Rat Dorsal Hippocampus Research Articles

Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus

A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aβ injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.

Dissociations in ensemble dynamics between rat dorsal striatum, ventral striatum, and hippocampus

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Psychological prenatal stress reduced the number of BrdU immunopositive cells in the dorsal hippocampus without affecting the open field behavior of male and female rats at one month of age

We examined whether prenatal psychological stress with little physical stress causes changes in the behavior and neurogenesis of the offspring of Sprague–Dawley rats at one month. Dams in the last trimester of gestation were psychologically stressed by placing them in a social communication box and shocking a rat on the other side of a transparent wall. They suffered little physical stress. Male and female offspring from the dams showed little change in an open field test at postnatal day (PND) 30. To evaluate neurogenesis in the brain, BrdU was intraperitoneally injected at PND 35 into offspring not used in the open field test. Immunohistochemical examinations of BrdU in their dorsal hippocampus at PNDs 42 and 112 revealed that the number of BrdU immunopositive cells in the offspring of prenatally stressed rats was significantly smaller than in the offspring of unstressed ones. These results together with our previous finding that prenatal psychological stress can alter specific behaviors suggest that prenatal psychological stress can suppress neurogenesis in the dorsal hippocampus of rats of both sexes at PND 35 even though impairment in the behavioral task has not yet appeared.

Cross-Talk between Dopaminergic and Noradrenergic Systems in the Rat Ventral Tegmental Area, Locus Ceruleus, and Dorsal Hippocampus

A decreased central dopaminergic and/or noradrenergic transmission is believed to be involved in the pathophysiology of depression. It is known that dopamine (DA) neurons in the ventral tegmental area (VTA) and norepinephrine (NE) neurons in the locus ceruleus (LC) are autoregulated by somatodendritic D(2)-like and alpha(2)-adrenoceptors, respectively. Complementing these autoreceptor-mediated inhibitory feedbacks, anatomical and functional studies have established a role for noradrenergic inputs in regulating dopaminergic activity, and reciprocally. In the present study, a microiontophoretic approach was used to characterize the postsynaptic catecholamine heteroreceptors involved in such regulations. In the VTA, the application of DA and NE significantly reduced the firing activity of DA neurons. In addition to a role for D(2)-like receptors in the inhibitory effects of both catecholamines, it was demonstrated that the alpha(2)-adrenoceptor antagonist idazoxan dampened the DA- and NE-induced attenuations of DA neuronal activity, indicating that both of these receptors are involved in the responsiveness of VTA DA neurons to catecholamines. In the LC, the effectiveness of iontophoretically applied NE and DA to suppress NE neuronal firing was blocked by idazoxan but not by the D(2)-like receptor antagonist raclopride, which suggested that only alpha(2)-adrenoceptors were involved. In the dorsal hippocampus, a forebrain region having a sparse dopaminergic innervation but receiving a dense noradrenergic input, the suppressant effects of DA and NE on pyramidal neurons were attenuated by idazoxan but not by raclopride. The suppressant effect of DA was prolonged by administration of the selective NE reuptake inhibitor desipramine and, to lesser extent, of the selective DA reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)-piperazine (GBR12909), suggesting that both the NE and DA transporters were involved in DA uptake in the hippocampus. These findings might help in designing new antidepressant strategies aimed at enhancing DA and NE neurotransmission.

TGF-β1 protects against Aβ-neurotoxicity via the phosphatidylinositol-3-kinase pathway

β-Amyloid (Aβ) injection into the rat dorsal hippocampus had a small neurotoxic effect that was amplified by i.c.v. injection of SB431542, a selective inhibitor of transforming growth factor-β (TGF-β) receptor. This suggested that TGF-β acts as a factor limiting Aβ toxicity. We examined the neuroprotective activity of TGF-β1 in pure cultures of rat cortical neurons challenged with Aβ. Neuronal death triggered by Aβ is known to proceed along an aberrant re-activation of the cell cycle, and involves late β-catenin degradation and tau hyperphosphorylation. TGF-β1 was equally protective when added either in combination with, or 6 h after Aβ. Co-added TGF-β1 prevented Aβ-induced cell cycle reactivation, whereas lately added TGF-β1 had no effect on the cell cycle, but rescued the late β-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-β1 blocks the whole cascade of events leading to Aβ neurotoxicity by activating the PI-3-K pathway.

Differential cholinergic modulation of synaptic encoding and gain control mechanisms in rat hippocampus

Recent studies have highlighted a variety of cognitive effects caused by cholinolytic drug injections into different cortical structures. These findings were largely interpreted as evidence for location-specific cholinergic modulation of synaptic encoding mechanisms. Here, using evoked field responses in anaesthetized rat dorsal hippocampus we show that in addition to reinforcement of synaptic connections (long-term potentiation, LTP), endogenous acetylcholine also regulates firing gain of CA1 pyramidal neurons (EPSP-spike potentiation). Gain augmentation upon increase in cholinergic drive involves evoked synchronous firing at both apical and basal afferent projections, unlike enhancement of activity-induced LTP constrained to the basal afferent system. These data indicate that acetylcholine can act as an effective input and gain controller in the hippocampus. Modulation of synaptic plasticity would determine the relative dominance of afferent inputs while the facilitation of synchronous firing is likely to promote a more generalized spread of excitation and long range communication within the limbic cortex.

Extremely low-frequency electromagnetic field exposure during chronic morphine treatment strengthens downregulation of dopamine D2 receptors in rat dorsal hippocampus after morphine withdrawal

The aim of this study was to investigate the effect of extremely low-frequency electromagnetic field (ELF-EMF) exposure during morphine treatment on dopamine D2 receptor (D2R) density in the rat dorsal hippocampus following withdrawal. Rats were exposed to ELF-EMF (20 Hz, 14 mT) or sham exposed for 1h per day before injection of morphine (10mg/kg, i.p.) once daily for 12 days. The saline control group was sham exposed for the same period. Immunohistochemistry was used to detect the density of D2Rs on the 1st, 3rd and 5th morphine withdrawal days. The results showed that the density of D2Rs in sham-exposed morphine-treated rats on the 1st and 3rd days of morphine withdrawal was significantly lower than that of the saline control group. The ELF-EMF-exposed morphine group also exhibited a significantly lower density of D2Rs on the 1st and 3rd withdrawal days relative to the sham-exposed morphine group. However, the D2R density in both groups tended to recover as morphine withdrawal days increased. The results suggest that dorsal hippocampal D2Rs are sensitive to morphine withdrawal and that this is potentiated by ELF-EMF pre-exposure during morphine treatment.

Administration of Triiodo-l-thyronine into Dorsal Hippocampus Alters Phosphorylation of Akt, Mammalian Target of Rapamycin, p70S6 Kinase and 4E-BP1 in Rats

Thyroid hormones play critical roles in brain functions. The underlying mechanisms remain unknown but classical regulation of gene expression through binding to nuclear thyroid hormone receptors has been widely implicated. Evidence has also accumulated suggesting that thyroid hormone can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the brain is not fully understood. In this study, we administrated 3,5,3'-triiodo-L: -thyronine (T3) into rat dorsal hippocampus and determined the phosphorylation of Akt and its downstream targets, mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6k) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) signaling molecules. T3 caused specific rapid and persistent activation of phosphatidylinositol 3-kinase (PI3K)/Akt-mTOR signaling pathway, which was mediated by thyroid hormone receptors. Furthermore, the rapid action of T3 did not require protein or RNA synthesis, whereas, the persistent action of T3 was translational and transcriptional activities-dependent. These findings indicated that activation of PI3K/Akt-mTOR signaling pathway provides a new molecular mechanism for thyroid hormone actions in the hippocampus and this new mechanism may contribute to some effects of thyroid hormones in the central nervous system.

Time-dependent changes in distribution of basic fibroblast growth factor immunoreactive cells in rat hippocampus after status epilepticus

Objective: In this study, we aimed to examine time-dependent morphologic changes and quantitative alterations in the density of basic fibroblast growth factor (bFGF)-immunoreactive (ir) astrocytes and CA2 pyramidal neurons in dorsal hippocampus of rats after status epilepticus (SE) induced by kainic acid (KA) injection.Methods: Wistar albino rats were injected with saline or KA i.p. to investigate time-dependent alterations in morphology and the number of bFGF-ir astrocytes and neurons in the dorsal hippocampus 15, 30 and 90 days after KA injection.Results: Fifteen days after KA injection, gliosis was present throughout the hippocampus and neuronal loss was evident in CA1 and CA3 regions, which was more severe after 30 and 90 days. KA-injected rats demonstrated significantly increased number of both bFGF-ir astrocytes throughout the hippocampus and pyramidal neurons in CA2 after 15 days and decreased number after 30 and 90 days.Conclusion: The decrease in the number of bFGF-ir astroglia and neurons in long term after KA injection may indicate a decrease in the production of bFGF and/or number of bFGF-ir cells, suggesting that protective effects of bFGF might be altered during epileptogenesis in the hippocampus.

In vivo electrophysiological assessment of the putative antidepressant Wf-516 in the rat raphe dorsalis, locus coeruleus and hippocampus

Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.

Postpubertal feeding experience affects sex-specific spatial ability in rats

We previously reported that feeding with powdered diet after weaning (3 weeks of age) enhanced spatial ability, and increased the amount of acetylcholine (ACh) released in the dorsal hippocampus in female rats. In the present study, to specify the time when feeding conditions caused these effects, a radial 8-arm maze task and an in vivo microdialysis study were performed in both sexes of rats. In rats fed standard laboratory diet (i.e., pelleted diet), males learned the radial 8-arm maze faster than females. Moreover, the ACh release showed a distinct diurnal rhythm which was high during the dark phase and low during the light phase, but males showed a greater amount of ACh released in the dorsal hippocampus than females. However, in rats fed powdered diet after 6 weeks of age, no significant sex differences were observed in the radial 8-arm maze task or in the amount of ACh released, since feeding with powdered diet enhanced spatial ability, and increased the amount of ACh released only in females. These results suggest that feeding conditions after 6 weeks of age may contribute to the sex difference in the spatial ability associated with the changes in the amount of ACh released in the dorsal hippocampus in rats.

Δ 9-Tetrahydrocannabinol-induced cognitive deficits are reversed by olanzapine but not haloperidol in rats

Cannabis is the most widely used illicit substance. Δ 9-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to induce cognitive impairment that closely resembles the impairment observed in schizophrenic patients. THC has also been known to impair spatial memory in rats tested in the eight-arm radial maze. We previously reported that microinjection of THC (20 μg/side) into the rat dorsal hippocampus impaired spatial memory and that i.p. injection of THC (6 mg/kg) decreased the extracellular levels of acetylcholine (ACh) in the dorsal hippocampus. In the present study, we compared the effects of olanzapine, an atypical antipsychotic, with those of haloperidol, a typical neuroleptic, on the impairments of spatial memory and decreased ACh levels induced by THC (6 mg/kg, i.p.) in rats. We found that olanzapine (0.1 mg/kg, i.p.) reversed the THC-induced memory deficits and decrease in extracellular ACh levels, whereas haloperidol (0.03–0.3 mg, i.p.) had no effect. These results suggest that olanzapine may improve the THC-induced impairment of spatial memory, partly by enhancing ACh release in the dorsal hippocampus. Therefore, olanzapine could attenuate the acute short-term and working memory deficits induced by cannabis.

Lack of correlation between synaptopodin expression and the ability to induce LTP in the rat dorsal and ventral hippocampus

Synaptopodin (SP), an actin binding protein associated with the spine apparatus, has been proposed to affect the ability of neurons to undergo synaptic plasticity. In the present study, we compared the density of SP puncta in stratum radiatum of the dorsal hippocampus (DH) with that of the ventral hippocampus (VH), a region that expresses only small and short lived LTP. Surprisingly, the VH contains significantly higher density of SP puncta than the DH. Following exposure to an acute stress, LTP was enhanced in the VH and suppressed in the DH. While SP density did change following stress, no similar trends were seen in the two sectors of the hippocampus. Thus, our results indicate a lack of clear interrelation between the density of SP and the ability to express LTP in the hippocampus.

Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat

Marked hippocampal changes in response to excitatory amino acid agonists occur during pregnancy (e.g. decreased frequency in spontaneous recurrent seizures in rats with KA lesions of the hippocampus) and lactation (e.g. reduced c-Fos expression in response to N-methyl- d, l-aspartic acid but not to kainic acid). In this study, the possibility that lactation protects against the excitotoxic damage induced by KA in hippocampal areas was explored. We compared cell damage induced 24 h after a single systemic administration of KA (5 or 7.5 mg/kg bw) in regions CA1, CA3, and CA4 of the dorsal hippocampus of rats in the final week of lactation to that in diestrus phase. To determine cellular damage in a rostro-caudal segment of the dorsal hippocampus, we used NISSL and Fluorojade staining, immunohistochemistry for active caspase-3 and TUNEL, and we observed that the KA treatment provoked a significant loss of neurons in diestrus rats, principally in the pyramidal cells of CA1 region. In contrast, in lactating rats, pyramidal neurons from CA1, CA3, and CA4 in the dorsal hippocampus were significantly protected against KA-induced neuronal damage, indicating that lactation may be a natural model of neuroprotection.

Anxiolytic effects induced by inhibition of the nitric oxide–cGMP pathway in the rat dorsal hippocampus

Conflicting results have been reported regarding the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the hippocampus on anxiety modulation. To investigate the effects of intrahippocampal injections of drugs that modify the NO-cGMP pathway in rats submitted to two animal models that are sensitive to anxiolytic drugs, the elevated plus-maze and the Vogel punished licking test. Male Wistar rats with cannulae aimed at the dentate gyrus of the dorsal hippocampus received microinjections of the NO synthase (NOS) inhibitors N (G)-nitro-L: -arginine methyl ester (LNAME, 15-300 nmol/0.2 microl), N (G)-nitro-L: -arginine (LNOARG, 50-300 nmol/0.2 microl), 7-nitroindazole (7NI, 10-100 nmol/0.2 microl), or the soluble guanylate cyclase inhibitor 1H-oxadiazolo-quinoxalin-1 one (ODQ, 10-100 nmol/0.2 microl), and were submitted to the elevated plus-maze. In a second group, the animals received 7NI, LNAME, or ODQ and were submitted to the Vogel punished licking test. To control for drug-induced changes in locomotor behavior, the animals were submitted to an open arena or to the Rota-rod test. All drugs increased the exploration of the open arms of the elevated plus-maze. They also increased the number of punished licks in the Vogel test, indicating an anxiolytic effect. The anxiolytic effect of LNAME was prevented by previous treatment with L: -arginine (300 nmol/0.2 microl). Except for the lower dose of LNAME (15 nmol), administration of the NOS inhibitors or ODQ did not change exploratory activity in the open field nor cause any gross locomotor impairment in the Rota-rod test. The results suggest that NO plays an anxiogenic role in the dentate gyrus of the dorsal hippocampus.

Electrical stimulation of dorsal, but not ventral hippocampus reduces behavioral defense in the elevated plus maze and shock-probe burying test in rats

Recent evidence indicates that the hippocampus contributes to the control of defensive behaviors in rodents. Here, electrical stimulation (1s, 60Hz) of the rat dorsal hippocampus inhibited defense in the elevated plus maze (increased open arm exploration) and shock-probe burying test (reduced burying duration), while ventral hippocampal stimulation had no effects. Thus, the dorsal hippocampus may play an important role in modulating a range of defensive strategies.

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze–fracture replica immunogold labeling

Gap junctions have been postulated to exist between the axons of excitatory cortical neurons based on electrophysiological, modeling, and dye-coupling data. Here, we provide ultrastructural evidence for axoaxonic gap junctions in dentate granule cells. Using combined confocal laser scanning microscopy, thin-section transmission electron microscopy, and grid-mapped freeze-fracture replica immunogold labeling, 10 close appositions revealing axoaxonic gap junctions ( approximately 30-70 nm in diameter) were found between pairs of mossy fiber axons ( approximately 100-200 nm in diameter) in the stratum lucidum of the CA3b field of the rat ventral hippocampus, and one axonal gap junction ( approximately 100 connexons) was found on a mossy fiber axon in the CA3c field of the rat dorsal hippocampus. Immunogold labeling with two sizes of gold beads revealed that connexin36 was present in that axonal gap junction. These ultrastructural data support computer modeling and in vitro electrophysiological data suggesting that axoaxonic gap junctions play an important role in the generation of very fast (>70 Hz) network oscillations and in the hypersynchronous electrical activity of epilepsy.

On the participation of hippocampal PKC in acquisition, consolidation and reconsolidation of spatial memory

Memory consolidation involves a sequence of temporally defined and highly regulated changes in the activation state of several signaling pathways that leads to the lasting storage of an initially labile trace. Despite appearances, consolidation does not make memories permanent. It is now known that upon retrieval well-consolidated memories can become again vulnerable to the action of amnesic agents and in order to persist must undergo a protein synthesis–dependent process named reconsolidation. Experiments with genetically modified animals suggest that some PKC isoforms are important for spatial memory and earlier studies indicate that several PKC substrates are activated following spatial learning. Nevertheless, none of the reports published so far analyzed pharmacologically the role played by PKC during spatial memory processing. Using the conventional PKC and PKCμ inhibitor 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrollo[3,4-c]carbazole (Gö6976) we found that the activity of these kinases is required in the CA1 region of the rat dorsal hippocampus for acquisition and consolidation of spatial memory in the Morris water maze learning task. Our results also show that when infused into dorsal CA1 after non-reinforced retrieval, Gö6976 produces a long-lasting amnesia that is independent of the strength of the memory trace, suggesting that post-retrieval activation of hippocampal PKC is essential for persistence of spatial memory.

Basic Fibroblast Growth Factor Prevents the Memory Impairment Induced by Gastrin-Releasing Peptide Receptor Antagonism in Area CA1 of the Rat Hippocampus

Increasing evidence indicates that the gastrin-releasing peptide receptor (GRPR) is implicated in regulating synaptic plasticity and memory formation in the hippocampus and other brain areas. However, the molecular mechanisms underlying the memory-impairing effects of GRPR antagonism have remained unclear. Here we report that basic fibroblast growth factor (bFGF/FGF-2) rescues the memory impairment induced by GRPR antagonism in the rat dorsal hippocampus. The GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095) at 1.0 microg impaired, whereas bFGF at 0.25 microg enhanced, 24 h retention of inhibitory avoidance (IA) when infused immediately after training into the CA1 hippocampal area in male rats. Coinfusion with an otherwise ineffective dose of bFGF blocked the memory-impairing effect of RC-3095. These findings suggest that the memory-impairing effects of GRPR antagonists might be partially mediated by an inhibition in the function and/or expression of neuronal bFGF or diminished activation of intracellular protein kinase pathways associated with bFGF signaling.

Dynamics of dopamine and norepinephrine contents in the dorsal hippocampus of rats during immunization with dopamine conjugate

The dynamics of dopamine and norepinephrine contents in the dorsal hippocampus of rats immunized with a dopamine-BSA conjugate was studied during immobilization stress by mean of the microdialysis technique. Immunization with dopamine conjugate was accompanied by intensive production of antibodies against dopamine in rat blood and a tendency toward an increase in dopamine content in the dorsal hippocampus even in the basal state (before stress exposure). Under stress conditions, dopamine content in the dorsal hippocampus of immunized rats significantly increased. In control rats, stress was accompanied by a significant increase in norepinephrine content in the dorsal hippocampus. The observed peculiarities in dopamine and norepinephrine contents in the dorsal hippocampus of rats immunized with a dopamine conjugate were typical of active animals more resistant to emotional stress.