our previous findings based on ibotenic-acid induced hippocampal lesion, these data support the hypothesis that loss or impairment of hippocampal function can enhance specific task performance, especially when it is dependent on procedural (striatum-dependent) mechanisms with minimal spatial requirements. As the animal model used here exhibits the defining characteristics of MTLE-HS, these findings may have implications for the study and management of patients with MTLE. Copyright © 2013 Elsevier B.V. All rights reserved.

MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

PubMed

Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

2017-03-15

Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

Neuroprotective effect and mechanism of daucosterol palmitate in ameliorating learning and memory impairment in a rat model of Alzheimer's disease.

PubMed

Ji, Zhi-Hong; Xu, Zhong-Qi; Zhao, Hong; Yu, Xin-Yu

2017-03-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory decline and cognitive impairment. Amyloid beta (Aβ) has been proposed as the causative role for the pathogenesis of AD. Accumulating evidence demonstrates that Aβ neurotoxicity is mediated by glutamate excitotoxicity. Daucosterol palmitate (DSP), a plant steroid with anti-glutamate excitotoxicity effect, was isolated from the anti-aging traditional Chinese medicinal herb Alpinia oxyphylla Miq. in our previous study. Based on the anti-glutamate excitotoxicity effect of DSP, in this study we investigated potential benefit and mechanism of DSP in ameliorating learning and memory impairment in AD model rats. Results from this study showed that DSP administration effectively ameliorated Aβ-induced learning and memory impairment in rats, markedly inhibited Aβ-induced hippocampal ROS production, effectively prevented Aβ-induced hippocampal neuronal damage and significantly restored hippocampal synaptophysin expression level. This study suggests that DSP may be a potential candidate for development as a therapeutic agent for AD cognitive decline. Copyright © 2017 Elsevier Inc. All rights reserved.

Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

PubMed Central

Tong, Jian-Bin; Wong, Richard; Ching, Yick-Pang; Qiu, Guang; Tang, Siu-Wa; Lee, Tatia M. C.; So, Kwok-Fai

2011-01-01

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress. PMID:21935393

Treatment Planning and Delivery of Whole Brain Irradiation with Hippocampal Avoidance in Rats.

PubMed

Cramer, C K; Yoon, S W; Reinsvold, M; Joo, K M; Norris, H; Hood, R C; Adamson, J D; Klein, R C; Kirsch, D G; Oldham, M

2015-01-01

Despite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats. The technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5 cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13 mA filtered through 0.3 mm of copper using a 40x40 mm square collimator and the lead blocks. A single fraction of 4 Gy was delivered (2 Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4 Gy fraction either with or without HA using γ-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls). The mean dose delivered to radiochromic film beneath the hippocampal block was 0.52 Gy compared to 3.93 Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from γ-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012). Despite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique.

Elevation of naloxone-sensitive /sup 3/H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats

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

Savage, D.D.; Mills, S.A.; Jobe, P.C.

1988-01-01

/sup 3/H-Dihydromorphine (DHM) binding sites were measured in the brain of non-epileptic control and GEPR rats using in vitro autoradiographic techniques. The number of naloxone-sensitive /sup 3/H-DHM binding sites was increased 38-57% in the pyramidal cell layer of ventral hippocampal CA/sub 3/ and CA/sub 1/ of GEPR-3 and GEPR-9 rats compared to non-epileptic controls. No significant differences in /sup 3/H-DHM binding were observed in dorsal hippocampal formation, lateral entorhinal cortex, lateral geniculate or cerebellum. The results suggest that an increase in the number of opioid receptors in ventral hippocampus of GEPR rats may be one factor contributing to the enhancedmore » sensitivity of GEPR-9 rats to the proconvulsant effects of morphine.« less

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 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.

Different patterns of morphological changes in the hippocampus and dentate gyrus accompany the differential expression of disability following nerve injury.

PubMed

Kalman, Eszter; Keay, Kevin A

2014-12-01

Physical and psychological trauma which results in mood disorders and the disruption of complex behaviours is associated with reductions in hippocampal volume. Clinical evaluation of neuropathic pain reveals mood and behavioural change in a significant number of patients. A rat model of neuropathic injury results in complex behavioural changes in a subpopulation (~30%) of injured rats; these changes are co-morbid with a range of other 'disabilities'. The specific objective of this study was to determine in rats the morphology of the hippocampus and dentate gyrus in individuals with and without complex behavioural disruptions following a constriction injury of the sciatic nerve, and to determine whether rats that develop disabilities following nerve injury have a reduced hippocampal volume compared with injured rats with no disabilities. The social behaviours of nerve-injured rats were evaluated before and after nerve injury. The morphology of the hippocampus of rats with and without behavioural disruptions was compared in serial histological sections. Single-housing and repeated social-interaction testing had no effect on the morphology of either the hippocampus or the dentate gyrus. Rats with transient or ongoing disability identified by behavioural disruption following sciatic nerve injury, show bilateral reductions in hippocampal volume, and lateralised reduction in the dentate gyrus (left side). Disabled rats display a combination of behavioural and physiological changes, which resemble many of the criteria used clinically to diagnose mood disorders. They also show reductions in the volume of the hippocampus similar to people with clinically diagnosed mood disorders. The sciatic nerve injury model reveals a similarity to the human neuropathic pain presentation presenting an anatomically specific focus for the investigation of the neural mechanisms underpinning the co-morbidity of chronic pain and mood disorder. © 2014 Anatomical Society.

Gonadal Steroids: Effects on Excitability of Hippocampal Pyramidal Cells

NASA Astrophysics Data System (ADS)

Teyler, Timothy J.; Vardaris, Richard M.; Lewis, Deborah; Rawitch, Allen B.

1980-08-01

Electrophysiological field potentials from hippocampal slices of rat brain show sex-linked differences in response to 1 × 10-10M concentrations of estradiol and testosterone added to the incubation medium. Slices from male rats show increased excitability to estradiol and not to testosterone. Slices from female rats are not affected by estradiol, but slices from female rats in diestrus show increased excitability in response to testosterone whereas slices from females in proestrus show decreased excitability.

Spatial memory: a Rosetta stone for rat and human hippocampal discourse: Theoretical comment on Goodrich-Hunsaker and Hopkins (2010).

PubMed

Sutherland, Robert J

2010-06-01

The article by Goodrich-Hunsaker and Hopkins (2010, this issue) takes up an important place among in the recent contributions on the role of the hippocampus in memory. They evaluate the effect of bilateral damage to the hippocampus on performance by human participants in a virtual 8-arm radial maze. The hippocampal damage appears to be highly selective and nearly complete. Exactly as with selective hippocampal damage in rats, the human participants showed a deficit in accurately choosing rewarded versus never-rewarded arms and a deficit in avoiding reentering recently visited arms. The results are triply significant: (1) They provide good support for the idea that the wealth of neurobiological information, from network to synapse to gene, on spatial memory in the rat may apply as a whole to the human hippocampal memory system; (2) They affirm the utility of human virtual task models of rat spatial memory tasks; (3) They support one interpretation of the dampening of the hippocampal functional MRI (fMRI) blood oxygen level-dependent (BOLD) signal during performance of the virtual radial arm maze observed by Astur et al. (2005).

Insulin-like growth factor 2 rescues aging-related memory loss in rats.

PubMed

Steinmetz, Adam B; Johnson, Sarah A; Iannitelli, Dylan E; Pollonini, Gabriella; Alberini, Cristina M

2016-08-01

Aging is accompanied by declines in memory performance, and particularly affects memories that rely on hippocampal-cortical systems, such as episodic and explicit. With aged populations significantly increasing, the need for preventing or rescuing memory deficits is pressing. However, effective treatments are lacking. Here, we show that the level of the mature form of insulin-like growth factor 2 (IGF-2), a peptide regulated in the hippocampus by learning, required for memory consolidation and a promoter of memory enhancement in young adult rodents, is significantly reduced in hippocampal synapses of aged rats. By contrast, the hippocampal level of the immature form proIGF-2 is increased, suggesting an aging-related deficit in IGF-2 processing. In agreement, aged compared to young adult rats are deficient in the activity of proprotein convertase 2, an enzyme that likely mediates IGF-2 posttranslational processing. Hippocampal administration of the recombinant, mature form of IGF-2 rescues hippocampal-dependent memory deficits and working memory impairment in aged rats. Thus, IGF-2 may represent a novel therapeutic avenue for preventing or reversing aging-related cognitive impairments. Copyright © 2016 Elsevier Inc. All rights reserved.

Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor.

PubMed

McFadden, Lisa M; Vieira-Brock, Paula L; Hanson, Glen R; Fleckenstein, Annette E

2014-08-01

Preclinical studies suggest that prior treatment with escalating doses of methamphetamine (METH) attenuates the persistent deficits in hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) function resulting from a subsequent 'binge' METH exposure. Previous work also demonstrates that brain-derived neurotrophic factor (BDNF) exposure increases SERT function. The current study investigated changes in hippocampal BDNF protein and SERT function in rats exposed to saline or METH self-administration prior to a binge exposure to METH or saline. Results revealed that METH self-administration increased hippocampal mature BDNF (mBDNF) immunoreactivity compared to saline-treated rats as assessed 24 h after the start of the last session. Further, mBDNF immunoreactivity was increased and SERT function was not altered in rats that self-administered METH prior to the binge METH exposure as assessed 24 h after the binge exposure. These results suggest that prior exposure to contingent METH increases hippocampal mBDNF, and this may contribute to attenuated deficits in SERT function.

Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis - related proteins in a rat model of post-traumatic stress disorder.

PubMed

Shafia, Sakineh; Vafaei, Abbas Ali; Samaei, Seyed Afshin; Bandegi, Ahmad Reza; Rafiei, Alireza; Valadan, Reza; Hosseini-Khah, Zahra; Mohammadkhani, Raziyeh; Rashidy-Pour, Ali

2017-03-01

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. Currently, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are the first-line choice in PTSD drug treatment but their moderate response rates and side effects indicate an urgent need for the development of new treatment. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. The present study investigated the effects of moderate treadmill exercise, the antidepressant fluoxetine and the combined treatment on behavioural deficits, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We also examined alternations in hippocampal brain-derived neurotrophic factor (BDNF) and mRNA expression of apoptosis - related proteins in a rat model of PTSD: the single prolonged stress (SPS) model. Rats were exposed to SPS (restraint for 2h, forced swimming for 20min and ether anaesthesia) and were then kept undisturbed for 14days. After that, SPS rats were subjected to chronic treatment with fluoxetine (10mg/kg/day, for 4weeks), moderate treadmill running (4weeks, 5day per week) and the combined treatment (fluoxetine plus treadmill exercise), followed by behavioural, biochemical and apoptosis markers assessments. SPS rats exhibited increased anxiety levels in the elevated plus maze and light/dark box, impaired fear conditioning and extinction in inhibitory avoidance (IA) task, impaired spatial memory in a recognition location memory task and enhanced negative feedback on the HPA axis following a dexamethasone suppression test. SPS rats also showed reduced hippocampal BDNF and enhanced apoptosis. Moderate treadmill exercise, fluoxetine and the combined treatment alleviated the SPS-induced alterations in terms of anxiety levels, HPA axis inhibition, IA conditioning and extinction, hippocampal BDNF and apoptosis markers. Furthermore, the combined treatment was more effective than fluoxetine alone, but in most tests, the effects of the combined treatment were similar to those of exercise alone, suggesting that exercise is the main factor in the beneficial effects of the combined therapy in PTSD patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Agmatine inhibits chronic morphine exposure-induced impairment of hippocampal neural progenitor proliferation in adult rats.

PubMed

Liu, Ying; Lu, Guan-Yi; Chen, Wen-Qiang; Li, Yun-Feng; Wu, Ning; Li, Jin

2018-01-05

Our previous studies have shown that agmatine inhibited opioid dependence, yet the neural mechanism remains unclear. Growing evidence showed that opioids decrease neurogenesis in the adult hippocampal subgranular zone by inhibiting neural progenitor proliferation. However, whether agmatine affects chronic opioid exposure-induced impairment to hippocampal neural progenitor cell proliferation remains unknown. In the present study, we investigated the role of agmatine in hippocampal neural progenitors in morphine dependence rats. We found that chronic administration of morphine for 12 days induced morphine dependence in rats. This treatment not only decreased the proliferation of hippocampal neural progenitors in the granule cell layer, but also decreased the levels of hippocampal cAMP, pCREB and BDNF. However, these alterations can be restored to normal levels by co-treatment of agmatine (10mg/kg, s.c.). In vitro treatment with agmatine (10µM) for two days significantly increased proliferation of the cultured hippocampal neural progenitors. Concurrent treatment of agmatine (10µM) with morphine (10 or 50µM) reversed the supression of morphine-induced neural progenitor proliferation. In conclusion, we found that agmatine abolished chronic morphine-induced decrease in proliferation of hippocampal progenitors in vivo and in vitro, which may be due to the increase in cAMP-CREB-BDNF signaling. The enhancement of agmatine to proliferation of hippocampal progenitors may be one of the important mechanisms involved in the inhibition of morphine dependence by agmatine. Copyright © 2017. Published by Elsevier B.V.

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

Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

PubMed

Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

2017-08-01

The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

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.

BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs.

PubMed

Lipska, B K; Khaing, Z Z; Weickert, C S; Weinberger, D R

2001-07-01

Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions.

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

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

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.

Early-life sugar consumption has long-term negative effects on memory function in male rats.

PubMed

Noble, Emily E; Hsu, Ted M; Liang, Joanna; Kanoski, Scott E

2017-09-25

Added dietary sugars contribute substantially to the diet of children and adolescents in the USA, and recent evidence suggests that consuming sugar-sweetened beverages (SSBs) during early life has deleterious effects on hippocampal-dependent memory function. Here, we test whether the effects of early-life sugar consumption on hippocampal function persist into adulthood when access to sugar is restricted to the juvenile/adolescent phase of development. Male rats were given ad libitum access to an 11% weight-by-volume sugar solution (made with high fructose corn syrup-55) throughout the adolescent phase of development (post-natal day (PN) 26-56). The control group received a second bottle of water instead, and both groups received ad libitum standard laboratory chow and water access throughout the study. At PN 56 sugar solutions were removed and at PN 175 rats were subjected to behavioral testing for hippocampal-dependent episodic contextual memory in the novel object in context (NOIC) task, for anxiety-like behavior in the Zero maze, and were given an intraperitoneal glucose tolerance test. Early-life exposure to SSBs conferred long-lasting impairments in hippocampal-dependent memory function later in life- yet had no effect on body weight, anxiety-like behavior, or glucose tolerance. A second experiment demonstrated that NOIC performance was impaired at PN 175 even when SSB access was limited to 2 hours daily from PN 26-56. Our data suggest that even modest SSB consumption throughout early life may have long-term negative consequences on memory function during adulthood.

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats.

PubMed

Tong, Jia-Qing; Zhang, Jun; Hao, Ming; Yang, Ju; Han, Yu-Fei; Liu, Xiao-Jie; Shi, Hui; Wu, Mei-Na; Liu, Qing-Song; Qi, Jin-Shun

2015-07-01

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1μg) effectively alleviated Aβ1-42 (20μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1-42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP. Copyright © 2015 Elsevier Inc. All rights reserved.

High-frequency electroacupuncture evidently reinforces hippocampal synaptic transmission in Alzheimer's disease rats

PubMed Central

Li, Wei; Kong, Li-hong; Wang, Hui; Shen, Feng; Wang, Ya-wen; Zhou, Hua; Sun, Guo-jie

2016-01-01

The frequency range of electroacupuncture in treatment of Alzheimer's disease in rats is commonly 2–5 Hz (low frequency) and 50–100 Hz (high frequency). We established a rat model of Alzheimer's disease by injecting β-amyloid 1–42 (Aβ1–42) into the bilateral hippocampal dentate gyrus to verify which frequency may be better suited in treatment. Electroacupuncture at 2 Hz or 50 Hz was used to stimulate Baihui (DU20) and Shenshu (BL23) acupoints. The water maze test and electrophysiological studies demonstrated that spatial memory ability was apparently improved, and the ranges of long-term potentiation and long-term depression were increased in Alzheimer's disease rats after electroacupuncture treatment. Moreover, the effects of electroacupuncture at 50 Hz were better than that at 2 Hz. These findings suggest that high-frequency electroacupuncture may enhance hippocampal synaptic transmission and potentially improve memory disorders in Alzheimer's disease rats. PMID:27335565

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.

Cognitive differences between Sprague-Dawley rats selectively bred for sensitivity or resistance to diet induced obesity.

PubMed

Gurung, Sunam; Agbaga, Martin-Paul; Myers, Dean A

2016-09-15

Epidemiological studies have shown strong correlations between high fat diets, diet-induced obesity and cognitive impairment, primarily focusing on cognitive defects after the onset of obesity. A remaining question is whether cognitive impairment precedes obesity in individuals metabolically prone to diet-induced obesity. The inbred diet-induced obesity sensitive (DIO) and resistant (DR) strains of Sprague-Dawley rats serve as models for human polygenic obesity. DIO rats become overweight on a standard rat chow and have metabolic symptoms similar to overweight humans. We hypothesized that cognitive impairment pre-exists in adult male DIO rats prior to exposure to high fat diet. Male DIO and DR rats were fed a standard rat chow diet from 4 through 20 weeks of age and subjected to the Morris water maze at 12 weeks of age. At 5 and 20 weeks of age, brains of DIO and DR males were examined for indices of inflammation, lipid peroxidation and neuroproliferation. DIO rats showed significant memory impairment on water maze and increased indices of hippocampal inflammation at 20 weeks of age compared to DR rats. At 5 weeks of age, DIO rats exhibited significantly less neural progenitor cell (NPCs) proliferation in the dentate gyrus and increased hippocampal lipid peroxidation compared to DR rats. Therefore, we conclude that DIO rats exhibit early post-weaning indices of hippocampal inflammation, lipid peroxidation and decreased NPC proliferation, as well as impaired hippocampal dependent memory by early adulthood suggesting that inherent metabolic differences predispose the DIO strain to cognitive deficit prior to exposure to high fat diet and/or obesity. Copyright © 2016. Published by Elsevier B.V.

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.

The Role of the Two-Pore Domain Potassium Channel TREK-1 in the Therapeutic Effects of Escitalopram in a Rat Model of Poststroke Depression.

PubMed

Lin, Dai-Hua; Zhang, Xiang-Rong; Ye, Dong-Qing; Xi, Guang-Jun; Hui, Jiao-Jie; Liu, Shan-Shan; Li, Lin-Jiang; Zhang, Zhi-Jun

2015-06-01

Poststroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. TREK-1, a two-pore-domain potassium channel, has been implicated in the pathogenesis of stroke and depression. The aim of this study was to investigate whether TREK-1 plays a role in the therapeutic effects of the selective serotonin reuptake inhibitor (SSRI) escitalopram in a rat PSD model. The whole-cell patch-clamp technique was performed to assess the effect of escitalopram on recombinant TREK-1 currents in HEK293 cells. The expression of TREK-1 mRNA and protein was measured in the hippocampus and prefrontal cortex (PFC), and neural stem cell (NSC) proliferation was detected in the hippocampal dentate gyrus (DG) in PSD rats after 3 weeks of escitalopram administration. Escitalopram reversibly inhibited TREK-1 currents in a concentration-dependent manner. Chronic treatment with escitalopram significantly reversed the reductions in weight gain, locomotor activity, and sucrose preference in PSD rats. The expressions of TREK-1 mRNA and protein were significantly increased in hippocampal CA1, CA3, DG, and PFC in PSD rats, with the exception of TREK-1 mRNA in hippocampal CA1. NSC proliferation was significantly decreased in hippocampal DG of PSD rats. Escitalopram significantly reversed the regional increases of TREK-1 expression and the reduction of hippocampal NSC proliferation in PSD rats. TREK-1 plays an important role in the therapeutic effects of the SSRI escitalopram in PSD model, making TREK-1 an attractive candidate molecule for further understanding the pathophysiology and treatment of PSD. © 2015 John Wiley & Sons Ltd.

Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

PubMed

Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

2010-08-18

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

High intraocular pressure produces learning and memory impairments in rats.

PubMed

Yuan, Yuxiang; Chen, Zhiqi; Li, Lu; Li, Xing; Xia, Qian; Zhang, Hong; Duan, Qiming; Zhao, Yin

2017-11-15

Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Previous MRI studies have revealed that POAG can be associated with alterations in hippocampal function. Thus, the aim of this study was to investigate a relationship between chronic high intraocular pressure (IOP) and hippocampal changes in a rat model. We used behavioural tests to assess learning and memory ability, and additionally investigated the hippocampal expression of pathological amyloid beta (Aβ), phospho-tau, and related pathway proteins. Chronic high IOP impaired learning and memory in rats and concurrently increased Aβ and phospho-tau expression in the hippocampus by altering the activation of different kinase (GSK-3β, BACE1) and phosphatase (PP2A) proteins in the hippocampus. This study provides novel evidence for the relationship between high IOP and hippocampal alterations, especially in the context of learning and memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Prenatal ethanol exposure decreases hippocampal /sup 3/H-vinylidene kainic acid binding in 45-day-old rats

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

Farr, K.L.; Montano, C.Y.; Paxton, L.L.

1988-11-01

The effect of prenatal ethanol exposure on the kainate-sensitive subtype of glutamate receptor binding sites was studied using in vitro /sup 3/H-vinylidene kainic acid (VKA) autoradiography. Pregnant Sprague-Dawley rats were fed a liquid diet containing either 3.35% or 6.7% ethanol throughout gestation. Pair-fed dams received isocalorically matched liquid diets and a lab chow ad lib group served as control for paired feeding. At 45 days of age, the offspring were sacrificed and their brains analyzed for specific /sup 3/H-VKA binding. Compared to pair-fed controls, specific /sup 3/H-VKA binding was reduced by 13% to 32% in dorsal and ventral hippocampal CA3more » stratum lucidum, entorhinal cortex and cerebellum of 45-day-old rats whose mothers consumed either 3.35% or 6.7% ethanol diets. The binding site reductions were statistically significant only in the ventral hippocampal formation and entorhinal cortex of the 3.35% ethanol diet group rats. Saturation of binding studies in the ventral hippocampal formation of 3.35% ethanol rats indicated that the decrease in specific /sup 3/H-VKA binding was due to a decrease in the total number of binding sites. Given the excitatory effect of kainic acid on the spontaneous firing rate of hippocampal CA3 pyramidal neurons, the reduction of kainate-sensitive glutamate binding in this region is consistent with the electrophysiological observation of decreased spontaneous activity of CA3 pyramidal neurons in fetal alcohol rats.« less

Effects of lead exposure on hippocampal metabotropic glutamate receptor subtype 3 and 7 in developmental rats.

PubMed

Xu, Jian; Yan, Huai C; Yang, Bo; Tong, Lu S; Zou, Yu X; Tian, Ying

2009-04-20

A complete explanation of the mechanisms by which Pb2+ exerts toxic effects on developmental central nervous system remains unknown. Glutamate is critical to the developing brain through various subtypes of ionotropic or metabotropic glutamate receptors (mGluRs). Ionotropic N-methyl-D-aspartate receptors have been considered as a principal target in lead-induced neurotoxicity. The relationship between mGluR3/mGluR7 and synaptic plasticity had been verified by many recent studies. The present study aimed to examine the role of mGluR3/mGluR7 in lead-induced neurotoxicity. Twenty-four adult and female rats were randomly selected and placed on control or 0.2% lead acetate during gestation and lactation. Blood lead and hippocampal lead levels of pups were analyzed at weaning to evaluate the actual lead content at the end of the exposure. Impairments of short -term memory and long-term memory of pups were assessed by tests using Morris water maze and by detection of hippocampal ultrastructural alterations on electron microscopy. The impact of lead exposure on mGluR3 and mGluR7 mRNA expression in hippocampal tissue of pups were investigated by quantitative real-time polymerase chain reaction and its potential role in lead neurotoxicity were discussed. Lead levels of blood and hippocampi in the lead-exposed rats were significantly higher than those in the controls (P < 0.001). In tests using Morris Water Maze, the overall decrease in goal latency and swimming distance was taken to indicate that controls had shorter latencies and distance than lead-exposed rats (P = 0.001 and P < 0.001 by repeated-measures analysis of variance). On transmission electron microscopy neuronal ultrastructural alterations were observed and the results of real-time polymerase chain reaction showed that exposure to 0.2% lead acetate did not substantially change gene expression of mGluR3 and mGluR7 mRNA compared with controls. Exposure to lead before and after birth can damage short-term and long-term memory ability of young rats and hippocampal ultrastructure. However, the current study does not provide evidence that the expression of rat hippocampal mGluR3 and mGluR7 can be altered by systemic administration of lead during gestation and lactation, which are informative for the field of lead-induced developmental neurotoxicity noting that it seems not to be worthwhile to include mGluR3 and mGluR7 in future studies.

Regulation of Hippocampal α1d Adrenergic Receptor mRNA by Corticosterone in Adrenalectomized Rats

PubMed Central

Day, Heidi E.W.; Kryskow, Elisa M.; Watson, Stanley J.; Akil, Huda; Campeau, Serge

2008-01-01

The hippocampal formation receives extensive noradrenergic projections and expresses high levels of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Considerable evidence suggests that the noradrenergic system influences hippocampal corticosteroid receptors. However, there is relatively little data describing the influence of glucocorticoids on noradrenergic receptors in the hippocampal formation. α1d adrenergic receptor (ADR) mRNA is expressed at high levels in the hippocampal formation, within cells that express MR or GR. In order to determine whether expression of α1d ADR mRNA is influenced by circulating glucocorticoids, male rats underwent bilateral adrenalectomy (ADX) or sham surgery, and were killed after 1, 3, 7 or 14 days. Levels of α1d ADR mRNA were profoundly decreased in hippocampal subfields CA1, CA2 and CA3 and the medial and lateral blades of the dentate gyrus, as early as 1 day after ADX, as determined by in situ hybridization. The effect was specific for the hippocampal formation, with levels of α1d mRNA unaltered by ADX in the lateral amygdala, reticular thalamic nucleus, retrosplenial cortex or primary somatosensory cortex. Additional rats underwent ADX or sham surgery and received a corticosterone pellet (10 or 50 mg) or placebo for 7 days. Corticosterone replacement prevented the ADX-induced decrease in hippocampal α1d ADR mRNA, with the magnitude of effect depending on corticosterone dose and hippocampal subregion. These data indicate that α1d ADR mRNA expression in the hippocampal formation is highly sensitive to circulating levels of corticosterone, and provides further evidence for a close interaction between glucocorticoids and the noradrenergic system in the hippocampus. PMID:18534559

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

Enduring, Handling-Evoked Enhancement of Hippocampal Memory Function and Glucocorticoid Receptor Expression Involves Activation of the Corticotropin-Releasing Factor Type 1 Receptor

PubMed Central

Fenoglio, Kristina A.; Brunson, Kristen L.; Avishai-Eliner, Sarit; Stone, Blake A.; Kapadia, Bhumika J.; Baram, Tallie Z.

2011-01-01

Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d 2–9 (P2–9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression. However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear. In this study we administered selective antagonist for the type 1 CRF receptor, NBI 30775, to nonhandled rats post hoc from P10–17 and examined hippocampus-dependent learning and memory later (on P50–70), using two independent paradigms, compared with naive and vehicle-treated nonhandled, and naive and antagonist-treated handled rats. Hippocampal GR and hypothalamic CRF mRNA levels and stress-induced plasma corticosterone levels were also examined. Transient, partial selective blockade of CRF1 in nonhandled rats improved memory functions on both the Morris watermaze and object recognition tests to levels significantly better than in naive and vehicle-treated controls and were indistinguishable from those in handled (naive, vehicle-treated, and antagonist-treated) rats. GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF1-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts. Thus, the extent of CRF1 activation, probably involving changes in hypothalamic CRF levels and release, contributes to the changes in hippocampal GR expression and learning and memory functions. PMID:15932935

Various ketogenic diets can differently support brain resistance against experimentally evoked seizures and seizure-induced elemental anomalies of hippocampal formation.

PubMed

Chwiej, J; Patulska, A; Skoczen, A; Matusiak, K; Janeczko, K; Ciarach, M; Simon, R; Setkowicz, Z

2017-07-01

In this paper the influence of two different ketogenic diets (KDs) on the seizure-evoked elemental anomalies of hippocampal formation was examined. To achieve this purpose normal and pilocarpine treated rats previously fed with one of the two high fat and carbohydrate restricted diets were compared with animals on standard laboratory diet. The ketogenic ratios of the examined KDs were equal to 5:1 (KD1) and 9:1 (KD2). KD1 and standard diet fed animals presented similar patterns of seizure-evoked elemental changes in hippocampal formation. Also the analysis of behavioral data recorded after pilocarpine injection did not show any significant differences in intensity and duration of seizures between KD1 and standard diet fed animals. Higher ketogenic ratio KD2 introduced in the normal hippocampal formation prolonged changes in the accumulation of P, K, Zn and Ca. Despite this, both the intensity and duration of seizures were significantly reduced in rats fed with KD2 which suggests that its saving action on the nerve tissue may protect brain from seizure propagation. Also seizure-evoked elemental anomalies in KD2 animals were different than those observed for rats both on KD1 and standard diets. The comparison of seizure experiencing and normal rats on KD2, did not show any statistically significant differences in elemental composition of CA1 and H hippocampal areas whilst in CA3 area only Zn level changed as a result of seizures. DG was the area mostly affected by seizures in KD2 fed rats but areal densities of all examined elements increased in this hippocampal region. Copyright © 2017 Elsevier GmbH. All rights reserved.

Inter-relationships among Diet, Obesity and Hippocampal-dependent Cognitive Function

PubMed Central

Davidson, Terry L.; Hargrave, Sara L.; Swithers, Susan E.; Sample, Camille H.; Fu, Xue; Kinzig, Kimberly P.; Zheng, Wei

2013-01-01

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased BBB permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity was more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO) with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent feature negative discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity. PMID:23999121

Postoperative intermittent fasting prevents hippocampal oxidative stress and memory deficits in a rat model of chronic cerebral hypoperfusion.

PubMed

Hu, Yuan; Zhang, Miao; Chen, Yunyun; Yang, Ying; Zhang, Jun-Jian

2018-01-11

Whether intermittent fasting (IF) treatment after stroke can prevent its long-term detrimental effects remains unknown. Here, we investigate the effects of postoperative IF on cognitive deficits and its underlying mechanisms in a permanent two-vessel occlusion (2VO) vascular dementia rat model. Rats were subjected to either IF or ad libitum feeding 1 week after 2VO surgery. The cognition of rats was assessed using the novel object recognition (NOR) task and Morris water maze (MWM) 8 weeks after surgery. After behavioral testing, hippocampal malondialdehyde (MDA) and glutathione (GSH) concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein levels, and microglia density were determined. Postoperative IF significantly ameliorated the cognitive performance of 2VO rats in the NOR and MWM tests. Cognitive enhancement paralleled preservation of the PSD95 and BDNF levels in the 2VO rat hippocampus. Mechanistically, postoperative IF mitigated hippocampal oxidative stress in 2VO rats, as indicated by the reduced MDA concentration and mRNA and the protein levels of the reactive oxygen species-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase 1. IF treatment also preserved the GSH level and SOD activity, as well as the levels of their upstream regulating enzymes, resulting in preserved antioxidative capability. In addition, postoperative IF prevented hippocampal microglial activation and elevation of sphingosine 1-phosphate receptor 1 and inflammatory cytokines in 2VO rats. Our results suggest that postoperative IF suppresses neuroinflammation and oxidative stress induced by chronic cerebral ischemia, thereby preserving cognitive function in a vascular dementia rat model.

ACUTE EXPOSURE TO TRIS (2-CHLOROETHYL) PHOSPHATE HIPPOCAMPAL NEURONAL LOSS AND IMPAIRS LEARNING IN RATS

EPA Science Inventory

Adult female, Fischer 344 rats were exposed to 275 mg/kg of tris(2- chloroethyl)phosphate (TRCP) by gavage. RCP produced consistent signs of convulsive activity within 60-90 minutes after dosing and extensive loss of CA1 hippocampal pyramidal cells when examined 7 days after dosi...

Interleukin-1β increases neuronal death in the hippocampal dentate gyrus associated with status epilepticus in the developing rat.

PubMed

Rincón-López, C; Tlapa-Pale, A; Medel-Matus, J-S; Martínez-Quiroz, J; Rodríguez-Landa, J F; López-Meraz, M-L

Interleukin-1β (IL-1β) increases necrotic neuronal cell death in the CA1 area after induced status epilepticus (SE) in developing rats. However, it remains uncertain whether IL-1β has a similar effect on the hippocampal dentate gyrus (DG). In this study, we analysed the effects of IL-1β on 14-day-old Wistar rats experiencing DG neuronal death induced by SE. SE was induced with lithium-pilocarpine. Six hours after SE onset, a group of pups was injected with IL-1β (at 0, 0.3, 3, 30, or 300ng/μL) in the right ventricle; another group was injected with IL-1β receptor (IL-1R1) antagonist (IL-1Ra, at 30ng/μL) of IL-1RI antagonist (IL-1Ra) alone, and additional group with 30ng/μL of IL-1Ra plus 3ng/μL of IL-1β. Twenty-four hours after SE onset, neuronal cell death in the dentate gyrus of the dorsal hippocampus was assessed using haematoxylin-eosin staining. Dead cells showed eosinophilic cytoplasm and condensed and fragmented nuclei. We observed an increased number of eosinophilic cells in the hippocampal DG ipsilateral to the site of injection of 3ng/μL and 300ng/μL of IL-1β in comparison with the vehicle group. A similar effect was observed in the hippocampal DG contralateral to the site of injection of 3ng/μL of IL-1β. Administration of both of IL-1β and IL-1Ra failed to prevent an increase in the number of eosinophilic cells. Our data suggest that IL-1β increases apoptotic neuronal cell death caused by SE in the hippocampal GD, which is a mechanism independent of IL-1RI activation. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Curcumin Enhances Neurogenesis and Cognition in Aged Rats: Implications for Transcriptional Interactions Related to Growth and Synaptic Plasticity

PubMed Central

Mitchell, E. Siobhan; Xiu, Jin; Tiwari, Jyoti K.; Hu, Yinghe; Cao, Xiaohua; Zhao, Zheng

2012-01-01

Background Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. Methodology We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. Conclusions The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity. PMID:22359574

Long-term consequences of a prolonged febrile seizure in a dual pathology model.

PubMed

Gibbs, Steve; Chattopadhyaya, Bidisha; Desgent, Sébastien; Awad, Patricia N; Clerk-Lamalice, Olivier; Levesque, Maxime; Vianna, Rose-Mari; Rébillard, Rose-Marie; Delsemme, Andrée-Anne; Hébert, David; Tremblay, Luc; Lepage, Martin; Descarries, Laurent; Di Cristo, Graziella; Carmant, Lionel

2011-08-01

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits. Copyright © 2011 Elsevier Inc. All rights reserved.

Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

PubMed

Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

2011-03-23

Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis.

PubMed

Okamoto, Masahiro; Hojo, Yasushi; Inoue, Koshiro; Matsui, Takashi; Kawato, Suguru; McEwen, Bruce S; Soya, Hideaki

2012-08-07

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5'-bromo-2'deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5'-bromo-2'deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

PubMed Central

Okamoto, Masahiro; Hojo, Yasushi; Inoue, Koshiro; Matsui, Takashi; Kawato, Suguru; McEwen, Bruce S.; Soya, Hideaki

2012-01-01

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5′-bromo-2′deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5′-bromo-2′deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation. PMID:22807478

Comparison of the influence of two models of mild stress on hippocampal brain-derived neurotrophin factor (BDNF) immunoreactivity in old age rats.

PubMed

Badowska-Szalewska, Ewa; Ludkiewicz, Beata; Krawczyk, Rafał; Melka, Natalia; Moryś, Janusz

2017-01-01

The way hippocampal neurons function during stress in old age (critical times of life) is dependent on brain derived neurotrophin factor (BDNF). This study examined the influence of acute and chronic forced swim (FS) or high-light open field (HL‑OF) stimulation on the density of BDNF immunoreactive (ir) neurons in the hippocampal pyramidal layers of CA1, CA2, CA3 regions and the granular layer of dentate gyrus (DG) in old (postnatal day 720; P720) Wistar Han rats. Our data showed that in comparison with non-stressed rats, acute FS caused a significant increase in the density of BDNF-ir neurons in CA2 and CA3, while acute HL-OF led to an increase in this factor in all hippocampal subfields with the exception of DG. However, the density of BDNF-ir cells remained unchanged after exposure to chronic FS or HL‑OF in the hippocampal regions in relation to the control rats. These results indicate that acute FS or HL-OF proved to be a stressor that induces an increase in the density of BDNF-ir pyramidal neurons, which was probably connected with up-regulation of HPA axis activity and short‑time memory processing of the stressful situation. Moreover, as far as the influence on BDNF-ir cells in hippocampus is concerned, chronic FS or HL-OF was not an aggravating factor for rats in the ontogenetic periods studied.

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

Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats

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

Li, Zheng-Qian; Rong, Xiao-Ying; Liu, Ya-Jie

Highlights: •Isoflurane induces hippocampal IL-1β elevation and cognitive deficits in aged rats. •Isoflurane transiently activates the canonical NF-κB pathway in aged rat hippocampus. •NF-κB inhibitor mitigates isoflurane-induced IL-1β elevation and cognitive deficits. •We report a linkage between NF-κB signaling, IL-1β expression, and cognitive changes. -- Abstract: Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-κB signaling, and to explore its association with hippocampal interleukin (IL)-1β levels andmore » anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in IκB kinase and IκB phosphorylation, as well as a reduction in the NF-κB inhibitory protein (IκBα), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-κB p65 nuclear translocation at 6 h after isoflurane exposure and hippocampal IL-1β elevation from 1 to 6 h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-κB activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1β increase and NF-κB signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal IL-1β, partially via activation of the canonical NF-κB pathway, in aged rats.« less

Current source density analysis of the hippocampal theta rhythm: associated sustained potentials and candidate synaptic generators.

PubMed

Brankack, J; Stewart, M; Fox, S E

1993-07-02

Single-electrode depth profiles of the hippocampal EEG were made in urethane-anesthetized rats and rats trained in an alternating running/drinking task. Current source density (CSD) was computed from the voltage as a function of depth. A problem inherent to AC-coupled profiles was eliminated by incorporating sustained potential components of the EEG. 'AC' profiles force phasic current sinks to alternate with current sources at each lamina, changing the magnitude and even the sign of the computed membrane current. It was possible to include DC potentials in the profiles from anesthetized rats by using glass micropipettes for recording. A method of 'subtracting' profiles of the non-theta EEG from theta profiles was developed as an approach to including sustained potentials in recordings from freely-moving animals implanted with platinum electrodes. 'DC' profiles are superior to 'AC' profiles for analysis of EEG activity because 'DC'-CSD values can be considered correct in sign and more closely represent the actual membrane current magnitudes. Since hippocampal inputs are laminated, CSD analysis leads to straightforward predictions of the afferents involved. Theta-related activity in afferents from entorhinal neurons, hippocampal interneurons and ipsi- and contralateral hippocampal pyramids all appear to contribute to sources and sinks in CA1 and the dentate area. The largest theta-related generator was a sink at the fissure, having both phasic and tonic components. This sink may reflect activity in afferents from the lateral entorhinal cortex. The phase of the dentate mid-molecular sink suggests that medial entorhinal afferents drive the theta-related granule and pyramidal cell firing. The sustained components may be simply due to different average rates of firing during theta rhythm than during non-theta EEG in afferents whose firing rates are also phasically modulated.

Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation.

PubMed

Beilharz, J E; Maniam, J; Morris, M J

2016-06-01

Chronic high-energy diets are known to induce obesity and impair memory; these changes have been associated with inflammation in brain areas crucial for memory. In this study, we investigated whether inflammation could also be related to diet-induced memory deficits, prior to obesity. We exposed rats to chow, chow supplemented with a 10% sucrose solution (Sugar) or a diet high in fat and sugar (Caf+Sugar) and assessed hippocampal-dependent and perirhinal-dependent memory at 1 week. Both high-energy diet groups displayed similar, selective hippocampal-dependent memory deficits despite the Caf+Sugar rats consuming 4-5 times more energy, and weighing significantly more than the other groups. Extreme weight gain and excessive energy intake are therefore not necessary for deficits in memory. Weight gain across the diet period however, was correlated with the memory deficits, even in the Chow rats. The Sugar rats had elevated expression of a number of inflammatory genes in the hippocampus and WAT compared to Chow and Caf+Sugar rats but not in the perirhinal cortex or hypothalamus. Blood glucose concentrations were also elevated in the Sugar rats, and were correlated with the hippocampal inflammatory markers. Together, these results indicate that liquid sugar can rapidly elevate markers of central and peripheral inflammation, in association with hyperglycemia, and this may be related to the memory deficits in the Sugar rats. Copyright © 2016 Elsevier B.V. All rights reserved.

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...

Effect of Juvenile Pretraining on Adolescent Structural Hippocampal Attributes as a Substrate for Enhanced Spatial Performance

ERIC Educational Resources Information Center

Keeley, Robin J.; Wartman, Brianne C.; Hausler, Alexander N.; Holahan, Matthew R.

2010-01-01

Research has demonstrated that Long-Evans rats (LER) display superior mnemonic function over Wistar rats (WR). These differences are correlated with endogenous and input-dependent properties of the hippocampus. The present work sought to determine if juvenile pretraining might enhance hippocampal structural markers and if this would be associated…

Hippocampal cell proliferation regulation by repeated stress and antidepressants.

PubMed

Chen, Hu; Pandey, Ghanshyam N; Dwivedi, Yogesh

2006-06-26

A recent hypothesis suggests reduced hippocampal neurogenesis in depression. Here, we examined cell proliferation in the dentate gyrus and the subventricular zone of rats given repeated stress, a paradigm that prolongs learned helplessness behavior, and whether antidepressants modulate the learned helplessness-associated altered cell proliferation. Decreased cell proliferation, number of clusters, and cells/cluster were noted in the dentate gyrus, but not in the subventricular zone, of learned helplessness rats. Both fluoxetine and desipramine reversed the learned helplessness behavior and increased the cell proliferation and the number of clusters in learned helplessness rats; only fluoxetine did so significantly. Both fluoxetine and desipramine significantly increased the number of cells/cluster. Our results suggest modified hippocampal neurogenesis in prolonged depression and in the mechanism of antidepressant action.

[Protective effects of Fufangdengzhanhua dripping pill on apoptosis induced by glutamate in cultured primary hippocampal neurons of rats].

PubMed

Wang, Lijun; Wan, Lei

2010-03-01

To explore the protective effects and the inhibited mechanism of Fufangdengzhanhua dripping pill (FDD) on the apoptosis induced by glutamate (Glu) of cultured primary hippocampal neurons of rats. By the seropharmacological method, we obtained the drug-contained serum. The primary hippocampal neurons of rat cerebrum were cultured for 10 days, then exposed to 500 micromol x L(-1) glutamate acid (Glu) for 20 minutes to build the model. The 5% drug-contained sera which included normal, model, 0.05 g x kg(-1) nimodipine (Nim), 5.00 g x kg(-1) FDD and 1.25 g x kg(-1) FDD were added to the nutrient solution of cultured neurons. In this study, we observed the following indexes: the viability of cultured primary hippocampal neurons by MTT assay, the injured cell morphological changes with fluorescence microscope by using Hoechst 33342 & Propicium Iodide (PI) staining, intracellular Ca2+ concentration and the percentage of apoptosis by flow cytometry. When the hippocampal neurons were exposed to Glu, the cells were seriously damaged: nuclei were shrunken and cloven and the apoptosis body and the viability of cultured primary hippocampal neurons were decreased dramatically compared with the control. The FDD (5.00, 1.25 g x kg(-1)) and Nim could prevent the above changes Glu-induced. The necrosis rates and the percentage of cellular apoptosis of cultured hippocampal neurons pretreated with the serum of containing FDD decreased significantly and the number of surviving cells was increased significantly compared with model. Intracellular Ca2+ concentration Glu-induced were increased markedly compared with the control and the FDD (5.00, 1.25 g x kg(-1)) could prevent the above changes . FDD has protective effects on the apoptosis induced by glutamate (Glu) of cultured primary hippocampal neurons of rats, which possibly is related to reducing the intracellular Ca2+.

[Effect of electroacupuncture intervention on learning-memory ability and injured hippocampal neurons in depression rats].

PubMed

Bao, Wu-Ye; Jiao, Shuang; Lu, Jun; Tu, Ya; Song, Ying-Zhou; Wu, Qian; A, Ying-Ge

2014-04-01

To observe the effect of electroacupuncture (EA) stimulation of "Baihui" (GV 20)-"Yintang" (EX-HN 3) on changes of learning-memory ability and hippocampal neuron structure in chronic stress-stimulation induced depression rats. Forty-eight SD rats were randomly divided into normal, model, EA and medication (Fluoxetine) groups, with 12 rats in each group. The depression model was established by chronic unpredictable mild stress stimulation (swimming in 4 degrees C water, fasting, water deprivation, reversed day and night, etc). Treatment was applied to "Baihui" (GV 20) and "Yintang" (EX-HN 3) for 20 min, once every day for 21 days. For rats of the medication group, Fluoxetine (3.3 mg/kg) was given by gavage (p.o.), once daily for 21 days. The learning-memory ability was detected by Morris water maze tests. The pathological and ultrastructural changes of the hippocampal tissue and neurons were assessed by H.E. staining, light microscope and transmission electron microscopy, respectively. Compared to the normal group, the rats' body weight on day 14 and day 21 after modeling was significantly decreased in the model group (P < 0.01), the escape latency and total swimming distance in the 4 quadrants on day 10 and 21 were significantly increased in the model group (P < 0.01). In comparison with the model group, the body weight on day 14 and 21 were significantly increased (P < 0.05), and the escape latency and total swimming distance levels were significantly decreased in the EA group (P < 0.01), suggesting an improvement of learning-memory ability. Observations of light microscope and transmission electron microscope showed that modeling induced pathological changes such as reduction in hippocampal cell layers, vague and broken cellular membrane, and ultrastructural changes of hippocampal neurons including swelling and reduction of mitochondria and mitochondrial crests were relived after EA and Fluoxetine treatment. EA intervention can improve the learning-memory ability and relieving impairment of hippocampal neurons in depression rats, which may be one of its mechanisms underlying bettering depression.

Western diets induce blood-brain barrier leakage and alter spatial strategies in rats.

PubMed

Hargrave, Sara L; Davidson, Terry L; Zheng, Wei; Kinzig, Kimberly P

2016-02-01

Western diet (WD) intake induces obesity and metabolic dysfunction. The present study examined the effects of WD on hippocampal-dependent cognitive functioning and blood-brain barrier (BBB) permeability as a function of exposure duration, obesity phenotype, and peripheral markers of energy regulation. The use of hippocampal-dependent "place" or hippocampal-independent "response" strategies in a Y maze was assessed in male rats following 10, 40, and 90 days of WD exposure in diet-induced obese (DIO) rats, in diet resistant (DR) rats that are relatively insensitive to the obesogenic properties of WD, and in chow-fed controls. Insulin, glucose, and BBB permeability throughout several loci in the hippocampus, striatum, and cerebellum were evaluated in relation to duration of WD exposure, obesity phenotype, and type of strategy used. DIO rats had increased body weight and adiposity throughout the study, and elevated 10-day glucose and 90-day insulin levels. Throughout the study, chow-fed and DR rats reliably relied on a place strategy. DIO rats, in contrast, favored a response strategy at the 10- and 90-day time points. BBB leakage was observed in the dorsal striatum and multiple subregions of the hippocampus of DIO, but not DR or chow-fed rats. Increased ventral hippocampal BBB permeability and blood glucose levels were associated with reduced place strategy use. These data indicate that WD-induced BBB leakage is dependent on duration of diet exposure as well as obesity phenotype, and implicates BBB leakage and impaired glucoregulation in behavioral strategy and cognitive performance. (c) 2016 APA, all rights reserved).

Coherence between Rat Sensorimotor System and Hippocampus Is Enhanced during Tactile Discrimination

PubMed Central

Zuo, Yangfang; Stella, Federico; Diamond, Mathew E.

2016-01-01

Rhythms with time scales of multiple cycles per second permeate the mammalian brain, yet neuroscientists are not certain of their functional roles. One leading idea is that coherent oscillation between two brain regions facilitates the exchange of information between them. In rats, the hippocampus and the vibrissal sensorimotor system both are characterized by rhythmic oscillation in the theta range, 5–12 Hz. Previous work has been divided as to whether the two rhythms are independent or coherent. To resolve this question, we acquired three measures from rats—whisker motion, hippocampal local field potential (LFP), and barrel cortex unit firing—during a whisker-mediated texture discrimination task and during control conditions (not engaged in a whisker-mediated memory task). Compared to control conditions, the theta band of hippocampal LFP showed a marked increase in power as the rats approached and then palpated the texture. Phase synchronization between whisking and hippocampal LFP increased by almost 50% during approach and texture palpation. In addition, a greater proportion of barrel cortex neurons showed firing that was phase-locked to hippocampal theta while rats were engaged in the discrimination task. Consistent with a behavioral consequence of phase synchronization, the rats identified the texture more rapidly and with lower error likelihood on trials in which there was an increase in theta-whisking coherence at the moment of texture palpation. These results suggest that coherence between the whisking rhythm, barrel cortex firing, and hippocampal LFP is augmented selectively during epochs in which the rat collects sensory information and that such coherence enhances the efficiency of integration of stimulus information into memory and decision-making centers. PMID:26890254

Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats.

PubMed

Ghodrati-Jaldbakhan, Shahrbanoo; Ahmadalipour, Ali; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Miladi-Gorji, Hossein; Alizadeh, Maryam

2017-05-15

Previous studies from our laboratory have shown that treadmill exercise alleviates the deficits in cognitive functions and anxiety behaviors induced by chronic exposure to morphine in male rats. In this study, we investigated the effects of low and high intensities of treadmill exercise on spatial memory, anxiety-like behaviors, and biochemical changes in the hippocampus and serum of morphine-treated female rats. The adult virgin female rats were injected with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 10days. Following these injections, the rats were exercised under low or high intensities for 30min per session on five days a week for four weeks. After exercise training, object location memory, anxiety profile, hippocampal BDNF, and serum corticosterone and BDNF were examined. Morphine-treated animals exhibited increased anxiety levels, impaired object location memory, and reduced hippocampal BDNF. Exercise alleviated these impairing effects on anxiety profile and memory but not hippocampal BDNF. The high-intensity exercise even further reduced the hippocampal BDNF. Additionally, both exercise regimens in the morphine group and the high exercise in the saline group reduced serum BDNF. Finally, the high-intensity exercise enhanced corticosterone serum. These findings indicate that the negative cognitive and behavioral effects of chronic exposure to morphine could be relieved by forced exercise in female rats. However, the exercise intensity is an important factor to be considered during exercise training. Finally, the correlation between changes of brain and serum BDNF and cognitive functions following morphine exposure needs further research. Copyright © 2017 Elsevier B.V. All rights reserved.

Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

PubMed

Riordan, Alexander J; Schaler, Ari W; Fried, Jenny; Paine, Tracie A; Thornton, Janice E

2018-05-01

The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABA A agonist, GABA A antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABA A agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABA A receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them. Copyright © 2018 Elsevier Ltd. All rights reserved.

Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring.

PubMed

Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R

2016-01-15

Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Age-specific effects of voluntary exercise on memory and the older brain.

PubMed

Siette, Joyce; Westbrook, R Frederick; Cotman, Carl; Sidhu, Kuldip; Zhu, Wanlin; Sachdev, Perminder; Valenzuela, Michael J

2013-03-01

Physical exercise in early adulthood and mid-life improves cognitive function and enhances brain plasticity, but the effects of commencing exercise in late adulthood are not well-understood. We investigated the effects of voluntary exercise in the restoration of place recognition memory in aged rats and examined hippocampal changes of synaptic density and neurogenesis. We found a highly selective age-related deficit in place recognition memory that is stable across retest sessions and correlates strongly with loss of hippocampal synapses. Additionally, 12 weeks of voluntary running at 20 months of age removed the deficit in the hippocampally dependent place recognition memory. Voluntary running restored presynaptic density in the dentate gyrus and CA3 hippocampal subregions in aged rats to levels beyond those observed in younger animals, in which exercise had no functional or synaptic effects. By contrast, hippocampal neurogenesis, a possible memory-related mechanism, increased in both young and aged rats after physical exercise but was not linked with performance in the place recognition task. We used graph-based network analysis based on synaptic covariance patterns to characterize efficient intrahippocampal connectivity. This analysis revealed that voluntary running completely reverses the profound degradation of hippocampal network efficiency that accompanies sedentary aging. Furthermore, at an individual animal level, both overall hippocampal presynaptic density and subregional connectivity independently contribute to prediction of successful place recognition memory performance. Our findings emphasize the unique synaptic effects of exercise on the aged brain and their specific relevance to a hippocampally based memory system for place recognition. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders.

PubMed

Fortress, Ashley M; Smith, Ian M; Pang, Kevin C H

2018-05-08

Anxiety disorders and posttraumatic stress disorder (PTSD) share a common feature of pathological avoidance behavior. The Wistar Kyoto (WKY) rat has been used as a model of anxiety vulnerability, expressing a behaviorally inhibited temperament, acquiring avoidance behavior more rapidly and displaying extinction-resistant avoidance compared to Sprague Dawley (SD) rats. Subanesthetic levels of ketamine have gained attention as a rapid antidepressant in treatment-resistant depression. While traditional antidepressants are commonly used to treat anxiety disorders and PTSD, the therapeutic utility of ketamine for these disorders is much less understood. The hippocampus is critical for the actions of antidepressants, is a structure of implicated in anxiety disorders and PTSD, and is necessary for extinction of avoidance in SD rats. WKY rats have impaired hippocampal long-term potentiation (LTP), suggesting that persistent avoidance in WKY rats may be due to deficient hippocampal synaptic plasticity. In the present study, we hypothesized that ketamine would facilitate extinction of avoidance learning in WKY rats, and do so by enhancing hippocampal synaptic plasticity. As predicted, ketamine facilitated extinction of avoidance behavior in a subset of WKY rats (responders), with effects lasting at least three weeks. Additionally, LTP in these rats was enhanced by ketamine. Ketamine was not effective in facilitating avoidance extinction or in modifying LTP in WKY non-responders. The results suggest that subanesthetic levels of ketamine may be useful for treating anxiety disorders by reducing avoidance behaviors when combined with extinction conditions. Moreover, ketamine may have its long-lasting behavioral effects through enhancing hippocampal synaptic plasticity. Copyright © 2018. Published by Elsevier Ltd.

Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats.

PubMed

McCall, Nora; Mahadevia, Darshini; Corriveau, Jennifer A; Glenn, Melissa J

2015-03-14

The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non-supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4weeks on their respective diets, a subset of rats began 3weeks of behavioral testing, while the remaining behaviorally naïve rats were sacrificed after 6weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogen supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega-3 fatty acids have similar biological functions-affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies. Copyright © 2015 Elsevier Inc. All rights reserved.

Estradiol treatment in preadolescent females enhances adolescent spatial memory and differentially modulates hippocampal region-specific phosphorylated ERK labeling.

PubMed

Wartman, Brianne C; Keeley, Robin J; Holahan, Matthew R

2012-10-24

Estrogen levels in rats are positively correlated with enhanced memory function and hippocampal dendritic spine density. There is much less work on the long-term effects of estradiol manipulation in preadolescent rats. The present work examined how injections of estradiol during postnatal days 19-22 (p19-22; preadolescence) affected water maze performance and hippocampal phosphorylated ERK labeling. To investigate this, half of the estradiol- and vehicle-treated female rats were trained on a water maze task 24h after the end of estradiol treatment (p23-27) while the other half was not trained. All female rats were tested on the water maze from p40 to p44 (adolescence) and hippocampal pERK1/2 labeling was assessed as a putative marker of neuronal plasticity. During adolescence, preadolescent-trained groups showed lower latencies than groups without preadolescent training. Retention data revealed lower latencies in both estradiol groups, whether preadolescent trained or not. Immunohistochemical detection of hippocampal pERK1/2 revealed elevations in granule cell labeling associated with the preadolescent trained groups and reductions in CA1 labeling associated with estradiol treatment. These results show a latent beneficial effect of preadolescent estradiol treatment on adolescent spatial performance and suggest an organizational effect of prepubescent exogenously applied estradiol. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

EFFECTS OF MEDIAL SEPTAL LESION ON HIPPOCAMPAL EXTRACELLULAR GLUTAMATE AND GABA LEVELS DURING SPATIAL ALTERNATION TESTING.

PubMed

Mataradze, S; Naneishvili, T; Sephashvili, M; Mikeladze, D; Dashniani, M

2016-10-01

The present study investigated spatial working memory assessed in spontaneous alternation (SA) task and hippocampal glutamate and GABA release prior to, during, and after SA test in sham-operated and electrolytic medial septal (MS) lesioned rats. Also, have been investigated the effects of MS lesion on KCl-stimulated release of glutamate and GABA in the hippocampus. Behavioral study showed that electrolytic lesion of MS significantly impaired SA performance. Although both groups of animals had an insignificant rise in their respective hippocampal glutamate efflux during the SA, the rise of MS lesioned animals was blunted when compared with control animals. Hippocampal GABA levels did not change during behavioral testing in both groups. Most of control animals showed increase in KCl-stimulated glutamate release. By contrast, only one MS lesioned rat showed increase in glutamate release in response to KCl stimulation. Most of control and MS lesioned rats were non-responders in GABA release in response to KCl stimulation. Decreased glutamate release (upon stimulation) in the MS lesioned rats may contribute to spatial working memory impairment in these animals. We propose that SA testing coupled with in vivo microdialysis sampling represents a suitable approach to revealing the neurochemical correlates of hippocampal-dependent memory function, and thus could be a useful tool for better understanding of the neurochemical basis of cognitive decline associated with various disorders and neurodegenerative diseases.

Inter-relationships among diet, obesity and hippocampal-dependent cognitive function.

PubMed

Davidson, T L; Hargrave, S L; Swithers, S E; Sample, C H; Fu, X; Kinzig, K P; Zheng, W

2013-12-03

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet, which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased blood-brain barrier (BBB) permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet-resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity were more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO), with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent FN discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats.

PubMed

Veena, J; Srikumar, B N; Mahati, K; Raju, T R; Shankaranarayana Rao, B S

2011-09-01

Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function. In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals. Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator. Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume. These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.

Neuroprotective effects of MK-801 against traumatic brain injury in immature rats.

PubMed

Sönmez, Ataç; Sayın, Oya; Gürgen, Seren Gülşen; Çalişir, Meryem

2015-06-15

Traumatic brain injury (TBI) is a major health problem in pediatric ages and also has major social, economic, and emotional outcomes, with diverse sequelae in many spheres of everyday life. We aimed to investigate the effect of MK-801, a competitive NMDA receptor antagonist, on hippocampal damage and behavioral deficits on 10-day-old rat pups subjected to contusion injury. The aims of the present study were to determine: (i) the short term effects of MK-801 on hippocampal BDNF, NGF and NMDA receptor immunoreactivity and neuron density in hippocampus (ii) long term effects of MK-801 on cognitive dysfunction following TBI in the immature rats. MK-801, was injected intraperitoneally at the doses of 1mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining, BDNF, NGF and NMDAR receptor immunohistochemistry on P10 day and behavioral alterations were evaluated using elevated plus maze and novel object recognition tests two months after the trauma. Histopathological and immunohistochemical evaluations showed that treatment with a single dose of 1mg/kg MK-801 (i.p.) significantly ameliorated the trauma induced hippocampal neuron loss and decreased BDNF, NGF and NMDAR expressions in CA1, CA3 and DG hippocampal brain regions. Additionally, treatment with MK-801 ameliorated anxiety and hippocampus dependent memory of animals subjected to trauma. These results show that acute treatment of MK-801 has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in immature rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Short exposure to a diet rich in both fat and sugar or sugar alone impairs place, but not object recognition memory in rats.

PubMed

Beilharz, Jessica E; Maniam, Jayanthi; Morris, Margaret J

2014-03-01

High energy diets have been shown to impair cognition however, the rapidity of these effects, and the dietary component/s responsible are currently unclear. We conducted two experiments in rats to examine the effects of short-term exposure to a diet rich in sugar and fat or rich in sugar on object (perirhinal-dependent) and place (hippocampal-dependent) recognition memory, and the role of inflammatory mediators in these responses. In Experiment 1, rats fed a cafeteria style diet containing chow supplemented with lard, cakes, biscuits, and a 10% sucrose solution performed worse on the place, but not the object recognition task, than chow fed control rats when tested after 5, 11, and 20 days. In Experiment 2, rats fed the cafeteria style diet either with or without sucrose and rats fed chow supplemented with sucrose also performed worse on the place, but not the object recognition task when tested after 5, 11, and 20 days. Rats fed the cafeteria diets consumed five times more energy than control rats and exhibited increased plasma leptin, insulin and triglyceride concentrations; these were not affected in the sucrose only rats. Rats exposed to sucrose exhibited both increased hippocampal inflammation (TNF-α and IL-1β mRNA) and oxidative stress, as indicated by an upregulation of NRF1 mRNA compared to control rats. In contrast, these markers were not significantly elevated in rats that received the cafeteria diet without added sucrose. Hippocampal BDNF and neuritin mRNA were similar across all groups. These results show that relatively short exposures to diets rich in both fat and sugar or rich in sugar, impair hippocampal-dependent place recognition memory prior to the emergence of weight differences, and suggest a role for oxidative stress and neuroinflammation in this impairment. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

PubMed

Yoshimoto, M; Higuchi, H; Kamata, M; Yoshida, K; Shimizu, T; Hishikawa, Y

1999-01-01

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

PubMed Central

Pettigrew, L. Creed; Kryscio, Richard J.; Norris, Christopher M.

2016-01-01

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO. PMID:27144978

Changes in the Hippocampal Proteome Associated with Spatial Memory Impairment after Exposure to Low (20 cGy) Doses of 1 GeV/n 56Fe Radiation.

PubMed

Britten, Richard A; Jewell, Jessica S; Davis, Leslie K; Miller, Vania D; Hadley, Melissa M; Semmes, O John; Lonart, György; Dutta, Sucharita M

2017-03-01

Exposure to low (∼20 cGy) doses of high-energy charged (HZE) particles, such as 1 GeV/n 56 Fe, results in impaired hippocampal-dependent learning and memory (e.g., novel object recognition and spatial memory) in rodents. While these findings raise the possibility that astronauts on deep-space missions may develop cognitive deficits, not all rats develop HZE-induced cognitive impairments, even after exposure to high (200 cGy) HZE doses. The reasons for this differential sensitivity in some animals that develop HZE-induced cognitive failure remain speculative. We employed a robust quantitative mass spectrometry-based workflow, which links early-stage discovery to next-stage quantitative verification, to identify differentially active proteins/pathways in rats that developed spatial memory impairment at three months after exposure to 20 cGy of 1 GeV/n 56 Fe (20/impaired), and in those rats that managed to maintain normal cognitive performance (20/functional). Quantitative data were obtained on 665-828 hippocampal proteins in the various cohorts of rats studied, of which 580 were expressed in all groups. A total of 107 proteins were upregulated in the irradiated rats irrespective of their spatial memory performance status, which included proteins involved in oxidative damage response, calcium transport and signaling. Thirty percent (37/107) of these "radiation biomarkers" formed a functional interactome of the proteasome and the COP9 signalosome. These data suggest that there is persistent oxidative stress, ongoing autophagy and altered synaptic plasticity in the irradiated hippocampus, irrespective of the spatial memory performance status, suggesting that the ultimate phenotype may be determined by how well the hippocampal neurons compensate to the ongoing oxidative stress and associated side effects. There were 67 proteins with expression that correlated with impaired spatial memory performance. Several of the "impaired biomarkers" have been implicated in poor spatial memory performance, neurodegeneration, neuronal loss or neuronal susceptibility to apoptosis, or neuronal synaptic or structural plasticity. Therefore, in addition to the baseline oxidative stress and altered adenosine metabolism observed in all irradiated rats, the 20/impaired rats expressed proteins that led to poor spatial memory performance, enhanced neuronal loss and apoptosis, changes in synaptic plasticity and dendritic remodeling. A total of 46 proteins, which were differentially upregulated in the sham-irradiated and 20/functional rat cohorts, can thus be considered as markers of good spatial memory, while another 95 proteins are associated with the maintenance of good spatial memory in the 20/functional rats. The loss or downregulation of these "good spatial memory" proteins would most likely exacerbate the situation in the 20/impaired rats, having a major impact on their neurocognitive status, given that many of those proteins play an important role in neuronal homeostasis and function. Our large-scale comprehensive proteomic analysis has provided some insight into the processes that are altered after exposure, and the collective data suggests that there are multiple problems with the functionality of the neurons and astrocytes in the irradiated hippocampi, which appear to be further exacerbated in the rats that have impaired spatial memory performance or partially compensated for in the rats with good spatial memory.

Reduction of adult hippocampal neurogenesis is amplified by aluminum exposure in a model of type 2 diabetes

PubMed Central

Nam, Sung Min; Kim, Jong Whi; Yoo, Dae Young; Jung, Hyo Young; Choi, Jung Hoon; Hwang, In Koo; Seong, Je Kyung

2016-01-01

In this study, we investigated the effects of chronic aluminum (Al) exposure for 10 weeks on cell proliferation and neuroblast differentiation in the hippocampus of type 2 diabetic rats. Six-week-old Zucker diabetic fatty (ZDF) and Zucker lean control (ZLC) rats were selected and randomly divided into Al- and non-Al-groups. Al was administered via drinking water for 10 weeks, after which the animals were sacrificed at 16 weeks of age. ZDF rats in both Al- and non-Al-groups showed increases in body weight and blood glucose levels compared to ZLC rats. Al exposure did not significantly affect body weight, blood glucose levels or pancreatic β-cells and morphology of the pancreas in either ZLC or ZDF rats. However, exposure to Al reduced cell proliferation and neuroblast differentiation in both ZLC and ZDF rats. Exposure to Al resulted in poor development of the dendritic processes of neuroblasts in both ZLC and ZDF rats. Furthermore, onset and continuation of diabetes reduced cell proliferation and neuroblast differentiation, and Al exposure amplified reduction of these parameters. These results suggest that Al exposure via drinking water aggravates the impairment in hippocampal neurogenesis that is typically observed in type 2 diabetic animals. PMID:27051335

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.

Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats.

PubMed

Kennedy, Bruce C; Dimova, Jiva G; Siddappa, Asha J M; Tran, Phu V; Gewirtz, Jonathan C; Georgieff, Michael K

2014-11-01

Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal-neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. Pregnant rat dams were administered an iron-deficient (2-6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11-18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. © 2014 American Society for Nutrition.

Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ9-THC exposure.

PubMed

Beggiato, Sarah; Borelli, Andrea Celeste; Tomasini, Maria Cristina; Morgano, Lucia; Antonelli, Tiziana; Tanganelli, Sergio; Cuomo, Vincenzo; Ferraro, Luca

2017-03-01

The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta 9 -tetrahydrocannabinol (Δ 9 -THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ 9 -THC induced a significant reduction (p<0.05) in basal and K + -evoked [ 3 H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [ 3 H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ 9 -THC induced a significant reduction of CB1 receptor binding (B max ) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ 9 -THC (0.1μM) or WIN55,212-2 (2μM), similarly reduced K + -evoked [ 3 H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported. Copyright © 2017 Elsevier Inc. All rights reserved.

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

PubMed Central

Greenwood, Benjamin N.; Strong, Paul V.; Foley, Teresa E.; Thompson, Robert; Fleshner, Monika

2007-01-01

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 hours later. Finally, bilateral injections of BDNF (1 μg) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness. PMID:17161541

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus.

PubMed

Greenwood, B N; Strong, P V; Foley, T E; Thompson, R S; Fleshner, M

2007-02-23

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Alcohol Alert: Alcohol's Damaging Effects on the Brain

MedlinePlus

... early stages of development, as researchers strive to design therapies that can help prevent alcohol’s harmful effects ... of postnatal hippocampal neurogenesis in rats. Journal of Comparative Neurology 124(3):319–335, 1965. (30) Crews, ...

Effects of prenatal low-dose beta radiation from tritiated water on learning and memory in rats and their possible mechanisms.

PubMed

Gao, W M; Wang, B; Zhou, X Y

1999-09-01

Pregnant adult Wistar rats were randomly divided into four groups. Three of these groups were irradiated with beta rays by a single intraperitoneal injection of tritiated water ((3)H(2)O) administered on the 13th day of gestation. The doses absorbed by their offspring were estimated to be 4.6, 9.2 and 27.3 cGy. The influence of radiation on the postnatal learning ability and memory behavior and on brain development of the offspring was investigated. The number of pyramidal cells (in areas CA1, CA2, CA3 and CA4) and neurons in the hippocampus of the offspring was also measured. In addition, the Ca(++) conductance of hippocampal pyramidal cells cultured in vitro was observed. The results showed that an exposure to 4.6 cGy could prolong avoidance response time significantly and decrease the number of hippocampal pyramidal cells in the CA1 area compared to controls. An exposure to 9.2 cGy significantly decreased the establishment of conditioned reflexes and the number of hippocampal pyramidal cells in the CA3 area. This exposure also induced the degeneration and malformation of hippocampal neurons cultured in vitro, in addition to decreasing the number of hippocampal neurons observed on each culture day. A dose of 27.3 cGy significantly decreased brain and body weights and the maximum electric conductance of Ca(++) in hippocampal pyramidal neurons. In general, dose-dependent effects were observed for most of the parameters assessed in the present study. Possible mechanisms are discussed.

Cerveau isolé and pretrigeminal rat preparations.

PubMed

Zernicki, B; Gandolfo, G; Glin, L; Gottesmann, C

1985-01-01

Cortical and hippocampal EEG activity was analysed in cerveau isolé and and pretrigeminal rats. In the acute stage, waking EEG patterns were absent in the cerveau isolé, whereas sleep EGG patterns were absent in the preparations. However, already on the second day the EEG waking sleep cycle recovered in the majority of rats. Paradoxically, stimuli directed to the caudal part of the preparations evoked stronger cortical and hippocampal EEG arousal than olfactory and visual stimuli. The rats exhibited some locomotor and grooming behaviour and could be fed orally. It is concluded that the activity of the isolated cerebrum of the rat is similar to that of cat preparations, but that functions of the caudal neuraxis are superior in rats.

Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats.

PubMed

Yau, S-Y; Lau, B W-M; Zhang, E-D; Lee, J C-D; Li, A; Lee, T M C; Ching, Y-P; Xu, A-M; So, K-F

2012-10-11

Previous studies have shown that a 2-week treatment with 40 mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running-elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5 days) and chronic (4 weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non-runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a significant alteration in hippocampal levels, suggesting that treatment with running/CORT for 4 weeks may induce a change in central levels of hippocampal BDNF level, which may not lead to a significant change in peripheral levels. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Possible cause for altered spatial cognition of prepubescent rats exposed to chronic radiofrequency electromagnetic radiation.

PubMed

Narayanan, Sareesh Naduvil; Kumar, Raju Suresh; Karun, Kalesh M; Nayak, Satheesha B; Bhat, P Gopalakrishna

2015-10-01

The effects of chronic and repeated radiofrequency electromagnetic radiation (RFEMR) exposure on spatial cognition and hippocampal architecture were investigated in prepubescent rats. Four weeks old male Wistar rats were exposed to RF-EMR (900 MHz; SAR-1.15 W/kg with peak power density of 146.60 μW/cm(2)) for 1 h/day, for 28 days. Followed by this, spatial cognition was evaluated by Morris water maze test. To evaluate the hippocampal morphology; H&E staining, cresyl violet staining, and Golgi-Cox staining were performed on hippocampal sections. CA3 pyramidal neuron morphology and surviving neuron count (in CA3 region) were studied using H&E and cresyl violet stained sections. Dendritic arborization pattern of CA3 pyramidal neuron was investigated by concentric circle method. Progressive learning abilities were found to be decreased in RF-EMR exposed rats. Memory retention test performed 24 h after the last training revealed minor spatial memory deficit in RF-EMR exposed group. However, RF-EMR exposed rats exhibited poor spatial memory retention when tested 48 h after the final trial. Hirano bodies and Granulovacuolar bodies were absent in the CA3 pyramidal neurons of different groups studied. Nevertheless, RF-EMR exposure affected the viable cell count in dorsal hippocampal CA3 region. RF-EMR exposure influenced dendritic arborization pattern of both apical and basal dendritic trees in RF-EMR exposed rats. Structural changes found in the hippocampus of RF-EMR exposed rats could be one of the possible reasons for altered cognition.

Locomotor damage in rats after X-irradiation in utero

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

Mullenix, Phyllis; Norton, Stata; Culver, Bruce

1975-08-01

Alterations in gait were found in rats after whole-body irradiation with 125 R on day 14, 15, and 16 of gestation. No effects on locomotion were detected after irradiation on day 17 with 125 R or after irradiation on day 14 with 50 R. A technique was set up for quantitative evaluation of locomotion based on a modification of other methods. Walking patterns of irradiated rats were recorded, when they were adults, by requiring them to walk up a 10$sup 0$ incline through a corridor after their feet had been dipped in ink. Rats irradiated on gestational day 14 hadmore » an in-phase, hopping gait with the sine of the angle between the hind feet and the direction of progression over 0.9. Rats irradiated on gestational days 15 and 16 had an alternating, waddling gait with wider stance and broader angle than control rats. Histologic examination of serial sections of the brains of these rats showed that the 14-day rats lacked all telencephalic commissures except for a few fibers which crossed in some rats. There was a progressive improvement in the condition of the anterior and ventral hippocampal commissures up to day 17, but the corpus callosum and doral hippocampal commissure were lacking or markedly reduced in all day 17 rats. No animals showed damage to the mesencephalic posterior commissure. Since rats which used the in-phase mode of locomotion were never observed to use alternating gait, the possible causal relationship of the commissural damage to the altered locomotor patterns was considered. In view of the restricted period of damage found for the anterior and ventral hippocampal commissures and the restriction of altered locomotion to damage in the same period, primary involvement of the corpus callosum and dorsal hippocampal commissure could be excluded, but a possible role for the other telencephalic commissures remained. (auth)« less

Fornix lesions decouple the induction of hippocampal arc transcription from behavior but not plasticity.

PubMed

Fletcher, Bonnie R; Calhoun, Michael E; Rapp, Peter R; Shapiro, Matthew L

2006-02-01

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity.

Stimulation of estradiol biosynthesis by tributyltin in rat hippocampal slices.

PubMed

Munetsuna, Eiji; Hattori, Minoru; Yamazaki, Takeshi

2014-01-01

Hippocampal functions are influenced by steroid hormones, such as testosterone and estradiol. It has been demonstrated that hippocampus-derived steroid hormones play important roles in neuronal protection and synapse formation. Our research groups have demonstrated that estradiol is de novo synthesized in the rat hippocampus. However, the mechanism(s) regulating this synthesis remains unclear. It has been reported that tributyltin, an environmental pollutant, binds to the retinoid X receptor (RXR) and modifies estrogen synthesis in human granulosa-like tumor cells. This compound can penetrate the blood brain barrier, and tends to accumulate in the brain. Based on these facts, we hypothesized that tributyltin could influence the hippocampal estradiol synthesis. A concentration of 0.1 μM tributyltin induced an increase in the mRNA content of P450(17α) and P450arom in hippocampal slices, as determined using real-time PCR. The transcript levels of other steroidogenic enzymes and a steroidogenic acute regulatory protein were not affected. The estradiol level in rat hippocampal slices was subsequently determined using a radioimmunoassay. We found that the estradiol synthesis was stimulated by ∼2-fold following a 48-h treatment with 0.1 μM tributyltin, and this was accompanied by transcriptional activation of P450(17α) and P450arom. Tributyltin stimulated de novo hippocampal estradiol synthesis by modifying the transcription of specific steroidogenic enzymes.

Spatial learning impairment induced by chronic stress is related to individual differences in novelty reactivity: search for neurobiological correlates.

PubMed

Touyarot, K; Venero, C; Sandi, C

2004-02-01

Although chronic stress has been reported to induce deleterious effects on hippocampal structure and function, the possible existence of individual differences in the vulnerability to develop stress-induced cognitive alterations was hypothesized. This study was designed to evaluate (i) whether individual variability in behavioural reactivity to novelty could be related to a differential vulnerability to show spatial learning deficits after chronic stress in young adult rats, and (ii) to what extent, could individual differences in stress-induced cognitive alterations be related to alterations in specific neurobiological substrates. Four month-old Wistar male rats were classified according to their locomotor reactivity to a novel environment, as either low (LR) or highly (HR) reactive, and then either submitted to psychosocial stress for 21-days (consisting of the daily cohabitation of each young adult rat with a new middle-aged rat) or left undisturbed. The results showed that psychosocial stress induced a marked deficit in spatial learning in the water maze in HR, but not in LR, rats. Then, a second experiment investigated the possible differential expression of corticosteroid receptors (MR and GR) and cell adhesion molecules (NCAM and L1) in the hippocampus of HR and LR rats, both under basal conditions and after exposure to chronic social stress. Although chronic stress induced a reduction on the hippocampal expression of MRs and the NCAM-140 isoform, the levels of these molecules did not differ between stressed rats with and without spatial learning impairments; i.e., between HR- and LR-stressed rats, respectively. Nevertheless, it should be noted that the reduction of the hippocampal expression of NCAM-140 induced by psychosocial stress was particularly marked in HR stressed rats. However, the expression of GRs, NCAM-120 and NCAM-180 isoforms, and L1, was not affected by stress, regardless of the reactivity of the animals. Therefore, although we failed to find a neurobiological substrate that specifically correlated with the differential cognitive vulnerability to chronic stress shown by animals with a different novelty reactivity, this study confirms the hypothesis that rats differ in their susceptibility to display stress-induced impairments in hippocampus-dependent spatial learning tasks. In addition, it provides a model to further search for the neurobiological substrate(s) involved in the differential susceptibility to develop stress-induced cognitive impairments.

Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

PubMed

Bulin, Sarah E; Mendoza, Matthew L; Richardson, Devon R; Song, Kwang H; Solberg, Timothy D; Yun, Sanghee; Eisch, Amelia J

2018-03-01

Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. © 2017 Society for the Study of Addiction.

RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.

PubMed

Sinkevicius, Kerstin W; Morrison, Thomas R; Kulkarni, Praveen; Caffrey Cagliostro, Martha K; Iriah, Sade; Malmberg, Samantha; Sabrick, Julia; Honeycutt, Jennifer A; Askew, Kim L; Trivedi, Malav; Ferris, Craig F

2018-06-27

RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function. © 2018. Published by The Company of Biologists Ltd.

Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters.

PubMed

Rosa, Suzan Gonçalves; Quines, Caroline Brandão; Stangherlin, Eluza Curte; Nogueira, Cristina Wayne

2016-03-01

Monosodium glutamate (MSG), a flavor enhancer used in food, administered to neonatal rats causes neuronal lesions and leads to anxiety when adulthood. We investigated the anxiolytic-like effect of diphenyl diselenide (PhSe)2 and its mechanisms on anxiety induced by MSG. Neonatal male and female Wistar rats received a subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 10th postnatal day. At 60 days of life, the rats received (PhSe)2 (1mg/kg/day) or vehicle by the intragastric route for 7 days. The spontaneous locomotor activity (LAM), elevated plus maze test (EPM) and contextual fear conditioning test (CFC) as well as neurochemical ([(3)H]GABA and [(3)H]5-HT uptake) and molecular analyses (Akt and p-Akt and BDNF levels) were carried out after treatment with (PhSe)2. Neonatal exposure to MSG increased all anxiogenic parameters in LAM, EPM and CFC tests. MSG increased GABA and 5-HT uptake in hippocampus of rats, without changing uptake in cerebral cortex. The levels of BDNF and p-Akt were reduced in hippocampus of rats treated with MSG. The administration of (PhSe)2 to rats reversed all behavioral anxiogenic parameters altered by MSG. The increase in hippocampal GABA and 5-HT uptake induced by MSG was reversed by (PhSe)2. (PhSe)2 reversed the reduction in hippocampal BDNF and p-Akt levels induced by MSG. In conclusion, the anxiolytic-like action of (PhSe)2 in rats exposed to MSG during their neonatal period is related to its modulation of hippocampal GABA and 5-HT uptake as well as the BDNF-Akt pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats.

PubMed

Langley, S C; York, D A

1990-09-01

The effects of RU 486 (mitepristone), an antagonist of type II glucocorticoid receptors (GR), on the development of obesity in young 5-wk-old obese fa/fa rats has been investigated. After 15 days of treatment, body composition of obese RU 486-treated rats was similar to that of lean-vehicle rats. Analysis of body composition changes showed that RU 486 effectively reversed the obesity. It stopped fat deposition in obese rats but increased protein deposition to the level of lean-vehicle rats. RU 486 prevented the development of hyperphagia and reduced gross energetic efficiency in the obese rats but had little effect on lean rats. Brown adipose tissue mitochondrial GDP binding was increased in obese rats but was reduced in lean rats by RU 486 treatment. RU 486 also reduced the elevated activity of hippocampal glycerophosphate dehydrogenase, a glucocorticoid-responsive enzyme, of obese rats to the level of lean rats. The evidence suggests that abnormal activity of glucocorticoid GR receptors or abnormal cellular responsiveness to corticosterone receptor complexes may be important in the development of obesity in the fa/fa rat.

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.

Role of silent information regulator 1 in the protective effect of hydrogen sulfide on homocysteine-induced cognitive dysfunction: Involving reduction of hippocampal ER stress.

PubMed

Tang, Yi-Yun; Wang, Ai-Ping; Wei, Hai-Jun; Li, Man-Hong; Zou, Wei; Li, Xiang; Wang, Chun-Yan; Zhang, Ping; Tang, Xiao-Qing

2018-04-16

Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H 2 S) attenuates Hcy-induced cognitive dysfunction and hippocampal ER stress. Silent information regulator 1 (Sirt-1) is indispensable in the formation of learning and memory. Therefore, the aim of this study was to explore the role of Sirt-1 in the protective effect of H 2 S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H 2 S) markedly up-regulated the expression of Sirt-1 in the hippocampus of Hcy-exposed rats. Sirtinol, a specific inhibitor of Sirt-1, reversed the improving role of NaHS in the cognitive function of Hcy-exposed rats, as evidenced by that sirtinol increased the escape latency and the swim distance in the acquisition trial of morris water maze (MWM) test, decreased the times crossed through and the time spent in the target quadrant in the probe trail of MWM test, and reduced the discrimination index in the novel object recognition test (NORT) in the rats cotreated with NaHS and Hcy. We also found that sirtinol reversed the protection of NaHS against Hcy-induced hippocampal ER-stress, as evidenced by up-regulating the expressions of GRP78, CHOP, and cleaved caspase-12 in the hippocampus of rats cotreated with NaHS and Hcy. These results suggested the contribution of upregulation of hippocampal Sirt-1 to the improving role of H 2 S in the cognitive function of Hcy-exposed rats, which involves suppression of hippocampal ER stress. Our finding provides a new insight into the mechanism underlying the inhibitory role of H 2 S in Hcy-induced cognitive dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

The Protective Effects of Insulin and Natural Honey against Hippocampal Cell Death in Streptozotocin-Induced Diabetic Rats

PubMed Central

Jafari Anarkooli, Iraj; Barzegar Ganji, Hossein; Pourheidar, Maryam

2014-01-01

We investigated the effects of insulin and honey as antioxidants to prevent the hippocampal cell death in streptozotocin-induced diabetic rats. We selected sixty Wister rats (5 groups of 12 animals each), including the control group (C), and four diabetic groups (control (D) and 3 groups treated with insulin (I), honey (H), and insulin plus honey (I + H)). Diabetes was induced by streptozotocin injection (IP, 60 mg/kg). Six weeks after the induction of diabetes, the group I received insulin (3-4 U/kg/day, SC), group H received honey (5 mg/kg/day, IP), and group I + H received a combination of the above at the same dose. Groups C and D received normal saline. Two weeks after treatment, rats were sacrificed and the hippocampus was extracted. Neuronal cell death in the hippocampal region was examined using trypan blue assay, “H & E” staining, and TUNEL assay. Cell viability assessment showed significantly lower number of living cells in group D than in group C. Besides, the mean number of living cells was significantly higher in group I, H, and I + H compared to group D. Therefore, it can be concluded that the treatment of the diabetic rats with insulin, honey, and a combination of insulin and honey can prevent neuronal cell death in different hippocampal areas of the studied samples. PMID:24745031

The protective effects of insulin and natural honey against hippocampal cell death in streptozotocin-induced diabetic rats.

PubMed

Jafari Anarkooli, Iraj; Barzegar Ganji, Hossein; Pourheidar, Maryam

2014-01-01

We investigated the effects of insulin and honey as antioxidants to prevent the hippocampal cell death in streptozotocin-induced diabetic rats. We selected sixty Wister rats (5 groups of 12 animals each), including the control group (C), and four diabetic groups (control (D) and 3 groups treated with insulin (I), honey (H), and insulin plus honey (I + H)). Diabetes was induced by streptozotocin injection (IP, 60 mg/kg). Six weeks after the induction of diabetes, the group I received insulin (3-4 U/kg/day, SC), group H received honey (5 mg/kg/day, IP), and group I + H received a combination of the above at the same dose. Groups C and D received normal saline. Two weeks after treatment, rats were sacrificed and the hippocampus was extracted. Neuronal cell death in the hippocampal region was examined using trypan blue assay, "H & E" staining, and TUNEL assay. Cell viability assessment showed significantly lower number of living cells in group D than in group C. Besides, the mean number of living cells was significantly higher in group I, H, and I + H compared to group D. Therefore, it can be concluded that the treatment of the diabetic rats with insulin, honey, and a combination of insulin and honey can prevent neuronal cell death in different hippocampal areas of the studied samples.

Distinct roles of hippocampus and medial prefrontal cortex in spatial and nonspatial memory.

PubMed

Sapiurka, Maya; Squire, Larry R; Clark, Robert E

2016-12-01

In earlier work, patients with hippocampal damage successfully path integrated, apparently by maintaining spatial information in working memory. In contrast, rats with hippocampal damage were unable to path integrate, even when the paths were simple and working memory might have been expected to support performance. We considered possible ways to understand these findings. We tested rats with either hippocampal lesions or lesions of medial prefrontal cortex (mPFC) on three tasks of spatial or nonspatial memory: path integration, spatial alternation, and a nonspatial alternation task. Rats with mPFC lesions were impaired on both spatial and nonspatial alternation but performed normally on path integration. By contrast, rats with hippocampal lesions were impaired on path integration and spatial alternation but performed normally on nonspatial alternation. We propose that rodent neocortex is limited in its ability to construct a coherent spatial working memory of complex environments. Accordingly, in tasks such as path integration and spatial alternation, working memory cannot depend on neocortex alone. Rats may accomplish many spatial memory tasks by relying on long-term memory. Alternatively, they may accomplish these tasks within working memory through sustained coordination between hippocampus and other cortical brain regions such as mPFC, in the case of spatial alternation, or parietal cortex in the case of path integration. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

PubMed

Chambers, R Andrew; Self, David W

2002-12-01

The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

Anti-kindling Effect of Bezafibrate, a Peroxisome Proliferator-activated Receptors Alpha Agonist, in Pentylenetetrazole Induced Kindling Seizure Model

PubMed Central

Saha, Lekha; Bhandari, Swati; Bhatia, Alka; Banerjee, Dibyajyoti; Chakrabarti, Amitava

2014-01-01

Background and Purpose: Studies in the animals suggested that Peroxisome proliferators activated receptors (PPARs) may be involved in seizure control and selective agonists of PPAR α or PPAR γ raise seizure thresholds. The present study was contemplated with the aim of evaluating the anti kindling effects and the mechanism of bezafibrate, a Peroxisome proliferator-activated receptors α (PPAR-α) agonist in pentylenetetrazole (PTZ) induced kindling model of seizures in rats. Methods: In a PTZ kindled Wistar rat model, different doses of bezafibrate (100 mg/kg, 200 mg/kg and 300 mg/kg) were administered intraperitoneally 30 minutes before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The parameters measured were the latency to develop kindling and incidence of kindling, histopathological study of hippocampus, hippocampal lipid peroxidation studies, serum neuron specific enolase, and hippocampal DNA fragmentation study. Results: In this study, bezafibrate significantly reduced the incidence of kindling in PTZ treated rats and exhibited a marked prolongation in the latencies to seizures. In the present study bezafibrate decreased the thiobarbituric acid-reactive substance i.e. Malondialdehyde levels, increased the reduced glutathione levels, catalase and superoxide dismutase activity in the brain. This added to its additional neuroprotective effects. Bezafibrate also reduced the neuronal damage and apoptosis in hippocampal area of the brain. Therefore bezafibrate exerted anticonvulsant properties in PTZ induced kindling model in rats. Conclusions: These findings may provide insights into the understanding of the mechanism of bezafibrate as an anti kindling agent and could offer a useful support to the basic antiepileptic therapy in preventing the development of PTZ induced seizures, suggesting its potential for therapeutic applications in temporal lobe epilepsy. PMID:25625088

Contribution of hippocampal area CA1 to acetone cyanohydrin-induced loss of motor coordination in rats.

PubMed

Rivadeneyra-Domínguez, E; Vázquez-Luna, A; Díaz-Sobac, R; Briones-Céspedes, E E; Rodríguez-Landa, J F

2017-05-01

Some vegetable foodstuffs contain toxic compounds that, when consumed, favour the development of certain diseases. Cassava (Manihot esculenta Crantz) is an important food source, but it contains cyanogenic glucosides (linamarin and lotaustralin) that have been associated with the development of tropical ataxic neuropathy and konzo. In rats, intraperitoneal administration of acetone cyanohydrin (a metabolite of linamarin) produces neurological disorders and neuronal damage in the hippocampus. However, it is unknown whether hippocampal area CA1 plays a role in neurological disorders associated with acetone cyanohydrin. A total of 32 male Wistar rats 3 months old were assigned to 4 groups (n=8 per group) as follows: vehicle (1μl physiological saline), and 3 groups with acetone cyanohydrin (1μl of 10, 15, and 20mM solution, respectively). The substances were microinjected intrahippocampally every 24hours for 7 consecutive days, and their effects on locomotor activity, rota-rod and swim tests were assessed daily. On the fifth day post-treatment, rats underwent further assessment with behavioural tests to identify or rule out permanent damage induced by acetone cyanohydrin. Microinjection of acetone cyanohydrin 20mM resulted in hyperactivity, motor impairment, and reduced exploration from the third day of treatment. All concentrations of acetone cyanohydrin produced rotational behaviour in the swim test from the first day of microinjection. The hippocampal area CA1 is involved in motor alterations induced by microinjection of acetone cyanohydrin, as has been reported for other cassava compounds. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Effects of third trimester-equivalent ethanol exposure on Cl(-) co-transporter expression, network activity, and GABAergic transmission in the CA3 hippocampal region of neonatal rats.

PubMed

Everett, Julie C; Licón-Muñoz, Yamhilette; Valenzuela, C Fernando

2012-09-01

Fetal alcohol spectrum disorders are often associated with structural and functional hippocampal abnormalities, leading to long-lasting learning and memory deficits. The mechanisms underlying these abnormalities are not fully understood. Here, we investigated whether ethanol exposure during the 3rd trimester-equivalent period alters spontaneous network activity that is involved in neuronal circuit development in the CA3 hippocampal region. This activity is driven by GABA(A) receptors, which can have excitatory actions in developing neurons as a consequence of greater expression of the Cl(-) importer, NKCC1, with respect to expression of the Cl(-) exporter, KCC2, resulting in high [Cl(-)](i). Rat pups were exposed to ethanol vapor from postnatal day (P) 2-16 (4 h/day). Weight gain was significantly reduced in pups exposed to ethanol compared to control at P15 and 16. Brain slices were prepared immediately after the end of the 4-h exposure on P4-16 and experiments were also performed under ethanol-free conditions at the end of the exposure paradigm (P17-22). Ethanol exposure did not significantly affect expression of KCC2 or NKCC1, nor did it affect network activity in the CA3 hippocampal region. Ethanol exposure significantly decreased the frequency (at P9-11) and increased the amplitude (at P5-8 and P17-21) of GABA(A) receptor-mediated miniature postsynaptic currents. These data suggest that repeated in vivo exposure to ethanol during the 3rd trimester-equivalent period alters GABAergic transmission in the CA3 hippocampal region, an effect that could lead to abnormal circuit maturation and perhaps contribute to the pathophysiology of fetal alcohol spectrum disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Developmental studies of the hippocampus and hippocampal-dependent behaviors: insights from interdisciplinary studies and tips for new investigators.

PubMed

Albani, Sarah H; McHail, Daniel G; Dumas, Theodore C

2014-06-01

The hippocampus is not fully developed at birth and, with respect to spatial cognition, only begins to show signs of adult-like function at three postnatal weeks in rodents. Studying the developmental period spanning roughly two to four weeks of age permits an understanding of the neural framework necessary for the emergence of spatial navigation and, quite possibly, human episodic memory. However, due to developmental factors, behavior data collection and interpretation can be severely compromised if inappropriate designs are applied. As such, we propose methodological considerations for the behavioral assessment of hippocampal function in developing rats that take into account animal size, growth rate, and sensory and motor ability. We further summarize recent key interdisciplinary studies that are beginning to unravel the molecular machinery and physiological alterations responsible for hippocampal maturation. In general, hippocampal development is a protracted process during which unique contributions to spatial cognition and complex recognition memory come "on line" at different postnatal ages creating a unique situation for elucidating the neural bases of specific components of higher cognitive abilities. Copyright © 2014 Elsevier Ltd. All rights reserved.

Developmental studies of the hippocampus and hippocampal-dependent behaviors: Insights from interdisciplinary studies and tips for new investigators

PubMed Central

Albani, Sarah H.; McHail, Daniel G.; Dumas, Theodore C.

2016-01-01

The hippocampus is not fully developed at birth and, with respect to spatial cognition, only begins to show signs of adult-like function at three postnatal weeks in rodents. Studying the developmental period spanning roughly two to four weeks of age permits an understanding of the neural framework necessary for the emergence of spatial navigation and, quite possibly, human episodic memory. However, due to developmental factors, behavior data collection and interpretation can be severely compromised if inappropriate designs are applied. As such, we propose methodological considerations for the behavioral assessment of hippocampal function in developing rats that take into account animal size, growth rate, and sensory and motor ability. We further summarize recent key interdisciplinary studies that are beginning to unravel the molecular machinery and physiological alterations responsible for hippocampal maturation. In general, hippocampal development is a protracted process during which unique contributions to spatial cognition and complex recognition memory come “on line” at different postnatal ages creating a unique situation for elucidating the neural bases of specific components of higher cognitive abilities. PMID:24769291

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.

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

PubMed

Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

2016-12-01

Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

Housing environment influences stress-related hippocampal substrates and depression-like behavior.

PubMed

Ashokan, Archana; Hegde, Akshaya; Balasingham, Anushanthy; Mitra, Rupshi

2018-03-15

Rats are widely used animal models for biological psychiatry and neuroscience. Laboratory rats are typically housed in impoverished sensory environments. The lack of species-typical sensory environment might radically change the response of individual animals to stressful and/or threatening episodes. In this report, we demonstrate that behavioral and neural sequelae of chronic stress were modified by sensory environment of adult male rats. This includes effects of stress on the density of spines on CA3 hippocampal neurons, hippocampal neurogenesis and abundance of glucocorticoid or mineralocorticoid receptors. Enrichment also reduced depression-like behavior in a forced swim task. Stress and sensory enrichment evoked opposing effects on all the above endpoints. The sensory enrichment used in this report is of a relatively short duration provided during adulthood. This period excludes critical windows of greater plasticity during pre- and peripubertal stages. Our results suggest that standard housing practices for laboratory rats remain austere concerning sensory requirements of this species. Thus, even a moderate sensory enrichment is capable of reducing high stress-sensitivity and depressive-like behavior in standard laboratory rats. Copyright © 2018. Published by Elsevier B.V.

MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity.

PubMed

Molet, Jenny; Maras, Pamela M; Kinney-Lang, Eli; Harris, Neil G; Rashid, Faisal; Ivy, Autumn S; Solodkin, Ana; Obenaus, Andre; Baram, Tallie Z

2016-12-01

Memory and related cognitive functions are progressively impaired in a subgroup of individuals experiencing childhood adversity and stress. However, it is not possible to identify vulnerable individuals early, a crucial step for intervention. In this study, high-resolution magnetic resonance imaging (MRI) and intra-hippocampal diffusion tensor imaging (DTI) were employed to examine for structural signatures of cognitive adolescent vulnerabilities in a rodent model of early-life adversity. These methods were complemented by neuroanatomical and functional assessments of hippocampal network integrity during adolescence, adulthood and middle-age. The high-resolution MRI identified selective loss of dorsal hippocampal volume, and intra-hippocampal DTI uncovered disruption of dendritic structure, consistent with disrupted local connectivity, already during late adolescence in adversity-experiencing rats. Memory deteriorated over time, and stunting of hippocampal dendritic trees was apparent on neuroanatomical analyses. Thus, disrupted hippocampal neuronal structure and connectivity, associated with cognitive impairments, are detectable via non-invasive imaging modalities in rats experiencing early-life adversity. These high-resolution imaging approaches may constitute promising tools for prediction and assessment of at-risk individuals in the clinic. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats

PubMed Central

Pyter, Leah M.; Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2013-01-01

Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective-like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37–48) and were challenged with lipopolysaccharide (LPS; 250 μg/kg, i.p.) or saline 4.5 weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective-like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation. PMID:23348027

Aging is accompanied by a subfield-specific reduction of serotonergic fibers in the tree shrew hippocampal formation.

PubMed

Keuker, Jeanine I H; Keijser, Jan N; Nyakas, Csaba; Luiten, Paul G M; Fuchs, Eberhard

2005-12-01

The hippocampal formation is a crucial structure for learning and memory, and serotonin together with other neurotransmitters is essential in these processes. Although the effects of aging on various neurotransmitter systems in the hippocampus have been extensively investigated, it is not entirely clear whether or how the hippocampal serotonergic innervation changes during aging. Rat studies, which have mostly focused on aging-related changes in the dentate gyrus, have implied a loss of hippocampal serotonergic fibers. We used the tree shrew (Tupaia belangeri), an intermediate between insectivores and primates, as a model of aging. We applied immunocytochemistry with an antibody against serotonin to assess serotonergic fiber densities in the various hippocampal subfields of adult (0.9-1.3 years) and old (5-7 years) tree shrews. Our results have revealed a reduction of serotonergic fiber densities in the stratum radiatum of CA1 and CA3, and in the stratum oriens of CA3. A partial depletion of serotonin in the hippocampal formation, as can be expected from our current observations, will probably have an impact on the functioning of hippocampal principal neurons. Our findings also indicate that the rat and the tree shrew hippocampal serotonergic innervation show some variations that seem to be differentially affected during aging.

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.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats.

PubMed

Pudell, Claudia; Vicente, Bianca A; Delattre, Ana M; Carabelli, Bruno; Mori, Marco A; Suchecki, Deborah; Machado, Ricardo B; Zanata, Sílvio M; Visentainer, Jesuí V; de Oliveira Santos Junior, Oscar; Lima, Marcelo M S; Ferraz, Anete C

2014-01-01

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

PubMed Central

2014-01-01

Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats

PubMed Central

Glenn, Melissa J.; Kirby, Elizabeth D.; Gibson, Erin M.; Wong-Goodrich, Sarah; Mellott, Tiffany J.; Blusztajn, Jan K.; Williams, Christina L.

2008-01-01

Supplemental choline in the maternal diet produces a lasting enhancement in memory in offspring that resists age-related decline and is accompanied by neuroanatomical, neurophysiological and neurochemical changes in the hippocampus. The present study was designed to examine: 1) if prenatal choline supplementation alters behaviors that contribute to risk or resilience in cognitive aging, and 2) whether, at old age (25 months), prenatally choline supplemented rats show evidence of preserved hippocampal plasticity. A longitudinal design was used to look at exploration of an open field, with and without objects, at 1 and 24 months of age in male and female rats whose mothers were fed a diet supplemented with choline (SUP; 5 mg/kg choline chloride) or not supplemented (CON; 1.1 mg/kg choline chloride) on embryonic days 12–17. Aging caused a significant decline in open field exploration that was more pronounced in males but interest in novel objects was maintained in both sexes. Prenatal choline supplementation attenuated, but did not prevent age-related decline in exploration in males and increased object exploration in young females. Following behavioral assessment, rats were euthanized to assess markers of hippocampal plasticity. Aged SUP males and females had more newly proliferated cells in the hippocampal dentate gyrus and protein levels of vascular-endothelial growth factor (VEGF) and neurotrophin-3 (NT-3) were significantly elevated in female SUP rats in comparison to all other groups. Taken together, these findings provide the first evidence that prenatal cholinesupplementation causes changes in exploratory behaviors over the lifespan and preserves some features of hippocampal plasticity that can be seen even at 2 years of age. PMID:18786518

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats

PubMed Central

2012-01-01

Background Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment. Methods The experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia. Results The present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non-diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin. Conclusion The present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury. PMID:22830525

Erythropoietin Improved Cognitive Function and Decreased Hippocampal Caspase Activity in Rat Pups after Traumatic Brain Injury

PubMed Central

Requena, Daniela F.; Block, Benjamin; Davis, Lizeth J.; Rodesch, Christopher; Casper, T. Charles; Juul, Sandra E.; Kesner, Raymond P.; Lane, Robert H.

2014-01-01

Abstract Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model. Hypothesis: We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI). Methods: EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2. Results: EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury. PMID:23972011

Beneficial effects of exercise and its molecular mechanisms on depression in rats

PubMed Central

Zheng, Hang; Liu, Yanyou; Li, Wei; Yang, Bo; Chen, Dengbang; Wang, Xiaojia; Jiang, Zhou; Wang, Hongxing; Wang, Zhengrong; Cornelisson, G.; Halberg, F.

2008-01-01

Exercise showed the beneficial effects on mental health in depressed sufferers, whereas, its underlying mechanisms remained unresolved. This study utilized the chronic unpredictable stress (CNS) animal model of depression to evaluate the effects of exercise on depressive behaviors and spatial performance in rats. Furthermore, we tested the hypothesis that the capacity of exercise to reverse the harmful effects of CNS was relative to the hypothalamo–pituitary–adrenal (HPA) system and brain-derived neurotrophic factor (BDNF) in the hippocampus. Animal groups were exposed to CNS for 4 weeks with and without access to voluntary wheel running. Stressed rats consumed significantly less of a 1% sucrose solution during CNS and exhibited a significant decrease in open field behavior. On the other hand, they showed impaired spatial performance in Morris water maze test 2 weeks after the end of CNS. Further, CNS significantly decreased hippocampal BDNF mRNA levels. However, voluntary exercise improved or even reversed these harmful behavioral effects in stressed rats. Furthermore, exercise counteracted a decrease in hippocampal BDNF mRNA caused by CNS. In addition, we also found that CMS alone increased circulating corticosterone (CORT) significantly and decreased hippocampal glucocorticoid receptor (GR) mRNA. At the same time, exercise alone increased CORT moderately and did not affect hippocampal GR mRNA levels. While, when both CNS and exercise were combined, exercise reduced the increase of CORT and the decrease of GR caused by CMS. The results demonstrated that: (1) exercise reversed the harmful effects of CNS on mood and spatial performance in rats and (2) the behavioral changes induced by exercise and/or CNS might be associated with hippocampal BDNF levels, and in addition, the HPA system might play different roles in the two different processes. PMID:16290283

Down-regulation of Long Noncoding RNA MALAT1 Protects Hippocampal Neurons Against Excessive Autophagy and Apoptosis via the PI3K/Akt Signaling Pathway in Rats with Epilepsy.

PubMed

Wu, Qiang; Yi, Xuewei

2018-06-01

Epilepsy is a common chronic brain disorder and is characterized by an enduring predisposition to generate seizures. The hippocampus is especially vulnerable to seizure-induced damage. In this study, we explore the ability of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) to influence the autophagy and apoptosis of hippocampal neurons in epilepsy and the underlying mechanism involving the PI3K/Akt signaling pathway. Seventy-two Sprague-Dawley rats were assigned to normal, sham, Ep, Ep + si-NC, Ep + si-MALAT1, and Ep + si-MALAT1 + LY groups. Fluorescence in situ hybridization kit was employed to determine the MALAT1 in the brain tissues. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the expression of MALAT1, mRNAs, and proteins. The autophagy of hippocampal neurons was evaluated under a transmission electron microscope and their apoptosis was evaluated using TUNEL staining. We found that MALAT1 and c-Met were enriched while microRNA-101 (miR-101) decreased in rats with epilepsy. The demonstration showed that MALAT1 binds to miR-101, thus regulating c-Met. In rats with epilepsy, MALAT1 depletion mediated by anti-MALAT1 siRNA resulted in activation of PI3K/Akt signaling pathway and loss of hippocampal neurons. LY294002, an inhibitor of PI3K/Akt signaling pathway, could reverse the events caused by MALAT1 knockdown. Taken together, these findings indicate that down-regulation of MALAT1 activates the PI3K/Akt signaling pathway to protect hippocampal neurons against autophagy and apoptosis in rats with epilepsy.

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.

[ERK activation effects on GABA secretion inhibition induced by SDF-1 in hippocampal neurons of rats].

PubMed

Zhang, Zi-juan; Guo, Mei-xia; Xing, Ying

2015-09-01

To investigate the effect of extracellular regulating kinase (ERK) signaling pathway on the secretion of gamma-aminobutyric acid (GABA) in cultured rat hippocampal neurons induced by stromal cell derived factor-1 (SDF-1). The hippocampal neurons of newborn SD rats were cultured and identified in vitro; the phosphorylation level of ERK1/2 was examined by Western blot; ELISA was used to detect the effect of PD98059, a ERK1/2 specific blocker on GABA secretion of cultured hippocampal neurons and Western blot were adopted to measure the protein expression levels of glutamate decarboxylase (GAD65/67) and gamma aminobutyric acid transporter (GAT); after blocking ERK1/2 signaling pathway with PD98059; RT-PCR was used to detect the mRNA expression levels of GAT-1 and GAD65 after treated with PD98059. The levels of ERKl/2 phosphorylation were increased significantly by SDF1 acting on hippocampal neurons, and CX-CR4 receptor blocker AMD3100, could inhibit SDF-1 induced ERK1/2 activation; SDF-1 could inhibit the secretion of GABA in cultured hippocampal neurons, and ERK1/2 specific inhibitor PD98059, could partly reverse the inhibition of GABA secretion by SDF-1. The effects of SDF-1 on cultured hippocampal neurons was to decrease the mRNA genesis of glutamic acid decarboxylase GAD65 and GABA transporter GAT-1, besides, ERK inhibitor PD98059 could effectively flip the effect of SDF-1. The results of Western blot showed that SDF-1 could inhibit the protein expression of GAT-1 and GAD65/67 in hippocampal neurons and the inhibition of GAT-1 and GAD65/67 protein expression could be partially restored by ERK1/2 blocker. SDF-1 acts on the CXCR4 of hippocampal neurons in vitro, and inhibits the expression of GAD by activating the ERK1/2 signaling pathway, and this may represent one possible pathway of GABA secretion inhibition.

Attenuating brain edema, hippocampal oxidative stress, and cognitive dysfunction in rats using hyperbaric oxygen preconditioning during simulated high-altitude exposure.

PubMed

Lin, Hung; Chang, Ching-Ping; Lin, Hung-Jung; Lin, Mao-Tsun; Tsai, Cheng-Chia

2012-05-01

We assessed whether hyperbaric oxygen preconditioning (HBO2P) in rats induced heat shock protein (HSP)-70 and whether HSP-70 antibody (Ab) preconditioning attenuates high altitude exposure (HAE)-induced brain edema, hippocampal oxidative stress, and cognitive dysfunction. Rats were randomly divided into five groups: the non-HBO2P + non-HAE group, the HBO2P + non-HAE group, the non-HBO2P + HAE group, the HBO2P + HAE group, and the HBO2P + HSP-70 Abs + HAE group. The HBO2P groups were given 100% O2 at 2.0 absolute atmospheres for 1 hour per day for 5 consecutive days. The HAE groups were exposed to simulated HAE (9.7% O2 at 0.47 absolute atmospheres of 6,000 m) in a hypobaric chamber for 3 days. Polyclonal rabbit anti-mouse HSP-70-neutralizing Abs were intravenously injected 24 hours before the HAE experiments. Immediately after returning to normal atmosphere, the rats were given cognitive performance tests, overdosed with a general anesthetic, and then their brains were excised en bloc for water content measurements and biochemical evaluation and analysis. Non-HBO2P group rats displayed cognitive deficits, brain edema, and hippocampal oxidative stress (evidenced by increased toxic oxidizing radicals [e.g., nitric oxide metabolites and hydroxyl radicals], increased pro-oxidant enzymes [e.g., malondialdehyde and oxidized glutathione] but decreased antioxidant enzymes [e.g., reduced glutathione, glutathione peroxide, glutathione reductase, and superoxide dismutase]) in HAE. HBO2P induced HSP-70 overexpression in the hippocampus and significantly attenuated HAE-induced brain edema, cognitive deficits, and hippocampal oxidative stress. The beneficial effects of HBO2P were significantly reduced by HSP-70 Ab preconditioning. Our results suggest that high-altitude cerebral edema, cognitive deficit, and hippocampal oxidative stress can be prevented by HSP-70-mediated HBO2P in rats.

Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

PubMed Central

Barmashenko, Gleb; Buttgereit, Jens; Herring, Neil; Bader, Michael; Özcelik, Cemil; Manahan-Vaughan, Denise; Braunewell, Karl H.

2014-01-01

The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1–100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning. PMID:25520616

Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats.

PubMed

Cansev, Mehmet; van Wijk, Nick; Turkyilmaz, Mesut; Orhan, Fulya; Sijben, John W C; Broersen, Laus M

2015-01-01

Fortasyn Connect (FC) is a specific nutrient combination designed to target synaptic dysfunction in Alzheimer's disease by providing neuronal membrane precursors and other supportive nutrients. The aim of the present study was to investigate the effects of FC on hippocampal cholinergic neurotransmission in association with its effects on synaptic membrane formation in aged rats. Eighteen-month-old male Wistar rats were randomized to receive a control diet for 4 weeks or an FC-enriched diet for 4 or 6 weeks. At the end of the dietary treatments, acetylcholine (ACh) release was investigated by in vivo microdialysis in the right hippocampi. On completion of microdialysis studies, the rats were sacrificed, and the left hippocampi were obtained to determine the levels of choline, ACh, membrane phospholipids, synaptic proteins, and choline acetyltransferase. Our results revealed that supplementation with FC diet for 4 or 6 weeks, significantly enhanced basal and stimulated hippocampal ACh release and ACh tissue levels, along with levels of phospholipids. Feeding rats the FC diet for 6 weeks significantly increased the levels of choline acetyltransferase, the presynaptic marker Synapsin-1, and the postsynaptic marker PSD-95, but decreased levels of Nogo-A, a neurite outgrowth inhibitor. These data show that the FC diet enhances hippocampal cholinergic neurotransmission in aged rats and suggest that this effect is mediated by enhanced synaptic membrane formation. These data provide further insight into cellular and molecular mechanisms by which FC may support memory processes in Alzheimer's disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The synchronous activity of lateral habenular neurons is essential for regulating hippocampal theta oscillation.

PubMed

Aizawa, Hidenori; Yanagihara, Shin; Kobayashi, Megumi; Niisato, Kazue; Takekawa, Takashi; Harukuni, Rie; McHugh, Thomas J; Fukai, Tomoki; Isomura, Yoshikazu; Okamoto, Hitoshi

2013-05-15

Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase-locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons.

Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.

PubMed

Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L; Szigeti-Buck, Klara; Sallam, Nermin L; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S

2009-03-01

Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects. These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.

Effects of undernourishment, recurrent seizures and enriched environment during early life in hippocampal morphology.

PubMed

Alvarez, Paula Steffen; Simão, Fabrício; Hemb, Marta; Xavier, Léder Leal; Nunes, Magda Lahorgue

2014-04-01

It has been recently shown that enriched environment led to a significant benefit in learning and retention of visual-spatial memory, being able to reverse the cognitive impairment generated by undernourishment and recurrent seizures. We investigated the hippocampal morphological effects of recurrent seizures and undernourishment early in life in Wistar rats and the possible benefits produced by the enriched environment in these conditions. The morphological parameters stereologically evaluated were hippocampal volume, thickness of pyramidal stratum of the CA1 subfield and neuronal and glial densities in the same subfield. Male Wistar rats were divided into eight groups including nourished, nourished+enriched environment, nourished+recurrent seizures, nourished+recurrent seizures+enriched environment, undernourished, undernourished+enriched environment, undernourished+recurrent seizures and undernourished+recurrent seizures+enriched environment. Undernourishment model consisted in nutritional deprivation regimen from post-natal day 2 (P2) to P15. From P8 to P10, recurrent seizures group were induced by flurothyl three times per day. Enriched environment groups were exposed between P21 and P51. Our main findings were: (1) animals submitted to the enriched environment showed an increased hippocampal volume; (2) enriched environment promotes increases in the thickness of the pyramidal layer in hippocampal CA1 subfield in animals nourished and undernourished with recurrent seizures; (3) undernourishment during early development decreased neuronal density in CA1 and CA3 subfields. Our findings show that these three conditions induces important changes in hippocampal morphology, the most deleterious changes are induced by undernourishment and recurrent seizures, while more beneficial morphological changes are produced by enriched environment. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Aged rats show dominant modulation of lower frequency hippocampal theta rhythm during running.

PubMed

Li, Jia-Yi; Kuo, Terry B J; Yang, Cheryl C H

2016-10-01

Aging causes considerable decline in both physiological and mental functions, particularly cognitive function. The hippocampal theta rhythm (4-12Hz) is related to both cognition and locomotion. Aging-related findings of the frequency and amplitude of hippocampal theta oscillations are inconsistent and occasionally contradictory. This inconsistency may be due to the effects of the sleep/wake state and different frequency subbands being overlooked. We assumed that aged rats have lower responses of the hippocampal theta rhythm during running, which is mainly due to the dominant modulation of theta frequency subbands related to cognition. By simultaneously recording electroencephalography, physical activity (PA), and the heart rate (HR), this experiment explored the theta oscillations before, during, and after treadmill running at a constant speed in 8-week-old (adult) and 60-week-old (middle-aged) rats. Compared with adult rats, the middle-aged rats exhibited lower theta activity in all frequency ranges before running. Running increased the theta frequency (Frq, 4-12Hz), total activity of the whole theta band (total power, TP), activity of the middle theta frequency (MT, 6.5-9.5Hz), and PA in both age groups. However, the middle-aged rats still showed fewer changes in these parameters during the whole running process. After the waking baseline values were substracted, middle-aged rats showed significantly fewer differences in ΔFrq, ΔTP, and ΔMT but significantly more differences in low-frequency theta activity (4.0-6.5Hz) and HR than the adult rats did. Therefore, the decreasing activity and response of the whole theta band in the middle-aged rats resulted in dominant modulation of the middle to lower frequency (4.0-9.5Hz) theta rhythm. The different alterations in the theta rhythm during treadmill running in the two groups may reflect that learning decline with age. Copyright © 2016 Elsevier Inc. All rights reserved.

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…

Active coping of prenatally stressed rats in the forced swimming test: involvement of the Nurr1 gene.

PubMed

Montes, Pedro; Ruiz-Sánchez, Elizabeth; Calvillo, Minerva; Rojas, Patricia

2016-09-01

Depending on genetic predisposition, prenatal stress may result in vulnerability or resilience to develop psychiatric disorders in adulthood. Nurr1 is an immediate early gene, important in the brain for the stress response. We tested the hypothesis that prenatal stress and the decrease of hippocampal Nurr1 alter offspring behavioral responses in the forced swimming test (FST). Pregnant Wistar rats were exposed to restraint stress (45 min, thrice daily) from gestation day 14. Prenatally stressed (PS) and non-prenatally stressed (NPS) male offspring were treated bilaterally with a Nurr1 antisense oligodeoxynucleotide (ODN; or control) into the hippocampus at 97 d of age. After 1 h, the rats were exposed to the FST (acute stressor) to analyze their behavioral responses. Thirty minutes after the FST, we analyzed the gene expression of Nurr1, Bdnf and Nr3c1 (genes for Nurr1, brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), respectively) in the hippocampus, prefrontal cortex (PFC) and hypothalamus. Results showed that the decrease of hippocampal Nurr1 after the antisense ODN in adult NPS rats induces immobility (indicating depressive-like behavior). The PS adult rats, including the group with decreased hippocampal Nurr1, presented low immobility in the FST. This low immobility was concordant with maintenance of Nurr1 and Bdnf expression levels in the three analyzed brain regions; Nr3c1 gene expression was also maintained in the PFC and hypothalamus. These findings suggest that Nurr1 and associated genes could participate in the brain modifications induced by prenatal stress, allowing active coping (resilience) with acute stress in adulthood.

Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry.

PubMed

Markgraf, Carrie G; DeBoer, Erik; Zhai, Jin; Cornelius, Lara; Zhou, Ying Ying; MacSweeney, Cliona

2014-01-01

Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039. Rat hippocampal slices (n=5) were prepared and Org 306039 was applied over a concentration range of 0-1000μM. Male Sprague-Dawley rats, implanted with telemetry EEG recording electrodes received either vehicle (n=4) or 100mg/kg Org 306039 (n=4) by oral gavage daily for 10days. EEG was recorded continuously for 22±1h post-dose each day. Post-dose behavior observations were conducted daily for 2h. Body temperature was measured at 1 and 2h post-dose. On Day 7, blood samples were drawn for pharmacokinetic analysis of Org 306039. In hippocampal slice, Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from CA1 area, indicating seizure-genic potential. In telemetered rats, Org 306039 was associated with a decrease in body weight, a decrease in body temperature and the appearance of seizure-related behaviors and pre-seizure waveforms on EEG. One rat exhibited an overt seizure. Plasma concentrations of Org 306039 were similar among the 4 rats in the Org-treated group. Small group size made it difficult to determine a PK-PD relationship. These results indicate that the in vitro and in vivo models complement each other in the characterization of the seizure potential of CNS-targeted compounds such as the 5-HT2c agonist Org 306039. Copyright © 2014 Elsevier Inc. All rights reserved.

Hippocampal Neuron Number Is Unchanged 1 Year After Fractionated Whole-Brain Irradiation at Middle Age

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

Shi Lei; Molina, Doris P.; Robbins, Michael E.

2008-06-01

Purpose: To determine whether hippocampal neurons are lost 12 months after middle-aged rats received a fractionated course of whole-brain irradiation (WBI) that is expected to be biologically equivalent to the regimens used clinically in the treatment of brain tumors. Methods and Materials: Twelve-month-old Fischer 344 X Brown Norway male rats were divided into WBI and control (CON) groups (n = 6 per group). Anesthetized WBI rats received 45 Gy of {sup 137}Cs {gamma} rays delivered as 9 5-Gy fractions twice per week for 4.5 weeks. Control rats were anesthetized but not irradiated. Twelve months after WBI completion, all rats weremore » anesthetized and perfused with paraformaldehyde, and hippocampal sections were immunostained with the neuron-specific antibody NeuN. Using unbiased stereology, total neuron number and the volume of the neuronal and neuropil layers were determined in the dentate gyrus, CA3, and CA1 subregions of hippocampus. Results: No differences in tissue integrity or neuron distribution were observed between the WBI and CON groups. Moreover, quantitative analysis demonstrated that neither total neuron number nor the volume of neuronal or neuropil layers differed between the two groups for any subregion. Conclusions: Impairment on a hippocampal-dependent learning and memory test occurs 1 year after fractionated WBI at middle age. The same WBI regimen, however, does not lead to a loss of neurons or a reduction in the volume of hippocampus.« less

[Lessening effect of hypoxia-preconditioned rat cerebrospinal fluid on oxygen-glucose deprivation-induced injury of cultured hippocampal neurons in neonate rats and possible mechanism].

PubMed

Niu, Jing-Zhong; Zhang, Yan-Bo; Li, Mei-Yi; Liu, Li-Li

2011-12-25

The present study was to investigate the effect of cerebrospinal fluid (CSF) from the rats with hypoxic preconditioning (HPC) on apoptosis of cultured hippocampal neurons in neonate rats under oxygen glucose deprivation (OGD). Adult Wistar rats were exposed to 3 h of hypoxia for HPC, and then their CSF was taken out. Cultured hippocampal neurons from the neonate rats were randomly divided into four groups (n = 6): normal control group, OGD group, normal CSF group and HPC CSF group. OGD group received 1.5 h of incubation in glucose-free Earle's solution containing 1 mmol/L Na2S2O4, and normal and HPC CSF groups were subjected to 1 d of corresponding CSF treatments followed by 1.5 h OGD. The apoptosis of neurons was analyzed by confocal laser scanning microscope and flow cytometry using Annexin V/PI double staining. Moreover, protein expressions of Bcl-2 and Bax were detected by immunofluorescence. The results showed that few apoptotic cells were observed in normal control group, whereas the number of apoptotic cells was greatly increased in OGD group. Both normal and HPC CSF could decrease the apoptosis of cultured hippocampal neurons injured by OGD (P < 0.01). Notably, the protective effect of HPC CSF was stronger than that of normal one (P < 0.01). Compared to OGD group, normal and HPC CSF groups both showed significantly higher levels of Bcl-2 (P < 0.01), and Bcl-2 expression level in HPC CSF group was even higher than that in normal CSF group (P < 0.01). Whereas the expressions of Bax in normal and HPC CSF groups were significantly lower than that in OGD group (P < 0.01), and the Bax expression in HPC CSF group was even lower than that in normal CSF group (P < 0.01). These results suggest that CSF from hypoxic-preconditioned rats could degrade apoptotic rate of OGD-injured hippocampal neurons by up-regulating expression of Bcl-2 and down-regulating expression of Bax.

Prenatal Choline Supplementation Ameliorates the Long-Term Neurobehavioral Effects of Fetal-Neonatal Iron Deficiency in Rats123

PubMed Central

Kennedy, Bruce C.; Dimova, Jiva G.; Siddappa, Asha J. M.; Tran, Phu V.; Gewirtz, Jonathan C.; Georgieff, Michael K.

2014-01-01

Background: Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults. Objective: The objective of this study was to determine whether prenatal choline supplementation prevents the long-term effects of fetal-neonatal iron deficiency on cognitive and social behaviors and hippocampal gene expression. Methods: Pregnant rat dams were administered an iron-deficient (2–6 g/kg iron) or iron-sufficient (IS) (200 g/kg iron) diet from embryonic day (E) 3 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline chloride, E11–18). Novel object recognition (NOR) in the test vs. acquisition phase, social approach (SA), and hippocampal mRNA expression were compared at P65 in 4 male adult offspring groups: formerly iron deficient (FID), FID with choline supplementation (FID-C), IS, and IS with choline supplementation. Results: Relative to the intact NOR in IS rats (acquisition: 47.9%, test: 60.2%, P < 0.005), FID adult rats had impaired recognition memory at the 6-h delay (acquisition: 51.4%, test: 55.1%, NS), accompanied by a 15% reduction in hippocampal expression of brain-derived neurotrophic factor (Bdnf) (P < 0.05) and myelin basic protein (Mbp) (P < 0.05). Prenatal choline supplementation in FID rats restored NOR (acquisition: 48.8%, test: 64.4%, P < 0.0005) and increased hippocampal gene expression (FID-C vs. FID group: Bdnf, Mbp, P < 0.01). SA was also reduced in FID rats (P < 0.05 vs. IS rats) but was only marginally improved by prenatal choline supplementation. Conclusions: Deficits in recognition memory, but not social behavior, resulting from gestational iron deficiency are attenuated by prenatal choline supplementation, potentially through preservation of hippocampal Bdnf and Mbp expression. Prenatal choline supplementation may be a promising adjunct treatment for fetal-neonatal iron deficiency. PMID:25332485

Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.

PubMed

Rao, Kalyan N; Sentir, Alena M; Engleman, Eric A; Bell, Richard L; Hulvershorn, Leslie A; Breier, Alan; Chambers, R Andrew

2016-12-01

Prefrontal cortical (PFC)-hippocampal-striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability. In healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes. Rats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n = 80) or nicotine self-administration (experiment 2; n = 12). In experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio ("FLETR"; p < 0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R 2  = 0.14, p < 0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R 2  = 0.47, p < 0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement. These findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC-hippocampal-striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.

Cerveau isolé and pretrigeminal rats.

PubMed

Zernicki, B; Gandolfo, G; Glin, L; Gottesmann, C

1984-01-01

Cortical and hippocampal EEG activity was analysed in 14 cerveau isole and 8 pretrigerninal rats. In the acute stage, waking EEG patterns were absent in the cerveau isole, whereas sleep EEG patterns were absent in the pretrigeminal preparations. However, already on the second day the EEG waking-sleep cycle recovered in the majority of rats. Paradoxically, stimuli directed to the caudal part of preparations evoked stronger cortical and hippocampal EEG arousal than olfactory and visual stimuli. The behavior of the caudal part was observed in 25 preparations. Although in abortive form, the rats did show some locomotor and grooming behavior, and could be fed orally. The peripheral events of paradoxical sleep appeared only on the fourth or fifth day of survival of the cerveau isole rats. It is concluded that the activity of the isolated cerebrum of the rat is similar to that of cat preparations, but that functions of the caudal neuraxis are superior in rats.

Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors

PubMed Central

Ivy, Autumn S.; Rex, Christopher S.; Chen, Yuncai; Dubé, Céline; Maras, Pamela M.; Grigoriadis, Dimitri E.; Gall, Christine M.; Lynch, Gary; Baram, Tallie Z.

2010-01-01

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF1) located on pyramidal cell dendrites. Additionally, chronic CRF1 occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH-expression is augmented in hippocampus of middle-aged CES rats, and then tested if the morphological defects and poor memory performance in these animals involve excessive activation of CRF1 receptors. Central or peripheral administration of a CRF1 blocker following the stress period improved memory performance of CES rats in novel object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF1 interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF1 occupancy post-hoc normalized hippocampal function during middle-age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress. PMID:20881118

BDNF/TrkB Pathway Mediates the Antidepressant-Like Role of H2S in CUMS-Exposed Rats by Inhibition of Hippocampal ER Stress.

PubMed

Wei, Le; Kan, Li-Yuan; Zeng, Hai-Ying; Tang, Yi-Yun; Huang, Hong-Lin; Xie, Ming; Zou, Wei; Wang, Chun-Yan; Zhang, Ping; Tang, Xiao-Qing

2018-06-01

Our previous works have shown that hydrogen sulfide (H 2 S) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that H 2 S upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of H 2 S by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of H 2 S) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of H 2 S in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of H 2 S against CUMS-induced depressive-like behaviors.

The Beneficial Effect of Prior Experience on the Acquisition of Spatial Memory in Rats with CA1, but Not Large Hippocampal Lesions: A Possible Role for Schema Formation

ERIC Educational Resources Information Center

Ocampo, Amber C.; Squire, Larry R.; Clark, Robert E.

2018-01-01

Prior experience has been shown to improve learning in both humans and animals, but it is unclear what aspects of recent experience are necessary to produce beneficial effects. Here, we examined the capacity of rats with complete hippocampal lesions, restricted CA1 lesions, or sham surgeries to benefit from prior experience. Animals were tested in…

The antidepressant effects of running and escitalopram are associated with levels of hippocampal NPY and Y1 receptor but not cell proliferation in a rat model of depression.

PubMed

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

2010-07-01

One hypothesis of depression is that it is caused by reduced neuronal plasticity including hippocampal neurogenesis. In this study, we compared the effects of three long-term antidepressant treatments: escitalopram, voluntary running, and their combination on hippocampal cell proliferation, NPY and the NPY-Y1 receptor mRNAs, targets assumed to be important for hippocampal plasticity and mood disorders. An animal model of depression, the Flinders Sensitive Line (FSL) rat, was used and female rats were chosen because the majority of the depressed population is females. We investigated if these treatments were correlated to immobility, swimming, and climbing behaviors, which are associated with an overall, serotonergic-like and noradrenergic-like antidepressant response, in the Porsolt swim test (PST). Interestingly, while escitalopram, running and their combination increased the number of hippocampal BrdU immunoreactive cells, the antidepressant-like effect was only detected in the running group and the group with access both to running wheel and escitalopram. Hippocampal NPY mRNA and the NPY-Y1 receptor mRNA were elevated by running and the combined treatment. Moreover, correlations were detected between NPY mRNA levels and climbing and cell proliferation and NPY-Y1 receptor mRNA levels and swimming. Our results suggest that increased cell proliferation is not necessarily associated with an antidepressant effect. However, treatments that were associated with an antidepressant-like effect did regulate hippocampal levels of mRNAs encoding NPY and/or the NPY-Y1 receptor and support the notion that NPY can stimulate cell proliferation and induce an antidepressant-like response. Copyright 2009 Wiley-Liss, Inc.

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.

Microinjection of procaine and electrolytic lesion in the ventral tegmental area suppresses hippocampal theta rhythm in urethane-anesthetized rats.

PubMed

Orzeł-Gryglewska, Jolanta; Jurkowlaniec, Edyta; Trojniar, Weronika

2006-01-30

The midbrain ventral tegmental area (VTA), a key structure of the mesocorticolimbic system is anatomically connected with the hippocampal formation. In addition mesocortical dopamine was found to influence hippocampus-related memory and hippocampal synaptic plasticity, both being linked to the theta rhythm. Therefore, the aim of the present study was to evaluate the possible role of the VTA in the regulation of the hippocampal theta activity. The study was performed on urethane-anesthetized male Wistar rats in which theta rhythm was evoked by tail pinch. It was found that unilateral, temporal inactivation of the VTA by means of direct procaine injection resulted in bilateral suppression of the hippocampal theta which manifested as a loss of synchronization of hippocampal EEG and respective reduction of the power and also the frequency of the 3-6 Hz theta band. Depression of the power of the 3-6 Hz component of the EEG signal was also seen in spontaneous hippocampal EEG after procaine. The permanent destruction of the VTA by means of unilateral electrocoagulation evoked a long-lasting, mainly ipsilateral depression of the power of the theta with some influence on its frequency. Simultaneously, there was a substantial increase of the power in higher frequency bands indicating decrease of a synchrony of the hippocampal EEG activity. On the basis of these results indicating impairment of synchronization of the hippocampal activity the VTA may be considered as another part of the brainstem theta synchroning system.

Alterations in hippocampal and cortical densities of functionally different interneurons in rat models of absence epilepsy.

PubMed

Papp, Péter; Kovács, Zsolt; Szocsics, Péter; Juhász, Gábor; Maglóczky, Zsófia

2018-05-31

Recent data from absence epileptic patients and animal models provide evidence for significant impairments of attention, memory, and psychosocial functioning. Here, we outline aspects of the electrophysiological and structural background of these dysfunctions by investigating changes in hippocampal and cortical GABAergic inhibitory interneurons in two genetically absence epileptic rat strains: the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Using simultaneously recorded field potentials from the primary somatosensory cortex (S1 cortex, seizure focus) and the hippocampal hilus, we demonstrated that typical frequencies of spike-wave discharges (SWDs; 7-8 Hz, GAERS; 7-9 Hz, WAG/Rij) and their harmonics appeared and their EEG spectral power markedly increased on recordings not only from the S1 cortex, but also from the hilus in both GAERS and WAG/Rij rats during SWDs. Moreover, we observed an increased synchronization between S1 cortex and hilus at 7-8 Hz (GAERS) and 7-9 Hz (WAG/Rij) and at their harmonics when SWDs occurred in the S1 cortex in both rat strains. In addition, using immunohistochemistry we demonstrated changes in the densities of perisomatic (parvalbumin-immunopositive, PV+) and interneuron-selective (calretinin-immunopositive, CR+) GABAergic inhibitory interneuron somata. Specifically, GAERS and WAG/Rij rats displayed lower densities of PV-immunopositivity in the hippocampal hilus compared to non-epileptic control (NEC) and normal Wistar rats. GAERS and WAG/Rij rats also show a marked reduction in the density of CR + interneurons in the same region in comparison with NEC rats. Data from the S1 cortex reveals bidirectional differences in PV + density, with GAERS displaying a significant increase, whereas WAG/Rij a reduction compared to control rat strains. Our results suggest an enhanced synchronization and functional connections between the hippocampus and S1 cortex as well as thalamocortical activities during SWDs and a functional alteration of inhibitory mechanisms in the hippocampus and S1 cortex of two genetic models of absence epilepsy, presumably in relation with increased neuronal activity and seizure-induced neuronal injury. Copyright © 2018 Elsevier B.V. All rights reserved.

Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin

PubMed Central

Grace, Curtis E.; Schaefer, Tori L.; Gudelsky, Gary A.; Williams, Michael T.; Vorhees, Charles V.

2010-01-01

Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11–20 (10 mg/kg/dose x 4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30 min following the first treatment on each day between postnatal days 11–20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by ~70% initially, ~55% midway through treatment, and ~25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus to the same degree as in sham-surgery rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induce corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should is applicable to other models of developmental stress/corticosterone release. PMID:20153424

Effects of a Saturated Fat and High Cholesterol Diet on Memory and Hippocampal Morphology in the Middle-Aged Rat

PubMed Central

Granholm, Ann-Charlotte; Bimonte-Nelson, Heather A.; Moore, Alfred B.; Nelson, Matthew E.; Freeman, Linnea R.; Sambamurti, Kumar

2009-01-01

Diets rich in cholesterol and/or saturated fats have been shown to be detrimental to cognitive performance. Therefore, we fed a cholesterol (2%) and saturated fat (hydrogenated coconut oil, Sat Fat 10%) diet to 16-month old rats for 8 weeks to explore the effects on the working memory performance of middle-aged rats. Lipid profiles revealed elevated plasma triglycerides, total cholesterol, HDL, and LDL for the Sat-Fat group as compared to an iso-caloric control diet (12% soybean oil). Weight gain and food consumption were similar in both groups. Sat-Fat treated rats committed more working memory errors in the water radial arm maze, especially at higher memory loads. Cholesterol, amyloid-β peptide of 40 (Aβ40) or 42 (Aβ42) residues, and nerve growth factor in cortical regions was unaffected, but hippocampal Map-2 staining was reduced in rats fed a Sat-Fat diet, indicating a loss of dendritic integrity. Map-2 reduction correlated with memory errors. Microglial activation, indicating inflammation and/or gliosis, was also observed in the hippocampus of Sat-Fat fed rats. These data suggest that saturated fat, hydrogenated fat and cholesterol can profoundly impair memory and hippocampal morphology. PMID:18560126

A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat.

PubMed

Sutherland, R J; Whishaw, I Q; Kolb, B

1983-02-01

This experiment examines the notion that in the rat the hippocampal formation is an essential structure in the neurological representation of spatial abilities. Spatial localization by rats with different types of hippocampal damage, including bilateral electrolytic lesions, unilateral and bilateral kainic acid-induced CA3-CA4 lesions, and unilateral and bilateral colchicine-induced dentate gyrus lesions, was compared with vehicle-injected and normal control groups in the Morris water task. The task required the rats to escape from cold water by finding a submerged and hidden platform located at a fixed place within the room. The start point was varied randomly from trial to trial and there were no local cues available to indicate the position of the hidden platform. After training, the platform was moved. Escape latencies and the initial swimming headings revealed that all lesion groups, except the unilateral CA3-damaged group, were impaired at finding the platform: the dentate-damaged rats exhibited the greatest deficit. When the platform was moved the control rats swam mainly in the part of the pool that had previously contained the platform and, on finding it in the new location, they showed a marked dishabituation of rearing. None of the bilateral lesion groups showed these effects.

DNA microarray‐based analysis of voluntary resistance wheel running reveals novel transcriptome leading robust hippocampal plasticity

PubMed Central

Lee, Min Chul; Rakwal, Randeep; Shibato, Junko; Inoue, Koshiro; Chang, Hyukki; Soya, Hideaki

2014-01-01

Abstract In two separate experiments, voluntary resistance wheel running with 30% of body weight (RWR), rather than wheel running (WR), led to greater enhancements, including adult hippocampal neurogenesis and cognitive functions, in conjunction with hippocampal brain‐derived neurotrophic factor (BDNF) signaling (Lee et al., J Appl Physiol, 2012; Neurosci Lett., 2013). Here we aimed to unravel novel molecular factors and gain insight into underlying molecular mechanisms for RWR‐enhanced hippocampal functions; a high‐throughput whole‐genome DNA microarray approach was applied to rats performing voluntary running for 4 weeks. RWR rats showed a significant decrease in average running distances although average work levels increased immensely, by about 11‐fold compared to WR, resulting in muscular adaptation for the fast‐twitch plantaris muscle. Global transcriptome profiling analysis identified 128 (sedentary × WR) and 169 (sedentary × RWR) up‐regulated (>1.5‐fold change), and 97 (sedentary × WR) and 468 (sedentary × RWR) down‐regulated (<0.75‐fold change) genes. Functional categorization using both pathway‐ or specific‐disease‐state‐focused gene classifications and Ingenuity Pathway Analysis (IPA) revealed expression pattern changes in the major categories of disease and disorders, molecular functions, and physiological system development and function. Genes specifically regulated with RWR include the newly identified factors of NFATc1, AVPR1A, and FGFR4, as well as previously known factors, BDNF and CREB mRNA. Interestingly, RWR down‐regulated multiple inflammatory cytokines (IL1B, IL2RA, and TNF) and chemokines (CXCL1, CXCL10, CCL2, and CCR4) with the SYCP3, PRL genes, which are potentially involved in regulating hippocampal neuroplastic changes. These results provide understanding of the voluntary‐RWR‐related hippocampal transcriptome, which will open a window to the underlying mechanisms of the positive effects of exercise, with therapeutic value for enhancing hippocampal functions. PMID:25413326

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.

Involvement of hippocampal NMDA receptors in encoding and consolidation, but not retrieval, processes of spontaneous object location memory in rats.

PubMed

Yamada, Kazuo; Arai, Misaki; Suenaga, Toshiko; Ichitani, Yukio

2017-07-28

The hippocampus is thought to be involved in object location recognition memory, yet the contribution of hippocampal NMDA receptors to the memory processes, such as encoding, retention and retrieval, is unknown. First, we confirmed that hippocampal infusion of a competitive NMDA receptor antagonist, AP5 (2-amino-5-phosphonopentanoic acid, 20-40nmol), impaired performance of spontaneous object location recognition test but not that of novel object recognition test in Wistar rats. Next, the effects of hippocampal AP5 treatment on each process of object location recognition memory were examined with three different injection times using a 120min delay-interposed test: 15min before the sample phase (Time I), immediately after the sample phase (Time II), and 15min before the test phase (Time III). The blockade of hippocampal NMDA receptors before and immediately after the sample phase, but not before the test phase, markedly impaired performance of object location recognition test, suggesting that hippocampal NMDA receptors play an important role in encoding and consolidation/retention, but not retrieval, of spontaneous object location memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Cortico-hippocampal representations in simultaneous odor discrimination: a computational interpretation of Eichenbaum, Mathews, and Cohen (1989).

PubMed

Myers, C E; Gluck, M A

1996-08-01

A previous model of hippocampal region function in classical conditioning is generalized to H. Eichenbaum, A. Fagan, P. Mathews, and N.J. Cohen's (1989) and H. Eichenbaum, A. Fagan, and N.J. Cohen's (1989) simultaneous odor discrimination studies in rats. The model assumes that the hippocampal region forms new stimulus representations that compress redundant information while differentiating predictie information; the piriform (olfactory) cortex meanwhile clusters similar and co-occurring odors. Hippocampal damage interrupts the ability to differentiate odor representations, while leaving piriform-mediated odor clustering unchecked. The result is a net tendency to overcompress in the lesioned model. Behavior in the model is very similar to that of the rats, including lesion deficits, facilitation of successively learned tasks, and transfer performance. The computational mechanisms underlying model performance are consistent with the qualitative interpretations suggested by Eichen baum et al. to explain their empirical data.

Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF.

PubMed

Moy, Gregory A; McNay, Ewan C

2013-01-17

Obesity, high-fat diets, and subsequent type 2 diabetes (T2DM) are associated with cognitive impairment. Moreover, T2DM increases the risk of Alzheimer's disease (AD) and leads to abnormal elevation of brain beta-amyloid levels, one of the hallmarks of AD. The psychoactive alkaloid caffeine has been shown to have therapeutic potential in AD but the central impact of caffeine has not been well-studied in the context of a high-fat diet. Here we investigated the impact of caffeine administration on metabolism and cognitive performance, both in control rats and in rats placed on a high-fat diet. The effects of caffeine were significant: caffeine both (i) prevented the weight-gain associated with the high-fat diet and (ii) prevented cognitive impairment. Caffeine did not alter hippocampal metabolism or insulin signaling, likely because the high-fat-fed animals did not develop full-blown diabetes; however, caffeine did prevent or reverse a decrease in hippocampal brain-derived neurotrophic factor (BDNF) seen in high-fat-fed animals. These data confirm that caffeine may serve as a neuroprotective agent against cognitive impairment caused by obesity and/or a high-fat diet. Increased hippocampal BDNF following caffeine administration could explain, at least in part, the effects of caffeine on cognition and metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

The bidirectional effects of hypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats.

PubMed

Yu, Dafu; Zhou, Heng; Yang, Yuan; Jiang, Yong; Wang, Tianchao; Lv, Liang; Zhou, Qixin; Yang, Yuexiong; Dong, Xuexian; He, Jianfeng; Huang, Xiaoyan; Chen, Jijun; Wu, Kunhua; Xu, Lin; Mao, Rongrong

2015-03-01

Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using (131)iodine ((131)I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of (131)I (5mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Chronic sleep restriction causes a decrease in hippocampal volume in adolescent rats, which is not explained by changes in glucocorticoid levels or neurogenesis.

PubMed

Novati, A; Hulshof, H J; Koolhaas, J M; Lucassen, P J; Meerlo, P

2011-09-08

Sleep loss strongly affects brain function and may even predispose susceptible individuals to psychiatric disorders. Since a recurrent lack of sleep frequently occurs during adolescence, it has been implicated in the rise in depression incidence during this particular period of life. One mechanism through which sleep loss may contribute to depressive symptomatology is by affecting hippocampal function. In this study, we examined the effects of sleep loss on hippocampal integrity at young age by subjecting adolescent male rats to chronic sleep restriction (SR) for 1 month from postnatal day 30 to 61. They were placed in slowly rotating drums for 20 h per day and were allowed 4 h of rest per day at the beginning of the light phase. Anxiety was measured using an open field and elevated plus maze test, while saccharine preference was used as an indication of anhedonia. All tests were performed after 1 and 4 weeks of SR. We further studied effects of SR on hypothalamic-pituitary-adrenal (HPA) axis activity, and at the end of the experiment, brains were collected to measure hippocampal volume and neurogenesis. Behavior of the SR animals was not affected, except for a transient suppression of saccharine preference after 1 week of SR. Hippocampal volume was significantly reduced in SR rats compared to home cage and forced activity controls. This volume reduction was not paralleled by reduced levels of hippocampal neurogenesis and could neither be explained by elevated levels of glucocorticoids. Thus, our results indicate that insufficient sleep may be a causal factor in the reductions of hippocampal volume that have been reported in human sleep disorders and mood disorders. Since changes in HPA activity or neurogenesis are not causally implicated, sleep disturbance may affect hippocampal volume by other, possibly more direct mechanisms. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Saikosaponin D relieves unpredictable chronic mild stress induced depressive-like behavior in rats: involvement of HPA axis and hippocampal neurogenesis.

PubMed

Li, Hong-Yan; Zhao, Ying-Hua; Zeng, Min-Jie; Fang, Fang; Li, Min; Qin, Ting-Ting; Ye, Lu-Yu; Li, Hong-Wei; Qu, Rong; Ma, Shi-Ping

2017-11-01

Saikosaponin D (SSD), a major bioactive component isolated from Radix Bupleuri, has been reported to exert neuroprotective properties. The present study was designed to investigate the anti-depressant-like effects and the potential mechanisms of SSD. Behavioural tests including sucrose preference test (SPT), open field test (OFT) and forced swim test (FST) were performed to study the antidepressant-like effects of SSD. In addition, we examined corticosterone and glucocorticoid receptor (GR) levels to evaluate hypothalamic-pituitary-adrenal (HPA) axis function. Furthermore, hippocampal neurogenesis was assessed by testing doublecortin (DCX) levels, and neurotrophic molecule levels were also investigated in the hippocampus of rats. We found that unpredictable chronic mild stress (UCMS) rats displayed lost body weight, decreased sucrose consumption in SPT, reduced locomotive activity in OFT, and increased immobility time in FST. Chronic treatment with SSD (0.75, 1.50 mg/kg) remarkably ameliorated the behavioral deficiency induced by UCMS procedure. SSD administration downregulated elevated serum corticosterone levels, as well as alleviated the suppression of GR expression and nuclear translocation caused by UCMS, suggesting that SSD is able to remit the dysfunction of HPA axis. In addition, Western blot and immunohistochemistry analysis showed that SSD treatment significantly increased the generation of neurons in the hippocampus of UCMS rats indicated by elevated DCX levels. Moreover, hippocampal neurotrophic molecule levels of UCMS rats such as phosphorylated cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were raised after SSD treatment. Together, Our results suggest that SSD opposed UCMS-induced depressive behaviors in rats, which was mediated, partially, by the enhancement of HPA axis function and consolidation of hippocampal neurogenesis.

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.

Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats.

PubMed

Gebhardt, Nils; Bär, Karl-Jürgen; Boettger, Michael K; Grecksch, Gisela; Keilhoff, Gerburg; Reichart, Rupert; Becker, Axel

2013-01-01

Vagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear. Bilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research. We studied the effects of vagus nerve stimulation (VNS) on disturbed one-way active avoidance learning and neurogenesis in the hippocampal dentate gyrus of rats. After a stimulation period of 3 weeks, OBX rats acquired the learning task as controls. In addition, the OBX-related decrease of neuronal differentiated BrdU positive cells in the dentate gyrus was prevented by VNS. This suggests that chronic VNS and changes in hippocampal neurogenesis induced by VNS may also account for the amelioration of behavioral deficits in OBX rats. To the best of our knowledge, this is the first report on the restorative effects of VNS on behavioral function in an animal model of depression that can be compared with the effects of antidepressants. Copyright © 2013 Elsevier Inc. All rights reserved.

Developmental increase of asynchronic glutamate release from hippocampal synapses in mutant taiep rat.

PubMed

Fuenzalida, Marco; Aliaga, Esteban; Olivares, Virginia; Roncagliolo, Manuel; Bonansco, Christian

2009-06-01

During development, regulation of the strength of synaptic transmission plays a central role in the formation of mammalian brain circuitries. In taiep rat, a neurological mutant with severe reactive astrogliosis and demyelination, we have described alterations in the synaptic transmission in central neurons, characterized by asynchronous excitatory postsynaptic currents ((ASYN)EPSCs), because of delayed neurotransmitter release. This hippocampal synaptic dysfunction has been described in juvenile mutants, concomitantly with the appearance of their main glial alterations. However, it is unknown whether this abnormal synaptic activity is correlated with some alterations of synaptic maturation during the postnatal development. Using intracellular electrophysiological recordings and immunohistochemistry assays, we studied the maturation of CA3-CA1 synapses in taiep rats. In taiep, the number of (ASYN)EPSCs evoked by conventional stimulation of Schaffer collaterals increases with age (P7-P30) and can be evoked by stimulation of single fiber. The amplitude and frequency of spontaneous EPSC (sEPSC) increased during the postnatal development in both control and taiep rats. However, in taiep, the increase of sEPSC frequency was significantly higher than in the control rats. The frequency of miniature EPSC (mEPSC) increased over the studied age range, without differences between taiep and control rats. In both control and taiep groups, the synaptophysin immunostaining (SYP-IR) in the stratum radiatum of CA1 region was significantly lower in the juvenile (P30) than in the neonatal (P10) rats, suggesting that synaptic pruning is normally occurring in taiep, even when SYP-IR was higher in taiep than control in both ages studied. These results suggest that, in taiep mutants, the asynchronic transmission is due to a dysfunction in the glutamate release mechanisms that progressively increases during development, which is not attributable to the existence of aberrant synaptic contacts. Synapse 63:502-509, 2009. (c) 2009 Wiley-Liss, Inc.

Liver X receptor β in the hippocampus: A potential novel target for the treatment of major depressive disorder?

PubMed

Peng, Zhengwu; Deng, Bin; Jia, Ji; Hou, Wugang; Hu, Sheng; Deng, Jiao; Lin, Wei; Hou, Lichao; Sang, Hanfei

2018-06-01

Liver X receptors (LXRs), including LXRα and LXRβ isoforms, have been implicated in multiple physiological functions including promoting neurogenesis, improving synaptic plasticity, preventing neurodegeneration, inhibiting inflammation as well as regulating cholesterol metabolism. However, a potential role of LXRs in the treatment of major depressive disorder (MDD) has never been investigated previously. Our present results demonstrated that levels of hippocampal LXRβ but not LXRα were down-regulated in rats exposed to chronic unpredictable stress (CUS) and were negatively correlated with the severity of CUS-induced depressive-like behaviors. Furthermore, rats with LXRβ knockdown by short hairpin RNA (shRNA) in hippocampus displayed depressive-like behaviors and impaired hippocampal neurogenesis similar to those observed after CUS exposure. Conversely, LXRs activation by GW3965 (GW), a synthetic dual agonist for both LXRα and LXRβ isoforms, could improve depression-like behaviors and reverse the impaired hippocampal neurogenesis in rats exposed to CUS. LXRβ knockdown by shRNA completely abrogated the antidepressant and hippocampal neurogenesis-promoting effects of GW, suggesting that LXRβ isoform mediated the antidepressant and hippocampal neurogenesis-promoting effects of the LXRα/β dual agonist. However, ablation of hippocampal neurogenesis with x-irradiation only partly but not completely abolished the antidepressant effects of GW in the behavioral tests, implying that the antidepressant effects mediated by LXRβ isoform are likely through both neurogenesis-dependent and -independent pathways. Thus, our findings suggest that LXRβ activation may represent a potential novel target for the treatment of MDD and also provide a novel insight into the underlying mechanisms of MDD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease

PubMed Central

Kohl, Zacharias; Abdallah, Nada Ben; Vogelgsang, Jonathan; Tischer, Lucas; Deusser, Janina; Amato, Davide; Anderson, Scott; Müller, Christian P.; Riess, Olaf; Masliah, Eliezer; Nuber, Silke; Winkler, Jürgen

2016-01-01

Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus might contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, alterations of the hippocampal serotonergic system were associated with an anxiety-like behavior consisting of reduced exploratory behavior and feeding in transgenic rats. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and motor deficits in this transgenic rat model of PD. PMID:26523794

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness.

PubMed

Aznar, Susana; Klein, Anders B; Santini, Martin A; Knudsen, Gitte M; Henn, Fritz; Gass, Peter; Vollmayr, Barbara

2010-07-01

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Hypo-and hyperthyroidism affect the ATP, ADP and AMP hydrolysis in rat hippocampal and cortical slices.

PubMed

Bruno, Alessandra Nejar; Diniz, Gabriela Placoná; Ricachenevsky, Felipe Klein; Pochmann, Daniela; Bonan, Carla Denise; Barreto-Chaves, Maria Luiza M; Sarkis, João José Freitas

2005-05-01

The presence of severe neurological symptoms in thyroid diseases has highlighted the importance of thyroid hormones in the normal functioning of the mature brain. Since, ATP is an important excitatory neurotransmitter and adenosine acts as a neuromodulatory structure inhibiting neurotransmitters release in the central nervous system (CNS), the ectonucleotidase cascade that hydrolyzes ATP to adenosine, is also involved in the control of brain functions. Thus, we investigated the influence of hyper-and hypothyroidism on the ATP, ADP and AMP hydrolysis in hippocampal and cortical slices from adult rats. Hyperthyroidism was induced by daily injections of l-thyroxine (T4) 25 microg/100 g body weight, for 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water for 14 days. Hypothyroid rats were hormonally replaced by daily injections of T4 (5 microg/100 g body weight, i.p.) for 5 days. Hyperthyroidism significantly inhibited the ATP, ADP and AMP hydrolysis in hippocampal slices. In brain cortical slices, hyperthyroidism inhibited the AMP hydrolysis. In contrast, hypothyroidism increased the ATP, ADP and AMP hydrolysis in both hippocampal and cortical slices and these effects were reverted by T4 replacement. Furthermore, hypothyroidism increased the expression of NTPDase1 and 5'-nucleotidase, whereas hyperthyroidism decreased the expression of 5'-nucleotidase in hippocampus of adult rats. These findings demonstrate that thyroid disorders may influence the enzymes involved in the complete degradation of ATP to adenosine and possibly affects the responses mediated by adenine nucleotides in the CNS of adult rats.

The hippocampus, time and working memory.

PubMed

Rawlins, J N; Tsaltas, E

1983-12-01

Rats were trained on a discrete trial working memory leverpress alternation task, following hippocampal lesions (HC), cortical control lesions (CC) or sham operations (SO). Each trial consisted of a forced information response, for which a randomly selected lever was presented followed by a free choice stage, when both levers were presented. The rats were rewarded for pressing the lever which had not been presented at the information stage. When the information response was not rewarded, all rats learnt the task equally well at IRIs of up to 12.75 sec. When the information response was rewarded, the HC rats showed impaired choice accuracy. The extent of this impairment depended on the IRI, being greatest at long IRIs, and least at short ones. Varying the number of leverpresses required to complete the information response affected choice accuracy equivalently in all groups: all rats chose significantly less accurately when only one leverpress was required than when ten leverpresses were required. There was no interaction between the lesion treatments and the information response requirements. It was concluded that both the length of the IRI and the occurrence of events during the IRI determine the extent of the hippocampal lesion-induced performance deficit in working memory tasks. It is proposed that hippocampal damage disrupts an intermediate-term, high-capacity memory buffer, but leaves both a residual short-term memory system and the long-term retention of associations unaffected. This proposal leads to the prediction that reference memory tasks should also be affected by hippocampal lesions when a delay is introduced between making a response and being rewarded for doing so.

Infrasound increases intracellular calcium concentration and induces apoptosis in hippocampi of adult rats.

PubMed

Liu, Zhaohui; Gong, Li; Li, Xiaofang; Ye, Lin; Wang, Bin; Liu, Jing; Qiu, Jianyong; Jiao, Huiduo; Zhang, Wendong; Chen, Jingzao; Wang, Jiuping

2012-01-01

In the present study, we determined the effect of infrasonic exposure on apoptosis and intracellular free Ca²⁺ ([Ca²⁺]i) levels in the hippocampus of adult rats. Adult rats were randomly divided into the control and infrasound exposure groups. For infrasound treatment, animals received infrasonic exposure at 90 (8 Hz) or 130 dB (8 Hz) for 2 h per day. Hippocampi were dissected, and isolated hippocampal neurons were cultured. The [Ca²⁺]i levels in hippocampal neurons from adult rat brains were determined by Fluo-3/AM staining with a confocal microscope system on days 1, 7, 14, 21 and 28 following infrasonic exposure. Apoptosis was evaluated by Annexin V-FITC and propidium iodide double staining. Positive cells were sorted and analyzed by flow cytometry. Elevated [Ca²⁺]i levels were observed on days 14 and 21 after rats received daily treatment with 90 or 130 dB sound pressure level (SPL) infrasonic exposure (p<0.01 vs. control). The highest levels of [Ca²⁺]i were detected in the 130 dB SPL infrasonic exposure group. Meanwhile, apoptosis in hippocampal neurons was found to increase on day 7 following 90 dB SPL infrasound exposure, and significantly increased on day 14. Upon 130 dB infrasound treatment, apoptosis was first observed on day 14, whereas the number of apoptotic cells gradually decreased thereafter. Additionally, a marked correlation between cell apoptosis and [Ca²⁺]i levels was found on day 14 and 21 following daily treatment with 90 and 130 dB SPL, respectively. These results demonstrate that a period of infrasonic exposure induced apoptosis and upregulated [Ca²⁺]i levels in hippocampal neurons, suggesting that infrasound may cause damage to the central nervous system (CNS) through the Ca²⁺‑mediated apoptotic pathway in hippocampal neurons.

Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects.

PubMed

Palleria, Caterina; Leo, Antonio; Andreozzi, Francesco; Citraro, Rita; Iannone, Michelangelo; Spiga, Rosangela; Sesti, Giorgio; Constanti, Andrew; De Sarro, Giovambattista; Arturi, Franco; Russo, Emilio

2017-03-15

Diabetes has been identified as a risk factor for cognitive dysfunctions. Glucagone like peptide 1 (GLP-1) receptor agonists have neuroprotective effects in preclinical animal models. We evaluated the effects of GLP-1 receptor agonist, liraglutide (LIR), on cognitive decline associated with diabetes. Furthermore, we studied LIR effects against hippocampal neurodegeneration induced by streptozotocin (STZ), a well-validated animal model of diabetes and neurodegeneration associated with cognitive decline. Diabetes and/or cognitive decline were induced in Wistar rats by intraperitoneal or intracerebroventricular injection of STZ and then rats were treated with LIR (300μg/kg daily subcutaneously) for 6 weeks. Rats underwent behavioral tests: Morris water maze, passive avoidance, forced swimming (FST), open field, elevated plus maze, rotarod tests. Furthermore, LIR effects on hippocampal neurodegeneration and mTOR pathway (AKT, AMPK, ERK and p70S6K) were assessed. LIR improved learning and memory only in STZ-treated animals. Anxiolytic effects were observed in all LIR-treated groups but pro-depressant effects in CTRL rats were observed. At a cellular/molecular level, intracerebroventricular STZ induced hippocampal neurodegeneration accompanied by decreased phosphorylation of AMPK, AKT, ERK and p70S6K. LIR reduced hippocampal neuronal death and prevented the decreased phosphorylation of AKT and p70S6K; AMPK was hyper-phosphorylated in comparison to CTRL group, while LIR had no effects on ERK. LIR reduced animal endurance in the rotarod test and this effect might be also linked to a reduction in locomotor activity during only the last two minutes of the FST. LIR had protective effects on cognitive functions in addition to its effects on blood glucose levels. LIR effects in the brain also comprised anxiolytic and pro-depressant actions (although influenced by reduced endurance). Finally, LIR protected from diabetes-dependent hippocampal neurodegeneration likely through an effect on mTOR pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Environmental Novelty is Associated with a Selective Increase in Fos Expression in the Output Elements of the Hippocampal Formation and the Perirhinal Cortex

ERIC Educational Resources Information Center

VanElzakker, Michael; Fevurly, Rebecca D.; Breindel, Tressa; Spencer, Robert L.

2008-01-01

If the hippocampus plays a role in the detection of novel environmental features, then novelty should be associated with altered hippocampal neural activity and perhaps also measures of neuroplasticity. We examined Fos protein expression within subregions of rat hippocampal formation as an indicator of recent increases in neuronal excitation and…

Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

PubMed

Majkutewicz, Irena; Kurowska, Ewelina; Podlacha, Magdalena; Myślińska, Dorota; Grembecka, Beata; Ruciński, Jan; Plucińska, Karolina; Jerzemowska, Grażyna; Wrona, Danuta

2016-07-15

Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimer's disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

A weak magnetic field inhibits hippocampal neurogenesis in SD rats

NASA Astrophysics Data System (ADS)

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

2017-12-01

Geomagnetic field is an important barrier that protects life forms on Earth from solar wind and radiation. Paleomagnetic data have well demonstrated that the strength of ancient geomagnetic field was dramatically weakened during a polarity transition. Accumulating evidence has shown that weak magnetic field exposures has serious adverse effects on the metabolism and behaviors in organisms. Hippocampal neurogenesis occurs throughout life in mammals' brains which plays a key role in brain function, and can be influenced by animals' age as well as environmental factors, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we have investigated the weak magnetic field effects on hippocampal neurogenesis of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, a weak magnetic field (≤1.3 μT) and the geomagnetic fields (51 μT).The latter is treated as a control condition. SD rats were exposure to the weak magnetic field up to 6 weeks. We measured the changes of newborn nerve cells' proliferation and survival, immature neurons, neurons and apoptosis in the dentate gyrus (DG) of hippocampus in SD rats. Results showed that, the weak magnetic field (≤1.3 μT) inhibited their neural stem cells proliferation and significantly reduced the survival of newborn nerve cells, immature neurons and neurons after 2 or 4 weeks continuous treatment (i.e. exposure to weak magnetic field). Moreover, apoptosis tests indicated the weak magnetic field can promote apoptosis of nerve cells in the hippocampus after 4 weeks treatment. Together, our new data indicate that weak magnetic field decrease adult hippocampal neurogenesis through inhibiting neural stem cells proliferation and promoting apoptosis, which provides useful experimental constraints on better understanding the mechanism of linkage between life and geomagnetic field.

The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats.

PubMed

Robinson, L; Goonawardena, A V; Pertwee, R G; Hampson, R E; Riedel, G

2007-07-01

Previous work implied that the hippocampal cannabinoid system was particularly important in some forms of learning, but direct evidence for this hypothesis is scarce. We therefore assessed the effects of the synthetic cannabinoid HU210 on memory and hippocampal activity. HU210 (100 microg kg(-1)) was administered intraperitoneally to rats under three experimental conditions. One group of animals were pre-trained in spatial working memory using a delayed-matching-to-position task and effects of HU210 were assessed in a within-subject design. In another, rats were injected before acquisition learning of a spatial reference memory task with constant platform location. Finally, a separate group of animals was implanted with electrode bundles in CA1 and CA3 and single unit responses were isolated, before and after HU210 treatment. HU210 treatment had no effect on working or short-term memory. Relative to its control Tween 80, deficits in acquisition of a reference memory version of the water maze were obtained, along with drug-related effects on anxiety, motor activity and spatial learning. Deficits were not reversed by the CB(1) receptor antagonists SR141716A (3 mg kg(-1)) or AM281 (1.5 mg kg(-1)). Single unit recordings from principal neurons in hippocampal CA3 and CA1 confirmed HU210-induced attenuation of the overall firing activity lowering both the number of complex spikes fired and the occurrence of bursts. These data provide the first direct evidence that the underlying mechanism for the spatial memory deficits induced by HU210 in rats is the accompanying abnormality in hippocampal cell firing.

The hippocampus and appetitive Pavlovian conditioning: effects of excitotoxic hippocampal lesions on conditioned locomotor activity and autoshaping.

PubMed

Ito, Rutsuko; Everitt, Barry J; Robbins, Trevor W

2005-01-01

The hippocampus (HPC) is known to be critically involved in the formation of associations between contextual/spatial stimuli and behaviorally significant events, playing a pivotal role in learning and memory. However, increasing evidence indicates that the HPC is also essential for more basic motivational processes. The amygdala, by contrast, is important for learning about the motivational significance of discrete cues. This study investigated the effects of excitotoxic lesions of the rat HPC and the basolateral amygdala (BLA) on the acquisition of a number of appetitive behaviors known to be dependent on the formation of Pavlovian associations between a reward (food) and discrete stimuli or contexts: (1) conditioned/anticipatory locomotor activity to food delivered in a specific context and (2) autoshaping, where rats learn to show conditioned discriminated approach to a discrete visual CS+. While BLA lesions had minimal effects on conditioned locomotor activity, hippocampal lesions facilitated the development of both conditioned activity to food and autoshaping behavior, suggesting that hippocampal lesions may have increased the incentive motivational properties of food and associated conditioned stimuli, consistent with the hypothesis that the HPC is involved in inhibitory processes in appetitive conditioning. (c) 2005 Wiley-Liss, Inc.

Adolescent voluntary exercise attenuated hippocampal innate immunity responses and depressive-like behaviors following maternal separation stress in male rats.

PubMed

Sadeghi, Mahsa; Peeri, Maghsoud; Hosseini, Mir-Jamal

2016-09-01

Early life stressful events have detrimental effects on the brain and behavior, which are associated with the development of depression. Immune-inflammatory responses have been reported to contribute in the pathophysiology of depression. Many studies have reported on the beneficial effects of exercise against stress. However, underlying mechanisms through which exercise exerts its effects were poorly studied. Therefore, it applied maternal separation (MS), as a valid animal model of early-life adversity, in rats from postnatal day (PND) 2 to 14 for 180min per day. At PND 28, male Wistar albino rats were subjected to 5 experimental groups; 1) controls 2) MS rats 3) MS rats treated with fluoxetine 5mg/kg to PND 60, 4) MS rats that were subjected to voluntary running wheel (RW) exercise and 5) MS rats that were subjected to mandatory treadmill (TM) exercise until adulthood. At PND 60, depressive-like behaviors were assessed by using forced swimming test (FST), splash test, and sucrose preference test (SPT). Our results revealed that depressive-like behaviors following MS stress were associated with an increase in expression of toll-like receptor 4 (Tlr-4) and its main signaling protein, Myd88, in the hippocampal formation. Also, we found that voluntary (and not mandatory) physical exercise during adolescence is protected against depressant effects of early-life stress at least partly through mitigating the innate immune responses in the hippocampus. Copyright © 2016. Published by Elsevier Inc.

Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory

PubMed Central

Maher, Pamela; Akaishi, Tatsuhiro; Abe, Kazuho

2006-01-01

Small molecules that activate signaling pathways used by neurotrophic factors could be useful for treating CNS disorders. Here we show that the flavonoid fisetin activates ERK and induces cAMP response element-binding protein (CREB) phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice. Together, these data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders. PMID:17050681

Vinpocetine prevent ischemic cell damage in rat hippocampus

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

Sauer, D.; Rischke, R.; Beck, T.

1988-01-01

The effects of vinpocetine on hippocampal cell damage and local cerebral blood flow (LCBF) were measured in a rat model of forebrain ischemia. Duration of ischemia was 10 min. LCBF was determined after 2 min of recirculation using the /sup 14/C-iodoantipyrine technique. Hippocampal cell loss was quantified histologically 7 days post-ischemia. Intraperitoneal application of vinpocetine 15 min prior to ischemia significantly reduced neuronal cell loss in hippocampal CA 1 sector from 60% to 28%. The drug led to a marked increase in blood flow in cortical areas, whereas LCBF remained unchanged in hippocampus and all other structures measured. It ismore » suggested that the protective effect of vinpocetine does not depend on increased postischemic blood flow.« less

Delayed suppression of hippocampal cell proliferation in rats following inescapable shocks.

PubMed

Fornal, Casimir A; Stevens, Joanne; Barson, Jessica R; Blakley, Gregory G; Patterson-Buckendahl, Patricia; Jacobs, Barry L

2007-01-26

Adult Sprague-Dawley rats were exposed to a single session of 100 inescapable tail shocks (IS). Bromodeoxyuridine (BrdU) was administered 1 h, 2 days or 7 days later and hippocampal cell proliferation (CP) was assessed after a 2-h survival period. Measures of plasma corticosterone (CORT) levels were also obtained. Despite a large increase in CORT immediately following IS, no associated change in CP was observed. In fact, the only significant change in CP was seen 7 days after IS, at a time when CORT was unchanged from control levels. These data raise questions about the general nature of the relationship between CORT and CP. They also suggest that, under some conditions, changes in hippocampal CP may emerge only after an "incubation period".

Cyanidin-3-glucoside inhibits glutamate-induced Zn2+ signaling and neuronal cell death in cultured rat hippocampal neurons by inhibiting Ca2+-induced mitochondrial depolarization and formation of reactive oxygen species.

PubMed

Yang, Ji Seon; Perveen, Shazia; Ha, Tae Joung; Kim, Seong Yun; Yoon, Shin Hee

2015-05-05

Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. However, effects of C3G on glutamate-induced [Zn(2+)]i increase and neuronal cell death remain unknown. We studied the effects of C3G on glutamate-induced [Zn(2+)]i increase and cell death in cultured rat hippocampal neurons from embryonic day 17 maternal Sprague-Dawley rats using digital imaging methods for Zn(2+), Ca(2+), reactive oxygen species (ROS), mitochondrial membrane potential and a MTT assay for cell survival. Treatment with glutamate (100 µM) for 7 min induces reproducible [Zn(2+)]i increase at 35 min interval in cultured rat hippocampal neurons. The intracellular Zn(2+)-chelator TPEN markedly blocked glutamate-induced [Zn(2+)]i increase, but the extracellular Zn(2+) chelator CaEDTA did not affect glutamate-induced [Zn(2+)]i increase. C3G inhibited the glutamate-induced [Zn(2+)]i response in a concentration-dependent manner (IC50 of 14.1 ± 1.1 µg/ml). C3G also significantly inhibited glutamate-induced [Ca(2+)]i increase. Two antioxidants such as Trolox and DTT significantly inhibited the glutamate-induced [Zn(2+)]i response, but they did not affect the [Ca(2+)]i responses. C3G blocked glutamate-induced formation of ROS. Trolox and DTT also inhibited the formation of ROS. C3G significantly inhibited glutamate-induced mitochondrial depolarization. However, TPEN, Trolox and DTT did not affect the mitochondrial depolarization. C3G, Trolox and DTT attenuated glutamate-induced neuronal cell death in cultured rat hippocampal neurons, respectively. Taken together, all these results suggest that cyanidin-3-glucoside inhibits glutamate-induced [Zn(2+)]i increase through a release of Zn(2+) from intracellular sources in cultured rat hippocampal neurons by inhibiting Ca(2+)-induced mitochondrial depolarization and formation of ROS, which is involved in neuroprotection against glutamate-induced cell death. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of chronic cocaine treatment during adolescence in Lewis and Fischer-344 rats: Novel location recognition impairment and changes in synaptic plasticity in adulthood.

PubMed

Fole, A; Martin, M; Morales, L; Del Olmo, N

2015-09-01

The use of Lewis (LEW) together with Fischer-344 (F344) rats has been proposed as an addiction model because of the addiction behavior differences of these two strains. We have previously suggested that these differences could be related to learning and memory processes and that they depend on the genetic background of these two strains of rats. Adolescence is a period of active synaptic remodeling, plasticity and particular vulnerability to the effects of environmental insults such as drugs of abuse. We have evaluated spatial memory using novel location recognition in LEW and F344 adult rats undergoing a chronic treatment with cocaine during adolescence or adulthood. In order to study whether synaptic plasticity mechanisms were involved in the possible changes in learning after chronic cocaine treatment, we carried out electrophysiological experiments in hippocampal slices from treated animals. Our results showed that, in LEW cocaine-treated rats, hippocampal memory was only significantly impaired when the drug was administered during adolescence whereas adult administration did not produce any detrimental effect in spatial memory measured in this protocol. Moreover, F344 rats showed clear difficulties carrying out the protocol even in standard conditions, confirming the spatial memory problems observed in previous reports and demonstrating the genetic differences in spatial learning and memory. Our experiments show that the effects in behavioral experiments are related to synaptic plasticity mechanisms. Long-term depression induced by the glutamate agonist NMDA (LTD-NMDA) is partially abolished in cocaine-treated animals in hippocampal slices from LEW rats. Hippocampal LTD-NMDA is partially inhibited in F344 animals regardless of whether saline or cocaine administration, suggesting the lack of plasticity of this strain that could be related to the inability of these animals to carry out the novel object location protocol. Copyright © 2015 Elsevier Inc. All rights reserved.

Rats with hippocampal lesion show impaired learning and memory in the ziggurat task: a new task to evaluate spatial behavior.

PubMed

Faraji, Jamshid; Lehmann, Hugo; Metz, Gerlinde A; Sutherland, Robert J

2008-05-16

Spatial tasks are widely used to determine the function of limbic system structures in rats. The present study used a new task designed to evaluate spatial behavior, the ziggurat task (ZT), to examine the performance of rats with widespread hippocampal damage induced by N-methyl-d-aspartic acid (NMDA). The task consisted of an open field containing 16 identical ziggurats (pyramid shaped towers) arranged at equal distances. One of the ziggurats was baited with a food reward. The task required rats to navigate through the open field by using a combination of distal and/or proximal cues in order to locate the food reward. The ability to acquire and recall the location of the goal (baited) ziggurat was tested in consecutive training sessions of eight trials per day for 10 days. The location of the goal ziggurat was changed every second day, requiring the rats to learn a total of five different locations. Several parameters, including latency to find the target, distance traveled, the number of visits to non-baited ziggurats (errors), and the number of returns were used as indices of learning and memory. Control rats showed a significant decrease in distance traveled and reduced latency in locating the goal ziggurat across trials and days, suggesting that they learned and remembered the location of the goal ziggurat. Interestingly, the hippocampal-damaged group moved significantly faster, and traveled longer distances compared to the control group. Significant differences were observed between these groups with respect to the number of errors and returns on test days. Day 11 served as probe day, in which no food reward was given. The controls spent more time searching for the food in the previous training quadrant compared to the hippocampal group. The findings demonstrate that the ZT is a sensitive and efficient dry task for measuring hippocampus-dependent spatial performance in rats requiring little training and not associated with some of the disadvantages of water tasks.

Recognition Memory Is Impaired in Children after Prolonged Febrile Seizures

ERIC Educational Resources Information Center

Martinos, Marina M.; Yoong, Michael; Patil, Shekhar; Chin, Richard F. M.; Neville, Brian G.; Scott, Rod C.; de Haan, Michelle

2012-01-01

Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal…

Subcellular Localization of Patched and Smoothened, the Receptors for Sonic Hedgehog Signaling, in the Hippocampal Neuron

PubMed Central

Petralia, Ronald S.; Schwartz, Catherine M.; Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

2011-01-01

Cumulative evidence suggests that, aside from patterning the embryonic neural tube, Sonic hedgehog (Shh) signaling plays important roles in the mature nervous system. In this study, we investigate the expression and localization of the Shh signaling receptors, Patched (Ptch) and Smoothened (Smo), in the hippocampal neurons of young and mature rats. Reverse transcriptase-polymerase chain reaction and immunoblotting analyses show that the expression of Ptch and Smo remains at a moderate level in young postnatal and adult brains. By using immunofluorescence light microscopy and immunoelectron microscopy, we examine the spatial distribution of Ptch and Smo within the hippocampal neurons. In young developing neurons, Ptch and Smo are present in the processes and are clustered at their growth cones. In mature neurons, Ptch and Smo are concentrated in dendrites, spines, and postsynaptic sites. Synaptic Ptch and Smo often co-exist with unusual structures—synaptic spinules and autophagosomes. Our results reveal the anatomical organization of the Shh receptors within both the young and the mature hippocampal neurons. PMID:21618238

Antidepressant-like effects and possible mechanisms of amantadine on cognitive and synaptic deficits in a rat model of chronic stress.

PubMed

Yu, Mei; Zhang, Yuan; Chen, Xiaoyu; Zhang, Tao

2016-01-01

The aim of this study was to examine whether amantadine (AMA), as a low-affinity noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is able to improve cognitive deficits caused by chronic stress in rats. Male Wistar rats were divided into four groups: control, control + AMA, stress and stress + AMA groups. The chronic stress model combined chronic unpredictable stress (CUS) with isolated feeding. Animals were exposed to CUS continued for 21 days. AMA (25 mg/kg) was administrated p.o. for 20 days from the 4th day of CUS to the 23rd. Weight and sucrose consumption were measured during model establishing period. Spatial memory was evaluated using the Morris water maze (MWM) test. Following MWM testing, both long-term potentiation (LTP) and depotentiation were recorded in the hippocampal CA1 region. NR2B and postsynaptic density protein 95 (PSD-95) proteins were measured by Western-blot analysis. AMA increased weight and sucrose consumption of stressed rats. Spatial memory and reversal learning in stressed rats were impaired relative to controls, whereas AMA significantly attenuated cognitive impairment. AMA also mitigated the chronic stress-induced impairment of hippocampal synaptic plasticity, in which both the LTP and depotentiation were significantly inhibited in stressed rats. Moreover, AMA enhanced the expression of hippocampal NR2B and PSD-95 in stressed rats. The data suggest that AMA may be an effective therapeutic agent for depression-like symptoms and associated cognitive disturbances.

Sequential expression of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor in rat hippocampal neurons after fluid percussion injury

PubMed Central

Li, Zhiqiang; Shu, Qingming; Li, Lingzhi; Ge, Maolin; Zhang, Yongliang

2014-01-01

Traumatic brain injury causes gene expression changes in different brain regions. Occurrence and development of traumatic brain injury are closely related, involving expression of three factors, namely cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. However, little is known about the correlation of these three factors and brain neuronal injury. In this study, primary cultured rat hippocampal neurons were subjected to fluid percussion injury according to Scott's method, with some modifications. RT-PCR and semi-quantitative immunocytochemical staining was used to measure the expression levels of cyclooxygenase-2, glutamate receptor-2, and platelet activating factor receptor. Our results found that cyclooxygenase-2 expression were firstly increased post-injury, and then decreased. Both mRNA and protein expression levels reached peaks at 8 and 12 hours post-injury, respectively. Similar sequential changes in glutamate receptor 2 were observed, with highest levels mRNA and protein expression at 8 and 12 hours post-injury respectively. On the contrary, the expressions of platelet activating factor receptor were firstly decreased post-injury, and then increased. Both mRNA and protein expression levels reached the lowest levels at 8 and 12 hours post-injury, respectively. Totally, our findings suggest that these three factors are involved in occurrence and development of hippocampal neuronal injury. PMID:25206921

Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood-brain barrier in aged rats.

PubMed

Cao, Yiyun; Ni, Cheng; Li, Zhengqian; Li, Lunxu; Liu, Yajie; Wang, Chunyi; Zhong, Yanfeng; Cui, Dehua; Guo, Xiangyang

2015-02-05

The underlying mechanism of isoflurane-induced cognitive dysfunction in older individuals is unknown. In this study, the effects of isoflurane exposure on the hippocampal blood-brain barrier (BBB) in aged rats were investigated because it was previously shown that BBB disruption involves in cognitive dysfunction. Twenty-month-old rats randomly received 1.5% isoflurane or vehicle gas as control. Hippocampal BBB ultrastructure was analyzed by transmission electron microscopy and expression of tight junction proteins was measured by western blot analysis. BBB permeability was detected with sodium fluorescein extravasation and further confirmed by immunoglobulin G immunohistochemistry. Spatial learning and memory were assessed by the Morris water maze test. Isoflurane anesthesia resulted in reversible time-dependent BBB ultrastructure morphological damage and significant decreases in expression of the tight junction proteins occludin, which contributed to sodium fluorescein and IgG leakage. Rats with isoflurane exposure also showed significant cognitive deficits in the Morris water maze test. This in vivo data indicate that occludin down-regulation may be one of the mediators of isoflurane-induced hippocampus BBB disruption, and may contribute to hippocampus-dependent cognitive impairment after isoflurane exposure in aged rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

PubMed

Choi, Miyeon; Lee, Seung Hoon; Park, Min Hyeop; Kim, Yong-Seok; Son, Hyeon

2017-08-05

Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. Copyright © 2017 Elsevier Inc. All rights reserved.

The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weinberger, Daniel R

2003-12-01

The neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia, a human disorder associated with changes in markers of dopamine and gamma-aminobutyric acid (GABA) circuits in various regions of the brain. We investigated whether alterations in mRNA markers related to the activity of midbrain dopaminergic and GABAergic neurons are associated with this model. We used in situ hybridization histochemistry to assess expression of mRNAs for dopamine transporter (DAT), tyrosine hydroxylase (TH) and glutamate decarboxylase-67 (GAD67) in the midbrain of adult rats with neonatal and adult ibotenic acid lesions of the ventral hippocampus. Neonatally lesioned rats showed in adulthood significantly reduced expression of DAT mRNA in the substantia nigra and the ventral tegmental area but no changes in the expression of TH and GAD67 mRNAs in these midbrain regions. Adult lesioned rats showed no changes in the expression of any of these genes. As the neonatal ventral hippocampal lesion reproduces many aspects of schizophrenia and is used as an animal model of this disorder, these results suggest that the reduction in DAT mRNA could result from developmental neuropathology in the ventral hippocampus and may thus represent a molecular substrate of the disease process.

The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

PubMed

Babalola, P A; Fitz, N F; Gibbs, R B; Flaherty, P T; Li, P-K; Johnson, D A

2012-10-01

Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract. Copyright © 2012 Elsevier Inc. All rights reserved.

Action of AF64A on rat brain muscarinic receptors

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

Eva, C.; Costa, E.

ICV administration of compound AF64A (ethylcholine mustard aziridium ion) induces a long-term selective cholinergic hypofunction; however, it does not modify the characteristics of muscarinic receptors. In brain muscarinic receptor activation can either stimulate phosphoinositide turnover or inhibit adenylate cyclase. ICV infusion of AF64A (5 nmol/side/2.5 ..mu..l) reduced the hippocampal ACh content 10 or 30 days after the treatment to 75% of the control values. Under these conditions neither in the striatum nor in the frontal cortex ACh levels were decreased. The carbachol dose-dependent stimulation in hippocampal slices differed from that observed in control rats. The carbachol efficacy was increased butmore » its potency was unchanged by AF64A. In contrast, ICV administration of AF64A failed to alter the oxotremorine efficacy or potency in inhibiting the forskolin stimulated adenylate cyclase in rat hippocampal membranes. These results suggest the two transducer systems coupled to muscarinic receptors may be differentially regulatable by cholinergic input.« less

Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain.

PubMed

Huang, Lining; Liu, Ya; Jin, Wei; Ji, Xiaochen; Dong, Zhenming

2012-10-02

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a general pediatric anesthetic. Recent studies suggest that ketamine enhances neuronal apoptosis in developing rodents and nonhuman primates. The main goal of this study is to determine whether ketamine causes hippocampal neurodegeneration and behavioral deficits in adulthood, and if so, whether the effects of ketamine are associated with protein kinase C-gamma (PKCγ), extracellular signal regulated kinase (ERK)1/2 and Bcl-2 expression. Starting from postnatal day 7, Sprague-Dawley rat pups randomly received daily ketamine treatment (25, 50 and 75mg/kg, ip) for three consecutive days. Twenty-four hours after the last treatment with ketamine, the rats were decapitated, and the hippocampi were isolated for detection of neuronal apoptosis by TUNEL. The protein expression levels of PKCγ, ERK1/2 and Bcl-2 in the hippocampi were measured by western blot analysis. At 2months of age, learning and memory abilities were tested by the Morris water maze. Ketamine increased the number of apoptotic cells in the CA1 region and dentate gyrus at a dose of 75mg/kg but not at lower doses of 25 and 50mg/kg. The dose of 75mg/kg of ketamine suppressed p-PKCγ, p-ERK1/2 and Bcl-2 expression but not t-PKCγ or t-ERK expression. Ketamine administered to the developing brains of P7 rats at a dose of 75mg/kg caused learning and memory impairments in adulthood. Therefore, these data demonstrate that ketamine at a dose of 75mg/kg in the developing brain results in hippocampal neurodegeneration and persistent learning and memory impairment, which is associated with the PKCγ-ERK signaling pathway. This article is part of a Special Issue entitled: Brain Integration. Copyright © 2012 Elsevier B.V. All rights reserved.

Possible relationship between the stress-induced synaptic response and metaplasticity in the hippocampal CA1 field of freely moving rats.

PubMed

Hirata, Riki; Matsumoto, Machiko; Judo, Chika; Yamaguchi, Taku; Izumi, Takeshi; Yoshioka, Mitsuhiro; Togashi, Hiroko

2009-07-01

Hippocampal long-term potentiation (LTP) is suppressed not only by stress paradigms but also by low frequency stimulation (LFS) prior to LTP-inducing high frequency stimulation (HFS; tetanus), termed metaplasticity. These synaptic responses are dependent on N-methyl-D-aspartate receptors, leading to speculations about the possible relationship between metaplasticity and stress-induced LTP impairment. However, the functional significance of metaplasticity has been unclear. The present study elucidated the electrophysiological and neurochemical profiles of metaplasticity in the hippocampal CA1 field, with a focus on the synaptic response induced by the emotional stress, contextual fear conditioning (CFC). The population spike amplitude in the CA1 field was decreased during exposure to CFC, and LTP induction was suppressed after CFC in conscious rats. The synaptic response induced by CFC was mimicked by LFS, i.e., LFS impaired the synaptic transmission and subsequent LTP. Plasma corticosterone levels were increased by both CFC and LFS. Extracellular levels of gamma-aminobutyric acid (GABA), but not glutamate, in the hippocampus increased during exposure to CFC or LFS. Furthermore, electrical stimulation of the medial prefrontal cortex (mPFC), which caused decreases in freezing behavior during exposure to CFC, counteracted the LTP impairment induced by LFS. These findings suggest that metaplasticity in the rat hippocampal CA1 field is related to the neural basis of stress experience-dependent fear memory, and that hippocampal synaptic response associated stress-related processes is under mPFC regulation.

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

Chelation of hippocampal zinc enhances long-term potentiation and synaptic tagging/capture in CA1 pyramidal neurons of aged rats: implications to aging and memory.

PubMed

Shetty, Mahesh Shivarama; Sharma, Mahima; Sajikumar, Sreedharan

2017-02-01

Aging is associated with decline in cognitive functions, prominently in the memory consolidation and association capabilities. Hippocampus plays a crucial role in the formation and maintenance of long-term associative memories, and a significant body of evidence shows that impairments in hippocampal function correlate with aging-related memory loss. A number of studies have implicated alterations in hippocampal synaptic plasticity, such as long-term potentiation (LTP), in age-related cognitive decline although exact mechanisms underlying are not completely clear. Zinc deficiency and the resultant adverse effects on cognition have been well studied. However, the role of excess of zinc in synaptic plasticity, especially in aging, is not addressed well. Here, we have investigated the hippocampal zinc levels and the impairments in synaptic plasticity, such as LTP and synaptic tagging and capture (STC), in the CA1 region of acute hippocampal slices from 82- to 84-week-old male Wistar rats. We report increased zinc levels in the hippocampus of aged rats and also deficits in the tetani-induced and dopaminergic agonist-induced late-LTP and STC. The observed deficits in synaptic plasticity were restored upon chelation of zinc using a cell-permeable chelator. These data suggest that functional plasticity and associativity can be successfully established in aged neural networks by chelating zinc with cell-permeable chelating agents. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats.

PubMed

Ma, Jingyi; Stan Leung, L

2017-10-01

Decreased GABA B receptor function is proposed to mediate some symptoms of schizophrenia. In this study, we tested the effect of CGP7930, a GABA B receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15 min prior to ketamine (3 mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection. CGP7930 at doses of 1 mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1 mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65-100 Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3 mM/1 μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5 mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1 mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABA B receptor function in vivo. CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.

Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression.

PubMed

Baka, Judith; Csakvari, Eszter; Huzian, Orsolya; Dobos, Nikoletta; Siklos, Laszlo; Leranth, Csaba; MacLusky, Neil J; Duman, Ronald S; Hajszan, Tibor

2017-02-20

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Stress Induces Equivalent Remodeling of Hippocampal Spine Synapses in a Simulated Postpartum Environment and in a Female Rat Model of Major Depression

PubMed Central

Baka, Judith; Csakvari, Eszter; Huzian, Orsolya; Dobos, Nikoletta; Siklos, Laszlo; Leranth, Csaba; MacLusky, Neil J; Duman, Ronald S; Hajszan, Tibor

2017-01-01

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn ‘postpa rtum’, simulated proestrus, and hormone-treated ‘postpartum’ animals. After ‘postpartum’ withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn ‘postpartum’ females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during ‘postpartum’ stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during ‘postpartum’ stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated ‘postpartum’ females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging ‘synaptogenic hypothesis’ of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. PMID:28012870

Long-term neurocognitive dysfunction in offspring via NGF/ ERK/CREB signaling pathway caused by ketamine exposure during the second trimester of pregnancy in rats.

PubMed

Li, Yanan; Li, Xinran; Guo, Cen; Li, Lina; Wang, Yuxin; Zhang, Yiming; Chen, Yu; Liu, Wenhan; Gao, Li

2017-05-09

Early life exposure to ketamine caused neurohistopathologic changes and persistent cognitive dysfunction. For this study, a pregnant rat model was developed to investigate neurocognitive effects in the offspring, following ketamine exposure during the second trimester. Pregnant rats on gestational day 14 (equal to midtrimester pregnancy in humans), intravenously received 200 mg/kg ketamine for 3 h. Their behavior was tested (Morris water maze, odor recognition test, and fear conditioning) at postnatal days (P25-30). Furthermore, hippocampal morphology of the offspring (P30) was examined via Nissl staining and hippocampal dendritic spine density was determined via Golgi staining. The hippocampal protein levels of nerve growth factor (NGF), extracellular signal-regulated kinase (ERK), phosphorylated-ERK (p-ERK), cyclic adenosine monophosphate response element-binding (CREB), p-CREB, synaptophysin (SYP), synapsin (SYN), and postsynaptic density-95 (PSD95) were measured via western blot. Additionally, SCH772984 (an ERK inhibitor) was used to evaluate both role and underlying mechanism of the ERK pathway in PC12 cells. We found that ketamine caused long-term neurocognitive dysfunction, reduced the density of the dendritic spin, caused neuronal loss, and down-regulated the expression of NGF, ERK, p-ERK, mitogen, and stress-activated protein kinase (MSK), CREB, p-CREB, SYP, SYN, and PSD95 in the hippocampus. These results suggest that ketamine induced maternal anesthesia during period of the fetal brain development can cause long-term neurocognitive dysfunction in the offspring, which likely happens via inhibition of the NGF-ERK-CREB pathway in the hippocampus. Our results highlight the central role of ERK in neurocognition.

Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats.

PubMed

Hsu, Ted M; Konanur, Vaibhav R; Taing, Lilly; Usui, Ryan; Kayser, Brandon D; Goran, Michael I; Kanoski, Scott E

2015-02-01

Excessive consumption of added sugars negatively impacts metabolic systems; however, effects on cognitive function are poorly understood. Also unknown is whether negative outcomes associated with consumption of different sugars are exacerbated during critical periods of development (e.g., adolescence). Here we examined the effects of sucrose and high fructose corn syrup-55 (HFCS-55) intake during adolescence or adulthood on cognitive and metabolic outcomes. Adolescent or adult male rats were given 30-day access to chow, water, and either (1) 11% sucrose solution, (2) 11% HFCS-55 solution, or (3) an extra bottle of water (control). In adolescent rats, HFCS-55 intake impaired hippocampal-dependent spatial learning and memory in a Barne's maze, with moderate learning impairment also observed for the sucrose group. The learning and memory impairment is unlikely based on nonspecific behavioral effects as adolescent HFCS-55 consumption did not impact anxiety in the zero maze or performance in a non-spatial response learning task using the same mildly aversive stimuli as the Barne's maze. Protein expression of pro-inflammatory cytokines (interleukin 6, interleukin 1β) was increased in the dorsal hippocampus for the adolescent HFCS-55 group relative to controls with no significant effect in the sucrose group, whereas liver interleukin 1β and plasma insulin levels were elevated for both adolescent-exposed sugar groups. In contrast, intake of HFCS-55 or sucrose in adults did not impact spatial learning, glucose tolerance, anxiety, or neuroinflammatory markers. These data show that consumption of added sugars, particularly HFCS-55, negatively impacts hippocampal function, metabolic outcomes, and neuroinflammation when consumed in excess during the adolescent period of development. © 2014 Wiley Periodicals, Inc.

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine.

PubMed

Forrest, C M; McNair, K; Pisar, M; Khalil, O S; Darlington, L G; Stone, T W

2015-12-03

Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine

PubMed Central

Forrest, C.M.; McNair, K.; Pisar, M.; Khalil, O.S.; Darlington, L.G.; Stone, T.W.

2015-01-01

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100 mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(−/−) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development. PMID:26365611

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy.

PubMed

Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen; Michel, Cole R; Gomez, Joe; Vassilopoulos, Athanassios; Reisdorph, Nichole; Fritz, Kristofer S; Patel, Manisha

2018-08-01

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy. Copyright © 2018 Elsevier Inc. All rights reserved.

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.

PubMed

Riga, Danai; Kramvis, Ioannis; Koskinen, Maija K; van Bokhoven, Pieter; van der Harst, Johanneke E; Heistek, Tim S; Jaap Timmerman, A; van Nierop, Pim; van der Schors, Roel C; Pieneman, Anton W; de Weger, Anouk; van Mourik, Yvar; Schoffelmeer, Anton N M; Mansvelder, Huib D; Meredith, Rhiannon M; Hoogendijk, Witte J G; Smit, August B; Spijker, Sabine

2017-12-20

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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

Effects of inorganic lead on the differentiation and growth of cultured hippocampal and neuroblastoma cells.

PubMed

Audesirk, T; Audesirk, G; Ferguson, C; Shugarts, D

1991-01-01

Lead exposure has devastating effects on the developing nervous system, and has been implicated in variety of behavioral and cognitive deficits as well as neural morphological abnormalities. Since lead impacts many calcium-dependent processes, one likely mechanism of lead toxicity is its disruption of calcium dependent processes, among which is neuronal differentiation. We investigated the effects of inorganic lead on survival and several parameters of differentiation of cultured neurons. Three different cell types were used: Rat hippocampal neurons (a primary CNS cell type), B50 rat neuroblastoma cells (a transformed CNS-derived cell line), and N1E-115 mouse neuroblastoma cells (a transformed peripherally-derived cell line). Lead concentrations ranged from low nM to 1 mM. Lead effects differed considerably among the three cell types, with B50 cells least affected. Lead effects were generally multimodal, with fewest effects observed at intermediate concentrations. Lead inhibited neurite initiation in hippocampal neurons, but stimulated initiation in N1E-115 cells. In those cells that differentiated, lead increased dendrite numbers in hippocampal neurons and neurite numbers in N1E-115 cells. Lead exposure increased both the length and the degree of branching of axons in hippocampal neurons and the length of neurites in N1E-115 cells. We hypothesize that lead impacts multiple regulatory processes that influence neuron survival and differentiation, and that its effects show differing dose-dependencies. The differing responses of the different cell types to lead suggests that differentiation may be regulated in different ways by the three types of cells. Alternatively, or additionally, the cell types may differ in their ability to compensate for, sequester, or expel lead.

PI3K/AKT/mTOR-mediated autophagy in the development of autism spectrum disorder.

PubMed

Zhang, Jun; Zhang, Ji-Xiang; Zhang, Qin-Liang

2016-07-01

To investigate the association between PI3K/AKT/mTOR-mediated autophagy and the pathogenesis of autism spectrum disorder (ASD). A sodium valproate (VPA)-induced baby rat model of ASD was built. Nine pregnant rats were randomly assigned into three groups, with three rats for each group: healthy control group, VPA group and mTOR inhibition group, receiving different drug administrations. Baby rats were grouped according to the maternal rats. Social interaction of baby rats (35days after birth) was observed and their bilateral hippocampes were sliced. We used electron microscope analysis for observation of autophagosome formation, double immunofluorescence staining for location of LC3 II, TUNEL assay for observation of cell apoptosis, Western Blot assay was used for measurement of LC3 II, P62, p53, Bcl-2, PI3K/AKT/mTOR-related proteins and p-S6. VPA group had significantly lowered ability of social interaction than the control group and mTOR inhibition group (both P<0.05). The control group and the mTOTR inhibition group presented the visual of autophagosomes, while VPA group seldom had autophagosomes. By comparison with VPA group, mTOR group had a remarkable green fluorescence in the hippocampal CA1 (P<0.05). Western Blot assay revealved that mTOR inhibition group had a significantly higher LC3 II expression, higher LC3 II/LC3 I ratio, higher Bcl-2 expression and lower p53 than VPA group (all P<0.05). TUNEL assay showed that mTOR inhibition group had a significant smaller number of apoptotic cells in the hippocampal CA1. Besides, lowered expressions of p-PI3K, p-AKT and p-S6 were identified in the baby rats in mTOR inhibition group compared with VPA group (all P<0.05). mTOR inhibition can increase PI3K/AKT/mTOR-mediated autophagic activity and improve social interaction in VPA-induced ASD, providing a novel target and direction for the treatment of ASD. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1☆

PubMed Central

Li, Yuhong; Shi, Changhua; Lu, Guobing; Xu, Qian; Liu, Shaochen

2012-01-01

In this study, we investigated the effects of mobile phone radiation on spatial learning, reference memory, and morphology in related brain regions. After the near-field radiation (0.52–1.08 W/kg) was delivered to 8-week-old Wistar rats 2 hours per day for 1 month, behavioral changes were examined using the Morris water maze. Compared with the sham-irradiated rats, the irradiated rats exhibited impaired performance. Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus. Using the physical dissector technique, the number of pyramidal neurons, the synaptic profiles, and the length of postsynaptic densities in the CA1 region were quantified stereologically. The morphological changes included mitochondrial degenerations, fewer synapses, and shorter postsynaptic densities in the radiated rats. These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region. PMID:25709623

Can Molecular Hippocampal Alterations Explain Behavioral Differences in Prenatally Stressed Rats?

EPA Science Inventory

Studies in both humans and animals have shown that prenatal stress can alter cognitive function and other neurological behaviors in adult offspring. One possible underlying mechanism for this may lie with alterations in hippocampal gene expression. The present study examined geno...

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.

Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

PubMed

Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

2014-06-01

Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS)

PubMed Central

Diamond, David M.

2004-01-01

Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people. PMID:19330152

Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo

PubMed Central

Tukker, John J; Klausberger, Thomas; Somogyi, Peter

2015-01-01

Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation. PMID:24141313

Hippocampal FXR plays a role in the pathogenesis of depression: A preliminary study based on lentiviral gene modulation.

PubMed

Chen, Wei-Guan; Zheng, Jia-Xuan; Xu, Xi; Hu, Yu-Ming; Ma, Yu-Min

2018-06-01

As a well-known bile acid receptor, the role of Farnesoid X receptor (FXR) in the digestive system and cardiovascular system has been widely explored. However, there are very few studies involving FXR in the central nervous system. In this study, we explored the role of FXR in the pathogenesis of depression, a serious and worldwide neuropsychiatric disease. It was found that chronic unpredictable mild stress (CUMS) fully enhanced the protein and mRNA expressions of FXR in hippocampus, but not medial prefrontal cortex (mPFC). Overexpression of hippocampal FXR induced notable depressive-like behaviors and decreased expression of brain-derived neurotrophic factor (BDNF) in naïve rats, while knockdown of hippocampal FXR fully prevented the effects of CUMS on rat behaviors and hippocampal BDNF expression. Taken together, our research extends the knowledge of FXR's role in the central nervous system, and may provide a potential and novel therapeutic target for treating depression. Copyright © 2018 Elsevier B.V. All rights reserved.

Influence of late-life exposure to environmental enrichmentor exercise on hippocampal function and CA1 senescent physiology

PubMed Central

Kumar, A.; Rani, A.; Tchigranova, Olga; Lee, Wei-Hua; Foster, T.C.

2011-01-01

Aged (20–22 months) male Fischer 344 rats were randomly assigned to sedentary (A-SED), environmentally enriched (A-ENR) or exercise (A-EX) conditions. After 10–12 weeks of differential experience, the three groups of aged rats and young sedentary controls were tested for physical and cognitive function. Spatial discrimination learning and memory consolidation, tested on the water maze, were enhanced in A-ENR compared to A-SED. A-EX exhibited improved and impaired performance on the cue and spatial task, respectively. Impaired spatial learning in A-EX was likely due to a bias in response selection associated with exercise training, as object recognition memory improved for A-EX rats. An examination of senescent hippocampal physiology revealed that enrichment and exercise reversed age-related changes in long-term depression (LTD) and long-term potentiation (LTP). Rats in the enrichment group exhibited an increase in cell excitability compared to the other two groups of aged animals. The results indicate that differential experience biased the selection of a spatial or a response strategy and factors common across the two conditions, such as increased hippocampal activity associated with locomotion, contribute to reversal of senescent synaptic plasticity. PMID:21820213

Swimming exercise enhances the hippocampal antioxidant status of female Wistar rats.

PubMed

Stone, Vinícius; Kudo, Karen Yurika; Marcelino, Thiago Beltram; August, Pauline Maciel; Matté, Cristiane

2015-05-01

Moderate exercise is known to have health benefits, while both sedentarism and strenuous exercise have pro-oxidant effects. In this study, we assessed the effect of moderate exercise on the antioxidant homeostasis of rats' hippocampi. Female Wistar rats were submitted to a 30-minute swimming protocol on 5 days a week, for 4 weeks. Control rats were immersed in water and carefully dried. Production of hippocampal reactive species, activity of antioxidant enzymes, and glutathione levels in these animals were determined up to 30 days after completion of the 4-week protocol. Production of reactive species and hippocampal glutathione levels were increased 1 day after completion of the 4-week protocol, and returned to control levels after 7 days. Antioxidant enzyme activities were increased both 1 day (catalase) and 7 days (superoxide dismutase and glutathione peroxidase) after completion of the protocol. Thirty days after completion of the protocol, none of the antioxidant parameters evaluated differed from those of controls. Our results reinforce the benefits of aerobic exercise, which include positive modulation of antioxidant homeostasis in the hippocampi. The effects of exercise are not permanent; rather, an exercise regimen must be continued in order to maintain the neurometabolic adaptations.

ToF-SIMS cluster ion imaging of hippocampal CA1 pyramidal rat neurons

NASA Astrophysics Data System (ADS)

Francis, J. T.; Nie, H.-Y.; Taylor, A. R.; Walzak, M. J.; Chang, W. H.; MacFabe, D. F.; Lau, W. M.

2008-12-01

Recent studies have demonstrated the power of time-of-flight secondary ion mass spectrometry (ToF-SIMS) cluster ion imaging to characterize biological structures, such as that of the rat central nervous system. A large number of the studies to date have been carried out on the "structural scale" imaging several mm 2 using mounted thin sections. In this work, we present our ToF-SIMS cluster ion imaging results on hippocampal rat brain neurons, at the cellular and sub-cellular levels. As a part of an ongoing investigation to examine gut linked metabolic factors in autism spectrum disorders using a novel rat model, we have observed a possible variation in hippocampal Cornu ammonis 1 (CA1) pyramidal neuron geometry in thin, paraformaldehyde fixed brain sections. However, the fixation process alters the tissue matrix such that much biochemical information appears to be lost. In an effort to preserve as much as possible this original information, we have established a protocol using unfixed thin brain sections, along with low dose, 500 eV Cs + pre-sputtering that allows imaging down to the sub-cellular scale with minimal sample preparation.

Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats.

PubMed

Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

2015-01-01

Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test

PubMed Central

Hu, Yi-Min; Zhou, Zhi-Qiang; Zhang, Guang-Fen

2013-01-01

Introduction Previous studies have shown that a single sub-anesthetic dose of ketamine exerts fast-acting antidepressant effects in patients and in animal models of depression. However, the underlying mechanisms are not totally understood. This study aims to investigate the effects of acute administration of different doses of ketamine on the immobility time of rats in the forced swimming test (FST) and to determine levels of hippocampal brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). Methods Forty male Wistar rats weighing 180–220 g were randomly divided into four groups (n = 10 each): group saline and groups ketamine 5, 10, and 15 mg/kg. On the first day, all animals were forced to swim for 15 min. On the second day ketamine (5, 10, and 15 mg/kg, respectively) was given intraperitoneally, at 30 min before the second episode of the forced swimming test. Immobility times of the rats during the forced swimming test were recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and mTOR levels. Results Compared with group saline, administration of ketamine at a dose of 5, 10, and 15 mg/kg decreased the duration of immobility (P < 0.05 for all doses). Ketamine at doses of both 10 and 15 mg/kg showed a significant increase in the expression of hippocampal BDNF (P < 0.05 for both doses). Ketamine given at doses of 5, 10, and 15 mg/kg showed significant increases in relative levels of hippocampal p-mTOR (P < 0.05 for all doses) Conclusion The antidepressant effect of ketamine might be related to the increased expression of BDNF and mTOR in the hippocampus of rats. PMID:22970723

Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.

PubMed

Yang, Chun; Hu, Yi-Min; Zhou, Zhi-Qiang; Zhang, Guang-Fen; Yang, Jian-Jun

2013-03-01

Previous studies have shown that a single sub-anesthetic dose of ketamine exerts fast-acting antidepressant effects in patients and in animal models of depression. However, the underlying mechanisms are not totally understood. This study aims to investigate the effects of acute administration of different doses of ketamine on the immobility time of rats in the forced swimming test (FST) and to determine levels of hippocampal brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). Forty male Wistar rats weighing 180-220 g were randomly divided into four groups (n = 10 each): group saline and groups ketamine 5, 10, and 15 mg/kg. On the first day, all animals were forced to swim for 15 min. On the second day ketamine (5, 10, and 15 mg/kg, respectively) was given intraperitoneally, at 30 min before the second episode of the forced swimming test. Immobility times of the rats during the forced swimming test were recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and mTOR levels. Compared with group saline, administration of ketamine at a dose of 5, 10, and 15 mg/kg decreased the duration of immobility (P < 0.05 for all doses). Ketamine at doses of both 10 and 15 mg/kg showed a significant increase in the expression of hippocampal BDNF (P < 0.05 for both doses). Ketamine given at doses of 5, 10, and 15 mg/kg showed significant increases in relative levels of hippocampal p-mTOR (P < 0.05 for all doses) The antidepressant effect of ketamine might be related to the increased expression of BDNF and mTOR in the hippocampus of rats.

Immunotoxic cholinergic lesions in the basal forebrain reverse the effects of entorhinal cortex lesions on conditioned odor aversion in the rat.

PubMed

Ferry, Barbara; Herbeaux, Karin; Cosquer, Brigitte; Traissard, Natalia; Galani, Rodrigue; Cassel, Jean-Christophe

2007-07-01

Conditioned odor aversion (COA) corresponds to the avoidance of an odorized-tasteless solution (conditioned stimulus, CS) previously paired with toxicosis. COA occurs only when the interstimulus interval (ISI) is kept short, suggesting that the memory trace of the odor is subject to rapid decay. Previous experiments have shown that the entorhinal cortex (EC) is involved in the acquisition of COA, since lesion of the EC rendered COA tolerant to long ISI. Because EC lesions induce a septo-hippocampal cholinergic sprouting, the present experiment investigated whether COA tolerance to long ISI may be linked to this sprouting reaction. In a first experiment, male Long-Evans rats subjected to bilateral excitotoxic EC lesions combined to intracerebroventricular infusions of the selective cholinergic immunotoxin 192 IgG-saporin were exposed to odor-toxicosis pairing using a long ISI (120 min). Results showed that EC-lesioned rats displayed COA with the long ISI but not the control groups. In rats with EC combined to 192 IgG-saporin lesions, histological analysis demonstrated no evidence for cholinergic septo-hippocampal sprouting. In a second experiment, animals with 192-IgG saporin lesion showed a marked COA with a short ISI (5 min). These results suggest that the COA with the long ISI found in rats with EC lesions might involve a functional activity related to the EC lesion-induced hippocampal cholinergic sprouting. As the injection of 192 IgG-saporin alone did not affect COA with a short ISI, our data also point to a possible role of hippocampal cholinergic neurons in the modulation of memory processes underlying COA.

Enriched environment influences hormonal status and hippocampal brain derived neurotrophic factor in a sex dependent manner.

PubMed

Bakos, J; Hlavacova, N; Rajman, M; Ondicova, K; Koros, C; Kitraki, E; Steinbusch, H W M; Jezova, D

2009-12-01

The present study is aimed at testing the hypothesis that an enriched environment (EE) induces sex-dependent changes in stress hormone release and in markers of increased brain plasticity. The focus was on hypothalamic-pituitary-adrenocortical (HPA) axis activity, plasma levels of stress hormones, gene expression of glutamate receptor subunits and concentrations of brain-derived neurotrophic factor (BDNF) in selected brain regions. Rats exposed to EE were housed in groups of 12 in large cages with various objects, which were frequently changed, for 6 weeks. Control animals were housed four per cage under standard conditions. In females the EE-induced rise in hippocampal BDNF, a neurotrophic factor associated with increased neural plasticity, was more pronounced than in males. Similar sex-specific changes were observed in BDNF concentrations in the hypothalamus. EE also significantly attenuated oxytocin and aldosterone levels only in female but not male rats. Plasma testosterone positively correlated with hippocampal BDNF in female but not male rats housed in EE. In male rats housing in EE led to enhanced levels of testosterone and adrenocorticotropic hormone (ACTH), this was not seen in females. Hippocampal glucocorticoid but not mineralocorticoid receptor levels decreased in rats housed in EE irrespective of sex. Housing conditions failed to modify mRNA levels of glutamate receptor type 1 (Glur1) and metabotropic glutamate receptor subtype 5 (mGlur5) subunits of glutamate receptors in the forebrain. Moreover, a negative association between corticosterone and BDNF was observed in both sexes. The results demonstrate that the association between hormones and changes in brain plasticity is sex related. In particular, testosterone seems to be involved in the regulatory processes related to neuroplasticity in females.

The possible mechanism of silver nanoparticle impact on hippocampal synaptic plasticity and spatial cognition in rats.

PubMed

Liu, Ye; Guan, Wei; Ren, Guogang; Yang, Zhuo

2012-03-25

Silver nanoparticles (Ag-np) are very promising engineered nanomaterials which play an important role in the world biomedical, healthcare and in general nanotechnology applications. With the most impressive effect in antibacterial and many other broad-spectrum biotechnological advantages, Ag-np in real applications is still a controversial issue. This study investigated effects of the Ag-np on hippocampal synaptic plasticity and spatial cognition in rats and followed with the research on their possible mechanism. In this study, twenty-four adult male Wister rats were randomly divided into 3 groups: control group, low-dose group (Ag-np, 3 mg/kg) and high-dose group (Ag-np, 30 mg/kg). After two-week exposure to Ag-np through the nasal administration, Morris water maze (MWM) test was performed for the spatial cognition, followed by the long-term potentiation (LTP) recording and reactive oxygen species (ROS) detection in hippocampal homogenate. Results showed that compared with the control group, both LTP and MWM were abnormal in low-dose group and high-dose group. The quantity of ROS in hippocampal homogenate was increased significantly in low-dose group and high-dose group, which may be the reason of the neural damage caused by Ag-np. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Head west or left, east or right: interactions between memory systems in neurocognitive aging

PubMed Central

Pereira, Inês Tomás; Gallagher, Michela; Rapp, Peter R.

2018-01-01

Cognitive aging is accompanied by decline in multiple domains of memory. Here, we developed a T-maze task that required rats to learn competing hippocampal, and striatal navigation strategies in succession, across days. A final session increased demands on cognitive flexibility and required within-day switching between strategies, emphasizing capacities that engage the prefrontal cortex. Background characterization in young and aged rats used a water maze protocol optimized for individual differences in hippocampal integrity. Consistent with earlier work, young adults acquired place strategies in the T-maze faster than response, whereas the opposite was observed in aged rats with impaired spatial memory. The novel result was that aged animals with preserved spatial memory displayed a qualitatively distinct pattern, acquiring place and response strategies equally rapidly, without disruption when switching between them. Subsequent in situ hybridization for the plasticity-related immediate-early gene Arc revealed that while increasing demands on cognitive flexibility and within-day strategy switching potently engaged the prefrontal cortex in young adult and aged-impaired rats, Arc expression was insensitive in aged rats with normal spatial memory and superior switching abilities. Together, the results indicate that cognitive aging is an emergent property of the interactions between memory systems, and that successful cognitive outcomes reflect a distinct neuroadaptive process rather than a slower rate of aging. PMID:26281759

Protective Effects of 17β-Estradiol on Hippocampal Myelinated Fibers in Ovariectomized Middle-aged Rats.

PubMed

Xiao, Qian; Luo, Yanmin; Lv, Fulin; He, Qi; Wu, Hong; Chao, Fenglei; Qiu, Xuan; Zhang, Lei; Gao, Yuan; Huang, Chunxia; Wang, Sanrong; Zhou, Chunni; Zhang, Yi; Jiang, Lin; Tang, Yong

2018-06-14

Estrogen replacement therapy (ERT) improves hippocampus-dependent cognition. This study investigated the impact of estrogen on hippocampal volume, CA1 subfield volume and myelinated fibers in the CA1 subfield of middle-aged ovariectomized rats. Ten-month-old bilaterally ovariectomized (OVX) female rats were randomly divided into OVX + E2 and OVX + Veh groups. After four weeks of subcutaneous injection with 17β-estradiol or a placebo, the OVX + E2 rats exhibited significantly short mean escape latency in a spatial learning task than that in the OVX + Veh rats. Using stereological methods, we did not observe significant differences in the volumes of the hippocampus and CA1 subfields between the two groups. However, using stereological methods and electron microscopy techniques, the total length of myelinated fibers and the total volumes of myelinated fibers, myelin sheaths and myelinated axons in the CA1 subfields of OVX + E2 rats were significantly 38.1%, 34.2%, 36.1% and 32.5%, respectively, higher than those in the OVX + Veh rats. After the parameters were calculated according to different diameter ranges, the estrogen replacement-induced remodeling of myelinated fibers in CA1 was mainly manifested in the myelinated fibers with a diameter of <1.0 μm. Therefore, four weeks of continuous E2 replacement improved the spatial learning capabilities of middle-aged ovariectomized rats. The E2 replacement-induced protection of spatial learning abilities might be associated with the beneficial effects of estrogen on myelinated fibers, particularly those with the diameters less than 1.0 μm, in the hippocampal CA1 region of middle-aged ovariectomized rats. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Selective Androgen Receptor Modulator RAD140 Is Neuroprotective in Cultured Neurons and Kainate-Lesioned Male Rats

PubMed Central

Jayaraman, Anusha; Christensen, Amy; Moser, V. Alexandra; Vest, Rebekah S.; Miller, Chris P.; Hattersley, Gary

2014-01-01

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed “selective androgen receptor modulators” (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases. PMID:24428527

Long-lasting desynchronization in rat hippocampal slice induced by coordinated reset stimulation

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

Tass, P. A.; Barnikol, U. B.; Department of Stereotaxic and Functional Neurosurgery, University of Cologne, D-50931 Cologne

2009-07-15

In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with amore » widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude.« less

Alkaloid fraction of Uncaria rhynchophylla protects against N-methyl-D-aspartate-induced apoptosis in rat hippocampal slices.

PubMed

Lee, Jongseok; Son, Dongwook; Lee, Pyeongjae; Kim, Sun-Yeou; Kim, Hocheol; Kim, Chang-Ju; Lim, Eunhee

2003-09-04

Uncaria rhynchophylla is a medicinal herb which has sedative and anticonvulsive effects and has been applied in the treatment of epilepsy in Oriental medicine. In this study, the effect of alkaloid fraction of U. rhynchophylla against N-methyl-D-aspartate (NMDA)-induced neuronal cell death was investigated. Pretreatment with an alkaloid fraction of U. rhynchophylla for 1 h decreased the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices and also inhibited NMDA-induced enhanced expressions of apoptosis-related genes such as c-jun, p53, and bax. In the present study, the alkaloid fraction of U. rhynchophylla was shown to have a protective property against NMDA-induced cytotoxicity by suppressing the NMDA-induced apoptosis in rat hippocampal slices.

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.

A Novel Nonparametric Approach for Neural Encoding and Decoding Models of Multimodal Receptive Fields.

PubMed

Agarwal, Rahul; Chen, Zhe; Kloosterman, Fabian; Wilson, Matthew A; Sarma, Sridevi V

2016-07-01

Pyramidal neurons recorded from the rat hippocampus and entorhinal cortex, such as place and grid cells, have diverse receptive fields, which are either unimodal or multimodal. Spiking activity from these cells encodes information about the spatial position of a freely foraging rat. At fine timescales, a neuron's spike activity also depends significantly on its own spike history. However, due to limitations of current parametric modeling approaches, it remains a challenge to estimate complex, multimodal neuronal receptive fields while incorporating spike history dependence. Furthermore, efforts to decode the rat's trajectory in one- or two-dimensional space from hippocampal ensemble spiking activity have mainly focused on spike history-independent neuronal encoding models. In this letter, we address these two important issues by extending a recently introduced nonparametric neural encoding framework that allows modeling both complex spatial receptive fields and spike history dependencies. Using this extended nonparametric approach, we develop novel algorithms for decoding a rat's trajectory based on recordings of hippocampal place cells and entorhinal grid cells. Results show that both encoding and decoding models derived from our new method performed significantly better than state-of-the-art encoding and decoding models on 6 minutes of test data. In addition, our model's performance remains invariant to the apparent modality of the neuron's receptive field.

The cumulative analgesic effect of repeated electroacupuncture involves synaptic remodeling in the hippocampal CA3 region☆

PubMed Central

Xu, Qiuling; Liu, Tao; Chen, Shuping; Gao, Yonghui; Wang, Junying; Qiao, Lina; Liu, Junling

2012-01-01

In the present study, we examined the analgesic effect of repeated electroacupuncture at bilateral Zusanli (ST36) and Yanglingquan (GB34) once a day for 14 consecutive days in a rat model of chronic sciatic nerve constriction injury-induced neuropathic pain. In addition, concomitant changes in calcium/calmodulin-dependent protein kinase II expression and synaptic ultrastructure of neurons in the hippocampal CA3 region were examined. The thermal pain threshold (paw withdrawal latency) was increased significantly in both groups at 2 weeks after electroacupuncture intervention compared with 2 days of electroacupuncture. In ovariectomized rats with chronic constriction injury, the analgesic effect was significantly reduced. Electroacupuncture for 2 weeks significantly diminished the injury-induced increase in synaptic cleft width and thinning of the postsynaptic density, and it significantly suppressed the down-regulation of intracellular calcium/calmodulin-dependent protein kinase II expression in the hippocampal CA3 region. Repeated electroacupuncture intervention had a cumulative analgesic effect on injury-induced neuropathic pain reactions, and it led to synaptic remodeling of hippocampal neurons and upregulated calcium/calmodulin-dependent protein kinase II expression in the hippocampal CA3 region. PMID:25657670

A three-plane architectonic atlas of the rat hippocampal region.

PubMed

Boccara, Charlotte N; Kjonigsen, Lisa J; Hammer, Ingvild M; Bjaalie, Jan G; Leergaard, Trygve B; Witter, Menno P

2015-07-01

The hippocampal region, comprising the hippocampal formation and the parahippocampal region, has been one of the most intensively studied parts of the brain for decades. Better understanding of its functional diversity and complexity has led to an increased demand for specificity in experimental procedures and manipulations. In view of the complex 3D structure of the hippocampal region, precisely positioned experimental approaches require a fine-grained architectural description that is available and readable to experimentalists lacking detailed anatomical experience. In this paper, we provide the first cyto- and chemoarchitectural description of the hippocampal formation and parahippocampal region in the rat at high resolution and in the three standard sectional planes: coronal, horizontal and sagittal. The atlas uses a series of adjacent sections stained for neurons and for a number of chemical marker substances, particularly parvalbumin and calbindin. All the borders defined in one plane have been cross-checked against their counterparts in the other two planes. The entire dataset will be made available as a web-based interactive application through the Rodent Brain WorkBench (http://www.rbwb.org) which, together with this paper, provides a unique atlas resource. © 2014 Wiley Periodicals, Inc.

Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats.

PubMed

Ahmadalipour, A; Sadeghzadeh, J; Vafaei, A A; Bandegi, A R; Mohammadkhani, R; Rashidy-Pour, A

2015-10-01

Prenatal morphine exposure throughout pregnancy can induce a series of neurobehavioral and neurochemical disturbances by affecting central nervous system development. This study was designed to investigate the effects of an enriched environment on behavioral deficits and changes in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by prenatal morphine in rats. On pregnancy days 11-18, female Wistar rats were randomly injected twice daily with saline or morphine. Offspring were weaned on postnatal day (PND) 21. They were subjected to a standard rearing environment or an enriched environment on PNDs 22-50. On PNDs 51-57, the behavioral responses including anxiety and depression-like behaviors, and passive avoidance memory as well as hippocampal BDNF levels were investigated. The light/dark (L/D) box and elevated plus maze (EPM) were used for the study of anxiety, forced swimming test (FST) was used to assess depression-like behavior and passive avoidance task was used to evaluate learning and memory. Prenatal morphine exposure caused a reduction in time spent in the EPM open arms and a reduction in time spent in the lit side of the L/D box. It also decreased step-through latency and increased time spent in the dark side of passive avoidance task. Prenatal morphine exposure also reduced immobility time and increased swimming time in FST. Postnatal rearing in an enriched environment counteracted with behavioral deficits in the EPM and passive avoidance task, but not in the L/D box. This suggests that exposure to an enriched environment during adolescence period alters anxiety profile in a task-specific manner. Prenatal morphine exposure reduced hippocampal BDNF levels, but enriched environment significantly increased BDNF levels in both saline- and morphine-exposed groups. Our results demonstrate that exposure to an enriched environment alleviates behavioral deficits induced by prenatal morphine exposure and up-regulates the decreased levels of BDNF. BDNF may contribute to the beneficial effects of an enriched environment on prenatal morphine-exposed to rats. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Levels of Neural Progenitors in the Hippocampus Predict Memory Impairment and Relapse to Drug Seeking as a Function of Excessive Methamphetamine Self-Administration

PubMed Central

Recinto, Patrick; Samant, Anjali Rose H; Chavez, Gustavo; Kim, Airee; Yuan, Clara J; Soleiman, Matthew; Grant, Yanabel; Edwards, Scott; Wee, Sunmee; Koob, George F; George, Olivier; Mandyam, Chitra D

2012-01-01

Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2′-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on cognitive performance and relapse to drug seeking and may contribute to the impairments that perpetuate the addiction cycle. PMID:22205547

DIFFERENTIAL EFFECTS OF CAFFEINE, PICROTOXIN, AND PENTYLENETETRAZOL ON HIPPOCAMPAL AFTERDISCHARGE ACTIVITY AND WET DOG SHAKES (JOURNAL VERSION)

EPA Science Inventory

The present experiment was conducted to identify changes in hippocampal after discharge (AD) parameters following administration of subconvulsant dosages (half of the convulsant dosage) of analeptics with known pharmacological action. Long Evans rats (N=104) with chronic bipolar ...

Modulation of hippocampal ACh release by chronic nicergoline treatment in freely moving young and aged rats.

PubMed

Carfagna, N; Di Clemente, A; Cavanus, S; Damiani, D; Gerna, M; Salmoiraghi, P; Cattaneo, B; Post, C

1995-09-15

The effects of nicergoline on basal and K(+)-stimulated release of ACh in the hippocampus of 3- and 19-month old rats has been studied by microdialysis. A significant decrease of basal ACh release (59%) was found in aged vehicle treated rats in comparison to young rats. High-K+ (100 mM) in the perfusate strongly increased the release of ACh by up to 6-fold over the baseline of both young and aged rats. Chronic oral administration of nicergoline to aged rats (5 mg/kg b.i.d. for 6 weeks) significantly reversed (93%) the age-related decrease of basal release of ACh, leaving the increase due to K+ depolarization unchanged. In young animals, nicergoline did not affect the basal output of ACh, but enhanced the K(+)-evoked release of ACh by 39%. Results from this study demonstrate that nicergoline treatment increases the ability of hippocampal cholinergic terminals to release ACh, and suggest that this drug can reset the cholinergic impairement associated with aging.

Involvement of P-type Ca2+ channels in the K(+)- and d-fenfluramine-induced [3H]5-HT release from rat hippocampal synaptosomes.

PubMed

Frittoli, E; Gobbi, M; Mennini, T

1994-06-01

The Ca2(+)-dependent [3H]5-HT release induced by depolarization or by 0.5 microM d-fenfluramine in rat hippocampal synaptosomes, was significantly reduced (35-42%) by three different P-type Ca2+ channels blockers (omega-Agatoxin-IVA, 100 nM, funnel-web spider toxin, FTX, 0.05 microliters/ml, and its synthetic analogue, sFTX, 1 mM), indicating the major role of these channels in the Ca2+ influx preceding neurotransmitter release.

Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD.

PubMed

Moorthi, P; Premkumar, P; Priyanka, R; Jayachandran, K S; Anusuyadevi, M

2015-08-20

Among vertebrates hippocampus forms the major component of the brain in consolidating information from short-term memory to long-term memory. Aging is considered as the major risk factor for memory impairment in sporadic Alzheimer's disease (SAD) like pathology. Present study thus aims at investigating whether age-specific degeneration of neuronal-circuits in hippocampal formation (neural-layout of Subiculum-hippocampus proper-dentate gyrus (DG)-entorhinal cortex (EC)) results in cognitive impairment. Furthermore, the neuroprotective effect of Resveratrol (RSV) was attempted to study in the formation of hippocampal neuronal-circuits. Radial-Arm-Maze was conducted to evaluate hippocampal-dependent spatial and learning memory in control and experimental rats. Nissl staining of frontal cortex (FC), subiculum, hippocampal-proper (CA1→CA2→CA3→CA4), DG, amygdala, cerebellum, thalamus, hypothalamus, layers of temporal and parietal lobe of the neocortex were examined for pathological changes in young and aged wistar rats, with and without RSV. Hippocampal trisynaptic circuit (EC layerII→DG→CA3→CA1) forming new memory and monosynaptic circuit (EC→CA1) that strengthen old memories were found disturbed in aged rats. Loss of Granular neuron observed in DG and polymorphic cells of CA4 can lead to decreased mossy fibers disturbing neural-transmission (CA4→CA3) in perforant pathway. Further, intensity of nissl granules (stratum lacunosum moleculare (SLM)-SR-SO) of CA3 pyramidal neurons was decreased, disturbing the communication in schaffer collaterals (CA3-CA1) during aging. We also noticed disarranged neuronal cell layer in Subiculum (presubiculum (PrS)-parasubiculum (PaS)), interfering output from hippocampus to prefrontal cortex (PFC), EC, hypothalamus, and amygdala that may result in interruption of thought processes. We conclude from our observations that poor memory performance of aged rats as evidenced through radial arm maze (RAM) analysis was due to the defect in neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) that were significantly damaged leading to memory impairment. Interestingly, RSV was observed to culminate pathological events in the hippocampal neuronal circuit during aging, proving them as potent therapeutic drug against age-associated neurodegeneration and memory loss. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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.

Roles of the µ-opioid receptor and its related signaling pathways in the pathogenesis of premenstrual syndrome liver-qi stagnation

PubMed Central

Song, Chunhong; Xue, Ling

2017-01-01

The present study aimed to investigate the roles of the µ-opioid receptor (MOR) and its related signaling pathways in the pathogenesis of premenstrual syndrome (PMS) liver-qi stagnation, along with the therapeutic effects of the Shu-Yu capsule in treating the condition. A PMS liver-qi stagnation rat model was established using a chronic restraint stress method. The protein expression level of MOR within rat hippocampal tissue was detected via western blot analysis and cyclic adenosine monophosphate (cAMP) levels within the supernatant of a rat hippocampal cell culture were determined by ELISA. The western blot analysis indicated that the hippocampal expression level of MOR was significantly elevated in the PMS liver-qi stagnation model group. However, subsequent treatment with a Shu-Yu capsule was found to significantly decrease the level of MOR expression. In addition, in vitro experiments were performed, whereby primary hippocampal neurons were treated with model rat serum. It was observed that the level of MOR expression was significantly elevated, while brain-derived neurotrophic factor (BDNF) and cAMP levels in the culture supernatant were significantly decreased. These effects were reversed by treatment with serum from the Shu-Yu capsule-treated rats. Furthermore, when treated with the MOR activator DAMGO, the following were significantly decreased in the primary neurons: Phosphorylation levels of cAMP response element binding protein and extracellular signal-regulated protein kinases (ERK); BDNF expression; and cAMP content in the culture supernatant. These effects were reversed in primary neurons treated with DAMGO and Shu-Yu-containing rat serum. Collectively, the data suggest that increased MOR expression and activation of the cAMP/ERK signaling pathway in the hippocampus may be involved in the pathogenesis of PMS liver-qi stagnation. Furthermore, the efficacy of the Shu-Yu capsule in treating the condition may be via its regulation of MOR receptor signaling. PMID:28587388

Protective effects of notoginsenoside R1 on cerebral ischemia-reperfusion injury in rats.

PubMed

Zou, Shun; Zhang, Mingxiong; Feng, Limei; Zhou, Yuanfang; Li, Li; Ban, Lili

2017-12-01

The objective of this study was to investigate the protective effect of notoginsenoside R1 (NGR1) on cerebral ischemia-reperfusion injury (CIRI) in rats, and its molecular mechanism, to provide new insights into the diagnosis and treatment of CIRI. Sixty Sprague-Dawley rats were randomly divided into four groups including the sham-operation group (Sham), cerebral ischemia-reperfusion model group (CIR), NGR1 treatment group (NGR1), and nimodipine positive control group (NDC) with 15 rats each. Bilateral common carotid arteries occlusion was used to establish the rat CIRI model. The area of cerebral infarction at the end of reperfusion was calculated by triphenyl tetrazolium chloride staining. Apoptosis of hippocampal neurons in each group was detected by Annexin V/propidium iodide double staining. Hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA, and Bcl-2 and Bax protein at the end of reperfusion were measured by RT-qPCR and western blot analysis, respectively. Data were analyzed by SPSS software analysis to ensure statistical significance. At the end of reperfusion, the area of cerebral infarction in the NGR1 and NDC groups was significantly smaller than that of the CIR group. Apoptosis analysis showed that compared with the CIR group, the apoptosis rate of hippocampal neurons was significantly decreased in the NGR1 and NDC groups. RT-qPCR and western blot analysis showed that at the end of reperfusion, higher levels of BDNF mRNA and the anti-apoptotic factor, Bcl-2, and lower levels of the pro-apoptotic factor, Bax, in the hippocampus were found in the NGR1 and NDC groups compared with the CIR group. The protective effect of NGR1 on CIRI was significantly stronger than that of nimodipine. In conclusion, NGR1 can reduce the area of cerebral infarction, reduce apoptosis of hippocampal neurons, and protect rats from CIRI. Those effects were achieved by activating the expression of BDNF and Bcl-2, and by inhibiting the expression of Bax.

Neuroprotective, Neurotrophic and Anti-oxidative Role of Bacopa monnieri on CUS Induced Model of Depression in Rat.

PubMed

Kumar, Sourav; Mondal, Amal Chandra

2016-11-01

Major depression is a life threatening neuropsychiatric disorder that produces mental illness and major cause of morbidity. The present study was conducted to evaluate the neuroprotective, neurotrophic and antioxidant potential of Bacopa monnieri extract (BME) on chronic unpredictable stress (CUS) induced behavioral depression in rats. Behavioral tests were carried out for investigation of antidepressant like effects of BME, and potential mechanism was assessed by determining neurotrophin level and hippocampal neurogenesis. Depressive-like behavior was assessed by shuttle-box escape test, forced swim test and tail suspension test. Effect of BME on hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring the plasma level of adrenocorticotropic hormone (ACTH) and corticosterone. The expression of brain derived neurotrophic factor (BDNF), neuronal marker doublecortin (DCX) in the hippocampus were measured and hippocampal neurogenesis was investigated by 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN). In addition, effects of BME on oxidative stress markers were also measured in the hippocampus of CUS exposed rats. The results indicated that BME significantly able to attenuate the depressive-like behaviors, normalized the levels of ACTH, corticosterone, and up-regulate the expression of BDNF, DCX and BrdU/NeuN in CUS induced rats compared to BME treated rats. It is also found that BME significantly increased the activity of antioxidant enzymes on CUS induced rats. These findings revealed that BME exerted neuroprotective effects possibly by promoting hippocampal neurogenesis with elevation of BDNF level and antioxidant defense against oxidative stress.

Melatonin Attenuates Histopathological Changes in the Hippocampus of Infantile Rats with Kaolin-Induced Hydrocephalus.

PubMed

Turgut, Mehmet; Baka, Meral; Uyanıkgil, Yiğit

2018-05-23

Hydrocephalus is defined as an incapacitating neurological disorder characterized by ventricular enlargement in children, but the effects of melatonin on this hydrocephalus have not yet been fully elucidated. In the present experiment, we attempted to investigate the effects of exogenous melatonin administration on hydrocephalus-induced hippocampal changes in infantile rats. In this study, we randomly divided 45 Swiss albino rats aged 2 weeks into 3 groups: group I, the control group received a sham injection with needle insertion only; groups II and III were given kaolin injections before treatment - group II, the hydrocephalus group, was treated with an isotonic NaCl solution, and group III, the hydrocephalus plus melatonin group, was treated with 0.5 mg/100 g body weight of exogenous melatonin. Both immunohistochemical and histological analyses were performed after hydrocephalus induction and melatonin administration. Immunohistochemical staining consisted anti-glial fibrillary acidic protein staining. The TUNEL technique was used for defining quantitate apoptosis. Melatonin administration significantly attenuated chronic hydrocephalus-induced histopathological changes in the hippocampal subregions of infantile rats. Compared to hydrocephalic rats treated with saline solution, melatonin significantly decreased the number of apoptotic cells and pyknotic index values of each hippocampal subregion after the kaolin-induced hydrocephalus (p < 0.001). The present results demonstrate that the chronic hydrocephalus-induced histopathological changes in the hippocampus were partially reversible with melatonin treatment, suggesting its neuroprotective effects in infantile rats. However, these findings need to be confirmed by further experimental studies and clinical trials. © 2018 S. Karger AG, Basel.

Small GTPase Rab17 Regulates the Surface Expression of Kainate Receptors but Not α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors in Hippocampal Neurons via Dendritic Trafficking of Syntaxin-4 Protein*

PubMed Central

Mori, Yasunori; Fukuda, Mitsunori; Henley, Jeremy M.

2014-01-01

Glutamate receptors are fundamental for control synaptic transmission, synaptic plasticity, and neuronal excitability. However, many of the molecular mechanisms underlying their trafficking remain elusive. We previously demonstrated that the small GTPase Rab17 regulates dendritic trafficking in hippocampal neurons. Here, we investigated the role(s) of Rab17 in AMPA receptor (AMPAR) and kainate receptor (KAR) trafficking. Although Rab17 knockdown did not affect surface expression of the AMPAR subunit GluA1 under basal or chemically induced long term potentiation conditions, it significantly reduced surface expression of the KAR subunit GluK2. Rab17 co-localizes with Syntaxin-4 in the soma, dendritic shaft, the tips of developing hippocampal neurons, and in spines. Rab17 knockdown caused Syntaxin-4 redistribution away from dendrites and into axons in developing hippocampal neurons. Syntaxin-4 knockdown reduced GluK2 but had no effect on GluA1 surface expression. Moreover, overexpression of constitutively active Rab17 promoted dendritic surface expression of GluK2 by enhancing Syntaxin-4 translocation to dendrites. These data suggest that Rab17 mediates the dendritic trafficking of Syntaxin-4 to selectively regulate dendritic surface insertion of GluK2-containing KARs in rat hippocampal neurons. PMID:24895134

Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.

PubMed

Tamano, Haruna; Fukura, Kotaro; Suzuki, Miki; Sakamoto, Kazuhiro; Yokogoshi, Hidehiko; Takeda, Atsushi

2013-06-01

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine-administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect. Copyright © 2013 Elsevier Inc. All rights reserved.

The impact of a diphenyl diselenide-supplemented diet and aerobic exercise on memory of middle-aged rats.

PubMed

Cechella, José L; Leite, Marlon R; Gai, Rafaela M; Zeni, Gilson

2014-08-01

Selenium is an essential trace element for human health and has received attention for its role as a nutrient. The combination of exercise and nutrients has been proposed to promote health. The aim of this study was to determine the effects of a diet supplemented with diphenyl diselenide (PhSe)2 and swimming exercise on memory of middle-aged rats. Male Wistar rats (12months) received standard diet chow supplemented with 1ppm of (PhSe)2 for 4weeks. Rats were submitted to swimming training (20min per day for 4weeks). After 4weeks, memory was evaluated in the object recognition test (ORT) and in the object location test (OLT). The hippocampal levels of phosphorylated cAMP-response element-binding protein (CREB) were determined. The results of the present study demonstrated that the association of (PhSe)2-supplemented diet and swimming exercise improved short-term memory, long-term memory and spatial learning, and this effect was not related to the increase in hippocampal p-CREB levels in middle-age rats. This study also revealed that middle-aged rats in the swimming exercise group had the best performance in short- and long-term memory. In conclusion, we demonstrated that swimming exercise, (PhSe)2-supplemented diet or the association of these factors improved learning and memory functioning. The hippocampal levels of CREB were not directly related to the benefits of swimming exercise and (PhSe)2-supplemented diet association in memory of middle-aged rats. Copyright © 2014 Elsevier Inc. All rights reserved.

CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy.

PubMed

Zhou, Zhike; Liu, Tingting; Sun, Xiaoyu; Mu, Xiaopeng; Zhu, Gang; Xiao, Ting; Zhao, Mei; Zhao, Chuansheng

2017-03-30

It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE. Copyright © 2017 Elsevier B.V. All rights reserved.

MATERNAL HYPOTHYROXENEMIA LEADS TO PERSISTENT DEFICITS IN HIPPOCAMPAL SYNAPTIC TRANSMISSION AND LEARNING IN OFFSPRING.

EPA Science Inventory

MATERNAL HYPOTHYROXINEMIA LEADS TO PERSISTENT DEFICITS IN HIPPOCAMPAL SYNAPTIC TRANSMISSION AND LEARNING IN RAT OFFSPRING. M.E. Gilbert1 and Li Sui2, Neurotoxicology Division, 1US EPA and 2National Research Council, Research Triangle Pk, NC 27711.
While severe hypothyroidis...

Hippocampal Area CA1 and Remote Memory in Rats

ERIC Educational Resources Information Center

Ocampo, Amber C.; Squire, Larry R.; Clark, Robert E.

2017-01-01

Hippocampal lesions often produce temporally graded retrograde amnesia (TGRA), whereby recent memory is impaired more than remote memory. This finding has provided support for the process of systems consolidation. However, temporally graded memory impairment has not been observed with the watermaze task, and the findings have been inconsistent…

Effects of Post-Training Hippocampal Injections of Midazolam on Fear Conditioning

ERIC Educational Resources Information Center

Gafford, Georgette M.; Parsons, Ryan G.; Helmstetter, Fred J.

2005-01-01

Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA[subscript A]/benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained…

Repeated Stimulation of Cultured Networks of Rat Cortical Neurons Induces Parallel Memory Traces

ERIC Educational Resources Information Center

le Feber, Joost; Witteveen, Tim; van Veenendaal, Tamar M.; Dijkstra, Jelle

2015-01-01

During systems consolidation, memories are spontaneously replayed favoring information transfer from hippocampus to neocortex. However, at present no empirically supported mechanism to accomplish a transfer of memory from hippocampal to extra-hippocampal sites has been offered. We used cultured neuronal networks on multielectrode arrays and…

EFFECTS OF NGF AND FETAL CELL TRANSPLANTS ON SPATIAL LEARNING AFTER INTRADENTATE ADMINISTRATION OF COLCHICINE

EPA Science Inventory

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COL...

Long-term voluntary exercise prevents post-weaning social isolation-induced cognitive impairment in rats.

PubMed

Okudan, Nilsel; Belviranlı, Muaz

2017-09-30

This study aimed to determine the effect of exercise on locomotion, anxiety-related behavior, learning, and memory in socially isolated post-weaning rats, as well as the correlation between exercise and the concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus. Rats were randomly assigned to three groups: the control group; the social isolation group; the social isolation plus exercise (SIE) group. Social isolation conditions, with or without exercise were maintained for 90d, and then multiple behavioral tests, including the open-field test, elevated plus maze test, and Morris water maze (MWM) test were administered. Following behavioral assessment, hippocampal tissue samples were obtained for measurement of BDNF and NGF. There wasn't a significant difference in locomotor activity between the groups (P>0.05). Anxiety scores were higher in the socially isolated group (P<0.05) than in the SIE group (P<0.05). According to the probe trial session of the MWM test results, exercise training improved platform crossings' number in the socially isolated rats (P<0.05). Exercise training ameliorated social isolation-induced reduction in hippocampal BDNF and NGF content (P<0.05). These findings suggest that exercise training improves cognitive functions via increasing hippocampal BDNF and NGF concentrations in socially isolated post-weaning rats. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Alterations in neuronal morphology and synaptophysin expression in the rat brain as a result of changes in dietary n-6: n-3 fatty acid ratios.

PubMed

Hajjar, Toktam; Goh, Yong Meng; Rajion, Mohamed Ali; Vidyadaran, Sharmili; Li, Tan Ai; Ebrahimi, Mahdi

2013-07-26

Polyunsaturated fatty acids (PUFA) play important roles in brain fatty acid composition and behavior through their effects on neuronal properties and gene expression. The hippocampus plays an important role in the formation of memory, especially spatial memory and navigation. This study was conducted to examine the effects of PUFA and specifically different dietary n-6: n-3 fatty acid ratios (FAR) on the number and size of hippocampal neurons and the expression of synaptophysin protein in the hippocampus of rats. Forty 3-week old male Sprague-Dawley rats were allotted into 4 groups. The animals received experimental diets with different n-6: n-3 FAR of either 65:1, 26.5:1, 22:1 or 4.5:1 for 14 weeks. The results showed that a lowering dietary n-6: n-3 FAR supplementation can increase the number and size of neurons. Moreover, lowering the dietary n-6: n-3 FAR led to an increase in the expression of the pre-synaptic protein synaptophysin in the CA1 hippocampal subregion of the rat brain. These findings support the notion that decreasing the dietary n-6: n-3 FAR will lead to an intensified hippocampal synaptophysin expression and increased neuron size and proliferation in the rat brain.

[Effect of 5-HT1A receptors in the hippocampal DG on active avoidance learning in rats].

PubMed

Jiang, Feng-ze; Lv, Jing; Wang, Dan; Jiang, Hai-ying; Li, Ying-shun; Jin, Qing-hua

2015-01-01

To investigate the effects of serotonin (5-HTIA) receptors in the hippocampal dentate gyrus (DG) on active avoidance learning in rats. Totally 36 SD rats were randomly divided into control group, antagonist group and agonist group(n = 12). Active avoidance learning ability of rats was assessed by the shuttle box. The extracellular concentrations of 5-HT in the DG during active avoidance conditioned reflex were measured by microdialysis and high performance liquid chromatography (HPLC) techniques. Then the antagonist (WAY-100635) or agonist (8-OH-DPAT) of the 5-HT1A receptors were microinjected into the DG region, and the active avoidance learning was measured. (1) During the active avoidance learning, the concentration of 5-HT in the hippocampal DG was significantly increased in the extinction but not establishment in the conditioned reflex, which reached 164.90% ± 26.07% (P <0.05) of basal level. (2) The microinjection of WAY-100635 (an antagonist of 5-HT1A receptor) into the DG did not significantly affect the active avoidance learning. (3) The microinjection of 8-OH-DPAT(an agonist of 5-HT1A receptor) into the DG significantly facilitated the establishment process and inhibited the extinction process during active avoidance conditioned reflex. The data suggest that activation of 5-HT1A receptors in hipocampal DG may facilitate active avoidance learning and memory in rats.

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic-like effects in the elevated plus maze.

PubMed

Yeung, Michelle; Dickson, Clayton T; Treit, Dallas

2013-04-01

Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. (2012) Neuropharmacology 62:155-160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the Ih blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem-evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model. Copyright © 2012 Wiley Periodicals, Inc.

Lewis and Fischer 344 rats as a model for genetic differences in spatial learning and memory: Cocaine effects.

PubMed

Fole, Alberto; Miguéns, Miguel; Morales, Lidia; González-Martín, Carmen; Ambrosio, Emilio; Del Olmo, Nuria

2017-06-02

Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic treatment with the new anticonvulsant drug lacosamide impairs learning and memory processes in rats: A possible role of BDNF/TrkB ligand receptor system.

PubMed

Shishmanova-Doseva, Michaela; Peychev, Lyudmil; Koeva, Yvetta; Terzieva, Dora; Georgieva, Katerina; Peychev, Zhivko

2018-06-01

Cognitive impairment is considered a frequent side effect in the drug treatment of epilepsy. The objective of the present study was to investigate the effects of lacosamide (LCM) on learning and memory processes in rats, on the serum level of brain-derived neurotrophic factor (BDNF) and BDNF/TrkB ligand receptor system expression in the hippocampal formation. Male Wistar rats underwent long-term treatment with three different doses of lacosamide - 3 mg/kg (LCM 3), 10 mg/kg (LCM 10) and 30 mg/kg (LCM 30). All rats were subjected to one active and one passive avoidance tests. The BDNF/TrkB immunohistochemical expression in the hippocampus was measured and serum BDNF was determined. The LCM-treated rats made fewer avoidance responses than controls during acquisition training and in the memory retention test. The number of escapes in the LCM 10 and LCM 30 groups decreased throughout the test, while the rats in the LCM 3 group showed fewer escapes only in the memory test in the active avoidance task. In the step-down test, the latency time of the LCM-30 treated rats was reduced as compared with the controls during the learning session and the short- and long-term memory retention tests. Lacosamide induced a dose-dependent reduction of the hippocampal expression of BDNF and its receptor TrkB. We found no significant difference between BDNF serum levels in the test animals and controls. The results of the study suggest that LCM suppresses the learning and memory processes in rats, with the inhibition of hippocampal BDNF/TrkB ligand receptor system being one of the possible mechanisms causing this effect. Copyright © 2018 Elsevier Inc. All rights reserved.

Navigation Patterns and Scent Marking: Underappreciated Contributors to Hippocampal and Entorhinal Spatial Representations?

PubMed

Lebedev, Mikhail A; Pimashkin, Alexey; Ossadtchi, Alexei

2018-01-01

According to the currently prevailing theory, hippocampal formation constructs and maintains cognitive spatial maps. Most of the experimental evidence for this theory comes from the studies on navigation in laboratory rats and mice, typically male animals. While these animals exhibit a rich repertoire of behaviors associated with navigation, including locomotion, head movements, whisking, sniffing, raring and scent marking, the contribution of these behavioral patterns to the hippocampal spatially-selective activity has not been sufficiently studied. Instead, many publications have considered animal position in space as the major variable that affects the firing of hippocampal place cells and entorhinal grid cells. Here we argue that future work should focus on a more detailed examination of different behaviors exhibited during navigation to better understand the mechanism of spatial tuning in hippocampal neurons. As an inquiry in this direction, we have analyzed data from two datasets, shared online, containing recordings from rats navigating in square and round arenas. Our analyses revealed patchy navigation patterns, evident from the spatial maps of animal position, velocity and acceleration. Moreover, grid cells available in the datasets exhibited similar periodicity as the navigation parameters. These findings indicate that activity of grid cells could affect navigation parameters and/or vice versa. Additionally, we speculate that scent marks left by navigating animals could contribute to neuronal responses while rats and mice sniff their environment; the act of sniffing could modulate neuronal discharges even in virtual visual environments. Accordingly, we propose that future experiments should contain additional controls for navigation patterns, whisking, sniffing and maps composed of scent marks.

Lithium ameliorates autistic-like behaviors induced by neonatal isolation in rats

PubMed Central

Wu, Xiaoyan; Bai, Yanrui; Tan, Tao; Li, Hongjie; Xia, Shuting; Chang, Xinxia; Zhou, Zikai; Zhou, Weihui; Li, Tingyu; Wang, Yu Tian; Dong, Zhifang

2014-01-01

Neonatal isolation is a widely accepted model to study the long-term behavioral changes produced by the early life events. However, it remains unknown whether neonatal isolation can induce autistic-like behaviors, and if so, whether pharmacological treatment can overcome it. Here, we reported that newborn rats subjected to individual isolations from their mother and nest for 1 h per day from postnatal days 1–9 displayed apparent autistic-like symptoms including social deficits, excessive repetitive self-grooming behavior, and increased anxiety- and depressive-like behaviors tested in young adult (postnatal days 42–56) compared to normal reared controls. Furthermore, these behavioral changes were accompanied by impaired adult hippocampal neurogenesis and reduced the ratio of excitatory/inhibitory synaptic transmissions, as reflected by an increase in spontaneous inhibitory postsynaptic current (sIPSC) and normal spontaneous excitatory postsynaptic current (sEPSC) in the hippocampal CA1 pyramidal neuron. More importantly, chronic administration of lithium, a clinically used mood stabilizer, completely overcame neonatal isolation-induced autistic-like behaviors, and restored adult hippocampal neurogenesis as well as the balance between excitatory and inhibitory activities to physiological levels. These findings indicate that neonatal isolation may produce autistic-like behaviors, and lithium may be a potential therapeutic agent against autism spectrum disorders (ASD) during development. PMID:25018711

Anxiogenic effects of a Lactobacillus, inulin and the synbiotic on healthy juvenile rats.

PubMed

Barrera-Bugueño, Camila; Realini, Ornella; Escobar-Luna, Jorge; Sotomayor-Zárate, Ramón; Gotteland, Martin; Julio-Pieper, Marcela; Bravo, Javier A

2017-09-17

Gut microbiota interventions, including probiotic and prebiotic use can alter behavior in adult animals and healthy volunteers. However, little is known about their effects in younger individuals. To investigate this, male Sprague-Dawley rats (post-natal day 21, PND21) received Lactobacillus casei 54-2-33 (10 4 cfu/ml), inulin as prebiotic (16mg/ml), or both together (synbiotic) via drinking water for 14days. Control rats received water alone. Open field (OF) and elevated plus maze (EPM) behaviors were evaluated at PND34 and 35, respectively. 30min after EPM, brains and trunk blood were collected to evaluate hippocampal 5-HT 1A (mRNA and protein) and plasma corticosterone (CORT). Lactobacillus, inulin and synbiotic-treated rats had fewer entries to the OF's center and spent more time in its periphery than controls. Synbiotic-fed rats explored the EPM's open arms longer than probiotic and inulin-fed rats. Synbiotic, but not Lactobacillus nor inulin-fed rats had lower levels of EPM-evoked CORT than controls. Basal CORT levels, evaluated in a naïve cohort, were higher in Lactobacillus- and inulin-fed rats than controls. In naïve synbiotic-fed rats, 5-HT 1A mRNA levels were higher in dentate gyrus and cornus ammonis 1 layer (CA1), than in all other naïve groups, while hippocampal 5-HT 1A protein levels were lower in bacteria-fed rats than controls. 5-HT 1A mRNA changes suggest complex effects of gut microbes on hippocampal gene expression machinery, probably involving endogenous/exogenous bacteria and prebiotics interactions. Importantly, age might also influence their behavioral outcomes. Together, these data suggest that interventions in young rat microbiota evoke early behavioral changes upon stress, apparently in a hypothalamus-pituitary-adrenal axis independent fashion. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Neonatal lipopolysaccharide exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats.

PubMed

Wang, K-C; Fan, L-W; Kaizaki, A; Pang, Y; Cai, Z; Tien, L-T

2013-03-27

Infection during early neonatal period has been shown to cause lasting neurological disabilities and is associated with the subsequent impairment in development of learning and memory ability and anxiety-related behavior in adults. We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in cognitive deficits in juvenile rats (P21); thus, the goal of the present study was to determine whether neonatal LPS exposure has long-lasting effects in adult rats. After an LPS (1mg/kg) intracerebral (i.c.) injection in postnatal day 5 (P5) Sprague-Dawley female rat pups, neurobehavioral tests were carried out on P21 and P22, P49 and P50 or P70 and P71 and brain injury was examined at 66days after LPS injection (P71). Our data indicate that neonatal LPS exposure resulted in learning deficits in the passive avoidance task, less anxiety-like (anxiolytic-like) responses in the elevated plus-maze task, reductions in the hippocampal volume and the number of neuron-specific nuclear protein (NeuN)+ cells, as well as axonal injury in the CA1 region of the middle dorsal hippocampus in P71 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P71 rat hippocampus, as indicated by an increased number of activated microglia and elevation of interleukin-1β content in the rat hippocampus. This study reveals that neonatal LPS exposure causes persistent injuries to the hippocampus and results in long-lasting learning disabilities, and these effects are related to the chronic inflammation in the rat hippocampus. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Significant long-term, but not short-term, hippocampal-dependent memory impairment in adult rats exposed to alcohol in early postnatal life.

PubMed

Goodfellow, Molly J; Lindquist, Derick H

2014-09-01

In rodents, ethanol exposure in early postnatal life is known to induce structural and functional impairments throughout the brain, including the hippocampus. Herein, rat pups were administered one of three ethanol doses over postnatal days (PD) 4-9, a period of brain development comparable to the third trimester of human pregnancy. As adults, control and ethanol rats were trained and tested in a variant of hippocampal-dependent one-trial context fear conditioning. In Experiment 1, subjects were placed into a novel context and presented with an immediate footshock (i.e., within ∼8 sec). When re-exposed to the same context 24 hr later low levels of conditioned freezing were observed. Context pre-exposure 24 hr prior to the immediate shock reversed the deficit in sham-intubated and unintubated control rats, enhancing freezing behavior during the context retention test. Even with context pre-exposure, however, significant dose-dependent reductions in contextual freezing were seen in ethanol rats. In Experiment 2, the interval between context pre-exposure and the immediate shock was shortened to 2 hr, in addition to the standard 24 hr. Ethanol rats trained with the 2 hr, but not 24 hr, interval displayed retention test freezing levels roughly equal to controls. Results suggest the ethanol rats can encode a short-term context memory and associate it with the aversive footshock 2 hr later. In the 24 hr ethanol rats the short-term context memory is poorly transferred or consolidated into long-term memory, we propose, impeding the memory's subsequent retrieval and association with shock. © 2014 Wiley Periodicals, Inc.

Pregabalin attenuates excitotoxicity in diabetes.

PubMed

Huang, Chin-Wei; Lai, Ming-Chi; Cheng, Juei-Tang; Tsai, Jing-Jane; Huang, Chao-Ching; Wu, Sheng-Nan

2013-01-01

Diabetes can exacerbate seizures and worsen seizure-related brain damage. In the present study, we aimed to determine whether the standard antiepileptic drug pregabalin (PGB) protects against pilocarpine-induced seizures and excitotoxicity in diabetes. Adult male Sprague-Dawley rats were divided into either a streptozotocin (STZ)-induced diabetes group or a normal saline (NS) group. Both groups were further divided into subgroups that were treated intravenously with either PGB (15 mg/kg) or a vehicle; all groups were treated with subcutaneous pilocarpine (60 mg/kg) to induce seizures. To evaluate spontaneous recurrent seizures (SRS), PGB-pretreated rats were fed rat chow containing oral PGB (450 mg) for 28 consecutive days; vehicle-pretreated rats were fed regular chow. SRS frequency was monitored for 2 weeks from post-status epilepticus day 15. We evaluated both acute neuronal loss and chronic mossy fiber sprouting in the CA3 area. In addition, we performed patch clamp recordings to study evoked excitatory postsynaptic currents (eEPSCs) in hippocampal CA1 neurons for both vehicle-treated rats with SRS. Finally, we used an RNA interference knockdown method for Kir6.2 in a hippocampal cell line to evaluate PGB's effects in the presence of high-dose ATP. We found that compared to vehicle-treated rats, PGB-treated rats showed less severe acute seizure activity, reduced acute neuronal loss, and chronic mossy fiber sprouting. In the vehicle-treated STZ rats, eEPSC amplitude was significantly lower after PGB administration, but glibenclamide reversed this effect. The RNA interference study confirmed that PGB could counteract the ATP-sensitive potassium channel (KATP)-closing effect of high-dose ATP. By opening KATP, PGB protects against neuronal excitotoxicity, and is therefore a potential antiepileptogenic in diabetes. These findings might help develop a clinical algorithm for treating patients with epilepsy and comorbid metabolic disorders.

Hypoxic pretreatment protects against neuronal damage of the rat hippocampus induced by severe hypoxia.

PubMed

Gorgias, N; Maidatsi, P; Tsolaki, M; Alvanou, A; Kiriazis, G; Kaidoglou, K; Giala, M

1996-04-01

The present study investigates whether under conditions of successive hypoxic exposures pretreatment with mild (15% O(2)) or moderate (10% O(2)) hypoxia, protects hippocampal neurones against damage induced by severe (3% O(2)) hypoxia. The ultrastructural findings were also correlated with regional superoxide dismutase (SOD) activity changes. In unpretreated rats severe hypoxia induced ultrastructural changes consistent with the aspects of delayed neuronal death (DND). However, in preexposed animals hippocampal damage was attenuated in an inversely proportional way with the severity of the hypoxic pretreatment. The ultrastructural hypoxic tolerance findings were also closely related to increased regional SOD activity levels. Thus the activation of the endogenous antioxidant defense by hypoxic preconditioning, protects against hippocampal damage induced by severe hypoxia. The eventual contribution of increased endogenous adenosine and/or reduced excitotoxicity to induce hypoxic tolerance is discussed.

The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat.

PubMed

Cavdar, Safiye; Onat, Filiz Y; Cakmak, Yusuf Ozgür; Yananli, Hasan R; Gülçebi, Medine; Aker, Rezzan

2008-03-01

Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a 'canonical' circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6-1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex.

The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat

PubMed Central

Çavdar, Safiye; Onat, Filiz Y; Çakmak, Yusuf Özgür; Yananli, Hasan R; Gülçebi, Medine; Aker, Rezzan

2008-01-01

Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a ‘canonical’ circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6–1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex. PMID:18221482

Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats.

PubMed

Kitamura, Yoshihisa; Kanemoto, Erika; Sugimoto, Misaki; Machida, Ayumi; Nakamura, Yuka; Naito, Nanami; Kanzaki, Hirotaka; Miyazaki, Ikuko; Asanuma, Masato; Sendo, Toshiaki

2017-04-01

In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.

The effect of propofol on CA1 pyramidal cell excitability and GABAA-mediated inhibition in the rat hippocampal slice.

PubMed

Albertson, T E; Walby, W F; Stark, L G; Joy, R M

1996-05-24

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 microns thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7-28 microM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABAA antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepine antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABAA-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.

A calcium-permeable cGMP-activated cation conductance in hippocampal neurons

NASA Technical Reports Server (NTRS)

Leinders-Zufall, T.; Rosenboom, H.; Barnstable, C. J.; Shepherd, G. M.; Zufall, F.

1995-01-01

Whole-cell patch clamp recordings detected a previously unidentified cGMP-activated membrane conductance in cultured rat hippocampal neurons. This conductance is nonselectively permeable for cations and is completely but reversibly blocked by external Cd2+. The Ca2+ permeability of the hippocampal cGMP-activated conductance was examined in detail, indicating that the underlying ion channels display a high relative permeability for Ca2+. The results indicate that hippocampal neurons contain a cGMP-activated membrane conductance that has some properties similar to the cyclic nucleotide-gated channels previously shown in sensory receptor cells and retinal neurons. In hippocampal neurons this conductance similarly could mediate membrane depolarization and Ca2+ fluxes in response to intracellular cGMP elevation.

Age-dependent effect of high cholesterol diets on anxiety-like behavior in elevated plus maze test in rats.

PubMed

Hu, Xu; Wang, Tao; Luo, Jia; Liang, Shan; Li, Wei; Wu, Xiaoli; Jin, Feng; Wang, Li

2014-09-01

Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes. Young (3 weeks old) and adult (20 weeks old) rats were given a high cholesterol diet for 8 weeks. The anxiety-like behavior in elevated plus maze test and changes of central neurochemical implicated in anxiety were measured. In young rats, high cholesterol diet induced anxiolytic-like behavior, decreased serum corticosterone (CORT), increased hippocampal brain-derived neurotrophic factor (BDNF), increased hippocampal mineralocorticoid receptor (MR) and decreased glucocorticoid receptor (GR). In adult rats, high cholesterol diet induced anxiety-like behavior and increase of serum CORT and decrease of hippocampal BDNF comparing with their respective control group that fed the regular diet. High cholesterol diet induced age-dependent effects on anxiety-like behavior and central neurochemical changes. High cholesterol diet might affect the central nervous system (CNS) function differently, and resulting in different behavior performance of anxiety in different age period.

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

Subcellular localization of Patched and Smoothened, the receptors for Sonic hedgehog signaling, in the hippocampal neuron.

PubMed

Petralia, Ronald S; Schwartz, Catherine M; Wang, Ya-Xian; Mattson, Mark P; Yao, Pamela J

2011-12-15

Cumulative evidence suggests that, aside from patterning the embryonic neural tube, Sonic hedgehog (Shh) signaling plays important roles in the mature nervous system. In this study, we investigate the expression and localization of the Shh signaling receptors, Patched (Ptch) and Smoothened (Smo), in the hippocampal neurons of young and mature rats. Reverse transcriptase-polymerase chain reaction and immunoblotting analyses show that the expression of Ptch and Smo remains at a moderate level in young postnatal and adult brains. By using immunofluorescence light microscopy and immunoelectron microscopy, we examine the spatial distribution of Ptch and Smo within the hippocampal neurons. In young developing neurons, Ptch and Smo are present in the processes and are clustered at their growth cones. In mature neurons, Ptch and Smo are concentrated in dendrites, spines, and postsynaptic sites. Synaptic Ptch and Smo often co-exist with unusual structures-synaptic spinules and autophagosomes. Our results reveal the anatomical organization of the Shh receptors within both the young and the mature hippocampal neurons. Copyright © 2011 Wiley-Liss, Inc.

Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

PubMed Central

Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

2010-01-01

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

Additional Antiepileptic Mechanisms of Levetiracetam in Lithium-Pilocarpine Treated Rats

PubMed Central

Al-Shorbagy, Muhammad Y.; El Sayeh, Bahia M.; Abdallah, Dalaal M.

2013-01-01

Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide. PMID:24098559

NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells.

PubMed

Lu, Yong; Dang, Shaokang; Wang, Xu; Zhang, Junli; Zhang, Lin; Su, Qian; Zhang, Huiping; Lin, Tianwei; Zhang, Xiaoxiao; Zhang, Yurong; Sun, Hongli; Zhu, Zhongliang; Li, Hui

2018-01-01

Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K + ) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K + currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K + currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K + current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K + currents, and the NO pathway may be involved in this process. Copyright © 2017 Elsevier B.V. All rights reserved.

Hippocampal mGluR5 predicts an occurrence of helplessness behavior after repetitive exposure to uncontrollable stress.

PubMed

Yim, Yeong Shin; Lee, Jinu; Kim, Gun-Tae; Song, Teresa; Kim, Chul Hoon; Kim, Dong Goo

2012-06-21

An individual's behavior is generally based on genetic blueprint and previous experiences. A coping strategy, affected by personal interpretation of past events, can be determined by behavioral controllability of stress. In this study, we examined the relationship between the hippocampal mGluR5 expression and coping strategies to stress. Rats were exposed to stress via inescapable and unpredictable footshocks on PNDs 14 and 90. Coping strategies to stress were also measured. Hippocampal mGluR5 was found to be linked to the behavioral coping strategy, as it increased in rats that showed helplessness behavior (HL (+) group) and decreased in those that did not (HL (-) group). Also, the HL (+) group showed a lack of adaptation in a novel environment but the HL (-) group did not. The results suggest that mGluR5 has a pivotal role in the controllability-based coping strategy. Hippocampal mGluR5 could be a target molecule in the manipulation of neuropsychiatric conditions for which maladaptation is a part of behavioral consequences. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Melatonin protects against oxygen and glucose deprivation by decreasing extracellular glutamate and Nox-derived ROS in rat hippocampal slices.

PubMed

Patiño, Paloma; Parada, Esther; Farré-Alins, Victor; Molz, Simone; Cacabelos, Ramón; Marco-Contelles, José; López, Manuela G; Tasca, Carla I; Ramos, Eva; Romero, Alejandro; Egea, Javier

2016-12-01

Therapeutic interventions on pathological processes involved in the ischemic cascade, such as oxidative stress, neuroinflammation, excitotoxicity and/or apoptosis, are of urgent need for stroke treatment. Melatonin regulates a large number of physiological actions and its beneficial properties have been reported. The aim of this study was to investigate whether melatonin mediates neuroprotection in rat hippocampal slices subjected to oxygen-glucose-deprivation (OGD) and glutamate excitotoxicity. Thus, we describe here that melatonin significantly reduced the amount of lactate dehydrogenase released in the OGD-treated slices, reverted neuronal injury caused by OGD-reoxygenation in CA1 and CA3 hippocampal regions, restored the reduction of GSH content of the hippocampal slices induced by OGD, and diminished the oxidative stress produced in the reoxygenation period. Furthermore, melatonin afforded maximum protection against glutamate-induced toxicity and reversed the glutamate released almost basal levels, at 10 and 30μM concentration, respectively. Consequently, we propose that melatonin might strongly and positively influence the outcome of brain ischemia/reperfusion. Copyright © 2016 Elsevier B.V. All rights reserved.

Hippocampal gene expression in a rat model of depression after electroacupuncture at the Baihui and Yintang acupoints

PubMed Central

Duan, Dongmei; Yang, Xiuyan; Ya, Tu; Chen, Liping

2014-01-01

Preliminary basic research and clinical findings have demonstrated that electroacupuncture therapy exhibits positive effects in ameliorating depression. However, most studies of the underlying mechanism are at the single gene level; there are few reports regarding the mechanism at the whole-genome level. Using a rat genomic gene-chip, we profiled hippocampal gene expression changes in rats after electroacupuncture therapy. Electroacupuncture therapy alleviated depression-related manifestations in the model rats. Using gene-chip analysis, we demonstrated that electroacupuncture at Baihui (DU20) and Yintang (EX-HN3) regulates the expression of 21 genes. Real-time PCR showed that the genes Vgf, Igf2, Tmp32, Loc500373, Hif1a, Folr1, Nmb, and Rtn were upregulated or downregulated in depression and that their expression tended to normalize after electroacupuncture therapy. These results indicate that electroacupuncture at Baihui and Yintang modulates depression by regulating the expression of particular genes. PMID:25206746

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.

Prenatal choline supplementation attenuates MK-801-induced deficits in memory, motor function, and hippocampal plasticity in adult male rats.

PubMed

Nickerson, Chelsea A; Brown, Alexandra L; Yu, Waylin; Chun, Yoona; Glenn, Melissa J

2017-10-11

Choline is essential to the development and function of the central nervous system and supplemental choline during development is neuroprotective against a variety of insults, including neurotoxins like dizocilpine (MK-801). MK-801 is an NMDA receptor antagonist that is frequently used in rodent models of psychological disorders, particularly schizophrenia. At low doses, it causes cognitive impairments, and at higher doses it induces motor deficits, anhedonia, and neuronal degeneration. The primary goals of the present study were to investigate whether prenatal choline supplementation protects against the cognitive impairments, motor deficits, and neuropathologies that are precipitated by MK-801 administration in adulthood. Adult male Sprague-Dawley rats were fed a standard or supplemented choline diet prenatally. Using the novelty preference test of object recognition, we found that only prenatal standard-fed rats displayed memory consolidation deficits induced by low-dose MK-801 administered immediately following study of sample objects; all other groups, including prenatal choline supplemented rats given MK-801, showed intact memory. Following high-dose MK-801, prenatal choline supplementation significantly alleviated rats' motor response to MK-801, particularly ataxia. Using doublecortin and Ki67 to mark neurogenesis and cell division, respectively, in the hippocampus, we found that prenatal choline supplementation, in the face of MK-801 toxicity, protected against reduced hippocampal plasticity. Taken together, the current findings suggest that prenatal choline supplementation protects against a variety of behavioral and neural pathologies induced by the neurotoxin, MK-801. This research contributes to the growing body of evidence supporting the robust neuroprotective capacity of choline. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

PubMed

Shrot, Shai; Ramaty, Erez; Biala, Yoav; Bar-Klein, Guy; Daninos, Moshe; Kamintsky, Lyn; Makarovsky, Igor; Statlender, Liran; Rosman, Yossi; Krivoy, Amir; Lavon, Ophir; Kassirer, Michael; Friedman, Alon; Yaari, Yoel

2014-09-02

Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats.

PubMed

Brandt, Claudia; Glien, Maike; Gastens, Alexandra M; Fedrowitz, Maren; Bethmann, Kerstin; Volk, Holger A; Potschka, Heidrun; Löscher, Wolfgang

2007-08-01

Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.

BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power.

PubMed

Geist, Phillip A; Dulka, Brooke N; Barnes, Abigail; Totty, Michael; Datta, Subimal

2017-08-14

Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two. Copyright © 2017 Elsevier B.V. All rights reserved.

Reactive Transformation and Increased BDNF Signaling by Hippocampal Astrocytes in Response to MK-801

PubMed Central

Wang, Yueming; Li, Guanjun; Wang, Lihua; Li, Huafang

2015-01-01

MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP), a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10ml/kg body weight for 6 days) and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 μM for 24 h). Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling. PMID:26700309

Optical slicing and 3-D characterization of hippocampal capillaries in the rat visualized by autometallographic silver enhancement of colloidal gold particles.

PubMed

Andreasen, A; Danscher, G

1997-10-01

In order to visualize the vascular system of the rat brain, 10 Wistar rats were perfused transcardially with glutaraldehyde and a 40 degrees C gold-gelatine solution. The brains were post-fixed with glutaraldehyde and vibratomized into 100-micron-thick slices, and the gold particles were developed by autometallography. In this way, the colloidal gold particles in the vessels became encased in silver and thereby made visible. The developed gold staining is stable and does not interfere with further dehydration and counterstaining. Images were frame grabbed during optical slicing, and classic stereograms and 'shadow' 3-D images were produced. We found a high variation of capillary density in the hippocampal region reflecting known subregional structures. The silver-enhanced vessels acted as natural markers and made it possible to study and measure aspects of the complexity of dehydration and staining artifacts. We found a non-linear shrinking of 13-17% in the x- and y-directions and a spatial shrinking up to 50% in some regions after the dehydration and staining process. This observation may be of interest not only in relation to tissue subjected to this fixation protocol but also to other fixation procedures. The gold-gelatine autometallographic technique and the present stereograms can release data for stereological use as well.

Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat

PubMed Central

Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G.; Bhatt, Abhay J.; Savich, Renate D.; Fan, Lir-Wan

2016-01-01

The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

Oleuropein attenuates cognitive dysfunction and oxidative stress induced by some anesthetic drugs in the hippocampal area of rats.

PubMed

Alirezaei, Masoud; Rezaei, Maryam; Hajighahramani, Shahin; Sookhtehzari, Ali; Kiani, Katayoun

2017-01-01

The present study was designed to evaluate the antioxidant effects of oleuropein against oxidative stress in the hippocampal area of rats. We used seven experimental groups as follows: Control, Propofol, Propofol-Ketamine (Pro.-Ket.), Xylazine-Ketamine (Xyl.-Ket.), and three oleuropein-pretreated groups (Ole.-Pro., Ole.-Pro.-Ket. and Ole.-Xyl.-Ket.). The oleuropein-pretreated groups received oleuropein (15 mg/kg body weight as orally) for 10 consecutive days. Propofol 100 mg/kg, xylazine 3 mg/kg, and ketamine 75 mg/kg once as ip was used on the 11th day of treatment. Spatial memory impairment and antioxidant status of hippocampus were measured via Morris water maze, lipid peroxidation marker, and antioxidant enzyme activities. Spatial memory impairment and lipid peroxidation significantly increased in Xyl.-Ket.-treated rats in comparison to the control, propofol, Ole.-Pro. and Ole.-Pro.-Ket. groups. Oleuropein pretreatment significantly reversed spatial memory impairment and lipid peroxidation in the Ole.-Xyl.-Ket. group as compared to the Xyl.-Ket.-treated rats. There was no significant difference between the control and the propofol group in lipid peroxidation and spatial memory status. Superoxide dismutase and catalase activities both significantly decreased in Xyl.-Ket.-treated rats when compared to the control, propofol, Ole.-Pro., Ole.-Pro.-Ket., and Ole.-Xyl.-Ket. groups. In contrast, glutathione peroxidase activity in Xyl.-Ket.-treated rats significantly increased as compared to the control, propofol, Pro.-Ket., Ole.-Pro., and Ole.-Pro.-Ket. groups. We concluded that xylazine in combination with ketamine is an oxidative anesthetic drug and oleuropein pretreatment attenuates cognitive dysfunction and oxidative stress induced by anesthesia in the hippocampal area of rats. We also confirmed the antioxidant properties of propofol as a promising antioxidant anesthetic agent.

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.

Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

PubMed

Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

2014-01-01

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Ketogenic diet does not impair spatial ability controlled by the hippocampus in male rats.

PubMed

Fukushima, Atsushi; Ogura, Yuji; Furuta, Miyako; Kakehashi, Chiaki; Funabashi, Toshiya; Akema, Tatsuo

2015-10-05

A ketogenic diet was recently shown to reduce glutamate accumulation in synaptic vesicles, decreasing glutamate transmission. We questioned whether a ketogenic diet affects hippocampal function, as glutamate transmission is critically involved in visuospatial ability. In the present study, male Wistar rats were maintained on a ketogenic diet containing 10% protein and 90% fat with complements for 3 weeks to change their energy expenditure from glucose-dependent to fat-dependent. Control rats were fed a diet containing 10% protein, 10% fat, and 80% carbohydrates. The fat-dependent energy expenditure induced by the ketogenic diet led to decreased body weight and increased blood ketone production, though the rats in the two groups consumed the same number of calories. The ketogenic diet did not alter food preferences for the control or high-fat diet containing 10% protein, 45% fat, and 45% carbohydrates. Anxiety in the open field was not altered by ingestion the ketogenic diet. However, rats fed the ketogenic diet performed better in the Y-maze test than rats fed the control diet. No difference was observed between the two groups in the Morris water maze test. Finally, Western blot revealed that the hippocampal expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit 1 (GluR1) was significantly increased in mice fed a ketogenic diet. These results suggest that hippocampal function is not impaired by a ketogenic diet and we speculate that the fat-dependent energy expenditure does not impair visuospatial ability. Copyright © 2015 Elsevier B.V. All rights reserved.

Prenatal choline availability alters the context sensitivity of Pavlovian conditioning in adult rats

PubMed Central

Lamoureux, Jeffrey A.; Meck, Warren H.; Williams, Christina L.

2008-01-01

The effects of prenatal choline availability on Pavlovian conditioning were assessed in adult male rats (3–4 mo). Neither supplementation nor deprivation of prenatal choline affected the acquisition and extinction of simple Pavlovian conditioned excitation, or the acquisition and retardation of conditioned inhibition. However, prenatal choline availability significantly altered the contextual control of these learned behaviors. Both control and choline-deprived rats exhibited context specificity of conditioned excitation as exhibited by a loss in responding when tested in an alternate context after conditioning; in contrast, choline-supplemented rats showed no such effect. When switched to a different context following extinction, however, both choline-supplemented and control rats showed substantial contextual control of responding, whereas choline-deficient rats did not. These data support the view that configural associations that rely on hippocampal function are selectively sensitive to prenatal manipulations of dietary choline during prenatal development. PMID:19050158

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

[MORPHOLOGICAL DIFFERENCES BETWEEN THE EFFECTS OF VARIOUS MODES OF PRECONDITIONING AIMED AT CORRECTING THE DAMAGE TO THE HIPPOCAMPAL NEURONS BY SEVERE HYPOBARIC HYPOXIA].

PubMed

Samoilov, M O; Churilova, A V; Glushchenko, T S

2015-01-01

In 5 groups of rats (6 animals in each), the changes of neurons in hippocampal fields CA1 and CA4 were studied 7 days after severe hypobaric hypoxia (180 mm Hg, for 3 h) preceded by various numbers (1, 3 and 6) of sessions of preconditioning (PC) by mild hypobaric hypoxia (360 mm Hg, for 2 h, 24 h prior to severe hypoxia). It was found that a single session of PC did not prevent the damage to the structure of neurons and their death after exposure to severe hypoxia. Meanwhile, 6, and especially 3 sessions of PC induced protective mechanisms of neuronal damage prevention. In rats after 6 sessions of PC, unlike those exposed to 3 sessions, mild chromatolysis of hippocampal neurons was demonstrated. This could result from prolonged hypermetabolic activity of neurons and indicate their functional overloading.

An intra-hippocampal injection of nandrolone induces learning and memory impairments in rat.

PubMed

Karamian, A; Pakdel, F G; Ilkhanipoor, M; Farokhi, F; Ahmadi, A

2015-01-01

This study was investigated to evaluate the effect of intra-hippocampal injection of the nandrolone on spatial learning task in rats. The drug or vehicle was manually injected into the hippocampus with a 10-µl Hamilton syringe attached via polyethylene tubing to 27-gauge stainless-steel injection cannula. After 6 days of recovery, learning behaviors were evaluated using an 8-arm radial maze. The results showed that intra-hippocampal injection of nandrolone can impair trained spatial learning at a dose of 5 µl. We also observed a dense cytoplasm and nucleus in CA1 neurons as well as signs of necrosis. Nandrolone can impair the time required to reach the baited arm as well as the frequency of successful arm entries. At the 10 µl dose of nandrolone, neural hypertrophy and increased dentate gyrus volume were also observed. © Georg Thieme Verlag KG Stuttgart · New York.

The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat.

PubMed

Kanoski, Scott E; Zhang, Yanshu; Zheng, Wei; Davidson, Terry L

2010-01-01

Cognitive impairment and Alzheimer's disease are linked with intake of a Western diet, characterized by high levels of saturated fats and simple carbohydrates. In rats, these dietary components have been shown to disrupt hippocampal-dependent learning and memory processes, particularly those involving spatial memory. Using a rat model, the present research assessed the degree to which consumption of a high-energy (HE) diet, similar to those found in modern Western cultures, produces a selective impairment in hippocampal function as opposed to a more global cognitive disruption. Learning and memory performance was examined following 90-day consumption of an HE-diet in three nonspatial discrimination learning problems that differed with respect to their dependence on the integrity of the hippocampus. The results showed that consumption of the HE-diet impaired performance in a hippocampal-dependent feature negative discrimination problem relative to chow-fed controls, whereas performance was spared on two discrimination problems that do not rely on the hippocampus. To explore the mechanism whereby consuming HE-diets impairs cognitive function, we investigated the effect of HE-diets on the integrity of the blood-brain barrier (BBB). We found that HE-diet consumption produced a decrease in mRNA expression of tight junction proteins, particularly Claudin-5 and -12, in the choroid plexus and the BBB. Consequently, an increased blood-to-brain permeability of sodium fluorescein was observed in the hippocampus, but not in the striatum and prefrontal cortex following HE-diet access. These results indicate that hippocampal function may be particularly vulnerable to disruption by HE-diets, and this disruption may be related to impaired BBB integrity.

Exogenous galanin attenuates spatial memory impairment and decreases hippocampal β-amyloid levels in rat model of Alzheimer's disease.

PubMed

Li, Lei; Yu, Liling; Kong, Qingxia

2013-11-01

One of the major pathological characteristics of Alzheimer's disease (AD) is the presence of enhanced deposits of beta-amyloid peptide (Aβ). The neuropeptide galanin (GAL) and its receptors are overexpressed in degenerating brain regions in AD. The functional consequences of galaninergic systems plasticity in AD are unclear. The objective of the present study was to investigate whether exogenous galanin could attenuate spatial memory impairment and hippocampal Aβ aggregation in rat model of AD. The effects of Aβ, galanin, galanin receptor 1 agonist M617 and galanin receptor 2 agonist AR-M1896 on spatial memory were tested by Morris water maze. The effects of Aβ, galanin, M617 and AR-M1896 on hippocampal Aβ protein expression were evaluated by western blot assay. The expression of galanin, galanin receptors 1 and 2 in rats' hippocampus were detected by real time PCR and western blot assay. The results showed that (1) Galanin administration was effective in improving the spatial memory and decreasing hippocampal Aβ levels after intracerebroventricular injection of Aβ; (2) AR-M1896 rather than M617 could imitate these effects of galanin; (3) GAL and GALR2 mRNA and protein levels increased significantly in hippocampus after Aβ administration, while GALR1 mRNA and protein levels did not change; (4) GAL, AR-M1896 and M617 administration did not show significant effect on GAL, GalR1 and GalR2 mRNA and protein levels in hippocampus after Aβ administration. These results implied that galanin receptor 2, but not receptor 1 was involved in the protective effects against spatial memory impairment and hippocampal Aβ aggregation.

Septal serotonin depletion in rats facilitates working memory in the radial arm maze and increases hippocampal high-frequency theta activity.

PubMed

López-Vázquez, Miguel Ángel; López-Loeza, Elisa; Lajud Ávila, Naima; Gutiérrez-Guzmán, Blanca Erika; Hernández-Pérez, J Jesús; Reyes, Yoana Estrada; Olvera-Cortés, María Esther

2014-07-05

Hippocampal theta activity, which is strongly modulated by the septal medial/Broca׳s diagonal band neurons, has been linked to information processing of the hippocampus. Serotonin from the medial raphe nuclei desynchronises hippocampal theta activity, whereas inactivation or a lesion of this nucleus induces continuous and persistent theta activity in the hippocampus. Hippocampal serotonin depletion produces an increased expression of high-frequency theta activity concurrent with the facilitation of place learning in the Morris maze. The medial septum-diagonal band of Broca complex (MS/DBB) has been proposed as a key structure in the serotonin modulation of theta activity. We addressed whether serotonin depletion of the MS/DBB induces changes in the characteristics of hippocampal theta activity and whether the depletion is associated with learning in a working memory spatial task in the radial arm maze. Sprague Dawley rats were depleted of 5HT with the infusion of 5,7-dihydroxytriptamine (5,7-DHT) in MS/DBB and were subsequently trained in the standard test (win-shift) in the radial arm, while the CA1 EEG activity was simultaneously recorded through telemetry. The MS/DBB serotonin depletion induced a low level of expression of low-frequency (4.5-6.5Hz) and a higher expression of high-frequency (6.5-9.5Hz) theta activity concomitant to a minor number of errors committed by rats on the working memory test. Thus, the depletion of serotonin in the MS/DBB caused a facilitator effect on working memory and a predominance of high-frequency theta activity. Copyright © 2014 Elsevier B.V. All rights reserved.

Forebrain-specific, conditional silencing of Staufen2 alters synaptic plasticity, learning, and memory in rats.

PubMed

Berger, Stefan M; Fernández-Lamo, Iván; Schönig, Kai; Fernández Moya, Sandra M; Ehses, Janina; Schieweck, Rico; Clementi, Stefano; Enkel, Thomas; Grothe, Sascha; von Bohlen Und Halbach, Oliver; Segura, Inmaculada; Delgado-García, José María; Gruart, Agnès; Kiebler, Michael A; Bartsch, Dusan

2017-11-17

Dendritic messenger RNA (mRNA) localization and subsequent local translation in dendrites critically contributes to synaptic plasticity and learning and memory. Little is known, however, about the contribution of RNA-binding proteins (RBPs) to these processes in vivo. To delineate the role of the double-stranded RBP Staufen2 (Stau2), we generate a transgenic rat model, in which Stau2 expression is conditionally silenced by Cre-inducible expression of a microRNA (miRNA) targeting Stau2 mRNA in adult forebrain neurons. Known physiological mRNA targets for Stau2, such as RhoA, Complexin 1, and Rgs4 mRNAs, are found to be dysregulated in brains of Stau2-deficient rats. In vivo electrophysiological recordings reveal synaptic strengthening upon stimulation, showing a shift in the frequency-response function of hippocampal synaptic plasticity to favor long-term potentiation and impair long-term depression in Stau2-deficient rats. These observations are accompanied by deficits in hippocampal spatial working memory, spatial novelty detection, and in tasks investigating associative learning and memory. Together, these experiments reveal a critical contribution of Stau2 to various forms of synaptic plasticity including spatial working memory and cognitive management of new environmental information. These findings might contribute to the development of treatments for conditions associated with learning and memory deficits.

Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.

PubMed

Zamberletti, Erica; Gabaglio, Marina; Grilli, Massimo; Prini, Pamela; Catanese, Alberto; Pittaluga, Anna; Marchi, Mario; Rubino, Tiziana; Parolaro, Daniela

2016-09-01

Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its ability to trigger different region-dependent changes in glutamate synapse and glial cells. The phenotype observed in males is mainly associated with marked dysregulations in the hippocampus, whereas the prevalence of alterations in the emotional sphere in females is associated with profound changes in the PFC. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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.

Increased DNA double-strand break was associated with downregulation of repair and upregulation of apoptotic factors in rat hippocampus after alcohol exposure.

PubMed

Suman, Shubhankar; Kumar, Santosh; N'Gouemo, Prosper; Datta, Kamal

2016-08-01

Binge drinking is known to cause damage in critical areas of the brain, including the hippocampus, which is important for relational memory and is reported to be sensitive to alcohol toxicity. However, the roles of DNA double-strand break (DSB) and its repair pathways, homologous recombination (HR), and non-homologous end joining (NHEJ) in alcohol-induced hippocampal injury remain to be elucidated. The purpose of this first study was to assess alcohol-induced DNA DSB and the mechanism by which alcohol affects DSB repair pathways in rat hippocampus. Male Sprague-Dawley rats (8-10 weeks old) were put on a 4-day binge ethanol treatment regimen. Control animals were maintained under similar conditions but were given the vehicle without ethanol. All animals were humanely euthanized 24 h after the last dose of ethanol administration and the hippocampi were dissected for immunoblot and immunohistochemistry analysis. Ethanol exposure caused increased 4-hydroxynonenal (4-HNE) staining as well as elevated γH2AX and 53BP1 foci in hippocampal cells. Immunoblot analysis showed decreased Mre11, Rad51, Rad50, and Ku86 as well as increased Bax and p21 in samples from ethanol-treated rats. Additionally, we also observed increased activated caspase3 staining in hippocampal cells 24 h after ethanol withdrawal. Taken together, our data demonstrated that ethanol concurrently induced DNA DSB, downregulated DSB repair pathway proteins, and increased apoptotic factors in hippocampal cells. We believe these findings will provide the impetus for further research on DNA DSB and its repair pathways in relation to alcohol toxicity in brain. Copyright © 2016 Elsevier Inc. All rights reserved.

Continuous recognition of spatial and nonspatial stimuli in hippocampal-lesioned rats.

PubMed

Jackson-Smith, P; Kesner, R P; Chiba, A A

1993-03-01

The present experiments compared the performance of hippocampal-lesioned rats to control rats on a spatial continuous recognition task and an analogous nonspatial task with similar processing demands. Daily sessions for Experiment 1 involved sequential presentation of individual arms on a 12-arm radial maze. Each arm contained a Froot Loop reinforcement the first time it was presented, and latency to traverse the arm was measured. A subset of the arms were repeated, but did not contain reinforcement. Repeated arms were presented with lags ranging from 0 to 6 (0 to 6 different arm presentations occurred between the first and the repeated presentation). Difference scores were computed by subtracting the latency on first presentations from the latency on repeated presentations, and these scores were high in all rats prior to surgery, with a decreasing function across lag. There were no differences in performance following cortical control or sham surgery. However, there was a total deficit in performance following large electrolytic lesions of the hippocampus. The second experiment employed the same continuous recognition memory procedure, but used three-dimensional visual objects (toys, junk items, etc., in various shapes, sizes, and textures) as stimuli on a flat runway. As in Experiment 1, the stimuli were presented successively and latency to run to and move the object was measured. Objects were repeated with lags ranging from 0 to 4. Performance on this task following surgery did not differ from performance prior to surgery for either the control group or the hippocampal lesion group. These results provide support for Kesner's attribute model of hippocampal function in that the hippocampus is assumed to mediate data-based memory for spatial locations, but not three-dimensional visual objects.

Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors in rat hippocampal slices.

PubMed

Sperlágh, B; Zsilla, G; Baranyi, M; Kékes-Szabó, A; Vizi, E S

1997-10-01

The presynaptic neuromodulation of stimulation-evoked release of [3H]-acetylcholine by endogenous adenosine, via A1-adenosine receptors, was studied in superfused hippocampal slices taken from 4-, 12- and 24-month-old rats. 8-Cyclopentyl-1,3-dimethylxanthine (0.25 microM), a selective A1-receptor antagonist, increased significantly the electrical field stimulation-induced release of [3H]-acetylcholine in slices prepared from 4- and 12-month-old rats, showing a tonic inhibitory action of endogenous adenosine via stimulation of presynaptic A1-adenosine receptors. In contrast, 8-cyclopentyl-1,3-dimethylxanthine had no effect in 24-month-old rats. 2-Chloroadenosine (10 microM), an adenosine receptor agonist decreased the release of [3H]-acetylcholine in slices taken from 4- and 12-month-old rats, and no significant change was observed in slices taken from 24-month-old rats. In order to show whether the number/or affinity of the A1-receptors was affected in aged rats, [3H]-8-cyclopentyl-1,3-dimethylxanthine binding was studied in hippocampal membranes prepared from rats of different ages. Whereas the Bmax value was significantly lower in 2-year-old rats than in younger counterparts, the dissociation constant (Kd) was not affected by aging, indicating that the density rather than the affinity of adenosine receptors was altered. Endogenous adenosine levels present in the extracellular space were also measured in the superfusate by high performance liquid chromatography (HPLC) coupled with ultraviolet detection, and an age-related increase in the adenosine level was found. In summary, our results indicate that during aging the level of adenosine in the extracellular fluid is increased in the hippocampus. There is a downregulation and reduced responsiveness of presynaptic adenosine A1-receptors, and it seems likely that these changes are due to the enhanced adenosine level in the extracellular space.

Septohippocampal GABAergic neurons mediate the altered behaviors induced by n-methyl-D-aspartate receptor antagonists.

PubMed

Ma, Jingyi; Tai, Siew Kian; Leung, L Stan

2012-12-01

We hypothesize that selective lesion of the septohippocampal GABAergic neurons suppresses the altered behaviors induced by an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine or MK-801. In addition, we hypothesize that septohippocampal GABAergic neurons generate an atropine-resistant theta rhythm that coexists with an atropine-sensitive theta rhythm in the hippocampus. Infusion of orexin-saporin (ore-SAP) into the medial septal area decreased parvalbumin-immunoreactive (GABAergic) neurons by ~80%, without significantly affecting choline-acetyltransferase-immunoreactive (cholinergic) neurons. The theta rhythm during walking, or the immobility-associated theta induced by pilocarpine, was not different between ore-SAP and sham-lesion rats. Walking theta was, however, more disrupted by atropine sulfate in ore-SAP than in sham-lesion rats. MK-801 (0.5 mg/kg i.p.) induced hyperlocomotion associated with an increase in frequency, but not power, of the hippocampal theta in both ore-SAP and sham-lesion rats. However, MK-801 induced an increase in 71-100 Hz gamma waves in sham-lesion but not ore-SAP lesion rats. In sham-lesion rats, MK-801 induced an increase in locomotion and an impairment of prepulse inhibition (PPI), and ketamine (3 mg/kg s.c.) induced a loss of gating of hippocampal auditory evoked potentials. MK-801-induced behavioral hyperlocomotion and PPI impairment, and ketamine-induced auditory gating deficit were reduced in ore-SAP rats as compared to sham-lesion rats. During baseline without drugs, locomotion and auditory gating were not different between ore-SAP and sham-lesion rats, and PPI was slightly but significantly increased in ore-SAP as compared with sham lesion rats. It is concluded that septohippocampal GABAergic neurons are important for the expression of hyperactive and psychotic symptoms an enhanced hippocampal gamma activity induced by ketamine and MK-801, and for generating an atropine-resistant theta. Selective suppression of septohippocampal GABAergic activity is suggested to be an effective treatment of some symptoms of schizophrenia. Copyright © 2012 Wiley Periodicals, Inc.

Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

PubMed Central

Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I.; Romero, Juan I.; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J.; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

2015-01-01

Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA. PMID:26578900

Noise exposure of immature rats can induce different age-dependent extra-auditory alterations that can be partially restored by rearing animals in an enriched environment.

PubMed

Molina, S J; Capani, F; Guelman, L R

2016-04-01

It has been previously shown that different extra-auditory alterations can be induced in animals exposed to noise at 15 days. However, data regarding exposure of younger animals, that do not have a functional auditory system, have not been obtained yet. Besides, the possibility to find a helpful strategy to restore these changes has not been explored so far. Therefore, the aims of the present work were to test age-related differences in diverse hippocampal-dependent behavioral measurements that might be affected in noise-exposed rats, as well as to evaluate the effectiveness of a potential neuroprotective strategy, the enriched environment (EE), on noise-induced behavioral alterations. Male Wistar rats of 7 and 15 days were exposed to moderate levels of noise for two hours. At weaning, animals were separated and reared either in standard or in EE cages for one week. At 28 days of age, different hippocampal-dependent behavioral assessments were performed. Results show that rats exposed to noise at 7 and 15 days were differentially affected. Moreover, EE was effective in restoring all altered variables when animals were exposed at 7 days, while a few were restored in rats exposed at 15 days. The present findings suggest that noise exposure was capable to trigger significant hippocampal-related behavioral alterations that were differentially affected, depending on the age of exposure. In addition, it could be proposed that hearing structures did not seem to be necessarily involved in the generation of noise-induced hippocampal-related behaviors, as they were observed even in animals with an immature auditory pathway. Finally, it could be hypothesized that the differential restoration achieved by EE rearing might also depend on the degree of maturation at the time of exposure and the variable evaluated, being younger animals more susceptible to environmental manipulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Hippocampal “Time Cells”: Time versus Path Integration

PubMed Central

Kraus, Benjamin J.; Robinson, Robert J.; White, John A.; Eichenbaum, Howard; Hasselmo, Michael E.

2014-01-01

SUMMARY Recent studies have reported the existence of hippocampal “time cells,” neurons that fire at particular moments during periods when behavior and location are relatively constant. However, an alternative explanation of apparent time coding is that hippocampal neurons “path integrate” to encode the distance an animal has traveled. Here, we examined hippocampal neuronal firing patterns as rats ran in place on a treadmill, thus “clamping” behavior and location, while we varied the treadmill speed to distinguish time elapsed from distance traveled. Hippocampal neurons were strongly influenced by time and distance, and less so by minor variations in location. Furthermore, the activity of different neurons reflected integration over time and distance to varying extents, with most neurons strongly influenced by both factors and some significantly influenced by only time or distance. Thus, hippocampal neuronal networks captured both the organization of time and distance in a situation where these dimensions dominated an ongoing experience. PMID:23707613

Reinforcement of Rat Hippocampal LTP by Holeboard Training

ERIC Educational Resources Information Center

Frey, Julietta U.; Korz, Volker; Uzakov, Shukhrat

2005-01-01

Hippocampal long-term potentiation (LTP) can be dissociated in early-LTP lasting 4-5 h and late-LTP with a duration of more than 8 h, the latter of which requires protein synthesis and heterosynaptic activity during its induction. Previous studies in vivo have shown that early-LTP in the dentate gyrus can protein synthesis-dependently be…

Vector Symbolic Spiking Neural Network Model of Hippocampal Subarea CA1 Novelty Detection Functionality.

PubMed

Agerskov, Claus

2016-04-01

A neural network model is presented of novelty detection in the CA1 subdomain of the hippocampal formation from the perspective of information flow. This computational model is restricted on several levels by both anatomical information about hippocampal circuitry and behavioral data from studies done in rats. Several studies report that the CA1 area broadcasts a generalized novelty signal in response to changes in the environment. Using the neural engineering framework developed by Eliasmith et al., a spiking neural network architecture is created that is able to compare high-dimensional vectors, symbolizing semantic information, according to the semantic pointer hypothesis. This model then computes the similarity between the vectors, as both direct inputs and a recalled memory from a long-term memory network by performing the dot-product operation in a novelty neural network architecture. The developed CA1 model agrees with available neuroanatomical data, as well as the presented behavioral data, and so it is a biologically realistic model of novelty detection in the hippocampus, which can provide a feasible explanation for experimentally observed dynamics.

Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

PubMed

Rayen, Ine; van den Hove, Daniël L; Prickaerts, Jos; Steinbusch, Harry W; Pawluski, Jodi L

2011-01-01

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

Acute Seizures in Old Age Leads to a Greater Loss of CA1 Pyramidal Neurons, an Increased Propensity for Developing Chronic TLE and a Severe Cognitive Dysfunction.

PubMed

Hattiangady, Bharathi; Kuruba, Ramkumar; Shetty, Ashok K

2011-02-01

The aged population displays an enhanced risk for developing acute seizure (AS) activity. However, it is unclear whether AS activity in old age would result in a greater magnitude of hippocampal neurodegeneration and inflammation, and an increased predilection for developing chronic temporal lobe epilepsy (TLE) and cognitive dysfunction. Therefore, we addressed these issues in young-adult (5-months old) and aged (22-months old) F344 rats after three-hours of AS activity, induced through graded intraperitoneal injections of kainic acid (KA), and terminated through a diazepam injection. During the three-hours of AS activity, both young adult and aged groups exhibited similar numbers of stage-V motor seizures but the numbers of stage-IV motor seizures were greater in the aged group. In both age groups, three-hour AS activity induced degeneration of 50-55% of neurons in the dentate hilus, 22-32% of neurons in the granule cell layer and 49-52% neurons in the CA3 pyramidal cell layer without showing any interaction between the age and AS activity. However, degeneration of neurons in the CA1 pyramidal cell layer showed a clear interaction between the age and AS activity (12% in the young adult group and 56% in the aged group), suggesting that an advanced age makes the CA1 pyramidal neurons more susceptible to die with AS activity. The extent of inflammation measured through the numbers of activated microglial cells was similar between the two age groups. Interestingly, the predisposition for developing chronic TLE at 2-3 months after AS activity was 60% for young adult rats but 100% for aged rats. Moreover, both frequency & intensity of spontaneous recurrent seizures in the chronic phase after AS activity were 6-12 folds greater in aged rats than in young adult rats. Furthermore, aged rats lost their ability for spatial learning even in a scrupulous eleven-session water maze learning paradigm after AS activity, in divergence from young adult rats which retained the ability for spatial learning but had memory retrieval dysfunction after AS activity. Thus, AS activity in old age results in a greater loss of hippocampal CA1 pyramidal neurons, an increased propensity for developing robust chronic TLE, and a severe cognitive dysfunction.

Systemic Th17/IL-17A response appears prior to hippocampal neurodegeneration in rats exposed to low doses of ozone.

PubMed

Solleiro-Villavicencio, H; Rivas-Arancibia, S

2017-06-03

Exposure to low doses of O 3 leads to a state of oxidative stress. Some studies show that oxidative stress can modulate both the CNS and systemic inflammation, which are important factors in the development of Alzheimer disease (AD). This study aims to evaluate changes in the frequency of Th17-like cells (CD3 + CD4 + IL-17A + ), the concentration of IL-17A in peripheral blood, and hippocampal immunoreactivity to IL-17A in rats exposed to low doses of O 3 . One hundred eight male Wistar rats were randomly assigned to 6 groups (n=18) receiving the following treatments: control (O 3 free) or O 3 exposure (0.25ppm, 4hours daily) over 7, 15, 30, 60, and 90 days. Twelve animals from each group were decapitated and a peripheral blood sample was taken to isolate plasma and mononuclear cells. Plasma IL-17A was quantified using LUMINEX, while Th17-like cells were counted using flow cytometry. The remaining 6 rats were deeply anaesthetised and underwent transcardial perfusion for immunohistological study of the hippocampus. Results show that exposure to O 3 over 7 days resulted in a significant increase in the frequency of Th17-like cells and levels of IL-17A in peripheral blood. However, levels of Th17/IL-17A in peripheral blood were lower at day 15 of exposure. We also observed increased IL-17A in the hippocampus beginning at 30 days of exposure. These results indicate that O 3 induces a short-term, systemic Th17-like/IL-17A effect and an increase of IL-17A in the hippocampal tissue during the chronic neurodegenerative process. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

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

Zaja-Milatovic, Snjezana; Gupta, Ramesh C.; Aschner, Michael

Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treatedmore » acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p < 0.01) increases in biomarkers of ROS (F{sub 2}-isoprostanes, F{sub 2}-IsoPs; and F{sub 4}-neuroprostanes, F{sub 4}-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p < 0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-{alpha}-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F{sub 2}-IsoPs, F{sub 4}-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.« less

Garcinia mangostana Linn displays antidepressant-like and pro-cognitive effects in a genetic animal model of depression: a bio-behavioral study in the Flinders Sensitive Line rat.

PubMed

Oberholzer, Inge; Möller, Marisa; Holland, Brendan; Dean, Olivia M; Berk, Michael; Harvey, Brian H

2018-04-01

There is abundant evidence for both disorganized redox balance and cognitive deficits in major depressive disorder (MDD). Garcinia mangostana Linn (GM) has anti-oxidant activity. We studied the antidepressant-like and pro-cognitive effects of raw GM rind in Flinders Sensitive Line (FSL) rats, a genetic model of depression, following acute and chronic treatment compared to a reference antidepressant, imipramine (IMI). The chemical composition of the GM extract was analysed for levels of α- and γ-mangostin. The acute dose-dependent effects of GM (50, 150 and 200 mg/kg po), IMI (20 mg/kg po) and vehicle were determined in the forced swim test (FST) in FSL rats, versus Flinders Resistant Line (FRL) control rats. Locomotor testing was conducted using the open field test (OFT). Using the most effective dose above coupled with behavioral testing in the FST and cognitive assessment in the novel object recognition test (nORT), a fixed dose 14-day treatment study of GM was performed and compared to IMI- (20 mg/kg/day) and vehicle-treated animals. Chronic treated animals were also assessed with respect to frontal cortex and hippocampal monoamine levels and accumulation of malondialdehyde. FSL rats showed significant cognitive deficits and depressive-like behavior, with disordered cortico-hippocampal 5-hydroxyindole acetic acid (5-HIAA) and noradrenaline (NA), as well as elevated hippocampal lipid peroxidation. Acute and chronic IMI treatment evoked pronounced antidepressant-like effects. Raw GM extract contained 117 mg/g and 11 mg/g α- and γ-mangostin, respectively, with acute GM demonstrating antidepressant-like effects at 50 mg/kg/day. Chronic GM (50 mg/kg/d) displayed significant antidepressant- and pro-cognitive effects, while demonstrating parity with IMI. Both behavioral and monoamine assessments suggest a more prominent serotonergic action for GM as opposed to a noradrenergic action for IMI, while both IMI and GM reversed hippocampal lipid peroxidation in FSL animals. Concluding, FSL rats present with cognitive deficits and depressive-like behaviors that are reversed by acute and chronic GM treatment, similar to that of IMI.

The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt.

PubMed

Monk, Bradley R; Leslie, Frances M; Thomas, Jennifer D

2012-08-01

Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M(1) and M(2/4) muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human third trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30 through 33, and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first 2 days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M(1) receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M(2/4) receptor density, an effect mitigated by choline supplementation. In fact, M(2/4) receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems. Copyright © 2012 Wiley Periodicals, Inc.

The Effects of Perinatal Choline Supplementation on Hippocampal Cholinergic Development in Rats Exposed to Alcohol During the Brain Growth Spurt

PubMed Central

Monk, Bradley R.; Leslie, Frances M.; Thomas, Jennifer D.

2012-01-01

Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M1 and M2/4 muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human 3rd trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30-33 and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first two days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M1 receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M2/4 receptor density, an effect mitigated by choline supplementation. In fact, M2/4 receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems. PMID:22431326

Hippocampal Expression of Connexin36 and Connexin43 during Epileptogenesis in Pilocarpine Model of Epilepsy

PubMed Central

Motaghi, Sahel; Sayyah, Mohammad; Babapour, Vahab; Mahdian, Reza

2017-01-01

Background: Gap junctions (GJs) provide direct intercellular communications that are formed by hexameric protein subunits, called connexin (Cx). The role of Cxs in epileptogenesis has not received sufficient attention. Hippocampus with a critical function in epileptogenesis has a wide network of GJs. We examined the protein expression levels of hippocampal Cx36 (the prominent Cx present between GABAergic interneurons) and Cx43 (the main Cx expressed by astrocytes) during epileptogenesis in the pilocarpine model of epilepsy. Methods: Male Wistar rats received scopolamine (1 mg/kg, s.c.). Pilocarpine (380 mg/kg, i.p.) was administered 30 min thereafter to induce status epilepticus (SE). SE was stopped 2 h later by diazepam (10 mg/kg, i.p.). Cx36 and Cx43 protein expression was assessed by Western blot analysis in the hippocampus of SE-experienced rats, after injection of diazepam (F0 subgroup), after acquisition of focal seizures (F3 subgroup), and after development of generalized seizures (F5 subgroup). The control subgroups, C0, C3, and C5, were aged-matched rats, which received saline (1 ml/kg, i.p.) instead of pilocarpine. Injection of scopolamine and diazepam, and dissection of hippocampi were carried out at the same time interval as the test subgroups. Results: SE emerged in 67.1% of pilocarpine-treated animals. Focal and generalized seizures developed 3.8±0.4 and 7.0±0.5 days after SE, respectively. Cx36 protein abundance was not significantly different between test and control groups in the three time points. However, Cx43 protein level showed 40% increase in F3 subgroup (P<0.05 compared to C3, P<0.01 compared to F0 and F5). Conclusion: Hippocampal Cx43 is overexpressed in pilocarpine model of epileptogenesis after acquisition of focal seizures. PMID:28042145

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...

Xenon neurotoxicity in rat hippocampal slice cultures is similar to isoflurane and sevoflurane.

PubMed

Brosnan, Heather; Bickler, Philip E

2013-08-01

Anesthetic neurotoxicity in the developing brain of rodents and primates has raised concern. Xenon may be a nonneurotoxic alternative to halogenated anesthetics, but its toxicity has only been studied at low concentrations, where neuroprotective effects predominate in animal models. An equipotent comparison of xenon and halogenated anesthetics with respect to neurotoxicity in developing neurons has not been made. Organotypic hippocampal cultures from 7-day-old rats were exposed to 0.75, 1, and 2 minimum alveolar concentrations (MAC) partial pressures (60% xenon at 1.2, 2.67, and 3.67 atm; isoflurane at 1.4, 1.9, and 3.8%; and sevoflurane at 3.4 and 6.8%) for 6 h, at atmospheric pressure or in a pressure chamber. Cell death was assessed 24 h later with fluorojade and fluorescent dye exclusion techniques. Xenon caused death of hippocampal neurons in CA1, CA3, and dentate regions after 1 and 2 MAC exposures, but not at 0.75 MAC. At 1 MAC, xenon increased cell death 40% above baseline (P < 0.01; ANOVA with Dunnett test). Both isoflurane and sevoflurane increased neuron death at 1 but not 2 MAC. At 1 MAC, the increase in cell death compared with controls was 63% with isoflurane and 90% with sevoflurane (both P < 0.001). Pretreatment of cultures with isoflurane (0.75 MAC) reduced neuron death after 1 MAC xenon, isoflurane, and sevoflurane. Xenon causes neuronal cell death in an in vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations. Preconditioning with a subtoxic dose of isoflurane eliminates this toxicity.

Extracellular calcium controls the expression of two different forms of ripple-like hippocampal oscillations.

PubMed

Aivar, Paloma; Valero, Manuel; Bellistri, Elisa; Menendez de la Prida, Liset

2014-02-19

Hippocampal high-frequency oscillations (HFOs) are prominent in physiological and pathological conditions. During physiological ripples (100-200 Hz), few pyramidal cells fire together coordinated by rhythmic inhibitory potentials. In the epileptic hippocampus, fast ripples (>200 Hz) reflect population spikes (PSs) from clusters of bursting cells, but HFOs in the ripple and the fast ripple range are vastly intermixed. What is the meaning of this frequency range? What determines the expression of different HFOs? Here, we used different concentrations of Ca(2+) in a physiological range (1-3 mM) to record local field potentials and single cells in hippocampal slices from normal rats. Surprisingly, we found that this sole manipulation results in the emergence of two forms of HFOs reminiscent of ripples and fast ripples recorded in vivo from normal and epileptic rats, respectively. We scrutinized the cellular correlates and mechanisms underlying the emergence of these two forms of HFOs by combining multisite, single-cell and paired-cell recordings in slices prepared from a rat reporter line that facilitates identification of GABAergic cells. We found a major effect of extracellular Ca(2+) in modulating intrinsic excitability and disynaptic inhibition, two critical factors shaping network dynamics. Moreover, locally modulating the extracellular Ca(2+) concentration in an in vivo environment had a similar effect on disynaptic inhibition, pyramidal cell excitability, and ripple dynamics. Therefore, the HFO frequency band reflects a range of firing dynamics of hippocampal networks.

Resveratrol Ameliorates Tau Hyperphosphorylation at Ser396 Site and Oxidative Damage in Rat Hippocampal Slices Exposed to Vanadate: Implication of ERK1/2 and GSK-3β Signaling Cascades.

PubMed

Jhang, Kyoung A; Park, Jin-Sun; Kim, Hee-Sun; Chong, Young Hae

2017-11-08

The objective of this study was to investigate the effect of resveratrol (a natural polyphenolic phytostilbene) on tau hyperphosphorylation and oxidative damage induced by sodium orthovanadate (Na 3 VO 4 ), the prevalent species of vanadium (vanadate), in rat hippocampal slices. Our results showed that resveratrol significantly inhibited Na 3 VO 4 -induced hyperphosphorylation of tau at the Ser396 (p-S396-tau) site, which is upregulated in the hippocampus of Alzheimer's disease (AD) brains and principally linked to AD-associated cognitive dysfunction. Subsequent mechanistic studies revealed that reduction of ERK1/2 activation was involved in the inhibitory effect of resveratrol by inhibiting the ERK1/2 pathway with SL327 mimicking the aforementioned effect of resveratrol. Moreover, resveratrol potently induced GSK-3β Ser9 phosphorylation and reduced Na 3 VO 4 -induced p-S396-tau levels, which were markedly replicated by pharmacologic inhibition of GSK-3β with LiCl. These results indicate that resveratrol could suppress Na 3 VO 4 -induced p-S396-tau levels via downregulating ERK1/2 and GSK-3β signaling cascades in rat hippocampal slices. In addition, resveratrol diminished the increased extracellular reactive oxygen species generation and hippocampal toxicity upon long-term exposure to Na 3 VO 4 or FeCl 2 . Our findings strongly support the notion that resveratrol may serve as a potential nutraceutical agent for AD.

Effect of dopaminergic drugs on the reserpine-induced lowering of hippocampal theta wave frequency in rats.

PubMed

Nakagawa, T; Ukai, K; Ohyama, T; Gomita, Y; Okamura, H

2000-05-01

The effects of dopaminergic drugs on the lowering of hippocampal theta wave frequency induced by reserpine 1 mg/kg s.c. were examined. Sibutramine (monoamine reuptake inhibitor) 10 mg/kg p.o., methamphetamine (monoamine releaser) 1 mg/kg, quinpirole (dopamine D2 receptor agonist) 10 mg/kg i.p., and SKF 38393 (dopamine D1 receptor agonist) 10 mg/kg i.p. each antagonized the reserpine-induced lowering of hippocampal theta wave frequency in rats. Moreover, the combined administration of SKF 38393 1 mg/kg i.p. and quinpirole 1 mg/kg i.p. synergistically antagonized a reserpine-induced lowering of this frequency. Dosulepin, amitriptyline, and desipramine, which are weak inhibitors of dopamine reuptake, each had little effect on the reserpine-induced lowering of theta wave frequency at a dose of 40 mg/kg p.o. Furthermore, atropine (muscarinic anticholinergic drug) 20 mg/kg p.o. decreased theta wave power in the low-frequency range following a shift to the lower range by reserpine. A positive correlation was observed for each of the above drugs between a reversal of reserpine-induced lowering of theta wave frequency and a reversal of impairment of reserpine-induced conditioned avoidance responses (ACAR) in rats. These results suggest that the reserpine-induced lowering of hippocampal theta wave frequency plays a role in the impairment of reserpine-induced ACAR, and that dopamine D1 and D2 receptors play important roles in antagonizing this lowering of frequency.

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats.

PubMed

Zhang, Xiaosong; Wang, Qi; Wang, Yan; Hu, Jingmin; Jiang, Han; Cheng, Wenwen; Ma, Yuchao; Liu, Mengxi; Sun, Anji; Zhang, Xinxin; Li, Xiaobai

2016-12-01

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile.

PubMed

Zhao, Liqin; O'Neill, Kathleen; Brinton, Roberta Diaz

2006-12-01

The present study sought to determine the characteristics of ICI 182,780 (Faslodex) action in rat primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against neurodegenerative insults associated with Alzheimer's disease and related disorders. Dose-response analyses revealed that ICI 182,780, in a concentration-dependent manner, significantly promoted neuron survival following exposure to either excitotoxic glutamate (200 muM)- or beta-amyloid(1-42) (1.5 muM)-induced neurodegeneration of hippocampal neurons. At a clinically relevant concentration of 50 ng/ml, ICI 182,780 exerted nearly maximal neuroprotection against both insults with efficacy comparable with that induced by the endogenous estrogen 17beta-estradiol. Thereafter, we investigated the impact of 50 ng/ml ICI 182,780 on mechanisms of 17beta-estradiol-inducible neuronal plasticity and neuroprotection. Results of these analyses demonstrated that ICI 182,780 directly induced a series of rapid intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in a pattern comparable with that of 17beta-estradiol. In addition, ICI 182,780 exerted dual regulation of the glutamate-induced rise in [Ca(2+)](i) identical to that induced by 17beta-estradiol. Further analyses demonstrated that ICI 182,780 induced significant activation of extracellular signal-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expression of spinophilin and Bcl-2, with efficacy comparable with neurons treated with 17beta-estradiol. Taken together, results of these in vitro analyses of ICI 182,780 provide direct evidence of an estrogenic agonist profile of ICI 182,780 action in rat hippocampal neurons. Therapeutic development of neuroselective estrogen receptor modulators that mimic ICI 182,780 is discussed with respect to the potential of safe and efficacious alternatives to estrogen therapy for the prevention of postmenopausal cognitive decline and late-onset Alzheimer's disease.

The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.

PubMed

Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L; Alberini, Cristina M; Huntley, George W; Salton, Stephen R J

2008-09-24

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nm), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75(NTR) function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.

The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior Through a BDNF-Dependent Mechanism

PubMed Central

Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L.; Alberini, Cristina M.; Huntley, George W.; Salton, Stephen R. J.

2009-01-01

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, where it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knockout mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and by tPASTOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75NTR function-blocking antiserum, nor by prior tetanic stimulation. Although LTP was normal in slices from VGF knockout mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism, and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior. PMID:18815270

A fraction enriched in rat hippocampal mossy fibre synaptosomes contains trophic activities.

PubMed

Taupin, P; Roisin, M P; Ben-Ari, Y; Barbin, G

1994-06-27

Subcellular fractions prepared from the rat hippocampus, were assessed for the presence of trophic activities. The cytosol of synaptosomal fractions induced mitotic reinitiation of confluent 3T3 fibroblasts. The synaptosomal fraction, enriched in mossy fibre terminals, contained the highest mitotic activity. The mitogenic activity was heat and trypsin sensitive, suggesting that polypeptides are involved. The cytosol of the mossy fibre synaptosomal fraction promoted neuritic outgrowth of PC 12 cells and embryonic hippocampal neurones in primary cultures. These results suggest that mossy fibres contain both mitogenic and neurotrophic activities. These factors could participate in mossy fibre sprouting that occur following brief seizures or experimental lesions.

Fear conditioning is associated with altered integration of PLC and ERK signaling in the hippocampus.

PubMed

Buckley, Colin T; Caldwell, Kevin K

2004-12-01

The extracellular signal-regulated protein kinases (ERKs) are proline-directed, serine/threonine kinases that regulate a variety of cellular functions, including proliferation, differentiation, and plasticity. In the present report, we provide evidence that ERK2 and phosphatidylinositol-specific phospholipase C (PLC)-beta and -gamma isozymes interact in the rat hippocampal formation. We found that anti-PLC-beta1a, -beta2, -beta4, -gamma1 and -gamma2, but not -beta3, immune complexes isolated from rat hippocampal formation postnuclear fractions contain anti-ERK2 immunoreactivity. Further, we show that PLC catalytic activity is associated with anti-ERK2 immunoprecipitates isolated from the hippocampal formation, and that the amount of enzyme activity is significantly increased following fear-conditioned learning. The observed interactions may be mediated by consensus sequences conforming to an ERK2 docking site, termed a D-domain, that we identified in PLC-beta1a, -beta2, -beta4 -gamma1 and -gamma2. Based on these results, we propose that PLC-beta and PLC-gamma isozymes form signaling complexes with ERK2 in rat brain, and these complexes play critical roles in learning and memory, as well as a variety of other neuronal functions.

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

PubMed

Chao, Owen Y; Nikolaus, Susanne; Lira Brandão, Marcus; Huston, Joseph P; de Souza Silva, Maria A

2017-05-01

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl- D -aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component. Copyright © 2017 Elsevier Inc. All rights reserved.

Fish oil modulates glycogen synthase kinase-3 signaling pathway in diabetes-induced hippocampal neurons apoptosis.

PubMed

Sun, Li-Juan; Hou, Xiang-Hong; Xue, Sen-Hai; Yan, Feng; Dai, Yu-Jie; Zhao, Chang-Hai; Wang, Feng; Yang, Rui-Hua

2014-07-29

Previous research has demonstrated that diabetes induces learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. The present study investigated the effects of fish oil supplementation on the neuron apoptosis in the hippocampus of streptozotocin (STZ)-induced diabetes rats, further explored the effect of fish oil on the phosphorylation of protein kinase B and glycogen synthase kinase-3 beta. The effects of diabetes and fish oil treatment on the spatial learning and memory were also evaluated using the Morris Water Maze. STZ-induced diabetes impaired spatial learning and memory of rats, which was associated with the apoptosis of hippocampal neurons and oxidative stress. Fish oil administration ameliorated cognitive deficit, reduced oxidative stress, increased AKT phosphorylation, decreased GSK-3β phosphorylation, and decreased pro-apoptotic molecules expression, which protected the hippocampal neurons from apoptosis in diabetic rats. These results suggested a potential role for fish oil as an adjuvant therapy for the prevention and treatment of diabetic complications. Copyright © 2014 Elsevier B.V. All rights reserved.

[Effect of Moxibustion on Learning-memory Ability and Hippocampal Amyloid beta Protein Overexpression in Mild Cognitive Impairment Rats].

PubMed

Zhu, Cai-feng; Sun, Jian-jian; Han, Wei; Yang, Jun

2016-04-01

To observe the effect of moxibustion of "Baihui" (GV 20), etc. on learning-memory ability, hip- pocampal amyloid beta (AP) protein expression and immune activity in mild cognitive impairment (MCI) rats, so as to reveal its mechanism underlying improving cognitive impairment. A total of 48 SD rats were randomly divided into normal, model, moxibustion, and medication groups (n = 12 in each group). The MCI model was established by intraperitoneal injection of 2 mL mixture solution containing D-galactose (120 mg - kg- - d-) and Sodium Nitrite (90 mg x kg(-1) x d(-1)), once daily for 40 days. Moxibustion (separated by Radix Aconiti Praeparata cake) was applied to "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14) for 20 min, once daily for 2 weeks, with one day's rest between two weeks. The rats of the medication group were given with Nimodipine (2 mg x kg(-1) x d(-1), t.i.d.) by lavage for 2 weeks (except Sundays). The learning-memory ability was detected by Morris maze water swimming tasks. The expression level of hippocampal AP protein was detected by immunohistochemistry, and those of hippocampal presenilin-1 (PS-1) mRNA and cleaving enzyme (BACE-1) mRNA were detected by real time-PCR, and serum IL-6 level was assayed by ELISA. Following modeling, the average escape latency of location navigation tests of Morris maze water swimming tests, the expression levels of hippocampal Abeta protein, PS-1 mRNA and BACE-1 mRNA, and serum IL-6 content were significantly increased in the model group( P<0.01) , while the target-platform crossing times and the percentage of target-quadrant swimming duration of spacial probe trials were remarkably decreased in the model group (P<0.01). After moxibustion, the increased escape latency, hippocampal AP protein, PS-i mHNA and BACE-1 mRNA ex- pression and serum IL-6 content, and the decreased target-platform crossing times and the percentage of target-quadrant swim- ming duration were reversed in both moxibustion and medication groups (P<0.01). The effects of the moxibustion group were obviously superior to those of the medication group in decreasing the escape latency, and in up-regulating the target-platform crossing times, the percentage of target-quadrant swimming duration, and down-regulating hippocampal Abeta protein, PS-1 mHNA and BACE-1 mRNA expression levels and serum IL-6 content (P<0.05). Moxibustion is effective in improving MCI rats' learning-memory ability, which may be associated with its functions in down-regulating the levels of hippocampal Abeta protein, PS-1 mRNA and BACE-1 mRNA expression and serum IL-6 content, possibly by blocking Abeta overexpression-induced inflammation cascade.

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

Coordinated learning of grid cell and place cell spatial and temporal properties: multiple scales, attention and oscillations.

PubMed

Grossberg, Stephen; Pilly, Praveen K

2014-02-05

A neural model proposes how entorhinal grid cells and hippocampal place cells may develop as spatial categories in a hierarchy of self-organizing maps (SOMs). The model responds to realistic rat navigational trajectories by learning both grid cells with hexagonal grid firing fields of multiple spatial scales, and place cells with one or more firing fields, that match neurophysiological data about their development in juvenile rats. Both grid and place cells can develop by detecting, learning and remembering the most frequent and energetic co-occurrences of their inputs. The model's parsimonious properties include: similar ring attractor mechanisms process linear and angular path integration inputs that drive map learning; the same SOM mechanisms can learn grid cell and place cell receptive fields; and the learning of the dorsoventral organization of multiple spatial scale modules through medial entorhinal cortex to hippocampus (HC) may use mechanisms homologous to those for temporal learning through lateral entorhinal cortex to HC ('neural relativity'). The model clarifies how top-down HC-to-entorhinal attentional mechanisms may stabilize map learning, simulates how hippocampal inactivation may disrupt grid cells, and explains data about theta, beta and gamma oscillations. The article also compares the three main types of grid cell models in the light of recent data.

Effects of acute and chronic exposure to both 900 MHz and 2100 MHz electromagnetic radiation on glutamate receptor signaling pathway.

PubMed

Gökçek-Saraç, Çiğdem; Er, Hakan; Kencebay Manas, Ceren; Kantar Gok, Deniz; Özen, Şükrü; Derin, Narin

2017-09-01

To demonstrate the molecular effects of acute and chronic exposure to both 900 and 2100 MHz radiofrequency electromagnetic radiation (RF-EMR) on the hippocampal level/activity of some of the enzymes - including PKA, CaMKIIα, CREB, and p44/42 MAPK - from N-methyl-D-aspartate receptor (NMDAR)-related signaling pathways. Rats were divided into the following groups: sham rats, and rats exposed to 900 and 2100 MHz RF-EMR for 2 h/day for acute (1 week) or chronic (10 weeks), respectively. Western blotting and activity measurement assays were used to assess the level/activity of the selected enzymes. The obtained results revealed that the hippocampal level/activity of selected enzymes was significantly higher in the chronic groups as compared to the acute groups at both 900 and 2100 MHz RF-EMR exposure. In addition, hippocampal level/activity of selected enzymes was significantly higher at 2100 MHz RF-EMR than 900 MHz RF-EMR in both acute and chronic groups. The present study provides experimental evidence that both exposure duration (1 week versus 10 weeks) and different carrier frequencies (900 vs. 2100 MHz) had different effects on the protein expression of hippocampus in Wistar rats, which might encourage further research on protection against RF-EMR exposure.

Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease.

PubMed

Nilsen, Linn Hege; Witter, Menno P; Sonnewald, Ursula

2014-05-01

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer's disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using (1)H- and (13)C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate-glutamine cycle were found in McGill-R-Thy1-APP rats.

Age-dependent effect of high cholesterol diets on anxiety-like behavior in elevated plus maze test in rats

PubMed Central

2014-01-01

Background Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes. Methods Young (3 weeks old) and adult (20 weeks old) rats were given a high cholesterol diet for 8 weeks. The anxiety-like behavior in elevated plus maze test and changes of central neurochemical implicated in anxiety were measured. Results In young rats, high cholesterol diet induced anxiolytic-like behavior, decreased serum corticosterone (CORT), increased hippocampal brain-derived neurotrophic factor (BDNF), increased hippocampal mineralocorticoid receptor (MR) and decreased glucocorticoid receptor (GR). In adult rats, high cholesterol diet induced anxiety-like behavior and increase of serum CORT and decrease of hippocampal BDNF comparing with their respective control group that fed the regular diet. Discussion High cholesterol diet induced age-dependent effects on anxiety-like behavior and central neurochemical changes. High cholesterol diet might affect the central nervous system (CNS) function differently, and resulting in different behavior performance of anxiety in different age period. PMID:25179125

Species and Sex Differences in the Morphogenic Response of Primary Rodent Neurons to 3,3′-Dichlorobiphenyl (PCB 11)

PubMed Central

Sethi, Sunjay; Keil, Kimberly P.

2017-01-01

PCB 11 is an emerging global pollutant that we recently showed promotes axonal and dendritic growth in primary rat neuronal cell cultures. Here, we address the influence of sex and species on neuronal responses to PCB 11. Neuronal morphology was quantified in sex-specific primary hippocampal and cortical neuron-glia co-cultures derived from neonatal C57BL/6J mice and Sprague Dawley rats exposed for 48 h to vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM. Total axonal length was quantified in tau-1 immunoreactive neurons at day in vitro (DIV) 2; dendritic arborization was assessed by Sholl analysis at DIV 9 in neurons transfected with MAP2B-FusRed. In mouse cultures, PCB 11 enhanced dendritic arborization in female, but not male, hippocampal neurons and male, but not female, cortical neurons. In rat cultures, PCB 11 promoted dendritic arborization in male and female hippocampal and cortical neurons. PCB 11 also increased axonal growth in mouse and rat neurons of both sexes and neuronal cell types. These data demonstrate that PCB 11 exerts sex-specific effects on neuronal morphogenesis that vary depending on species, neurite type, and neuronal cell type. These findings have significant implications for risk assessment of this emerging developmental neurotoxicant. PMID:29295518

Species and Sex Differences in the Morphogenic Response of Primary Rodent Neurons to 3,3'-Dichlorobiphenyl (PCB 11).

PubMed

Sethi, Sunjay; Keil, Kimberly P; Lein, Pamela J

2017-12-23

PCB 11 is an emerging global pollutant that we recently showed promotes axonal and dendritic growth in primary rat neuronal cell cultures. Here, we address the influence of sex and species on neuronal responses to PCB 11. Neuronal morphology was quantified in sex-specific primary hippocampal and cortical neuron-glia co-cultures derived from neonatal C57BL/6J mice and Sprague Dawley rats exposed for 48 h to vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM. Total axonal length was quantified in tau-1 immunoreactive neurons at day in vitro (DIV) 2; dendritic arborization was assessed by Sholl analysis at DIV 9 in neurons transfected with MAP2B-FusRed. In mouse cultures, PCB 11 enhanced dendritic arborization in female, but not male, hippocampal neurons and male, but not female, cortical neurons. In rat cultures, PCB 11 promoted dendritic arborization in male and female hippocampal and cortical neurons. PCB 11 also increased axonal growth in mouse and rat neurons of both sexes and neuronal cell types. These data demonstrate that PCB 11 exerts sex-specific effects on neuronal morphogenesis that vary depending on species, neurite type, and neuronal cell type. These findings have significant implications for risk assessment of this emerging developmental neurotoxicant.

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

PubMed Central

2017-01-01

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71) nor due to the delay after the last stimulation dose (p = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200 μs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain. PMID:29065603

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

PubMed

Mucio-Ramírez, Samuel; Makeyev, Oleksandr

2017-01-01

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats ( n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals ( p  = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses ( p  = 0.71) nor due to the delay after the last stimulation dose ( p  = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200  μ s, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

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

Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.

PubMed

Haus, Daniel L; López-Velázquez, Luci; Gold, Eric M; Cunningham, Kelly M; Perez, Harvey; Anderson, Aileen J; Cummings, Brian J

2016-07-01

Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinson's rats.

PubMed

Cho, Han-Sam; Shin, Mal-Soon; Song, Wook; Jun, Tae-Won; Lim, Baek-Vin; Kim, Young-Pyo; Kim, Chang-Ju

2013-01-01

Progressive loss of dopaminergic neurons in substantia nigra is a key pathogenesis of Parkinson's disease. In the present study, we investigated the effects of treadmill exercise on short-term memory, apoptotic dopaminergic neuronal cell death and fiber loss in the nigrostriatum, and cell proliferation in the hippocampal dentate gyrus of Parkinson's rats. Parkinson's rats were made by injection of 6-hydroxydopamine (6-OHDA) into the striatum using stereotaxic instrument. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection group exhibited significant rotational asymmetry following apomorphine challenge. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the present results, extensive degeneration of the dopaminergic neurons in the substantia nigra with loss of dopaminergic fibers in the striatum were produced in the rats without treadmill running, which resulted in short-term memory impairment. However, the rats performing treadmill running for 2 weeks alleviated nigrostriatal dopaminergic cell loss and alleviated short-term memory impairment with increasing cell proliferation in the hippocampal dentate gyrus of Parkinson's rats. The present results show that treadmill exercise may provide therapeutic value for the Parkinson's disease.

Functional MRI during Hippocampal Deep Brain Stimulation in the Healthy Rat Brain.

PubMed

Van Den Berge, Nathalie; Vanhove, Christian; Descamps, Benedicte; Dauwe, Ine; van Mierlo, Pieter; Vonck, Kristl; Keereman, Vincent; Raedt, Robrecht; Boon, Paul; Van Holen, Roel

2015-01-01

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS.

Functional MRI during Hippocampal Deep Brain Stimulation in the Healthy Rat Brain

PubMed Central

Van Den Berge, Nathalie; Vanhove, Christian; Descamps, Benedicte; Dauwe, Ine; van Mierlo, Pieter; Vonck, Kristl; Keereman, Vincent; Raedt, Robrecht; Boon, Paul; Van Holen, Roel

2015-01-01

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS. PMID:26193653

Hippocampal Synaptic Expansion Induced by Spatial Experience in Rats Correlates with Improved Information Processing in the Hippocampus.

PubMed

Carasatorre, Mariana; Ochoa-Alvarez, Adrian; Velázquez-Campos, Giovanna; Lozano-Flores, Carlos; Ramírez-Amaya, Víctor; Díaz-Cintra, Sofía Y

2015-01-01

Spatial water maze (WM) overtraining induces hippocampal mossy fiber (MF) expansion, and it has been suggested that spatial pattern separation depends on the MF pathway. We hypothesized that WM experience inducing MF expansion in rats would improve spatial pattern separation in the hippocampal network. We first tested this by using the the delayed non-matching to place task (DNMP), in animals that had been previously trained on the water maze (WM) and found that these animals, as well as animals treated as swim controls (SC), performed better than home cage control animals the DNMP task. The "catFISH" imaging method provided neurophysiological evidence that hippocampal pattern separation improved in animals treated as SC, and this improvement was even clearer in animals that experienced the WM training. Moreover, these behavioral treatments also enhance network reliability and improve partial pattern separation in CA1 and pattern completion in CA3. By measuring the area occupied by synaptophysin staining in both the stratum oriens and the stratun lucidum of the distal CA3, we found evidence of structural synaptic plasticity that likely includes MF expansion. Finally, the measures of hippocampal network coding obtained with catFISH correlate significantly with the increased density of synaptophysin staining, strongly suggesting that structural synaptic plasticity in the hippocampus induced by the WM and SC experience is related to the improvement of spatial information processing in the hippocampus.

EPO improved neurologic outcome in rat pups late after traumatic brain injury.

PubMed

Schober, Michelle E; Requena, Daniela F; Rodesch, Christopher K

2018-05-01

In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Western Diet and the Weakening of the Interoceptive Stimulus Control of Appetitive Behavior

PubMed Central

Sample, Camille H.; Jones, Sabrina; Hargrave, Sara L.; Jarrard, Leonard E.; Davidson, Terry L.

2017-01-01

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0 ug but not 2.0 or 4.0 ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus. PMID:27312269

Inhibition of p38 mitogen-activated protein kinase signaling reduces multidrug transporter activity and anti-epileptic drug resistance in refractory epileptic rats.

PubMed

Shao, Yiye; Wang, Cuicui; Hong, Zhen; Chen, Yinghui

2016-03-01

It is widely recognized that P-glycoprotein (P-gp) mediates drug resistance in refractory epilepsy. However, the molecular mechanism underlying the up-regulation of P-gp expression remains unclear. Our previous studies have demonstrated that p38 mitogen-activated protein kinase (MAPK) regulates P-gp expression in cultured K562 cells. However, a lack of in vivo research leaves unanswered questions regarding whether p38MAPK regulates P-gp expression or drug resistance in refractory epilepsy. This in vivo study examined the effects of p38MAPK on the expression of P-gp and mdr1 in the rat brain and quantified antiepileptic drug (AED) concentrations in the hippocampal extracellular fluid. In addition, the role of p38MAPK in electrical and behavioral activity in a rat epilepsy model was studied. The results indicated that p38MAPK inhibition by SB202190 reduced P-gp expression, while increasing AED concentration in the hippocampal extracellular fluid in refractory epileptic rats. SB202190 also reduced the resistance to AEDs in drug-resistant rats and significantly reduced the severity of seizure activity. These results suggest that p38MAPK could participate in drug resistance in refractory epilepsy through the regulation of P-gp. We show that the specific inhibitor of p38MAPK could down-regulate the expression of multidrug transporter (P-glycoprotein) in blood-brain barrier, increase the concentration of antiepileptic drugs in the hippocampal extracellular fluid and reduce anti-epileptic drug resistance in refractory epileptic rats. We propose that the p38MAPK signaling pathway participates in drug resistance in refractory epilepsy through the regulation of P-glycoprotein expression. © 2015 International Society for Neurochemistry.

Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus☆

PubMed Central

Duffy, B.A.; Chun, K.P.; Ma, D.; Lythgoe, M.F.; Scott, R.C.

2014-01-01

Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10 mg/kg or 2 mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2 mg/kg and 10 mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus. PMID:24333865

Effects of continuous vs. cycling estrogen replacement on the acquisition, retention and expression of place- and response-learning in the open-field tower maze.

PubMed

Lipatova, Olga; Byrd, Dennis; Green, John T; Toufexis, Donna J

2014-10-01

Estrogen has been shown to either enhance or impair learning and memory in female rats. The use of different experimental paradigms or estrogen treatment regimens may contribute to these disparate findings. In order to assess the effect of different estradiol (E2) treatments on several aspects of cognition, we trained ovariectomized female rats with either continuous, cycling, or vehicle E2 replacement, in an open-field tower maze task (OFTM) designed to test reference memory in a low-stress environment. In addition, in order to compare two distinct learning and memory systems, rats were trained to use either a dorsolateral striatum-based response type learning or a hippocampal-based place type learning to solve the maze. Results showed that cyclic, but not continuous, E2 replacement facilitated the acquisition of spatial memory in place-learners. Neither E2 regimen affected acquisition in response-learners. Additionally, when all experimental groups were performing at asymptote, rats were evaluated for performance stability by changing the location of their start position in the OFTM. Both regimens of E2 disrupted the expression of spatial memory in place-learners following the novel start position. However, E2 replacement protected ovariectomized female rats from the disruption of memory expression following a start position change in response-learners. Additionally all experimental groups performed equally well when tested following a 21-day period during which rats were absent from the maze. These results suggest that E2 fluctuation is particularly important in the acquisition of hippocampal-mediated spatial learning, and that hippocampal-based memory may be subject to disruption following environmental change, while striatum-based memory is subject to protection. Copyright © 2014 Elsevier Inc. All rights reserved.

Differential Arc expression in the hippocampus and striatum during the transition from attentive to automatic navigation on a plus maze

PubMed Central

Gardner, Robert S.; Suarez, Daniel F.; Robinson-Burton, Nadira K.; Rudnicky, Christopher J.; Gulati, Asish; Ascoli, Giorgio A.; Dumas, Theodore C.

2016-01-01

The strategies utilized to effectively perform a given task change with practice and experience. During a spatial navigation task, with relatively little training, performance is typically attentive enabling an individual to locate the position of a goal by relying on spatial landmarks. These (place) strategies require an intact hippocampus. With task repetition, performance becomes automatic; the same goal is reached using a fixed response or sequence of actions. These (response) strategies require an intact striatum. The current work aims to understand the activation patterns across these neural structures during this experience-dependent strategy transition. This was accomplished by region-specific measurement of activity-dependent immediate early gene expression among rats trained to different degrees on a dual-solution task (i.e., a task that can be solved using either place or response navigation). As expected, rats increased their reliance on response navigation with extended task experience. In addition, dorsal hippocampal expression of the immediate early gene Arc was considerably reduced in rats that used a response strategy late in training (as compared with hippocampal expression in rats that used a place strategy early in training). In line with these data, vicarious trial and error, a behavior linked to hippocampal function, also decreased with task repetition. Although Arc mRNA expression in dorsal medial or lateral striatum alone did not correlate with training stage, the ratio of expression in the medial striatum to that in the lateral striatum was relatively high among rats that used a place strategy early in training as compared with the ratio among over-trained response rats. Altogether, these results identify specific changes in the activation of dissociated neural systems that may underlie the experience-dependent emergence of response-based automatic navigation. PMID:26976088

Modulation of Hippocampal Theta Oscillations and Spatial Memory by Relaxin-3 Neurons of the Nucleus Incertus

ERIC Educational Resources Information Center

Ma, Sherie; Olucha-Bordonau, Francisco E.; Hossain, M. Akhter; Lin, Feng; Kuei, Chester; Liu, Changlu; Wade, John D.; Sutton, Steven W.; Nunez, Angel; Gundlach, Andrew L.

2009-01-01

Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the…

Remodeling of Hippocampal Mossy Fibers Is Selectively Induced Seven Days after the Acquisition of a Spatial but Not a Cued Reference Memory Task

ERIC Educational Resources Information Center

Rekart, Jerome L.; Sandoval, C. Jimena; Bermudez-Rattoni, Federico; Routtenberg, Aryeh

2007-01-01

Relating storage of specific information to a particular neuromorphological change is difficult because behavioral performance factors are not readily disambiguated from underlying cognitive processes. This issue is addressed here by demonstrating robust reorganization of the hippocampal mossy fiber terminal field (MFTF) when adult rats learn the…

Discharge properties of hippocampal neurons during performance of a jump avoidance task

PubMed Central

Lenck-Santini, Pierre-Pascal; Fenton, André A.; Muller, Robert U.

2008-01-01

We recorded single hippocampal cells while rats performed a jump avoidance task. In this task, a rat was dropped onto the metal floor of a 33 cm gray wooden cube and was given a mild electric shock if it did not jump up onto the box rim in less than 15 sec. We found that many hippocampal pyramidal cells and most interneurons discharged preferentially at either the drop, the jump or on both events. By simultaneously recording the hippocampal EEG, we found that the discharge of most of the event-related pyramidal cells was modulated by the theta rhythm and moreover that discharge precessed with theta cycles in the same fashion seen for pyramidal cells in their role as place cells. The elevations of firing rate at drop and jump were accompanied by increases in theta frequency. We conclude that many of the features of event-related discharge can be interpreted as being equivalent to the activity of place cells with firing fields above the box floor. Nevertheless, there are sufficient differences between expectations from place cells and observed activity to indicate that pyramidal cells may be able to signal events as well as location. PMID:18596153

HSP70 protects rats and hippocampal neurons from central nervous system oxygen toxicity by suppression of NO production and NF-κB activation.

PubMed

Yi, Hongjie; Huang, Guoyang; Zhang, Kun; Liu, Shulin; Xu, Weigang

2018-05-01

During diving, central nervous system oxygen toxicity may cause drowning or barotrauma, which has dramatically limited the working benefits of hyperbaric oxygen in underwater operations and clinical applications. The aim of this study is to understand the effects and the underlying mechanism of heat shock protein 70 on central nervous system oxygen toxicity and its mechanisms in vivo and in vitro. Rats were given geranylgeranylacetone (800 mg/kg) orally to induce hippocampal expression of heat shock protein 70 and then treated with hyperbaric oxygen. The time course of hippocampal heat shock protein 70 expression after geranylgeranylacetone administration was measured. Seizure latency and first electrical discharge were recorded to evaluate the effects of HSP70 on central nervous system oxygen toxicity. Effects of inhibitors of nitric oxide synthase and nuclear factor-κB on the seizure latencies and changes in nitric oxide, nitric oxide synthase, and nuclear factor-κB levels in the hippocampus tissues were examined. In cell experiments, hippocampal neurons were transfected with a virus vector carrying the heat shock protein 70 gene (H3445) before hyperbaric oxygen treatment. Cell viability, heat shock protein 70 expression, nitric oxide, nitric oxide synthase, and NF-κB levels in neurons were measured. The results showed that heat shock protein 70 expression significantly increased and peaked at 48 h after geranylgeranylacetone was given. Geranylgeranylacetone prolonged the first electrical discharge and seizure latencies, which was reversed by neuronal nitric oxide synthase, inducible nitric oxide synthase and NF-κB inhibitors. Nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels in the hippocampus were significantly increased after hyperbaric oxygen exposure, but reversed by geranylgeranylacetone, while heat shock protein 70 inhibitor quercetin could inhibit this effect of geranylgeranylacetone. In the in vitro study, heat shock protein 70-overexpression decreased the nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels as well as the cytoplasm/nucleus ratio of nuclear factor-κB and protected neurons from hyperbaric oxygen-induced cell injury. In conclusion, overexpression of heat shock protein 70 in hippocampal neurons may protect rats from central nervous system oxygen toxicity by suppression of neuronal nitric oxide synthase and inducible nitric oxide synthase-mediated nitric oxide production and translocation of nuclear factor-κB to nucleus. Impact statement Because the pathogenesis of central nervous system oxygen toxicity (CNS-OT) remains unclear, there are few interventions available. To develop an efficient strategy against CNS-OT, it is necessary to understand its pathogenesis and in particular, the relevant key factors involved. This study examined the protective effects of heat shock protein 70 (HSP70) on CNS-OT via in vivo and in vitro experiments. Our results indicated that overexpression of HSP70 in hippocampal neurons may protect rats from CNS-OT by suppression of nNOS and iNOS-mediated NO production and the activation of NF-κB. These findings contribute to clarification of the role of HSP70 in CNS-OT and provide us a potential novel target to prevent CNS-OT. Clarification of the involvement of NO, NOS and NF-κB provides new insights into the mechanism of CNS-OT and may help us to develop new approach against it by interfering these molecules.

Biphasic effect of citral, a flavoring and scenting agent, on spatial learning and memory in rats.

PubMed

Yang, Zheqiong; Xi, Jinlei; Li, Jihong; Qu, Wen

2009-10-01

Although some central effects of citral have been reported, cognitive effects on spatial memory have not been investigated. The evidence showed that citral can regulate the synthesis of retinoic acid (RA), which exerts a vital function in the development and maintenance of spatial memory. In this study, we applied Morris water maze to test the effect of citral on animals' spatial learning and memory. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in rats' hippocampus by high performance liquid chromatography (HPLC). Our data implied biphasic effects of citral. The low dose (0.1 mg/kg) of citral improved the spatial learning capability, and enhanced the spatial reference memory of rats, whereas the high dose (1.0 mg/kg) was like to produce the opposite effects. Meanwhile, the low dose of citral increased the hippocampal retinoic acid concentration, while the high dose decreased it. Due to the quick elimination and non-bioaccumulation in the body, effects of citral on spatial memory in this study seemed to be indirect actions. The change in hippocampal retinoic acid concentration induced by different doses of citral might be responsible for the biphasic effect of citral on spatial learning and memory.

Voluntary Running Exercise-Mediated Enhanced Neurogenesis Does Not Obliterate Retrograde Spatial Memory.

PubMed

Kodali, Maheedhar; Megahed, Tarick; Mishra, Vikas; Shuai, Bing; Hattiangady, Bharathi; Shetty, Ashok K

2016-08-03

Running exercise (RE) improves cognition, formation of anterograde memories, and mood, alongside enhancing hippocampal neurogenesis. A previous investigation in a mouse model showed that RE-induced increased neurogenesis erases retrograde memory (Akers et al., 2014). However, it is unknown whether RE-induced forgetting is common to all species. We ascertained whether voluntary RE-induced enhanced neurogenesis interferes with the recall of spatial memory in rats. Young rats assigned to either sedentary (SED) or running exercise (RE) groups were first subjected to eight learning sessions in a water maze. A probe test (PT) conducted 24 h after the final training session confirmed that animals in either group had a similar ability for the recall of short-term memory. Following this, rats in the RE group were housed in larger cages fitted with running wheels, whereas rats in the SED group remained in standard cages. Animals in the RE group ran an average of 78 km in 4 weeks. A second PT performed 4 weeks after the first PT revealed comparable ability for memory recall between animals in the RE and SED groups, which was evidenced through multiple measures of memory retrieval function. The RE group displayed a 1.5- to 2.1-fold higher hippocampal neurogenesis than SED rats. Additionally, both moderate and brisk RE did not interfere with the recall of memory, although increasing amounts of RE proportionally enhanced neurogenesis. In conclusion, RE does not impair memory recall ability in a rat model despite substantially increasing neurogenesis. Running exercise (RE) improves new memory formation along with an increased neurogenesis in the hippocampus. In view of a recent study showing that RE-mediated increased hippocampal neurogenesis promotes forgetfulness in a mouse model, we ascertained whether a similar adverse phenomenon exists in a rat model. Memory recall ability examined 4 weeks after learning confirmed that animals that had run a mean of 78 km and displayed a 1.5- to 2.1-fold increase in hippocampal neurogenesis demonstrated similar proficiency for memory recall as animals that had remained sedentary. Furthermore, both moderate and brisk RE did not interfere with memory recall, although increasing amounts of RE proportionally enhanced neurogenesis, implying that RE has no adverse effects on memory recall. Copyright © 2016 the authors 0270-6474/16/368112-11$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

Effects of Chronic Fluoxetine Treatment on Neurogenesis and Tryptophan Hydroxylase Expression in Adolescent and Adult Rats

PubMed Central

Meerhoff, Gideon F.

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population. PMID:24827731

Early and sustained exposure to high-sucrose diet triggers hippocampal ER stress in young rats.

PubMed

Pinto, Bruno Araújo Serra; Melo, Thamys Marinho; Flister, Karla Frida Torres; França, Lucas Martins; Kajihara, Daniela; Tanaka, Leonardo Yuji; Laurindo, Francisco Rafael Martins; Paes, Antonio Marcus de Andrade

2016-08-01

Early-life environmental insults have been shown to promote long-term development of chronic non-communicable diseases, including metabolic disturbances and mental illnesses. As such, premature consumption of high-sugar foods has been associated to early onset of detrimental outcomes, whereas underlying mechanisms are still poorly understood. In the present study, we sought to investigate whether early and sustained exposure to high-sucrose diet promotes metabolic disturbances that ultimately might anticipate neurological injuries. At postnatal day 21, weaned male rats started to be fed a standard chow (10 % sucrose, CTR) or a high-sucrose diet (25 % sucrose, HSD) for 9 weeks prior to euthanasia at postnatal day 90. HSD did not alter weight gain and feed efficiency between groups, but increased visceral, non-visceral and brown adipose tissue accumulation. HSD rats demonstrated elevated blood glucose levels in both fasting and fed states, which were associated to impaired glucose tolerance. Peripheral insulin sensitivity did not change, whereas hepatic insulin resistance was supported by increased serum triglyceride levels, as well as higher TyG index values. Assessment of hippocampal gene expression showed endoplasmic reticulum (ER) stress pathways were activated in HSD rats, as compared to CTR. HSD rats had overexpression of unfolded protein response sensors, PERK and ATF6; ER chaperone, PDIA2 and apoptosis-related genes, CHOP and Caspase 3; but decreased expression of chaperone GRP78. Finally, HSD rats demonstrated impaired neuromuscular function and anxious behavior, but preserved cognitive parameters. In conclusion, our data indicate that early exposure to HSD promote metabolic disturbances, which disrupt hippocampus homeostasis and might precociously affect its neurobehavioral functions.

Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

PubMed

Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

PubMed

Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

2016-09-01

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Effect of Gallic Acid on Dementia Type of Alzheimer Disease in Rats: Electrophysiological and Histological Studies.

PubMed

Hajipour, Somayeh; Sarkaki, Alireza; Farbood, Yaghoob; Eidi, Akram; Mortazavi, Pejman; Valizadeh, Zohreh

2016-04-01

To study the effect of gallic acid (GA) on hippocampal long-term potentiation (LTP) and histological changes in animal model of Alzheimer disease (AD) induced by beta-amyloid (Aβ). Sixty-four adult male Wistar rats (300±20 g) were divided into 8 groups: 1) Control (Cont); 2) AD; 3) Sham; 4-7) AD+GA (50, 100, and 200 mg/kg for 10 days, orally) or vehicle, 8) Cont+GA100, Aβ (1μg/μL in each site) was infused into hippocampus bilaterally. Changes of amplitude and slope of LTP induced in hippocampal dentate gyrus (DG) were evaluated by high frequency stimulation (HFS) of perforant path (PP). Data showed that LTP amplitude and area under curve significantly impaired in AD rats (P<0.001), while significantly improved in AD rats treated with GA (P<0.05, P<0.01). Current findings suggest that GA reduces neural damage and brain amyloid neuropathology and improves cognitive function via free radicals scavenging and inhibiting oligomerization of Aβ but with no effect on healthy rats.

LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats.

PubMed

Warren, S G; Humphreys, A G; Juraska, J M; Greenough, W T

1995-12-12

Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 stratum radiatum decreases more than 30% between the proestrus (high estrogen) and estrus (low estrogen) phases of the rat estrous cycle [10,27]. In the present study, we investigated whether hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), might also vary across the estrous cycle of the female rat. Male rats, and female rats at each phase of the estrous cycle were tested in either the morning or afternoon. There were no significant group differences in the pre-LTP I/O curves. However, females examined during the afternoon of proestrus, the phase during which prior studies indicate synapse number to be highest, demonstrated the greatest degree of potentiation. Diestrus, proestrus and estrus females tested in the morning demonstrated similar amounts of potentiation. There were also significant differences in post-LTP I/O curves between the afternoon proestrus females and males tested in the afternoon. These results suggest that gonadal hormones, interacting with the time of day, may regulate neural processes underlying learning and memory.

Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats.

PubMed

Chaalal, Amina; Poirier, Roseline; Blum, David; Laroche, Serge; Enderlin, Valérie

2018-05-23

Hypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism.

MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis.

PubMed

Sun, Zu-Zhen; Lv, Zhan-Yun; Tian, Wen-Jing; Yang, Yan

2017-09-01

Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.

Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression

PubMed Central

Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L.; Szigeti-Buck, Klara; Sallam, Nermin L.; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S.

2009-01-01

Background Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. Methods We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Results Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for six days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared to nonstressed controls. Shorter, one-day or three-day desipramine treatments, however, had neither synaptic nor behavioral effects. Conclusions These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression. PMID:19006787

KCNQ/Kv7 channel activator flupirtine protects against acute stress-induced impairments of spatial memory retrieval and hippocampal LTP in rats.

PubMed

Li, C; Huang, P; Lu, Q; Zhou, M; Guo, L; Xu, X

2014-11-07

Spatial memory retrieval and hippocampal long-term potentiation (LTP) are impaired by stress. KCNQ/Kv7 channels are closely associated with memory and the KCNQ/Kv7 channel activator flupirtine represents neuroprotective effects. This study aims to test whether KCNQ/Kv7 channel activation prevents acute stress-induced impairments of spatial memory retrieval and hippocampal LTP. Rats were placed on an elevated platform in the middle of a bright room for 30 min to evoke acute stress. The expression of KCNQ/Kv7 subunits was analyzed at 1, 3 and 12 h after stress by Western blotting. Spatial memory was examined by the Morris water maze (MWM) and the field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 area was recorded in vivo. Acute stress transiently decreased the expression of KCNQ2 and KCNQ3 in the hippocampus. Acute stress impaired the spatial memory retrieval and hippocampal LTP, the KCNQ/Kv7 channel activator flupirtine prevented the impairments, and the protective effects of flupirtine were blocked by XE-991 (10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone), a selective KCNQ channel blocker. Furthermore, acute stress decreased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 in the hippocampus, and flupirtine inhibited the reduction. These results suggest that the KCNQ/Kv7 channels may be a potential target for protecting both hippocampal synaptic plasticity and spatial memory retrieval from acute stress influences. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Hippocampus, perirhinal cortex, and complex visual discriminations in rats and humans

PubMed Central

Hales, Jena B.; Broadbent, Nicola J.; Velu, Priya D.

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 perirhinal lesions were impaired and did not exhibit the normal preference for exploring the odd object. Notably, rats with hippocampal lesions exhibited the same impairment. Thus, the deficit is unlikely to illuminate functions attributed specifically to perirhinal cortex. Both lesion groups were able to acquire visual discriminations involving the same objects used in the oddity task. Patients with hippocampal damage or larger medial temporal lobe lesions were intact in a similar oddity task that allowed participants to explore objects quickly using eye movements. We suggest that humans were able to rely on an intact working memory capacity to perform this task, whereas rats (who moved slowly among the objects) needed to rely on long-term memory. PMID:25593294

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.

The Neonatal Ventral Hippocampal Lesion (NVHL) Rodent Model of Schizophrenia

PubMed Central

Brady, Anne Marie

2016-01-01

Animal models are crucial to the study of the neurobiological bases of psychiatric disorders, but schizophrenia is a particularly challenging disorder to model given the complexity and heavily verbal nature of its symptoms. This article describes a developmental surgical rodent model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. This widely used model produces reliable behavioral abnormalities that are comparable to those observed in patients, as well as anatomical and neurophysiological disruptions in forebrain areas that are also implicated in schizophrenia. A brief background of the development and validity of the NVHL model is discussed here, along with detailed procedures for producing the model in rats. Critical issues particular to neonatal surgery are discussed, and representative histological and behavioral results are presented. PMID:27696361

Schemas and memory consolidation.

PubMed

Tse, Dorothy; Langston, Rosamund F; Kakeyama, Masaki; Bethus, Ingrid; Spooner, Patrick A; Wood, Emma R; Witter, Menno P; Morris, Richard G M

2007-04-06

Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation.

GABA function may be related to the impairment of learning and memory caused by systemic prenatal hypoxia-ischemia.

PubMed

Cunha-Rodrigues, Marta Cristina; Balduci, Cassiana Thayara do Nascimento; Tenório, Frank; Barradas, Penha Cristina

2018-03-01

Intrauterine adverse conditions may be responsible for long-lasting damages which impact health even during adult phase. Hypoxic-ischemic (HI) events are a relevant cause of newborn mortality and the principal factor leading to permanent brain lesions. Using a model in which the ovarian and uterine flux of a pregnant rat is obstructed for 45 min we have described oligodendrocyte death, astrogliosis and neuronal loss. In this work we investigated hippocampal neuronal population and performed a functional evaluation of memory and learning of young rats that had been affected by prenatal HI. Anesthetized Wistar rats on the 18th gestation day had the uterine horns exposed and the ovarian and uterine arteries clamped for 45 min (HI group). Sham-operated rats (SH group) had the horns exposed but no arteries were clamped. We measured the levels of different proteins related to excitatory/inhibitory transmission in the hippocampi of young pups (P45). Histological evaluation was also performed in order to characterize hippocampal neuronal population. Rats from both groups were tested through Novel Object Recognition Test (NORT) using two inter-trial intervals: 5 min and 8 h. Here we show a loss in the total number of hippocampal neurons although the immunostaining of parvalbumin and levels of GAD enzyme were increased in HI group. Functional assessment indicated a marked difference concerning HI learning and memory abilities. Our results reflect permanent damages concerning GABA function which may disturb neurotransmitter homeostasis leading to the observed deficits in learning and memory. Copyright © 2018 Elsevier Inc. All rights reserved.

Daily Access to Sucrose Impairs Aspects of Spatial Memory Tasks Reliant on Pattern Separation and Neural Proliferation in Rats

ERIC Educational Resources Information Center

Reichelt, Amy C.; Morris, Margaret J.; Westbrook, Reginald Frederick

2016-01-01

High sugar diets reduce hippocampal neurogenesis, which is required for minimizing interference between memories, a process that involves "pattern separation." We provided rats with 2 h daily access to a sucrose solution for 28 d and assessed their performance on a spatial memory task. Sucrose consuming rats discriminated between objects…

Object/Context-Specific Memory Deficits Associated with Loss of Hippocampal Granule Cells after Adrenalectomy in Rats

ERIC Educational Resources Information Center

Spanswick, Simon C.; Sutherland, Robert J.

2010-01-01

Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the dentate gyrus (DG) of the rat. Here, we administered replacement corticosterone to rats beginning 10 wk after ADX. We then tested them in three discrimination tasks based on object novelty, location, or object/context association. Only during testing of the…

Antiamnesic and Antioxidants Effects of Ferulago angulata Essential Oil Against Scopolamine-Induced Memory Impairment in Laboratory Rats.

PubMed

Hritcu, Lucian; Bagci, Eyup; Aydin, Emel; Mihasan, Marius

2015-09-01

Ferulago angulata (Apiaceae) is a shrub indigenous to western Iran, Turkey and Iraq. In traditional medicine, F. angulata is recommended for treating digestive pains, hemorrhoids, snake bite, ulcers and as sedative. In the present study, the effects of inhaled F. angulata essential oil (1 and 3%, daily, for 21 days) on spatial memory performance were assessed in scopolamine-treated rats. Scopolamine-induced memory impairments were observed, as measured by the Y-maze and radial arm-maze tasks. Decreased activities of superoxide dismutase, glutathione peroxidase and catalase along with increase of acetylcholinesterase activity and decrease of total content of reduced glutathione were observed in the rat hippocampal homogenates of scopolamine-treated animals as compared with control. Production of protein carbonyl and malondialdehyde significantly increased in the rat hippocampal homogenates of scopolamine-treated animals as compared with control, as a consequence of impaired antioxidant enzymes activities. Additionally, in scopolamine-treated rats exposure to F. angulata essential oil significantly improved memory formation and decreased oxidative stress, suggesting memory-enhancing and antioxidant effects. Therefore, our results suggest that multiple exposures to F. angulata essential oil ameliorate scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

Chewing rescues stress-suppressed hippocampal long-term potentiation via activation of histamine H1 receptor.

PubMed

Ono, Yumie; Kataoka, Tsuyoshi; Miyake, Shinjiro; Sasaguri, Kenichi; Sato, Sadao; Onozuka, Minoru

2009-08-01

We have previously found in rats that chewing, an active behavioral strategy to cope with a stressful situation, rescues long-term potentiation (LTP) in the hippocampus through activating stress-suppressed N-methyl-D-aspartate (NMDA) receptor function. To further examine the mechanisms underlying this ameliorative effect of chewing, we studied the involvement of the histaminergic system, which has been shown to be activated by mastication, in the LTP of hippocampal slices of rats that were allowed to chew a wooden stick during exposure to immobilization stress. Chewing failed to rescue stress-suppressed LTP in the rats treated with histamine H1 receptor (H1R) antagonist pyrilamine (5 mg/kg, i.p.) before exposure to stress, although administration of pyrilamine did not affect LTP in naive rats and in stressed rats that did not chew. However, when pyrilamine was administrated immediately after exposure to stress, chewing rescued LTP whose magnitude was statistically comparable to that in the rats that chewed without drug treatment. These results suggest that chewing-induced histamine release in the hippocampus and the subsequent H1 receptor activation may be essential to rescue stress-suppressed synaptic plasticity.

[Neuroprotective effect of naloxone in brain damage caused by repeated febrile seizure].

PubMed

Shan, Ying; Qin, Jiong; Chang, Xing-zhi; Yang, Zhi-xian

2004-04-01

The brain damage caused by repeated febrile seizure (FS) during developing age is harmful to the intellectual development of children. So how to decrease the related damage is a very important issue. The main purpose of the present study was to find out whether the non-specific opiate antagonist naloxone at low dose has the neuroprotective effect on seizure-induced brain damage. Warm water induced rat FS model was developed in this study. Forty-seven rats were randomly divided into two groups: normal control group (n = 10) and hyperthermic seizure groups (n = 37). The latter was further divided into FS control group (n = 13) and naloxone-treated group (n = 24). The dose of naloxone is different in two naloxone-treated groups (12/each group), in one group the dose was 1 mg/kg, in the other one 2 mg/kg. Seven febrile seizures were induced in each rat of hyperthermic seizure groups with the interval of 2 days. The rats were weighed and injected intraperitoneally with naloxone once the FS occurred in naloxone-treated group, while the rats of the other groups were injected with 0.9% sodium chloride. Latency, duration and grade of FS in different groups were observed and compared. HE-staining and the electron microscopy (EM) were used to detect the morphologic and ultrastructural changes of hippocampal neurons. In naloxone-treated group, the rats' FS duration and FS grade (5.02 +/- 0.63, 2.63 +/- 0.72) were significantly lower (t = 5.508, P < 0.01; t = 8.439, P < 0.01) than those in FS control group (7.70 +/- 2.25 min, 4.52 +/- 0.49), although no significant gap was observed on FS latency between them. In FS control group, HE-staining pattern of hippocampal CA(1) and CA(2) showed lots of disordered neurons with confused polarity and vacuoles formed. Nuclei were with various size, some rounded and some oblong. While in naloxone-treated groups, the arrangement of neurons was regular, only a small quantity of neurons had changed polarity and vacuoles formed. Most nuclei were oblong and in the same size. In hippocampal CA(1) region and dentate gyrus of rats from FS control group, EM showed that the most mitochondrion volumes obviously increased with vacuoles formed, the matrix condensed, the ridge obscured or disappeared, apoptosis body emerged. Minor to moderate dilation of rough endoplasmic reticulum and Golgi's complex was also observed. However, in naloxone-treated groups, the number of neurons with swollen mitochondrion and endoplasmic reticulum was much fewer than that in FS control group. No apoptosis body was observed. The comparison between them showed much lighter brain damage in naloxone-treated groups than in FS control group. Although low-dose naloxone could not totally stop the occurrence of febrile seizure, it could lighten the brain damage resulted from repeated FS to some extent.

Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats

PubMed Central

Groveman, Bradley R.; Carrier, Nicole; Qiao, Haifa; Fang, Xiao-Qian; Wang, Hui; Xin, Wenkuan; Jiang, Xing-Hong; Salter, Michael W.; Ding, Xin-Sheng; Kabbaj, Mohamed

2018-01-01

Background Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. Methods A total of 300 adult male Sprague Dawley rats (250–280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 μL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. Results DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. Conclusion Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area. PMID:29614089

Effects of Microwave Radiation on Neuronal Activity

DTIC Science & Technology

1991-10-01

salivary glands and human cultured cells to extremely low- frequency (ELF) EMF alters patterns of polypeptide synthesis (18,19). The effects displayed...at 16 Hz. Continuous exposure to radio- frequency radiation for 4 consecutive days led to the development of a cell number density gradient. The...RADIATION ON NEURONAL ACTIVITY SUMMARY The effects of radiofrequency radiation on rat hippocampal fetal neurons were examined. Carrier frequencies of 300 to

Maternal Exercise during Pregnancy Increases BDNF Levels and Cell Numbers in the Hippocampal Formation but Not in the Cerebral Cortex of Adult Rat Offspring

ERIC Educational Resources Information Center

Gomes da Silva, Sérgio; de Almeida, Alexandre Aparecido; Fernandes, Jansen; Lopim, Glauber Menezes; Cabral, Francisco Romero; Scerni, Débora Amado; de Oliveira-Pinto, Ana Virgínia; Lent, Roberto; Arida, Ricardo Mario

2016-01-01

Clinical evidence has shown that physical exercise during pregnancy may alter brain development and improve cognitive function of offspring. However, the mechanisms through which maternal exercise might promote such effects are not well understood. The present study examined levels of brain-derived neurotrophic factor (BDNF) and absolute cell…

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.

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.

Zinc supplementation in rats impairs hippocampal-dependent memory consolidation and dampens post-traumatic recollection of stressful event.

PubMed

Contestabile, Antonio; Peña-Altamira, Emiliano; Virgili, Marco; Monti, Barbara

2016-06-01

Zinc is a trace element important for synaptic plasticity, learning and memory. Zinc deficiency, both during pregnancy and after birth, impairs cognitive performance and, in addition to memory deficits, also results in alterations of attention, activity, neuropsychological behavior and motor development. The effects of zinc supplementation on cognition, particularly in the adult, are less clear. We demonstrate here in adult rats, that 4 week-long zinc supplementation given by drinking water, and approximately doubling normal daily intake, strongly impairs consolidation of hippocampal-dependent memory, tested through contextual fear conditioning and inhibitory avoidance. Furthermore, the same treatment started after memory consolidation of training for the same behavioral tests, substantially dampens the recall of the stressful event occurred 4 weeks before. A molecular correlate of the amnesic effect of zinc supplementation is represented by a dysregulated function of GSK-3ß in the hippocampus, a kinase that participates in memory processes. The possible relevance of these data for humans, in particular regarding post-traumatic stress disorders, is discussed in view of future investigation. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

PubMed

Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

2016-06-01

Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques. © The Author(s) 2014.

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

Krueger, Katharina; Straub, Heidrun; Hirner, Alfred V.

Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krueger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Mu{beta}hoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501, Krueger, K., Straub, H., Binding, N., Mu{beta}hoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167-173, Krueger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Mu{beta}hoff, U., 2007. Effects of dimethylarsinicmore » and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40-46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMA{sup V}) and monomethylarsonous acid (MMA{sup III}) also influence the synaptic functions of the hippocampus. In hippocampal slices of young (14-21 days-old) and adult (2-4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds. MMA{sup V} had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMA{sup III} strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 {mu}mol/l (adult rats) and 25 {mu}mol/l (young rats) and LTP amplitudes at concentrations of 25 {mu}mol/l (adult rats) and 10 {mu}mol/l (young rats), respectively. In contrast, application of 1 {mu}mol/l MMA{sup III} led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at this concentration (Krueger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Mu{beta}hoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501). These effects are probably not mediated by changes in cell excitability or in presynaptic glutamate release rates, since antidromically induced population spikes and paired-pulse facilitation failed to show any MMA{sup III} effect. The impairment of the excitatory CA1 synapse is more likely caused by the action of MMA{sup III} on postsynaptic glutamatergic receptors and may be jointly responsible for dysfunctions of cognitive effects in arsenic toxicity.« less

Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy

PubMed Central

Polli, Roberson S.; Malheiros, Jackeline M.; dos Santos, Renan; Hamani, Clement; Longo, Beatriz M.; Tannús, Alberto; Mello, Luiz E.; Covolan, Luciene

2014-01-01

Kainic acid (KA) or pilocarpine (PILO) have been used in rats to model human temporal lobe epilepsy (TLE) but the distribution and severity of structural lesions between these two models may differ. Magnetic resonance imaging (MRI) studies have used quantitative measurements of hippocampal T2 (T2HP) relaxation time and volume, but simultaneous comparative results have not been reported yet. The aim of this study was to compare the MRI T2HP and volume with histological data and frequency of seizures in both models. KA- and PILO-treated rats were imaged with a 2 T MRI scanner. T2HP and volume values were correlated with the number of cells, mossy fiber sprouting, and spontaneous recurrent seizures (SRS) frequency over the 9 months following status epilepticus (SE). Compared to controls, KA-treated rats had unaltered T2HP, pronounced reduction in hippocampal volume and concomitant cell reduction in granule cell layer, CA1 and CA3 at 3 months post SE. In contrast, hippocampal volume was unchanged in PILO-treated animals despite detectable increased T2HP and cell loss in granule cell layer, CA1 and CA3. In the following 6 months, MRI hippocampal volume remained stable with increase of T2HP signal in the KA-treated group. The number of CA1 and CA3 cells was smaller than age-matched CTL group. In contrast, PILO group had MRI volumetric reduction accompanied by reduction in the number of CA1 and CA3 cells. In this group, T2HP signal was unaltered at 6 or 9 months after status. Reductions in the number of cells were not progressive in both models. Notably, the SRS frequency was higher in PILO than in the KA model. The volumetry data correlated well with tissue damage in the epileptic brain, suggesting that MRI may be useful for tracking longitudinal hippocampal changes, allowing the assessment of individual variability and disease progression. Our results indicate that the temporal changes in hippocampal morphology are distinct for both models of TLE and that these are not significantly correlated to the frequency of SRS. PMID:25071699

Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo.

PubMed

He, Wen-Bin; Abe, Kazuho; Akaishi, Tatsuhiro

2018-01-01

To explore memory enhancing effect of the flavonoid fisetin, we investigated the effect of oral administration of flavonoids on the induction of long-term potentiation (LTP) at hippocampal CA1 synapses of anesthetized rats. Among four flavonoids (fisetin, quercetin, luteolin and myricetin) tested, only fisetin significantly facilitated the induction of hippocampal LTP. The effect of oral fisetin was abolished by intracerebroventricular injection of U0126, an agent that was previously found to inhibit its effect in hippocampal slices in vitro. These results suggest that orally administered fisetin crosses the blood-brain barrier and promotes synaptic functions in the hippocampus. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task.

PubMed

Tanichi, Masaaki; Toda, Hiroyuki; Shimizu, Kunio; Koga, Minori; Saito, Taku; Enomoto, Shingo; Boku, Shuken; Asai, Fumiho; Mitsui, Yumi; Nagamine, Masanori; Fujita, Masanori; Yoshino, Aihide

2018-06-18

Life-threatening experiences can result in the development of post-traumatic stress disorder. We have developed an animal model for post-traumatic stress disorder (PTSD) using a shuttle box in rats. In this paradigm, the rats were exposed to inescapable foot-shock stress (IS) in a shuttle box, and then an avoidance/escape task was performed in the same box 2 weeks after IS. A previous study using this paradigm revealed that environmental enrichment (EE) ameliorated avoidance/numbing-like behaviors, but not hyperarousal-like behaviors, and EE also elevated hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the differential effects of EE components, i.e., running wheel (RW) or toy rotation, on PTSD-like behaviors has remained unclear. In this experiment, we demonstrated that RW, toy rotation, and EE (containing RW and toy rotation) ameliorated avoidance/numbing-like behaviors, induced learning of avoidance responses, and improved depressive-like behaviors in traumatized rats. The RW increased the hippocampal mRNA expression of neurotrophic factors, especially BDNF and glial-cell derived neurotrophic factor. Toy rotation influenced FK506 binding protein 5 mRNA expression, which is believed to be a regulator of the hypothalamic-pituitary-adrenal (HPA)-axis system, in the hippocampus and amygdala. This is the first report to elucidate the differential mechanistic effects of RW and toy rotation. The former appears to exert its effects via neurotrophic factors, while the latter exerts its effects via the HPA axis. Further studies will lead to a better understanding of the influence of environmental factors on PTSD. Copyright © 2018 Elsevier Inc. All rights reserved.

Reconceiving the hippocampal map as a topological template

PubMed Central

Dabaghian, Yuri; Brandt, Vicky L; Frank, Loren M

2014-01-01

The role of the hippocampus in spatial cognition is incontrovertible yet controversial. Place cells, initially thought to be location-specifiers, turn out to respond promiscuously to a wide range of stimuli. Here we test the idea, which we have recently demonstrated in a computational model, that the hippocampal place cells may ultimately be interested in a space's topological qualities (its connectivity) more than its geometry (distances and angles); such higher-order functioning would be more consistent with other known hippocampal functions. We recorded place cell activity in rats exploring morphing linear tracks that allowed us to dissociate the geometry of the track from its topology. The resulting place fields preserved the relative sequence of places visited along the track but did not vary with the metrical features of the track or the direction of the rat's movement. These results suggest a reinterpretation of previous studies and new directions for future experiments. DOI: http://dx.doi.org/10.7554/eLife.03476.001 PMID:25141375

An N-methyl-D-aspartate receptor-independent excitatory action of partial reduction of extracellular [Mg2+] in CA1-region of rat hippocampal slices.

PubMed

Hamon, B; Stanton, P K; Heinemann, U

1987-03-31

Partial reduction of [Mg2+]o from 2 to 1 mM markedly enhanced neuronal responses evoked by Schaffer collateral-commissural fiber stimulation in the CA1-region of rat hippocampal slices. The amplitude of extracellular population potentials recorded in the CA1-pyramidal cell layer and maximum dV/dt of extracellular population EPSP's recorded in the CA1-pyramidal apical dendritic layer were both increased. However, unlike findings from slices where Mg2+ was completely removed from the bathing medium, there was no spontaneous or evoked epileptiform activity, and the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (2-APV) did not antagonize the enhancement of evoked responses. These results indicate that, in addition to the participation of NMDA receptors in the epileptiform activity observed when Mg2+ is completely removed from the bathing medium, there is also an NMDA receptor-independent excitatory action of partial reduction of [Mg2+]o in hippocampal slices.

Hippocampal dendritic spines modifications induced by perinatal asphyxia.

PubMed

Saraceno, G E; Castilla, R; Barreto, G E; Gonzalez, J; Kölliker-Frers, R A; Capani, F

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although western blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA.

Hippocampal Dendritic Spines Modifications Induced by Perinatal Asphyxia

PubMed Central

Saraceno, G. E.; Castilla, R.; Barreto, G. E.; Gonzalez, J.; Kölliker-Frers, R. A.; Capani, F.

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although Western Blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA. PMID:22645692

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

PubMed Central

Sato, Satoru M; Woolley, Catherine S

2016-01-01

Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE. DOI: http://dx.doi.org/10.7554/eLife.12917.001 PMID:27083045

Hippocampus and cerebellum function following imipenem treatment in male and female rats: evaluation of sex differences during developmental stage.

PubMed

Golchin, Leila; Golchin, Lale; Vahidi, Ali Asghar; Shabani, Mohammad

2013-02-15

The B-Lactam antibiotics have been suggested to have some degree of neurotoxicity in experimental animals as well as in clinical situations. This study has been elucidated the alteration in hippocampal and cerebellum function following adolescent imipenem exposure in male and female rats. Hippocampus and cerebellum related behavioral dysfunction in imipenem -treated [intraperitoneally, 40 and 80 mg/kg/day for one week from 23-day-old] rats were analyzed using explorative, motor function, learning and memory tasks [grasping, rotarod, open field shuttle box and Morris water maze tests]. Exposure to imipenem especially in high dosage impaired the motor coordination in male and female rats. There weren't any differences in grasping time in male and female rats. When the rearing and grooming frequency of their recorded in open field test, both males and females were dramatically affected by exposure to imipenem. Compared to the saline, male and female rats trained one week after imipenem injection showed significant memory deficits in the shuttle box and Morris water maze tests. Results in this study suggested that animals treated with imipenem suffer from motor activity and cognitive impairment. However, hippocampal and cerebellum functions of male and female rats were profoundly affected by exposure to imipenem while no sex-differences in the most variable were evident.

Respective Role of the Dorsal Hippocampus and the Entorhinal Cortex during the Recombination of Previously Learned Olfactory-Tactile Associations in the Rat

ERIC Educational Resources Information Center

Boisselier, Lise; Ferry, Barbara; Gervais, Rémi

2017-01-01

The hippocampal formation has been extensively described as a key component for object recognition in conjunction with place and context. The present study aimed at describing neural mechanisms in the hippocampal formation that support olfactory-tactile (OT) object discrimination in a task where space and context were not taken into account. The…

Distinct Single but Not Necessarily Repeated Tetanization Is Required to Induce Hippocampal Late-LTP in the Rat CA1

ERIC Educational Resources Information Center

Sajikumar, Sreedharan; Navakkode, Sheeja; Frey, Julietta U.

2008-01-01

The protein synthesis-dependent form of hippocampal long-term potentiation (late-LTP) is thought to underlie memory. Its induction requires a distinct stimulation strength, and the common opinion is that only repeated tetani result in late-LTP whereas as single tetanus only reveals a transient early-LTP. Properties of LTP induction were compared…

[Protective effect of pretreatment of Salvia miltiorrhiza Bunge. f. alba plasma against oxygen-glucose deprivation-induced injury of cultured rat hippocampal neurons by inhibiting apoptosis].

PubMed

Li, Mei-Yi; Zhang, Yan-Bo; Zuo, Huan; Liu, Li-Li; Niu, Jing-Zhong

2012-02-25

The present study was to investigate the effect of Salvia miltiorrhiza Bunge. f. alba (SMA) pharmacological pretreatment on apoptosis of cultured hippocampal neurons from neonate rats under oxygen-glucose deprivation (OGD). Cultured hippocampal neurons were randomly divided into five groups (n = 6): normal plasma group, low dose SMA plasma (2.5%) group, middle dose SMA plasma (5%) group, high dose SMA plasma (10%) group and control group. The hippocampal neurons were cultured and treated with plasma from adult Wistar rats intragastrically administered with saline or aqueous extract of SMA. The apoptosis of neurons was induced by glucose-free Earle's solution containing 1 mmol/L Na2S2O4 and labeled by MTT and Annexin V/PI double staining. Moreover, protein expressions of Bcl-2 and Bax were detected by immunofluorescence. The results showed that few apoptotic cells were observed in control group, whereas the number of apoptotic cells was greatly increased in normal plasma group and low dose SMA plasma group. Both middle and high dose SMA plasma could protect cultured hippocampal neurons from apoptosis induced by OGD (P < 0.05). The protective effect of high dose SMA plasma was stronger than that of middle one (P < 0.05). Compared to control, normal plasma and low dose SMA plasma groups, middle and high dose SMA plasma groups both showed significantly higher levels of Bcl-2 (P < 0.05 or 0.01), whereas expressions of Bax was opposite. There were no significant differences of Bcl-2 and Bax expressions between middle and high dose SMA plasma groups. Number of Bcl-2- and Bax-positive cells had similar tendency. Bcl-2/Bax (number of positive cells) ratio was higher in high dose SMA plasma group than those of all the other groups (P < 0.05 or 0.01). These results suggest that pharmacological pretreatment of blood plasma containing middle and high dose SMA could raise viability and inhibit apoptosis of OGD-injured hippocampal neurons by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax.

Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane

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

Huang, Zhenlie; Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550; Ichihara, Sahoko

2015-01-15

1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins.more » Changes in selected proteins were further confirmed by Manganese II (Mn{sup 2+})-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p < 0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn{sup 2+}-Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. - Highlights: • 1-BP modified hippocampal phosphoproteome in rat and 23 altered proteins were identified. • 1-BP changed phosphorylation of GRP78, 14-3-3 θ, PSMC3, ST13, PURA, GNB2, APOE, PEA15 and ATP5H. • 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process.« less

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats

PubMed Central

Stevens, Karen E.; Adams, Catherine E.; Mellott, Tiffany J.; Robbins, Emily; Kisley, Michael A.

2008-01-01

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the α7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal α-bungarotoxin to visualize nicotinic α7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring. PMID:18778692

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats.

PubMed

Stevens, Karen E; Adams, Catherine E; Mellott, Tiffany J; Robbins, Emily; Kisley, Michael A

2008-10-27

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the alpha7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal alpha-bungarotoxin to visualize nicotinic alpha7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring.

Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling.

PubMed

Buchborn, Tobias; Schröder, Helmut; Höllt, Volker; Grecksch, Gisela

2014-06-01

A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling. © The Author(s) 2014.

Effect of forced exercise and exercise withdrawal on memory, serum and hippocampal corticosterone levels in rats.

PubMed

Radahmadi, Maryam; Alaei, Hojjatallah; Sharifi, Mohammad Reza; Hosseini, Nasrin

2015-10-01

Evidence suggests that there are positive effects of exercise on learning and memory. Moreover, some studies have demonstrated that forced exercise plays the role of a stressor. This study was aimed at investigating the effects of different timing of exercise and exercise withdrawal on memory, and serum and hippocampal corticosterone (CORT) levels. Wistar rats were randomly divided into five groups: control, sham, exercise-rest (exercise withdrawal), rest-exercise (exercised group), and exercise-exercise (continuous exercise). Rats were forced to run on a treadmill for 1 h/day at a speed 20-21-m/min. Memory function was evaluated by the passive avoidance test in different intervals (1, 7 and 21 days) after foot shock. Findings showed that after the exercise withdrawal, short-term and mid-term memories, had significant enhancement compared to the control group, while the long-term memory did not present this result. In addition, the serum and hippocampal CORT levels were at the basal levels after the rest period in the exercise-rest group. In the rest-exercise group, exercise improved mid- and long-term memories, whereas continuous exercise improved all types short-, mid- and long-term memories, particularly the mid-term memory. Twenty-one and forty-two days of exercise significantly decreased the serum and hippocampal CORT levels. It seems that exercise for at least 21 days with no rest could affect biochemical factors in the brain. Also, regular continuous exercise plays an important role in memory function. Hence, the duration and withdraw of exercise are important factors for the neurobiological aspects of the memory responses.

Different concentrations of docosahexanoic acid supplement during lactation result in different outcomes in preterm Sprague-Dawley rats.

PubMed

Wang, Qian; Jia, Chunhong; Tan, Xiaohua; Wu, Fan; Zhong, Xinqi; Su, Zhiwen; Sun, Weiwen; Cui, Qiliang

2018-01-01

In this study, we evaluated the effects of different concentrations of docosahexanoic acid (DHA) supplement on preterm Sprague-Dawley rat pups, and in parallel, measured the phosphorylation activity of the mTOR pathway in the hippocampal CA1 area. Preterm Sprague-Dawley rat pups were randomly assigned to experimental groups which included; a sufficient DHA group (100 mg/kg/day); an enriched DHA group (300 mg/kg/day); an excess DHA group (800 mg/kg/day); and a deficient DHA group (normal saline gavage 0.1 ml/10 g). Body weight (g) was measured at days 1/7/14/21/28/42, respectively. Spatial learning and memory were also tested using the Morris water maze at week 6 (day 42). Finally, activation of the mTOR signaling pathway in hippocampal CA1 area were evaluated by western blotting. Postnatal sufficient/enriched docosahexanoic acid supplement ameliorated body weight restriction, spatial learning and memory restriction, and decreased phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Furthermore, excess docosahexanoic acid supplement impeded weight gain and spatial learning and memory, perturbed serum unsaturated fatty acid, and downregulated phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Postnatal sufficient/enriched DHA supplement ameliorated growth and spatial learning and memory impairment and upregulated the mTOR pathway in preterm pups, although excessive DHA supplement did not have any beneficial effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of memantine on hippocampal long-term potentiation, gamma activity, and sensorimotor gating in freely moving rats.

PubMed

Ma, Jingyi; Mufti, Asfandyar; Stan Leung, L

2015-09-01

Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, is used for treatment of patients with Alzheimer's disease. The mechanisms of memantine in relieving cognitive and behavioral symptoms are unclear, and this study attempts to elucidate its action on network and synaptic functions of the hippocampus. The effects of memantine on electrographic activity and hippocampal long-term potentiation (LTP) were investigated in freely moving rats. Basal dendritic excitation on hippocampal CA1 pyramidal cells showed a robust LTP after theta-frequency primed bursts, and the LTP was higher after 5-10 mg/kg intraperitoneal (ip) memantine pretreatment, as compared with saline pretreatment. Injection of scopolamine (5 mg/kg ip) before memantine failed to block the LTP-enhancing effect of memantine. Memantine as compared with saline pretreatment did not affect the LTP after an afterdischarge induced by high-frequency (200-Hz) train stimulation. Memantine (5 or 10 mg/kg ip) significantly enhanced gamma oscillations in the hippocampal local field potentials of 40-100 Hz during walking and awake immobility. Memantine at 10 mg/kg ip, but not at 5 mg/kg ip, increased prepulse inhibition of the acoustic startle response, while both 5 and 10 mg/kg ip memantine enhanced the acoustic startle response as compared with saline-injected rats. These electrophysiological and behavioral effects of memantine are unique among N-methyl-D-aspartate receptor antagonists but are consistent with memantine's effects in improving cognitive and sensorimotor functions of Alzheimer's patients. Copyright © 2015 Elsevier Inc. All rights reserved.

The biochemical changes in hippocampal formation occurring in normal and seizure experiencing rats as a result of a ketogenic diet.

PubMed

Chwiej, Joanna; Skoczen, Agnieszka; Janeczko, Krzysztof; Kutorasinska, Justyna; Matusiak, Katarzyna; Figiel, Henryk; Dumas, Paul; Sandt, Christophe; Setkowicz, Zuzanna

2015-04-07

In this study, ketogenic diet-induced biochemical changes occurring in normal and epileptic hippocampal formations were compared. Four groups of rats were analyzed, namely seizure experiencing animals and normal rats previously fed with ketogenic (KSE and K groups respectively) or standard laboratory diet (NSE and N groups respectively). Synchrotron radiation based Fourier-transform infrared microspectroscopy was used for the analysis of distributions of the main organic components (proteins, lipids, compounds containing phosphate group(s)) and their structural modifications as well as anomalies in creatine accumulation with micrometer spatial resolution. Infrared spectra recorded in the molecular layers of the dentate gyrus (DG) areas of normal rats on a ketogenic diet (K) presented increased intensity of the 1740 cm(-1) absorption band. This originates from the stretching vibrations of carbonyl groups and probably reflects increased accumulation of ketone bodies occurring in animals on a high fat diet compared to those fed with a standard laboratory diet (N). The comparison of K and N groups showed, moreover, elevated ratios of absorbance at 1634 and 1658 cm(-1) for DG internal layers and increased accumulation of creatine deposits in sector 3 of the Ammon's horn (CA3) hippocampal area of ketogenic diet fed rats. In multiform and internal layers of CA3, seizure experiencing animals on ketogenic diet (KSE) presented a lower ratio of absorbance at 1634 and 1658 cm(-1) compared to rats on standard laboratory diet (NSE). Moreover, in some of the examined cellular layers, the increased intensity of the 2924 cm(-1) lipid band as well as the massifs of 2800-3000 cm(-1) and 1360-1480 cm(-1), was found in KSE compared to NSE animals. The intensity of the 1740 cm(-1) band was diminished in DG molecular layers of KSE rats. The ketogenic diet did not modify the seizure induced anomalies in the unsaturation level of lipids or the number of creatine deposits.

Learning-enhanced coupling between ripple oscillations in association cortices and hippocampus.

PubMed

Khodagholy, Dion; Gelinas, Jennifer N; Buzsáki, György

2017-10-20

Consolidation of declarative memories requires hippocampal-neocortical communication. Although experimental evidence supports the role of sharp-wave ripples in transferring hippocampal information to the neocortex, the exact cortical destinations and the physiological mechanisms of such transfer are not known. We used a conducting polymer-based conformable microelectrode array (NeuroGrid) to record local field potentials and neural spiking across the dorsal cortical surface of the rat brain, combined with silicon probe recordings in the hippocampus, to identify candidate physiological patterns. Parietal, midline, and prefrontal, but not primary cortical areas, displayed localized ripple (100 to 150 hertz) oscillations during sleep, concurrent with hippocampal ripples. Coupling between hippocampal and neocortical ripples was strengthened during sleep following learning. These findings suggest that ripple-ripple coupling supports hippocampal-association cortical transfer of memory traces. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Hippocampal-cortical interaction in decision making

PubMed Central

Yu, Jai Y.; Frank, Loren M.

2014-01-01

When making a decision it is often necessary to consider the available alternatives in order to choose the most appropriate option. This deliberative process, where the pros and cons of each option are considered, relies on memories of past actions and outcomes. The hippocampus and prefrontal cortex are required for memory encoding, memory retrieval and decision making, but it is unclear how these areas support deliberation. Here we examine the potential neural substrates of these processes in the rat. The rat is a powerful model to investigate the network mechanisms underlying deliberation in the mammalian brain given the anatomical and functional conservation of its hippocampus and prefrontal cortex to other mammalian systems. Importantly, it is amenable to large scale neural recording while performing laboratory tasks that exploit its natural decisionmaking behavior. Focusing on findings in the rat, we discuss how hippocampal-cortical interactions could provide a neural substrate for deliberative decision making. PMID:24530374

AGE-DEPENDENT CHANGES IN RECEPTOR-STIMULATED PHOSPHOINOSITIDE TURNOVER IN THE RAT HIPPOCAMPUS

EPA Science Inventory

To study the changes in the hippocampal cholinergic system of chronologically old and behaviorally impaired animals, old (21 months of age) and young (3 months of age) male, Fischer-344 rats were used. The aged animals were tested on a reference memory task (Morris water maze) an...

Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats.

PubMed

Dávila-Hernández, Amalia; Zamudio, Sergio R; Martínez-Mota, Lucía; González-González, Roberto; Ramírez-San Juan, Eduardo

2018-05-14

Given the importance of depression and the adverse effects of conventional treatment, it is necessary to seek complementary therapies. In a rat model of depression, this study aimed to assess the behavioral and morphological effects of embedding absorbable thread in acupoints (acu-catgut), and compare the results to those of fluoxetine treatment and the corresponding control groups. Therefore, depressive-like behavior was evaluated with the forced swimming test, and dendritic morphology (in the CA1 hippocampal region) with the Golgi-Cox technique and Sholl analysis. After weaning, male Sprague-Dawley rats were housed in social isolation for 8 weeks to induce depressive-like behavior. They were then given a 21-day treatment by stimulating acupoints with acu-catgut (AC) or fluoxetine (FX) (2 mg/kg). Rats were divided into six groups: Control (socially housed), social isolation (SI), SI + AC, SI + Sham (sham embedding of thread), SI + FX and SI + VH (vehicle). Compared to fluoxetine, acu-catgut treatment was more effective in reversing depressive-like behavior elicited by SI. The SI-induced reduction in dendritic length and spine density in hippocampal CA1 pyramidal neurons was attenuated after prolonged treatment with acu-catgut or fluoxetine. Hence, both treatments proved capable of reversing depressive-like alterations caused by SI, likely due to dendritic remodeling in the hippocampus. Copyright © 2018 Elsevier B.V. All rights reserved.