Rat CA1 Research Articles

Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing.

A synergistic combination of in vitro electrophysiology and multicompartmental modeling of rat CA1 pyramidal neurons identified TRPM4 channels as major drivers of cholinergic modulation of the firing rate during a triangular current ramp, which emulates the bump in synaptic input received while traversing the place field. In control, fewer spikes at lower frequencies are elicited on the down-ramp compared to the up-ramp due to long-term inactivation of the NaV channel. The cholinergic agonist carbachol (CCh) removes or even reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-ramp. CCh application during Schaffer collateral stimulation designed to simulate a ramp produces similar shifts in the center of mass of firing to later in the ramp. The non-specific TRP antagonist flufenamic acid and the TRPM4-specific blockers CBA and 9-phenanthrol, but not the TRPC-specific antagonist SKF96365, reverse the effect of CCh; this implicates the Ca2+-activated nonspecific cation current, ICAN, carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca2+ buffering but not by antagonists for IP3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca2+ stores. Pharmacology combined with modeling suggest that [Ca2+] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca2+ influx during the ramp. Activation of the regenerative inward TRPM4 current in the model qualitatively replicates and provides putative underlying mechanisms for the experimental observations.

Transcriptomic analysis reveals distinct adaptive molecular mechanism in the hippocampal CA3 from rats susceptible or not-susceptible to hyperthermia-induced seizures

Febrile seizures during early childhood are a relevant risk factor for the development of mesial temporal lobe epilepsy. Nevertheless, the molecular mechanism induced by febrile seizures that render the brain susceptible or not-susceptible to epileptogenesis remain poorly understood. Because the temporal investigation of such mechanisms in human patients is impossible, rat models of hyperthermia-induced febrile seizures have been used for that purpose. Here we conducted a temporal analysis of the transcriptomic and microRNA changes in the ventral CA3 of rats that develop (HS group) or not-develop (HNS group) seizures after hyperthermic insult on the eleventh postnatal day. The selected time intervals corresponded to acute, latent, and chronic phases of the disease. We found that the transcriptional differences between the HS and the HNS groups are related to inflammatory pathways, immune response, neurogenesis, and dendritogenesis in the latent and chronic phases. Additionally, the HNS group expressed a greater number of miRNAs (some abundantly expressed) as compared to the HS group. These results indicate that HNS rats were able to modulate their inflammatory response after insult, thus presenting better tissue repair and re-adaptation. Potential therapeutic targets, including genes, miRNAs and signaling pathways involved in epileptogenesis were identified.

Global Cerebral Ischemia Induces Short-Term Changes to Estrous Cycle Regularity and Alters Hypothalamic-Pituitary-Gonadal Axis Function

Global cerebral ischemia (GCI), which mimics cardiac arrest in humans, induces numerous functional alterations throughout the brain, but its impact on the hypothalamic-pituitary-gonadal (HPG) axis remains largely unknown. Importantly, the HPG axis modulates sex hormones and neuropeptides, such as estrogen and kisspeptin, as well as estrous cycle regularity. The goals of this study were to determine if estrous cycle regularity is affected by GCI and to characterize HPG axis functionality post-ischemia. Adult female Wistar rats underwent vaginal lavage for 2 weeks to confirm estrous cycle regularity before being subjected to GCI for 10 minutes or sham surgery. Estrous cycle regularity was monitored for 4 weeks following surgery, after which rats were euthanized. Immunofluorescence was used to detect kisspeptin receptors (Kiss1) and estrogen receptors alpha (ERα) and beta (ERβ) expression in the arcuate nucleus (ARC) of the hypothalamus, as well as the CA1 and dentate gyrus (DG) of the hippocampus. Following surgery, all sham subjects maintained a regular estrous cycle, whereas two thirds of ischemic rats presented a disrupted cycle following GCI (persistent diestrus, average length 13 days), before resuming regular cycling. T-test revealed a significant increase in Kiss1 receptors in the ARC of GCI rodents, as well as a trend for higher ERα expression in the CA1 of ischemic rats. Overall, our results highlight that while estrous cycle disruptions resolve within 2 weeks after the ischemic event, HPG axis dysregulation persists up to one month after GCI, hinting at possible long-term impacts on the reproductive axis.

Pharmacological Characterization of P626, a Novel Dual Adenosine A2A/A2B Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (A1AR, A2AAR, A2BAR, A3AR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of A2AAR or A2BAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus. Furthermore, the stimulation of A2AARs or A2BARs by respective selective agonists, CGS21680 and BAY60-6583, increases pre-synaptic neurotransmitter release, as shown by the decrease in paired-pulse facilitation (PPF) at Schaffer collateral-CA1 synapses. In the present research, we investigated the effect/s of the newly synthesized dual A2AAR/A2BAR antagonist, P626, in preventing A2AAR- and/or A2BAR-mediated effects by extracellular recordings of synaptic potentials in the CA1 rat hippocampal slices. We demonstrated that P626 prevented PPF reduction induced by CGS21680 or BAY60-6583 and delayed, in a concentration-dependent manner, AD appearance during a severe OGD. In conclusion, P626 may represent a putative neuroprotective compound for stroke treatment with the possible translational advantage of reducing side effects and bypassing differences in pharmacokinetics due to combined treatment.

Hippocampal and Medial Prefrontal Cortex Fractal Spiking Patterns Encode Episodes and Rules

A central question in neuroscience is how the brain represents and processes information to guide behavior. The principles that organize brain computations are not fully known, and could include scale-free, or fractal patterns of neuronal activity. Scale-free brain activity may be a natural consequence of the relatively small subsets of neuronal populations that respond to task features, i.e., sparse coding. The size of the active subsets constrains the possible sequences of inter-spike intervals (ISI), and selecting from this limited set may produce firing patterns across wide-ranging timescales that form fractal spiking patterns. To investigate the extent to which fractal spiking patterns corresponded with task features, we analyzed ISIs in simultaneously recorded populations of CA1 and medial prefrontal cortical (mPFC) neurons in rats performing a spatial memory task that required both structures. CA1 and mPFC ISI sequences formed fractal patterns that predicted memory performance. CA1 pattern duration, but not length or content, varied with learning speed and memory performance whereas mPFC patterns did not. The most common CA1 and mPFC patterns corresponded with each region's cognitive function: CA1 patterns encoded behavioral episodes which linked the start, choice, and goal of paths through the maze whereas mPFC patterns encoded behavioral “rules” which guided goal selection. mPFC patterns predicted changing CA1 spike patterns only as animals learned new rules. Together, the results suggest that CA1 and mPFC population activity may predict choice outcomes by using fractal ISI patterns to compute task features.

Vesicular acetylcholine transporter in the basal forebrain improves cognitive impairment in chronic cerebral hypoperfusion rats by modulating theta oscillations in the hippocampus

The cholinergic transmission in the medial septum and ventral limb of the diagonal band of broca (MS/VDB)-hippocampal circuit and its associated theta oscillations play a crucial role in chronic cerebral hypoperfusion (CCH)-related cognitive impairment. However, the contribution and mechanism of the vesicular acetylcholine transporter (VAChT), a vital protein that regulates acetylcholine (ACh) release, in CCH-related cognitive impairment are not well understood. To investigate this, we established a rat model of CCH by performing 2-vessel occlusion (2-VO) and overexpressed VAChT in the MS/VDB via stereotaxic injection of adeno-associated virus (AAV). We evaluated the cognitive function of the rats using the Morris Water Maze (MWM) and Novel Object Recognition Test (NOR). We employed enzyme-linked immunosorbent assay (ELISA), Western blot (WB), and immunohistochemistry (IHC) to assess hippocampal cholinergic levels. We also conducted in vivo local field potentials (LFPs) recording experiments to evaluate changes in hippocampal theta oscillations and synchrony. Our findings showed that VAChT overexpression shortened the escape latency in the hidden platform test, increased swimming time in the platform quadrant in probe trains, and increased the recognition index (RI) in NOR. Moreover, VAChT overexpression increased hippocampal cholinergic levels, improved theta oscillations, and improved the synchrony of theta oscillations between CA1 and CA3 in CCH rats. These results suggest that VAChT plays a protective role in CCH-induced cognitive deficits by regulating cholinergic transmission in the MS/VDB-hippocampal circuit and promoting hippocampal theta oscillations. Therefore, VAChT could be a promising therapeutic target for treating CCH-related cognitive impairments.

Hippocampal 4-Hz oscillations emerge during stationary running in a wheel and are resistant to medial septum inactivation.

Recent studies described 2-4 Hz oscillations in the hippocampus of rats performing stationary locomotion on treadmills and other apparatus. Since the 2-4 Hz rhythm shares common features with theta (5-12 Hz) oscillations-such as a positive amplitude-running speed relationship and modulation of spiking activity-many have questioned whether these rhythms are related or independently generated. Here, we analyzed local field potentials and spiking activity from the dorsal CA1 of rats executing a spatial alternation task and running for ~15 s in a wheel during the intertrial intervals both before and after muscimol injection into the medial septum. We observed remarkable 4-Hz oscillations during wheel runs, which presented amplitude positively correlated with running speed. Surprisingly, the amplitude of 4-Hz and theta oscillations were inversely related. Medial septum inactivation abolished hippocampal theta but preserved 4-Hz oscillations. It also affected the entrainment of pyramidal cells and interneurons by 4-Hz rhythmic activity. In all, these results dissociate the underlying mechanism of 4-Hz and theta oscillations in the rat hippocampus.

Hippocampus mitochondrial MnSOD activation by a SIRT3 activator, honokiol, correlates with its deacetylation and upregulation of FoxO3a and PGC1α in a rat model of ammonia neurotoxicity.

We have recently reported that honokiol (HKL), by activating mitochondrial SIRT3, normalizes reactive oxygen species level and mitochondrial integrity in hippocampus of the moderate grade hepatic encephalopathy (MoHE) rat model of ammonia neurotoxicity. To delineate the mechanism by which HKL does so, the present study describes activity versus level of the deacetylated mitochondrial Mn-superoxide dismutase (MnSOD) and expression of MnSOD versus levels of its main transcription regulators, FoxO3a and PGC1α, in the hippocampus of the MoHE rats. MoHE in rat was developed by administration of 100 mg/kg bw thioacetamide i.p. for 10 days. The study parameters were compared between the control, the MoHE rats and the MoHE rats treated with HKL (10 mg/Kg b.w.) for 7 days. As compared to control, the hippocampus mitochondria from MoHE rats showed a significantly declined activity of MnSOD vs enhanced lipid peroxidation coinciding with the increased level of its acetylated form. The HKL treatment could, however, normalize all these parameters in those MoHE rats. Also, a significantly reduced expression of MnSOD in the hippocampus of the MoHE rats coincided with a similar decline in transcript level of Foxo3a and Pgc1α. This was consistent with the reduced level of immuno-stained Foxo3a and Pgc1α proteins in hippocampus DG, CA1 and CA3 regions of those MoHE rats. However, all these factors were observed to be restored back to their normal levels due to the treatment with HKL. As HKL is a specific activator of mitochondrial SIRT3, these findings suggest involvement of Sirt3 activation led deacetylation of MnSOD and upregulation of its transcription activators, FoxO3a and PGC1α, in restoring mitochondrial MnSOD level in the hippocampus of the MoHE rat model of ammonia neurotoxicity.

Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1

Hypoxic postconditioning (HPC) has been reported to enhance Parkin-catalyzed mitochondrial ubiquitination to restore mitophagy in hippocampal CA1 against transient global cerebral ischemia (tGCI). However, the molecular mechanism leading ubiquitinated mitochondria to final clearance during HPC-mediated mitophagy after tGCI is unclear. This study aims to investigate whether HPC restores mitophagy after tGCI through Parkin-induced K63-linked poly-ubiquitination (K63-Ub) to activate tumor necrosis factor associated factor family member associated nuclear factor κB activator -binding kinase 1 (TBK1) in CA1 of male rats. We found that HPC maintained TBK1 expression, promoted p62 and TBK1 phosphorylation in mitochondria, and enhanced their recruitments to mitochondria in CA1 after tGCI. However, these effects were partially abolished by TBK1 inhibitor BX795. K63-Ub of mitochondrial TBK1 was disturbed at 26 h of reperfusion after tGCI, which was reversed by HPC. The maintenance of K63-Ub of mitochondrial TBK1 induced by HPC was counteracted under Parkin knockdown with AAV-mediated Prkn small-interfering RNA, accompanied by the suppression on TBK1 activation and the reduction of mitochondrial p62 phosphorylation. This innovative study indicated that HPC maintained K63-Ub of TBK1 in a Parkin-dependent manner to promote TBK1 phosphorylation, and then phosphorylated TBK1 activated p62 to restore mitophagy, thereby alleviating neuronal damage in CA1 after tGCI.

Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurrent visceral pain and altered bowel habits (diarrhea or constipation). However, the molecular and pathological mechanisms are poorly understood. This study found neonatal colorectal distension to induce visceral hypersensitivity and anxiety. The expression of hippocampal circKcnk9, a novel circRNA, was significantly increased in IBS-like rats. Interestingly, CA1 shcircKcnk9 treatment inhibited long-term potentiation (LTP) and alleviated visceral hypersensitivity and anxiety in IBS-like rats, whereas overexpression of CA1 circKcnk9 induced LTP, visceral hypersensitivity, and anxiety in controls. Several experiments indicated that increased CA1 circKcnk9 acted as a miR-124-3p sponge, which resulted in the inhibitory effect of miR-124-3p on gene silencing. There was a negative correlation between circKcnk9 and miR-124-3p expression. As expected, CA1 administration of agomiR-124-3p decreased CA1 LTP, visceral hypersensitivity, and anxiety in the IBS-like rats. In contrast, CA1 treatment with antagomiR-124-3p induced LTP, visceral hypersensitivity, and anxiety in the controls. Furthermore, bioinformatic analysis and experimental data showed that EZH2 is a circKcnk9/miR-124-3p target gene, and increased EZH2 expression was involved in visceral hypersensitivity and anxiety in IBS-like rats by enhancing hippocampal synaptic plasticity. In conclusion, early life stress induces increased expression of circKcnk9 in the CA1 of IBS-like rats. Increased circKcnk9 expression regulates synaptic transmission and enhances LTP, leading to visceral hypersensitivity and anxiety in IBS-like rats. The underlying circKcnk9 signaling pathway is miR124-3p/EZH2. Increased circKcnk9 reinforces its sponging of miR124-3p and strongly suppresses miR124-3p activity, resulting in increased expression of the target gene EZH2. This study provides a new epigenetic mechanism for visceral hypersensitivity and anxiety in IBS-like rats.

Maternal immune activation-induced proBDNF-mediated neural information processing dysfunction at hippocampal CA3-CA1 synapses associated with memory deficits in offspring.

Prenatal exposure to maternal infection increases the risk of offspring developing schizophrenia in adulthood. Current theories suggest that the consequences of MIA on mBDNF secretion may underlie the increased risk of cognitive disorder. There is little evidence for whether the expression of its precursor, proBDNF, is changed and how proBDNF-mediated signaling may involve in learning and memory. In this study, proBDNF levels were detected in the hippocampal CA1 and CA3 regions of male adult rats following MIA by prenatal polyI:C exposure. Behaviorally, learning and memory were assessed in contextual fear conditioning tasks. Local field potentials were recorded in the hippocampal CA3-CA1 pathway. The General Partial Directed Coherence approach was utilized to identify the directional alternation of neural information flow between CA3 and CA1 regions. EPSCs were recorded in CA1 pyramidal neurons to explore a possible mechanism involving the proBDNF-p75NTR signaling pathway. Results showed that the expression of proBDNF in the polyI:C-treated offspring was abnormally enhanced in both CA3 and CA1 regions. Meanwhile, the mBDNF expression was reduced in both hippocampal regions. Intra-hippocampal CA1 but not CA3 injection with anti-proBDNF antibody and p75NTR inhibitor TAT-Pep5 effectively mitigated the contextual memory deficits. Meanwhile, reductions in the phase synchronization between CA3 and CA1 and the coupling directional indexes from CA3 to CA1 were enhanced by the intra-CA1 infusions. Moreover, blocking proBDNF/p75NTR signaling could reverse the declined amplitude of EPSCs in CA1 pyramidal neurons, indicating the changes in postsynaptic information processing in the polyI:C-treated offspring. Therefore, the changes in hippocampal proBDNF activity in prenatal polyI:C exposure represent a potential mechanism involved in NIF disruption leading to contextual memory impairments.

TRPV1 channels in nitric oxide-mediated signalling: insight on excitatory transmission in rat CA1 pyramidal neurons.

Nitric oxide (NO) is a fascinating signalling molecule implicated in a plethora of biological functions, especially at the synaptic level. Exploring neurotransmission in the hippocampus could be instrumental in the individuation of putative targets for nitric-oxide mediated neuromodulation, especially in terms of the potential repercussions on fundamental processes i.e. synaptic plasticity and excitability-related phenomena. Among these targets, endovanilloid signalling constitutes an object of study since Transient Receptors Vanilloid type 1 (TRPV1) channels possess a NO-sensitive gate modulating its activation. Also, NO has been referred to as a mediator for numerous endocannabinoid effects. Notwithstanding, the linkage between TRPV1 and NO systems in neuromodulation still remains elusive. To this end, we aim at investigating the involvement of TRPV1 in nitric oxide-mediated influence on hippocampal processes. Electrophysiological whole-cell recordings in CA1 pyramidal neurons were applied to evaluate excitatory neurotransmission in rat brain slices. Indeed, miniature excitatory postsynaptic currents (mEPSCs) were analysed upon pharmacological manipulation of TRPV1 and NO signalling pathways. In detail, only the administration of the specific TRPV1 exogenous agonist - capsaicin - reduced the frequency and amplitude of mEPSC similarly to the inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (7NI). In contrast, capsazepine, TRPV1 antagonist, does not influence excitatory transmission. The combined TRPV1 activation and nNOS blockade confirm the presence of a putative common mechanism. When we administered the endovanilloid-endocannabinoid ligand, i.e. anandamide, we unveiled a potentiation of neurotransmission that was selectively reverted by 7NI. Our data suggest that nitric oxide influences TRPV1 hippocampal signalling since these channels are not constitutively active, but can be "on-demand" activated to modulate excitation in CA1 pyramidal neurons, and that this effect is linked to nitric oxide production.

Allopurinol attenuates repeated traumatic brain injury in old rats: A preliminary report

Traumatic brain injury (TBI) is an overlooked cause of morbidity, which was shown to accelerate inflammation, oxidative stress, and neuronal cell loss and is associated with spatial learning and memory impairments and some psychiatric disturbances in older adults. However, there is no effective treatment in order to offer a favorable outcome encompassing a good recovery after TBI in older adults. Hence, the present study aimed to investigate the histological and neurobehavioral effects of Allopurinol (ALL) in older rats that received repeated TBI (rTBI). For this purpose, a weight-drop rTBI model was used on old male Wistar rats. Rats received 5 repeated TBI/sham injuries 24 h apart and were treated with saline or Allopurinol 100 mg/kg, i.p. each time. They were randomly assigned to three groups: control group (no injury); rTBI group (received 5 rTBI and treated with saline); rTBI+ALL group (received 5 rTBI and treated with Allopurinol). Then, half of the animals from each group were sacrificed on day 6 and the remaining animals were assessed with Open field, Elevated plus maze and Morris Water Maze test. Basic neurological tasks were evaluated with neurological assessment protocol every other day until after the 19th day from the last injury. Brain sections were processed for neuronal cell count in the hippocampus (CA1), dentate gyrus (DG), and prefrontal cortex (PC). Also, an immunohistochemical assay was performed to determine NeuN, iNOS, and TNFα levels in the brain regions. The number of neurons was markedly reduced in CA1, GD, and PC in rats receiving saline compared to those receiving allopurinol treatment. Immunohistochemical analysis showed marked induction of iNOS and TNFα expression in the brain tissues which were reduced after allopurinol at 6 and 19 days post-injury. Also, ALL-treated rats demonstrated a remarkable induce in NeuN expression, indicating a reduction in rTBI-induced neuronal cell death. In neurobehavioral analyses, time spent in closed arms, in the corner of the open field, swimming latency, and distance were impaired in injured rats; however, all of them were significantly improved by allopurinol therapy.To sum up, this study demonstrated that ALL may mitigate rTBI-induced damage in aged rats, which suggests ALL as a potential therapeutic strategy for the treatment of recurrent TBI.

Electroacupuncture Promotes Autophagy by Regulating the AKT/mTOR Signaling Pathway in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is a complex neurological disease, and its occurrence and development are closely related to the autophagy signaling pathway. However, the mechanism by which electroacupuncture (EA) affects the regulation of autophagy has not been fully elucidated. TLE gene chip dataset GSE27166 and data from rats without epilepsy (n = 6) and rats with epilepsy (n = 6) were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) in the TLE and control groups were identified with the online tool GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyse the functional and pathway enrichment of genes in the most important modules. A rat model of TLE induced by lithium-pilocarpine treatment was established. EA treatment at DU20 and DU14 in TLE rats was performed for 2weeks. Neuronal regeneration was determined using immunofluorescence staining. The protein levels of AKT/mTOR signaling pathway and autophagy markers were detected through western blotting and immunohistochemistry. This study identified 1837 DEGs, including 798 upregulated genes and 1039 downregulated genes. GO enrichment and KEGG analyses were performed on DEGs and revealed functional enrichment mainly in the mTOR signaling pathway and autophagy-animal. Furthermore, the number of mature neurons was significantly increased upon coexpressing BrdU/NeuN in TLE rats treated with EA. Western blotting and immunohistochemistry results showed significantly decreased levels of the phosphorylated-AKT and p-mTOR in the hippocampal CA3 and DG regions of TLE rats with EA treatment. And increased p-ULK1/ULK1, LC3-II/LC3-I and p62 levels in TLE rats with EA stimulation. Therefore, this study suggested that EA promoted autophagy in hippocampal neurons during the onset of epilepsy by regulating the AKT/mTOR signaling pathway to treat epilepsy.

Loss of functional heterogeneity along the CA3 transverse axis in aging

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. Functional heterogeneity in CA3 was observed in Y and AU rats when the environmental similarity was high (altered cues or altered environment shapes in the same room), with more orthogonalized representations in proximal CA3 than in distal CA3. In contrast, AI rats showed reduced orthogonalization in proximal CA3 but showed normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. Under experimental conditions when the environmental similarity was low (different rooms), representations in proximal and distal CA3 remapped in all rats, showing that CA3 of AI rats is able to encode distinctive representations for inputs with greater dissimilarity. These experiments support the hypotheses that the age-related bias toward hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis.

Distinct Role of Mono-2-ethylhexyl Phthalate in Neuronal Transmission in Rat CA3 Hippocampal Neurons: Involvement of Ion Channels.

Mono-(2-ethylhexyl) phthalate (MEHP) is one of the main active metabolites of di-(2-ethylhexyl) phthalate (DEHP). In our previous works, by using rat and Drosophila models, we showed a disruption of neural function due to DEHP. However, the exact neural effects of MEHP are still unclear. To explore the effects of MEHP on the central nervous system, the electrophysiological properties of spontaneous action potential (sAP), mini-excitatory postsynaptic currents (mEPSCs), ion channels, including Na+, Ca2+, and K+ channels from rat CA3 hippocampal neurons area were assessed. Our data showed that MEHP (at the concentrations of 100 or 300 μM) decreased the amplitude of sAP and the frequency of mEPSCs. Additionally, MEHP (100 or 300 μM) significantly reduced the peak current density of Ca2+ channels, whereas only the concentration of 300 μM decreased the peak current density of Na+ and K+ channels. Therefore, our results indicate that exposure to MEHP could affect the neuronal excitability and synaptic plasticity of rat CA3 hippocampal neurons by inhibiting ion channels’ activity, implying the distinct role of MEHP in neural transmission.

Advanced age has dissociable effects on hippocampal CA1 ripples and CA3 high frequency events in male rats

Sharp wave/ripples/high frequency events (HFEs) are transient bursts of depolarization in hippocampal subregions CA3 and CA1 that occur during rest and pauses in behavior. Previous studies have reported that CA1 ripples in aged rats have lower frequency than those detected in young animals. While CA1 ripples are thought to be driven by CA3, HFEs in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings from CA1 and CA3 in young and aged rats to examine sharp wave/ripples/HFEs in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in the frequency of CA3 HFEs, although power and length were lower in old animals. While there was a proportion of CA1 ripples that co-occurred with a CA3 HFE, none of the age-related differences in CA1 ripples could be explained by alterations in CA3 HFE characteristics. These findings suggest that age differences in CA1 are not due to altered CA3 activity, but instead reflect distinct mechanisms of ripple generation with age.

Transcranial photobiomodulation (808nm) attenuates pentylenetetrazole-induced seizures by suppressing hippocampal neuroinflammation, astrogliosis, and microgliosis in peripubertal rats.

.Significance: Transcranial photobiomodulation (tPBM) at 808 nm attenuates pentylenetetrazole (PTZ)-induced seizures and convulsive status epilepticus (CSE) in peripubertal rats by protecting neurons from injury and parvalbumin-positive interneurons from apoptosis, and preserving the integrity of perisomatic inhibitory networks. However, the effects of tPBM on neuroinflammation, astrogliosis, and microgliosis in epileptic rat brains are unknown. Thus, further study to unveil these aspects is needed for understanding the phenomena of tPBM on pediatric CSE prevention.Aim: To evaluate the effects of tPBM on neuroinflammation, astrogliosis, and microgliosis in peripubertal rat hippocampus with PTZ-induced seizures and SE.Approach: An 808-nm diode laser was applied transcranially to peripubertal rats prior to PTZ injection. Immunofluorescence staining of neuron-specific enolase (NSE) was used as a marker of neuroinflammation, glial fibrillary acid protein (GFAP) for astrogliosis, ionized calcium-binding adapter molecule 1 (Iba-1) for microgliosis, and mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) for confirming the involvement of cytochrome c oxidase (CCO).Results: tPBM significantly reduced NSE immunoreactivity in CA3 in PTZ-treated rats, GFAP immunoreactivity in CA1, and Iba-1 immunoreactivity in CA3. Enhancement of hippocampal MT-CO1 reflected that tPBM acted in CCO-dependent manner.Conclusions: tPBM (808) attenuated PTZ-induced seizures and SE by suppressing neuroinflammation, astrogliosis, and microgliosis in peripubertal rats.

Behavioral and Cellular Tagging in Young and in Early Cognitive Aging.

The ability to maintain relevant information on a daily basis is negatively impacted by aging. However, the neuronal mechanism manifesting memory persistence in young animals and memory decline in early aging is not fully understood. A novel event, when introduced around encoding of an everyday memory task, can facilitate memory persistence in young age but not in early aging. Here, we investigated in male rats how sub-regions of the hippocampus are involved in memory representation in behavioral tagging and how early aging affects such representation by combining behavioral training in appetitive delayed-matching-to-place tasks with the “cellular compartment analysis of temporal activity by fluorescence in situ hybridization” technique. We show that neuronal assemblies activated by memory encoding were also partially activated by novelty, particularly in the distal CA1 and proximal CA3 subregions in young male rats. In early aging, both encoding- and novelty-triggered neuronal populations were significantly reduced with a more profound effect in encoding neurons. Thus, memory persistence through novelty facilitation engages overlapping hippocampal assemblies as a key cellular signature, and cognitive aging is associated with underlying reduction in neuronal activation.

Deficits of Learning and Spatial Memory are Associated with Increased Pyknosis of Pyramidal Neurons of the Hippocampus of Adult Rats with Chronic Hydrocephalus


 Background: The hippocampus is the brain's center for the consolidation of short-term and spatial memory that enables navigation. Hippocampal injury occurs in hydrocephalus and is associated with loss of memory.
 Objective: We assessed pyknotic changes in kaolin-induced chronic hydrocephalus in adult rats using qualitative and quantitative means, and related these to memory deficits in the rats.
 Methods: Adult rats were randomly divided into control and experimental groups. Hydrocephalus was induced by intracisternal injection of 0.1ml sterile kaolin suspension for 6weeks. Control rats received sham injections. Spatial memory was assessed with the Morris water maze test. Coronal sections of the brains were grouped into either mild or moderate hydrocephalus and then stained with H&E and cresyl violet stains. Thus, there were three groups: control, mild hydrocephalus and moderate hydrocephalus (n=10), respectively.
 Results: Shrinking and thinning of the hippocampal tissue, distortion of the pyramidal layer and pyknotic cells were observed in the CA1 and CA3 regions of the hydrocephalic rats. The pyknotic indices in the mild hydrocephalic rat (Cornus Ammonis, CA) CA1, CA2, CA3 (54.30±1.38; 27.62±0.83; 57.61±0.74) and moderate hydrocephalic rat CA1, CA2, CA3 (48.18±0.67; 32.00±0.84; 42.41±1.19) regions were significantly increased compared to the controls' CA1, CA2, CA3 (12.14±0.56; 9.21±0.36; 13.04±0.59).
 Conclusion: Chronic hydrocephalus in adult rats was associated with cell death in all the regions of the hippocampus, irrespective of the degree of ventricular enlargement. The extent of cell death corresponded with the severity of learning and memory deficits.
 Background: The hippocampus is the center of the brain for the consolidation of short-term memory and spatial memory that enables navigation. Hippocampal damage occurs in hydrocephalus and is associated with memory loss.
 Objective: We assessed pyknotic changes in chronic kaolin-induced hydrocephalus in adult rats using qualitative and quantitative means, and related them to memory deficits in rats.
 Methods: Adult rats were randomly assigned to control and experimental groups. Hydrocephalus was induced by intracisternal injection of 0.1 ml of sterile kaolin suspension for 6 weeks. Control rats received sham injections. Spatial memory was assessed by the Morris water maze test. Coronal sections of brains were grouped into mild or moderate hydrocephalus and then stained with H&E and cresyl violet. There were therefore three groups: control, mild hydrocephalus and moderate hydrocephalus (n=10), respectively.
 RESULTS: Shrinking and thinning of hippocampal tissue, distortion of the pyramidal layer, and pyknotic cells were observed in the CA1 and CA3 regions of hydrocephalic rats. The pyknotic indices in the CA1, CA2 and CA3 regions of mild hydrocephalic rats (Cornus Ammonis, CA) (54.30±1.38; 27.62±0.83; 57.61±0.74) and hydrocephalic rats moderate CA1, CA2 and CA3 (48.18±0.67; 32.00±0.84; 42.41±1.19) were significantly increased compared to the CA1, CA2, CA3 regions of controls (12.14±0.56; 9.21±0.36; 13.04±0.59).
 Conclusion: Chronic hydrocephalus in adult rats was associated with cell death in all regions of the hippocampus, regardless of the degree of ventricular enlargement. The extent of cell death corresponded to the severity of learning and memory deficits.
 Key words: Chronic hydrocephalus, hippocampus, adult rats, memory, pyknotic cells.
 
 Keywords: Adult rats; Chronic hydrocephalus; hippocampus; memory; pyknotic cells.