Activity In Rat Hippocampus Research Articles

Trigeminal nerve direct current stimulation causes sustained increase in neural activity in the rat hippocampus

BackgroundTranscranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent evidence suggests that tDCS memory effects may be caused by co-stimulation of scalp nerves such as the trigeminal nerve (TN), and not the electric field in the brain. The TN gives input to brainstem nuclei, including the locus coeruleus that controls noradrenaline release across brain regions, including hippocampus. However, the effects of TN direct current stimulation (TN-DCS) are currently not well understood. HypothesisIn this study we tested the hypothesis that stimulation of the trigeminal nerve with direct current manipulates hippocampal activity via an LC pathway. MethodsWe recorded neural activity in rat hippocampus using multichannel silicon probes. We applied 3 min of 0.25 mA or 1 mA TN-DCS, monitored hippocampal activity for up to 1 h and calculated spikes-rate and spike-field coherence metrics. Subcutaneous injections of xylocaine were used to block TN, while intraperitoneal and intracerebral injection of clonidine were used to block the LC pathway. ResultsWe found that 1 mA TN-DCS caused a significant increase in hippocampal spike-rate lasting 45 min in addition to significant changes in spike-field coherence, while 0.25 mA TN-DCS did not. TN blockage prevented spike-rate increases, confirming effects were not caused by the electric field in the brain. When 1 mA TN-DCS was delivered during clonidine blockage no increase in spike-rate was observed, suggesting an important role for the LC-noradrenergic pathway. ConclusionThese results support our hypothesis and provide a neural basis to understand the tDCS TN co-stimulation mechanism. TN-DCS emerges as an important tool to potentially modulate learning and memory.

Both acute glyphosate and the aminomethylphosphonic acid intoxication decreased the acetylcholinesterase activity in rat hippocampus, prefrontal cortex and gastrocnemius muscle

It has been reported that glyphosate, one of the most common herbicides used in agriculture, impairs locomotion and cognition. Glyphosate has a variable half-life in soil up to biotic and/or abiotic factors transform the molecule in metabolites such as the aminomethylphosphonic acid (AMPA) that has a longer half-life. In this study, female Sprague Dawley rats were acutely exposed to different doses of glyphosate or AMPA (i.e. 10, 56 or 100 mg/kg) and, subsequently, the acetylcholinesterase (AChE) activity was measured in the hippocampus, prefrontal cortex (PFC) and the gastrocnemius muscle. Both glyphosate and AMPA produced a similar decrease in the AChE activity in all the tissues tested. These results suggest that interference with normal cholinergic neurotransmission may be one of the mechanisms involved in glyphosate-induced motor alterations in rats. Moreover, our results highlight the biological importance of AMPA as a molecule with anticholinesterase action in brain and skeletal muscle. To our knowledge, this is the first report showing in vivo that AMPA, the major metabolite of glyphosate, behaves as an organophosphate.

Chronic paracetamol treatment induces neuroinflammation and microglia activation in rat hippocampus

Chronic paracetamol treatment induces neuroinflammation and microglia activation in rat hippocampus

Alpha7 Nicotinic Acetylcholine Receptor Down Regulation Impairs Mitochondrial Function in Streptozotocin-induced Sporadic Alzheimer's Disease Model in Rats

Abstract: Background/Aim: Alzheimer’s disease (AD), a type of neurodegenerative disorder, possesses significant memory loss as one of the cardinal manifestations. The pathophysiology of AD includes increased accumulation of Aβ, degeneration of cholinergic activity and mitochondrial dysfunction. Nicotinic acetylcholine receptors (nAChRs) especially alpha7 nicotinic acetylcholine receptors (α7 nAChRs) are widely distributed in brain and associated with memory function. Further, we explored the correlation between the mitochondrial dysfunction and the expression level of α7 nAChRs in STZ challenged brain regions of rats. Materials and Methods: The STZ group rats received intracerebroventricular infusion of STZ (3 mg/kg) on D-1 and D-3 of experimental design of 18 days. Behavioral parameters ware investigated using MWM and Y-maze test paradigm. Further, biochemical analysis was assessed in all three regions of rats. Results: STZ administration caused significant impairment in memory and learning of rats MWM and Y-maze test paradigm. There was significant decrease in level expression of α7 nAChRs and cholinergic functions in terms of elevated AChE activity and decreased ACh level and ChAT activity in rat hippocampus, pre-frontal cortex and amygdala. Further, STZ administration significantly attenuated the mitochondrial function, integrity and bioenergetics in all the selected brain regions. Interestingly, the intracerebroventricular infusion of STZ increased Aβ level in all the rat brain regions. Conclusion: The α7 nAChR down regulation may form a basis to cognitive deficits along with cholinergic dysfunction, Aβ accumulation and mitochondrial dysfunction in memory sensitive rat brain regions. Thus, α7 nAChR could be an alternative and potential target in the management of AD. Key words: Alzheimer’s disease, Streptozotocin, α7 nAChR, Mitochondria, Acetylcholine, Hippocampus.

The γ-Benzylidene Digoxin Derivative BD-15 Increases the α3-Na, K-ATPase Activity in Rat Hippocampus and Prefrontal Cortex and no Change on Heart.

Our study aimed to investigate the effects of the new cardiotonic steroid BD-15 (γ-benzylidene derivatives) in the behavioral parameters, oxidative stress and the Na, K-ATPase activity in the hippocampus, prefrontal cortex and heart from rats to verify the safety and possible utilization in brain disorders. For this study, groups of male Wistar rats were used after intraperitoneal injection of 20, 100 and 200µg/Kg with BD-15. The groups were treated for three consecutive days and the control group received 0.9% saline. BD-15 did not alter behavior of rats treated with different doses. An increase in the specific α2,3-Na, K-ATPase activity was observed for all doses of BD-15 tested in the hippocampus. However, in the prefrontal cortex, only the dose of 100µg/Kg increased the activity of all Na, K-ATPase isoforms. BD-15 did not cause alteration in the lipid peroxidation levels in the hippocampus, but in the prefrontal cortex, a decrease of lipid peroxidation (~ 25%) was observed. In the hippocampus, GSH levels increased with all doses tested, while in the prefrontal cortex no changes were found. Subsequently, when the effect of BD-15 on cardiac tissue was analyzed, no changes were observed in the tested parameters. BD-15 at a dosage of 100µg/Kg proved to be promising because it is considered therapeutic for brain disorders, since it increases the activity of the α3-Na, K-ATPase in the hippocampus and prefrontal cortex, as well as decreasing the oxidative stress in these brain regions. In addition, this drug did not cause changes in the tissues of the heart and kidneys, preferentially demonstrating specificity for the brain.

Effect of acute mitochondrial dysfunction on hyperexcitable network activity in rat hippocampus in vitro

Metabolic stress imposed by epileptic seizures can result in mitochondrial dysfunction, believed to act as positive feedback on epileptogenesis and seizure susceptibility. As the mechanism behind this positive feedback is unclear, the aim of the present study was to investigate the causal link between acute mitochondrial dysfunction and increased seizure susceptibility in hyperexcitable hippocampal networks. Following the induction of spontaneous interictal-like discharges, acute selective pharmacological blockade of either of the mitochondrial respiratory complexes (MRC) I-IV induced seizure-like events (SLE) in 78–100% of experiments. A similar result was obtained by uncoupling the oxidative phosphorylation (OXPHOS) but not by selective blockade of MRCV (ATP synthase) which did not induce SLE. The reactive oxygen species (ROS) scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol, 2 mM) significantly reduced the proconvulsant effect of blocking MRCI but did not reduce the proconvulsant effect of OXPHOS uncoupling. These findings indicate that acute mitochondrial dysfunction can lead to a convulsive state within a short timeframe, and that increased ROS production makes substantial contribution to such induction in addition to other mitochondrial related factors, which appears to be independent of changes in ROS and ATP production.

Curcumin Exerted Neuroprotection against Ozone-Induced Oxidative Damage and Decreased NF-κB Activation in Rat Hippocampus and Serum Levels of Inflammatory Cytokines.

Ozone is a harmful tropospheric pollutant, causing the formation of reactive oxygen and nitrogen species that lead to oxidative damage in living beings. NF-κB can be activated in response to oxidative damage, inducing an inflammatory response. Nowadays, there are no reliable results that consolidate the use of antioxidants to protect from damage caused by ozone, particularly in highly polluted cities. Curcumin has a strong antioxidant activity and is a potent inhibitor of NF-κB activation with no side effects. The aim of this study is to evaluate the effect of curcumin in preventive and therapeutic approaches against oxidative damage, NF-κB activation, and the rise in serum levels of IL-1β and TNF-α induced by acute and chronic exposure to ozone in rat hippocampus. One hundred male Wistar rats were distributed into five groups; the intact control, curcumin-fed control, the ozone-exposed group, and the preventive and therapeutic groups. These last two groups were exposed to ozone and received food supplemented with curcumin. Lipid peroxidation was determined by spectrophotometry, and protein oxidation was evaluated by immunodetection of carbonylated proteins and densitometry analysis. Activation of NF-κB was assessed by electrophoretic mobility shift assay (EMSA), and inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. Curcumin decreased NF-κB activation and serum levels of inflammatory cytokines as well as protein and lipid oxidation, in both therapeutic and preventive approaches. Curcumin has proven to be a phytodrug against the damage caused by the environmental exposure to ozone.

Salvianolic acid B protects against lipopolysaccharide-induced behavioral deficits and neuroinflammatory response: involvement of autophagy and NLRP3 inflammasome

BackgroundThe NLRP3 inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines. Given the emerging evidence that autophagy dysfunction plays an essential role in depression, it is very likely that autophagy may interact with the inflammatory process in the development and treatment of depression. Salvianolic acid B (SalB), a naturally occurring compound extracted from Salvia miltiorrhiza, contains anti-inflammatory and antidepression properties and has recently been proven to modulate autophagy. In this study, we sought to investigate whether autophagy is involved in the inflammation-induced depression and the antidepressant effects of SalB.MethodsThe effects of prolonged lipopolysaccharide (LPS) treatment and SalB administration on behavioral changes, neuroinflammation, autophagic markers and NLRP3 activation in rat hippocampus were determined by using behavioral tests, real-time PCR analysis, western blot, and immunostaining.ResultsOur data showed that periphery immune challenge by LPS for 2 weeks successfully induced the rats to a depression-like state, accompanied with enhanced expression of pro-inflammatory cytokines and NLRP3 inflammasome activation. Interestingly, autophagic markers, including Beclin-1, and the ratio of LC3II to LC3I were suppressed following prolonged LPS exposure. Meanwhile, co-treatment with SalB showed robust antidepressant effects and ameliorated the LPS-induced neuroinflammation. Additionally, SalB restored the compromised autophagy and overactivated NLRP3 inflammasome in LPS-treated rats.ConclusionsCollectively, these data suggest that autophagy may interact with NLRP3 activation to contribute to the development of depression, whereas SalB can promote autophagy and induce the clearance of NLRP3, thereby resulting in neuroprotective and antidepressant actions.

Alteration of Interneuron Immunoreactivity and Autophagic Activity in Rat Hippocampus after Single High-Dose Whole-Brain Irradiation.

The effects of high dose gamma radiation on brain tissue are poorly understood, with both limited and major changes reported. The present study compared the effects of gamma irradiation on the expression of interneuron markers within the hippocampal cornu ammonis 1 (CA1) region with expression in control matched rats. This area was chosen for study because of its well-characterized circuitry. Male Sprague-Dawley rats were exposed to 60 Gy of whole brain gamma radiation and after 24 or 48 hours, the brains were removed, fixed and sectioned to quantitate expression of parvalbumin (PV), calbindin-D28K (CB), reelin, neuropeptide-Y (NPY), and somatostatin. All of these markers increased in expression over the first 48 hours, except NPY, which decreased. This provides novel information on changes in gene expression in the hippocampal interneurons following radiation. Staining for Beclin 1, a marker of autophagy, increased most strongly in the subgranular zone (SGZ) of the dentate gyrus (DG). Overall, the results are consistent with the hypothesis that increased intracellular calcium follows irradiation, leading to an increased expression of calcium binding proteins. Increased autophagy occurs in the neurogenic zone of the dentate hilus, consistent with reduced effective neurogenesis after irradiation.

Effects of cadmium on Bcl-2/ Bax expression ratio in rat cortex brain and hippocampus.

To investigate the underlying mechanism of neurotoxicity of cadmium, we examined the effects of intraperitoneal injection of cadmium on messenger RNA (mRNA) expression of Bcl-2 (B-cell lymphoma 2) and Bax (Bcl2-associated x) genes and caspase-3/7 activation in rat hippocampus and frontal cortex. Twenty-eight male Wistar rats weighing 200-250 g were randomly divided into four groups. Control group received saline and three other groups received cadmium at doses of 1, 2 and 4 mg/kg (body weight) for 15 successive days. One day after the last injection, the hippocampus and frontal cortex were dissected and removed and then the expression of Bcl-2 and Bax genes was evaluated using real-time polymerase chain reaction and apoptotic studies was done using caspase-3/7 activation assay. Cadmium reduced the mRNA level of Bcl-2 in the control group at doses of 1 ( p < 0.01), 2 and 4 mg/kg ( p < 0.001) in rat hippocampus and cortex cells. The mRNA level of Bax increased significantly compared to the control group at the doses of 1 ( p < 0.05), 2 and 4 mg/kg ( p < 0.001) in rat hippocampus. The mRNA level of Bax was increased significantly compared to the control group at the doses of 2 and 4 mg/kg ( p < 0.001) in rat cortex cells. Cadmium increased caspase-3/7 activity at doses of 1, 2 and 4 mg/kg in rat hippocampus. Caspase-3/7 activity was increased significantly at dose of 4 mg/kg in rat cortex. This decreased Bcl-2/Bax mRNA ratio induces cell apoptosis. Apoptotic effect of cadmium may be through the mitochondrial pathway by the activation of caspase-3/7.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus

The recreational drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X7 receptor-mediated event which induces MMP-9 activity. Increased BBB permeability often causes plasma proteins and water to access cerebral tissue leading to vasogenic edema formation. The current study was performed to examine the effect of a single neurotoxic dose of MDMA (12.5 mg/kg, i.p.) on in vivo edema development associated with changes in the expression of the perivascular astrocytic water channel, AQP4, as well as in the expression of the tight-junction (TJ) protein, claudin-5 and Evans Blue dye extravasation in the hippocampus of adult male Dark Agouti rats. We also evaluated the ability of the MMP-9 inhibitor, SB-3CT (25 mg/kg, i.p.), to prevent these changes in order to validate the involvement of MMP-9 activation in MDMA-induced BBB disruption. The results show that MDMA produces edema of short duration temporally associated with changes in AQP4 expression and a reduction in claudin-5 expression, changes which are prevented by SB-3CT. In addition, MDMA induces a short-term increase in both tPA activity and expression, a serine-protease which is involved in BBB disruption and upregulation of MMP-9 expression. In conclusion, this study provides evidence enough to conclude that MDMA induces edema of short duration due to BBB disruption mediated by MMP-9 activation.

Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1.

Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1β, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.

Role of Sialidase in Long-Term Potentiation at Mossy Fiber-CA3 Synapses and Hippocampus-Dependent Spatial Memory.

Sialic acid bound to glycans in glycolipids and glycoproteins is essential for synaptic plasticity and memory. Sialidase (EC 3.2.1.18), which has 4 isozymes including Neu1, Neu2, Neu3 and Neu4, regulates the sialylation level of glycans by removing sialic acid from sialylglycoconjugate. In the present study, we investigated the distribution of sialidase activity in rat hippocampus and the role of sialidase in hippocampal memory processing. We previously developed a highly sensitive histochemical imaging probe for sialidase activity, BTP3-Neu5Ac. BTP3-Neu5Ac was cleaved efficiently by rat Neu2 and Neu4 at pH 7.3 and by Neu1 and Neu3 at pH 4.6. When a rat hippocampal acute slice was stained with BTP3-Neu5Ac at pH 7.3, mossy fiber terminal fields showed relatively intense sialidase activity. Thus, the role of sialidase in the synaptic plasticity was investigated at mossy fiber terminal fields. The long-term potentiation (LTP) at mossy fiber-CA3 pyramidal cell synapses was impaired by 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA), a sialidase inhibitor. DANA also failed to decrease paired-pulse facilitation after LTP induction. We also investigated the role of sialidase in hippocampus-dependent spatial memory by using the Morris water maze. The escape latency time to reach the platform was prolonged by DANA injection into the hippocampal CA3 region or by knockdown of Neu4 without affecting motility. The results show that the regulation of sialyl signaling by Neu4 is involved in hippocampal memory processing.

Anticonvulsant effect of argan oil on pilocarpine model induced status epilepticus in wistar rats

Argan oil (AO) is rich in oleic and linoleic acids, polyphenols, sterols, and tocopherols. This composition gives it numerous beneficial pharmacological effects such as hypolipemiant, hypotensive, and antiproliferative. Oxidative stress is a mechanism of cell death induced by seizures and status epilepticus (SE). This study aims at investigating AO effects on (i) latency to first seizure, seizure severity, weight loss, mortality rate, (ii) lipid peroxidation level, nitrite level, and catalase activity in the hippocampus after SE induced by pilocarpine (PC). Wistar rats (1-month old) were daily administered by oral gavage with AO (1 ml/100 g/day) or with NaCl 0.9% during 2 months before receiving PC (400 mg/kg). After the PC injection, all groups were observed for 24 h. The catalase activity, the lipid peroxidation, and nitrite concentrations were measured using spectrophotometric methods. AO pretreatment increased the latency to first seizures, decreased the weight loss, and reduced mortality rate after SE. AO pretreatment produces significant decrease of the lipid peroxidation and nitrite levels. On the contrary, AO increased the catalase activity in rat hippocampus after seizures. For the first time, our results suggest that AO pretreatment is capable of attenuating seizure severity and oxidative stress in the hippocampus of Wistar rats. This indicates that AO may exhibit a neuroprotection against the temporal lobe epilepsy. Further investigations are in progress to confirm this pharmacological property.

80 Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the A7 nicotinic acetylcholine receptor

Introduction A considerable number of studies have demonstrated that nicotine, a α 7-nicotinic acetylcholine receptor ( α 7-nAChR) agonist, can dampen immune response through the cholinergic anti-inflammatory pathway. Evidence suggests that inflammation plays a critical role in eclampsia, which contributes to maternal and fetal morbidity and mortality. Objectives In the present study, possible anti-inflammation and neuro-protective effects of nicotine via α 7-nAChRs have been investigated after inducing eclampsia-like seizures in rats. Methods Rat eclampsia-like models were established by administering lipopolysaccharide (LPS) plus pentylenetetrazol (PTZ) in pregnant rats. Rats were given nicotine from gestation day (GD) 14–19. Then, clinical symptoms were detected. Seizure severity was recorded by behavioral tests, serum levels of inflammatory cytokines were measured by Luminex assays, microglia and astrocyte expressions were detected by immunofluorescence, and changes in neuronal number in the hippocampal CA1 region among different groups were detected by Nissl staining. Results Our results revealed that nicotine effectively improved fetal outcomes. Furthermore, it significantly decreased systolic blood pressure, and maternal serum levels of Th1 cytokines (TNF- α , IL-1 β , IL-6 and IL-12P70) and an IL-17 cytokine (IL-17A), dramatically increased Th1 cytokine (IL-4) and eclampsia-like seizure threshold. Moreover, this attenuated neuronal loss and decreased the expression of microglial activation markers of the hippocampal CA1 region in the eclampsia-like group. Additionally, pretreatment with α -bungarotoxin, a selective α 7-nAChR antagonist could prevent the protective effects of nicotine in eclampsia-like model rats. Conclusion Our findings indicate that the administration of nicotine may increase eclampsia-like seizure threshold and attenuate microglial activity in rat hippocampus through the α 7 nicotinic receptor.

Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the α7 nicotinic acetylcholine receptor

ObjectiveA considerable number of studies have demonstrated that nicotine, a α7-nicotinic acetylcholine receptor (α7-nAChR) agonist, can dampen immune response through the cholinergic anti-inflammatory pathway. Evidence suggests that inflammation plays a critical role in eclampsia, which contributes to maternal and fetal morbidity and mortality. In the present study, possible anti-inflammation and neuro-protective effects of nicotine via α7-nAChRs have been investigated after inducing eclampsia-like seizures in rats. MethodsRat eclampsia-like models were established by administering lipopolysaccharide (LPS) plus pentylenetetrazol (PTZ) in pregnant rats. Rats were given nicotine from gestation day (GD) 14–19. Then, clinical symptoms were detected. Seizure severity was recorded by behavioral tests, serum levels of inflammatory cytokines were measured by Luminex assays, microglia and astrocyte expressions were detected by immunofluorescence, and changes in neuronal number in the hippocampal CA1 region among different groups were detected by Nissl staining. ResultsOur results revealed that nicotine effectively improved fetal outcomes. Furthermore, it significantly decreased systolic blood pressure, and maternal serum levels of Th1 cytokines (TNF-α, IL-1β, IL-6 and IL-12P70) and an IL-17 cytokine (IL-17A), and dramatically increased eclampsia-like seizure threshold. Moreover, this attenuated neuronal loss and decreased the expression of microglial activation markers of the hippocampal CA1 region in the eclampsia-like group. Additionally, pretreatment with α-bungarotoxin, a selective α7-nAChR antagonist could prevent the protective effects of nicotine in eclampsia-like model rats. ConclusionOur findings indicate that the administration of nicotine may attenuate microglial activity and increase eclampsia-like seizure threshold in rat hippocampus through the α7 nicotinic receptor.

Theta oscillation and neuronal activity in rat hippocampus are involved in temporal discrimination of time in seconds.

The discovery of time cells revealed that the rodent hippocampus has information regarding time. Previous studies have suggested that the role of hippocampal time cells is to integrate temporally segregated events into a sequence using working memory with time perception. However, it is unclear whether hippocampal cells contribute to time perception itself because most previous studies employed delayed matching-to-sample tasks that did not separately evaluate time perception from working memory processes. Here, we investigated the function of the rat hippocampus in time perception using a temporal discrimination task. In the task, rats had to discriminate between durations of 1 and 3 s to get a reward, and maintaining task-related information as working memory was not required. We found that some hippocampal neurons showed firing rate modulation similar to that of time cells. Moreover, theta oscillation of local field potentials (LFPs) showed a transient enhancement of power during time discrimination periods. However, there were little relationships between the neuronal activities and theta oscillations. These results suggest that both the individual neuronal activities and theta oscillations of LFPs in the hippocampus have a possibility to be engaged in seconds order time perception; however, they participate in different ways.

Post-occlusion administration of sodium butyrate attenuates cognitive impairment in a rat model of chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) has been commonly associated with Alzheimer's disease and other types of dementia, but therapies that can improve cerebral blood flow displayed little effect on impaired cognition. Epigenetic intervention with histone deacetylase inhibitors, such as sodium butyrate (SB), on the other hand has been shown to improve cognition in several animal models of dementia. To investigate the effect of SB on cognitive impairment induced by CCH in rats, adult male SD rats were given intraperitoneal injections of SB at a daily dose of 840mg/kg for 4weeks, from the 29th day after permanent occlusion of bilateral common carotid arteries (2VO). Learning and memory were assessed by Morris water maze and novel object recognition. Following behavioral tests, western blotting of histone acetylation, of transcription factors, of neuronal/synaptic proteins, were performed using rat hippocampus and cortex. The data showed that SB treatment alleviated hippocampal dependent spatial learning disability in 2VO rats, and altered HDAC1/2 mRNA level, histone H4 acetylation and Nrf2 transcriptional activation in rat hippocampus. Accordingly, cognition-protective effect of SB appeared to be partially mediated by enhancing histone acetylation and hence by facilitating the transcription of Nrf2 downstream genes in the hippocampus. Thus, SB might be considered for putative treatment for CCH-related cognitive impairment.

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

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

Clustered c-Fos Activation in Rat Hippocampus at the Acquisition Stage of Appetitive Instrumental Learning

To address the issue of how hippocampal neurons are involved into learning progress, we studied c-Fos expression in rat hippocampal subfields at different stages of appetitive instrumental learning. To model the first stage of learning, we pre-trained animals to approach the lever to obtain the food, and then made this behavior ineffective by not reinforcing it during the last session (“mismatch” group). Another group just acquired lever-pressing behavior at that day (“acquisition” group). Animals of the third group performed this well-trained behavior (“performance” group). The number of Fos-positive neurons in all hippocampal regions of the “mismatch” group animals was higher than in the ones of the home cage control group animals. The number of Fos-positive neurons was increased in CA1 and CA3 areas, but not in the dentate gyrus of both the “acquisition” and “performance” group animals as compared with the control group. We also found segmented c-Fos expression, which was more evident in “acquisition” group animals. Thus, our results suggest that during the first (mismatch) stage of learning hippocampal neurons are activated in an equally distributed manner. The following clustered pattern of activated CA1 neurons during the acquisition stage may reflect specialization of these neurons in respect to the specific lever-pressing behavior.