Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.

Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology.

Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.

Effects of hippocampal IP3R inhibition on contextual fear memory consolidation, retrieval, reconsolidation and extinction.

Intracellular calcium stores (ICS) play a dynamic role in neuronal calcium (Ca2+) homeostasis both by buffering Ca2+ excess in the cytoplasm or providing an additional source of Ca2+ when concentration increase is needed. However, in spite of the large body of evidence showing Ca2+ as an essential second messenger in many signaling cascades underlying synaptic plasticity, the direct involvement of the intracellular Ca2+-release channels (ICRCs) in memory processing has been highly overlooked. Here we investigated the role of the ICRC inositol 1,4,5-trisphosphate receptor (IP3R) activity during different memory phases using pharmacological inhibition in the dorsal hippocampus during contextual fear conditioning. We first found that post-training administration of the IP3R antagonist 2-aminoethyl diphenylborinate (2-APB) impaired memory consolidation in a dose and time-dependent manner. Inhibiting IP3Rs also disrupted memory retrieval. Contextual fear memory reconsolidation or extinction, however, were not sensitive to IP3R blockade. Taken together, our results indicate that hippocampal IP3Rs play an important role in contextual fear memory consolidation and retrieval.

Causal relationship of CA3 back-projection to the dentate gyrus and its role in CA1 fast ripple generation.

BACKGROUND: Pathophysiological evidence from temporal lobe epilepsy models highlights the hippocampus as the most affected structure due to its high degree of neuroplasticity and control of the dynamics of limbic structures, which are necessary to encode information, conferring to it an intrinsic epileptogenicity. A loss in this control results in observable oscillatory perturbations called fast ripples, in epileptic rats those events are found in CA1, CA3, and the dentate gyrus (DG), which are the principal regions of the trisynaptic circuit of the hippocampus. The present work used Granger causality to address which relationships among these three regions of the trisynaptic circuit are needed to cause fast ripples in CA1 in an in vivo model. For these purposes, male Wistar rats (210-300 g) were injected with a single dose of pilocarpine hydrochloride (2.4 mg/2 µl) into the right lateral ventricle and video-monitored 24 h/day to detect spontaneous and recurrent seizures. Once detected, rats were implanted with microelectrodes in these regions (fixed-recording tungsten wire electrodes, 60-µm outer diameter) ipsilateral to the pilocarpine injection. A total of 336 fast ripples were recorded and probabilistically characterized, from those fast ripples we made a subset of all the fast ripple events associated with sharp-waves in CA1 region (n = 40) to analyze them with Granger Causality. RESULTS: Our results support existing evidence in vitro in which fast ripple events in CA1 are initiated by CA3 multiunit activity and describe a general synchronization in the theta band across the three regions analyzed DG, CA3, and CA1, just before the fast ripple event in CA1 have begun. CONCLUSION: This in vivo study highlights the causal participation of the CA3 back-projection to the DG, a connection commonly overlooked in the trisynaptic circuit, as a facilitator of a closed-loop among these regions that prolongs the excitatory activity of CA3. We speculate that the loss of inhibitory drive of DG and the mechanisms of ripple-related memory consolidation in which also the CA3 back-projection to DG has a fundamental role might be underlying processes of the fast ripples generation in CA1.

Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests.

Charcot-Marie-Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We compared the behavior profile of TrJ/+ and +/+ (wild-type) in open-field and elevated-plus-maze anxiety tests. In these tests, TrJ/+ showed an exclusive head shake movement, a lower frequency of rearing, but a greater frequency of grooming. In elevated-plus-maze, TrJ/+ defecate more frequently, performed fewer total entries, and have fewer entries to closed arms. These hippocampus-associated behaviors in TrJ/+ are consistent with increased anxiety levels. The expression of pmp22 and soluble PMP22 were evaluated in E17-hippocampal neurons and adult hippocampus by in situ hybridization and successive immunohistochemistry. Likewise, the expression of pmp22 was confirmed by RT-qPCR in the entire isolated hippocampi of both genotypes. Moreover, the presence of aggregated PMP22 was evidenced in unmasked granular hippocampal adult neurons and shows genotypic differences. We showed for the first time a behavior profile trait associated with anxiety and a differential expression of pmp22/PMP22 in hippocampal neurons of TrJ/+ and +/+ mice, demonstrating the involvement at the central level in an animal model of peripheral neuropathy (CMT1E).

Metabotropic Glutamate Receptors at the Aged Mossy Fiber - CA3 Synapse of the Hippocampus.

Metabotropic glutamate receptors (mGluRs) are a group of G-protein-coupled receptors that exert a broad array of modulatory actions at excitatory synapses of the central nervous system. In the hippocampus, the selective activation of the different mGluRs modulates the intrinsic excitability, the strength of synaptic transmission, and induces multiple forms of long-term plasticity. Despite the relevance of mGluRs in the normal function of the hippocampus, we know very little about the changes that mGluRs functionality undergoes during the non-pathological aging. Here, we review data concerning the physiological actions of mGluRs, with particular emphasis on hippocampal area CA3. Later, we examine changes in the expression and functionality of mGluRs during the aging process. We complement this review with original data showing an array of electrophysiological modifications observed in the synaptic transmission and intrinsic excitability of aged CA3 pyramidal cells in response to the pharmacological stimulation of the different mGluRs.

Acute Effects of Two Different Species of Amyloid-ß on Oscillatory Activity and Synaptic Plasticity in the Commissural CA3-CA1 Circuit of the Hippocampus.

Recent evidence indicates that soluble amyloid-ß (Aß) species induce imbalances in excitatory and inhibitory transmission, resulting in neural network functional impairment and cognitive deficits during early stages of Alzheimer's disease (AD). To evaluate the in vivo effects of two soluble Aß species (Aß 25-35 and Aß 1-40) on commissural CA3-to-CA1 (cCA3-to-CA1) synaptic transmission and plasticity, and CA1 oscillatory activity, we used acute intrahippocampal microinjections in adult anaesthetized male Wistar rats. Soluble Aß microinjection increased cCA3-to-CA1 synaptic variability without significant changes in synaptic efficiency. High-frequency CA3 stimulation was rendered inefficient by soluble Aß intrahippocampal injection to induce long-term potentiation and to enhance synaptic variability in CA1, contrasting with what was observed in vehicle-injected subjects. Although soluble Aß microinjection significantly increased the relative power of γ-band and ripple oscillations and significantly shifted the average vector of θ-to-γ phase-amplitude coupling (PAC) in CA1, it prevented θ-to-γ PAC shift induced by high-frequency CA3 stimulation, opposite to what was observed in vehicle-injected animals. These results provide further evidence that soluble Aß species induce synaptic dysfunction causing abnormal synaptic variability, impaired long-term plasticity, and deviant oscillatory activity, leading to network activity derailment in the hippocampus.

Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. METHODS: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. RESULTS: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. SIGNIFICANCE: Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.

Differential navigational strategies during spatial learning in a new modified version of the Oasis maze.

During spatial navigation, some typical parameters of learning have been observed, such as latency or path length. However, these parameters are sensitive to patterns of navigation and orientation that are not easily measurable. In the present study, we used a modified version of the Oasis maze and evaluated different parameters of learning, navigation, and orientation in different animal groups. Through a PCA (Principal component analysis) we found different factors such as learning, navigation, speediness, anxiety, orientation, path variability, and turning behavior. Each factor gathers different groups of behavioral variables. ANOVA analysis of those factors demonstrates that some of them are more strongly modulated by trial progression, while others by animal group differences, indicating that each group of variables is better reflecting one of these dimensions. To understand the nature of these navigation differences, we studied orientation strategies between animal conditions and across trials. We found that the main navigational strategy used by the animals consist of locating the target and directing their behaviors towards this area. When testing how this strategy changed after cognitive impairment or enhancement, we found that AßOs treated animals (Amyloid ß Oligomers, Alzheimer animal model) have strong orientation difficulties at locating the target at longer distances. While animals with learning enhancement (exercised rat) do not show changes in orientation behaviors. These analyses highlight that experimental manipulations affect learning, but also induced changes in the navigational strategies. We concluded that both dimensions can explain the differences observed in typical learning variables, such as latency or path length, motivating the development of new tools that asses this two-dimension as a separate but, interacting phenomenon.

BDNF induces in vivo long-lasting enhancement of synaptic transmission and structural reorganization at the hippocampal mossy fibers in a transcription and translation-independent manner.

Brain-derived neurotrophic factor (BDNF) is an essential product of protein synthesis with a prominent impact on brain signaling and synaptic plasticity. Exogenous application of this neurotrophin is able to induce long-term potentiation (LTP) in several brain structures such as the hippocampus along with increases in gene transcription and translation of proteins involved in functional and structural plasticity. In this regard, our previous studies have demonstrated that acute intrahippocampal administration of BDNF induces long-lasting enhancement of synaptic transmission at the mossy fibers projection (MF) accompanied by a structural reorganization at the CA3 hippocampus area. Thus, considering the non-canonical molecular mechanisms underlying MF-CA3-LTP and the high expression of this neurotrophin in the CA3 area, we wonder whether transcriptional and translational inhibition interferes with the persistence of the MF functional and structural synaptic plasticity elicited by BDNF in adult rats in vivo. Our results show that BDNF is able to induce a lasting potentiation of synaptic efficacy at the MF projection accompanied by a structural reorganization at the CA3 area in an mRNA synthesis and protein translation-independent manner. The present findings support the idea that BDNF is an essential plasticity related product, which is necessary and sufficient to induce and maintain functional and structural synaptic plasticity at the MF-CA3 pathway.

Cognitive training increases dendritic arborization in the dorsal hippocampal CA1 and CA3 neurons of female and male Long-Evans rats.

Experiences influence the development of the central nervous system. Cognitive training promotes changes in the structure of the brain, such as in its weight and number of cells, as well as ability to perform dendritic remodeling. The present study was designed to detect possible differences in the neuronal morphology of the dorsal hippocampus between female and male Long-Evans rats after cognitive training (CT). CT was promoted through three learning and memory tests: the Morris water maze, the Barnes circular maze, and Novel object recognition tests. Our data revealed no differences in learning or memory capacities between female and male rats; rats of the two sexes solved the behavioral test with equal efficiency. CT caused an increase in the basilar and apical dendritic arborization of CA1 neurons in male rats, whereas female rats that underwent CT presented only remodeling in the apical arbors of CA1 neurons. The basilar arbors of CA3 neurons of female rats showed an increase in arborization, but their apical arbors were not modified; the arbors of CA3 neurons of male rats submitted to CT were not modified. Total dendritic length was modified by CT in the apical arbors of CA1 neurons of female and male rats and in the basilar CA1 arbors of male rats. There was a significant increase in dendritic spine density in all arbors of CA1 and CA3 neurons of females and males subjected to CT. These results suggest that dendritic remodeling after CT is similar between female and male rats.

Ginkgo biloba treatments reverse the impairment of conditioned suppression acquisition induced by GluN2B-NMDA and 5-HT1A receptor blockade: Modulatory effects of the circuitry of the dorsal hippocampal formation.

To improve our understanding of the effects of standardized extract of Ginkgo biloba (EGb) as a cognitive enhancer, we investigated the conditioned lick suppression-induced expression (mRNA and protein) of the GluN2B-containing N-methyl-D-aspartic acid receptor (GluN2B-NMDAR), serotonin (5-HT) 1A receptor (5-HT1AR), gamma-aminobutyric acid type A receptor (GABAAR) and glial fibrillary acidic protein (GFAP) in the dorsal hippocampal formation (dHF) of untreated and EGb-treated (0.25, 0.5 and 1.0 g.kg-1) groups of rats. To substantiate our data, we analysed the molecular changes in dHF following treatment with vehicle, with agonists or antagonists of GABAAR, GluN2B-NMDAR and 5-HT1AR or with one of these antagonists prior to EGb and fear memory acquisition. Additionally, we performed a pharmacological analysis of the drug-receptor-receptor interactions and their supplemental role in fear memory by blocking individual receptors and analysed the possible changes in expression level with each of the other receptors in the study as well as astrocytes. Our data show for the first time that EGb treatment not only upregulated GluN2B, GABAAR-α5, and GFAP compared with the control but also differentially upregulated GABAAR-α1 in the dHF and 5HT1AR in the CA3. We found that the activation of GABAARs (diazepam) and the inactivation of GluN2B-NMDARs (Ro25-6981) or 5-HT1AR ((S)-WAY100135) resulted in memory impairment. Further, higher doses of EGb treatment reversed the effect of blocking GluN2B (P < 0.001) and 5-HT1AR (P < 0.001). Here, treatment with Ro25-6981 + EGb or (S)-WAY100135 + EGb prevented the impairment of the acquisition of lick suppression in association with the upregulation or prevention of the downregulation of Grin2b expression as well as the expression of GluN2B-NMDA and/or α1 and α5 subunit-containing GABAAR in the CA1 (P < 0.0001). Our data are in line with previous findings concerning the necessity of GluN2B for fear memory formation and add to the current knowledge of the role of the GABAAR-α1 and -α5 subunits and of GluN2B as a target of cognitive enhancers. Furthermore, our data show that these receptors play a complementary role in controlling the neural circuitry in the dHF that seems to be essential to conditioned lick suppression and the modulatory effects of EGb.

Cyclohexane Inhalation Produces Long-Lasting Alterations in the Hippocampal Integrity and Reward-Seeking Behavior in the Adult Mouse.

Cyclohexane (CHX) is an organic solvent commonly used as a drug-of-abuse. This drug increases the oxidative stress and glial reactivity in the hippocampus, which suggests that this brain region is vulnerable to CHX effects. This study aimed to establish the behavioral changes and the pathological alterations that occur in the Cornu Ammonis 3 (CA3) and Dentate Gyrus (DG) after a long-lasting exposure to CHX. We exposed CD1 mice to a recreational-like dose of CHX (~ 30,000 ppm) for 30 days and explored its consequences in motor skills, reward-seeking behavior, and the CA3 and DG hippocampal subfields. Twenty-four hours after the last administration of CHX, we found a significant decrease in the number of c-Fos+ cells in the hippocampal CA3 and DG regions. This event coincided with an increased in NMDAR1 expression and apoptotic cells in the CA3 region. At day 13th without CHX, we found a persistent reduction in the number of c-Fos+ and TUNEL+ cells in DG. At both time points, the CHX-exposed mice showed a strong overexpression of neuropeptide Y (NPY) in the CA3 stratum lucidum and the hippocampal hilus. In parallel, we used an operant-based task to assess motor performance and operant conditioning learning. The behavioral analysis indicated that CHX did not modify the acquisition of operant conditioning tasks, but affected some motor skills and increased the reward-seeking behavior. Altogether, this evidence reveals that CHX exposure provokes long-lasting changes in the hippocampal subfields, induces motor impairments and increases the motivation-guided behavior. These findings can help understand the deleterious effect of CHX into the adult hippocampus and unveil its potential to trigger addiction-like behaviors.

Delayed creatine supplementation counteracts reduction of GABAergic function and protects against seizures susceptibility after traumatic brain injury in rats.

Traumatic brain injury (TBI) is a devastating disease frequently followed by behavioral disabilities including post-traumatic epilepsy (PTE). Although reasonable progress in understanding its pathophysiology has been made, treatment of PTE is still limited. Several studies have shown the neuroprotective effect of creatine in different models of brain pathology, but its effects on PTE is not elucidated. Thus, we decided to investigate the impact of delayed and chronic creatine supplementation on susceptibility to epileptic seizures evoked by pentylenetetrazol (PTZ) after TBI. Our experimental data revealed that 4 weeks of creatine supplementation (300 mg/kg, p.o.) initiated 1 week after fluid percussion injury (FPI) notably increased the latency to first myoclonic and tonic-clonic seizures, decreased the time spent in tonic-clonic seizure, seizure intensity, epileptiform discharges and spindle oscillations induced by a sub-convulsant dose of PTZ (35 mg/kg, i.p.). Interestingly, this protective effect persists for 1 week even when creatine supplementation is discontinued. The anticonvulsant effect of creatine was associated with its ability to reduce cell loss including the number of parvalbumin positive (PARV+) cells in CA3 region of the hippocampus. Furthermore, creatine supplementation also protected against the reduction of GAD67 levels, GAD activity and specific [3H]flunitrazepam binding in the hippocampus. These findings showed that chronic creatine supplementation may play a neuroprotective role on brain excitability by controlling the GABAergic function after TBI, providing a possible new strategy for the treatment of PTE.

JM-20 Treatment After MCAO Reduced Astrocyte Reactivity and Neuronal Death on Peri-infarct Regions of the Rat Brain.

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1ß levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.

1-triacontanol cerotate isolated from Marsilea quadrifolia Linn. safeguards hippocampal CA3 neurons and augments special memory deficit in chronic epileptic rats / Cerotato de 1-triacontanol aislado de Marsilea quadrifolia Linn. protege las neuronas CA3 del hipocampo y mejora el déficit de memoria especial en ratas epilépticas crónicas

SUMMARY: Currently many people with epilepsy do not have seizure control even with the best available medications. Moreover various antiepileptics have adverse cognitive impact with other side effect. Thus, need for new antiepileptic drugs still remains challenge. However, many of the natural components have antiepileptic action and this fact remains scientifically unexplored. This study was designed to check the behavioral and neuro-pathological outcome of 1-Triacontanol cerotate (1TAC), isolated from Marsilea quadrifolia Linn. (MQ) on chronic Pentylenetetrazol (PTZ) kindling model of epilepsy in rats. Two-month-old adult male Wistar rats (n=60) were randomly divided into six groups; Group I (Cage Control), II (Vehicle Control), III (Positive Control), IV (Standard drug treated), V (1TAC: 40 mg/kg) & VI (1TAC: 80 mg/kg). To induce kindling a 35 mg/kg dose of PTZ was injected i.p. in every 48 hrs for 30 days in Group III to VI. Spatial memory performance was tested using Morris water maze, following which brains were further processed for histopathological investigations. Interestingly, 1TAC was able to minimize the loss of pyramidal cells in hippocampal CA3 region. These cellular changes were behaviorally responded as improved special learning and memory, a better spatial navigation and object place configuration. The current study strongly implicates that 1TAC from MQ has potent neuroprotective role and augments special memory deficit in chronic epileptic rats. The isolated component which attenuates spatial memory performance could be beneficial outcome to retain cognitive blunting in chronic epilepsy.

RESUMEN: Actualmente, muchas personas con epilepsia no cuentan con un control adecuado de las convulsiones, incluso con los mejores medicamentos disponibles. Además, varios antiepilépticos tienen un impacto cognitivo adverso además de efectos secundarios. Por lo tanto, la necesidad de nuevos fármacos antiepilépticos sigue siendo un desafío. Sin embargo, muchos de los componentes naturales tienen acción antiepiléptica y este hecho permanece científicamente inexplorado. Este estudio se diseñó para verificar el resultado conductual y neuro-patológico del cerotato de 1-triacontanol (1TAC), aislado de Marsilea quadrifolia Linn. (MQ) en el modelo de epilepsia en ratas del pentilenetetrazol (PTZ) crónico (PTZ). Ratas Wistar adultas de dos meses de edad (n = 60) se dividieron aleatoriamente en seis grupos; Grupo I (Control de jaula), II (Control de vehículo), III (Control positivo), IV (Medicamento estándar de tratamiento), V (1TAC: 40 mg / kg) y VI (1TAC: 80 mg / kg). Para inducir la inflamación se inyectó una dosis de 35 mg / kg de PTZ i.p. en cada 48 horas durante 30 días en los grupos III a VI. El rendimiento de la memoria espacial se probó utilizando el laberinto de agua de Morris, después de lo cual se procesaron los cerebros para investigaciones histopatológicas. Curiosamente, 1TAC pudo minimizar la pérdida de células piramidales en la región CA3 del hipocampo. Estos cambios celulares respondieron de manera conductual como una mejora del aprendizaje especial y la memoria, una mejor navegación espacial y la configuración del lugar del objeto. El estudio actual implica fuertemente que 1TAC de MQ tiene un potente papel neuroprotector y mejora el déficit de memoria especial en ratas epilépticas crónicas. El componente aislado que atenúa el rendimiento de la memoria espacial podría ser un resultado beneficioso para retener la reducción cognitiva en la epilepsia crónica.

Intracerebroventricular streptozotocin induces impaired Barnes maze spatial memory and reduces astrocyte branching in the CA1 and CA3 hippocampal regions.

Sporadic Alzheimer's disease (SAD) is the most common form of dementia; therefore, there is an urgent need for a model that recapitulates the main pathologic hallmarks of this disease. The intracerebroventricular (icv) injection of streptozotocin (icv-STZ) in rats constitutes a promising model, and thus, icv-STZ rats develop insulin-resistant brain state and cognitive impairments. Even though a great piece of studies has hitherto described this system as a model for SAD, further behavioral and morphometric studies are still needed to fully characterize it. In this study, using Sprague Dawley rats, we evaluated short-term effects on behavior and hippocampus morphometry of the icv-STZ injection at two doses: 1 (STZ1) and 3 mg/kg (STZ3). We found that, following icv-STZ injection, STZ3 animals, but not STZ1, exhibited impairments in spatial reference learning and memory (Barnes maze test) and in recognition memory (object recognition test). Furthermore, the results from behavioral and morpho-histochemical data are compatible. STZ3 rats displayed Stratum Radiatum volume reduction and a decreased NeuN immunoreactivity (neuron loss) in hippocampal CA1 region, together with an increased immunoreactivity for microglial (Iba1) and astroglial (GFAP) markers (neuroinflammation). Sholl analysis revealed the vulnerability of hippocampal astrocytes to STZ in CA1 and CA3. Thus, both doses induced a reduction in process length and in the number of main processes, accompanied by a frank decrease in branching complexity. The present study provides important knowledge of this AD rat model. Overall, we found that the only high STZ dose induced severe and acute neurodegenerative lesions, associated with an inflammation process.

Different patterns of epileptiform-like activity are generated in the sclerotic hippocampus from patients with drug-resistant temporal lobe epilepsy.

Human hippocampal slice preparations from patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) are excellent material for the characterization of epileptiform-like activity. However, it is still unknown if hippocampal regions as cornu Ammonis (CA) 1, CA3 and CA4, generate population epileptiform-like activity. Here, we investigated epileptiform activities of the subiculum, CA1, CA2, CA3, CA4 (induced by elevation of extracellular potassium concentration) and the dentate gyrus (induced with hilar stimulation and elevation of potassium concentration) from sclerotic hippocampi of patients with drug-resistant TLE. Five types of epileptiform-like activity were observed: interictal-like events; periodic ictal spiking; seizure-like events; spreading depression-like events; tonic seizure-like events and no activity. Different susceptibilities to generate epileptiform activity among hippocampal regions were observed; the dentate gyrus was the most susceptible region followed by the subiculum, CA4, CA1, CA2 and CA3. The incidence of epileptiform activity pattern was associated with specific regions of the hippocampal formation. Moreover, it was observed that each region of the hippocampal formation exhibits frequency-specific ranges in each subfield of the sclerotic human tissue. In conclusion, this study demonstrates that epileptiform-like activity may be induced in different regions of the hippocampal formation, including regions that are severely affected by neuronal loss.

Increased dendritic length in CA1 and CA3 hippocampal neurons during the metestrus phase in Wistar rats.

Studies have shown that changes in ovarian hormone concentrations promote natural fluctuations in the density of dendritic spines of hippocampal neurons in female Sprague-Dawley rats, without changes in dendritic length, throughout the estrous cycle. However, it is still unknown whether these fluctuations are present in other rat strains. Due to our interest in Wistar rats, the objective of the present study was to determine if there is natural dendritic remodeling in the female Wistar rat throughout the estrous cycle. This study analyzed the dendritic arborization of pyramidal neurons CA1 and CA3 of the dorsal hippocampus in each phase of the estrous cycle. We used the Golgi-Cox staining method and Sholl analysis to evaluate the dendritic length and density of dendritic spines. Our results showed that the dendritic length of the basilar and apical trees of CA1 neurons was longer in the metestrus phase. In CA3 neurons, only the apical dendritic trees showed longer dendritic length during metestrus. There was no variation in the density of dendritic spines in relation to any of the phases of the estrous cycle. Taken together, these results indicated that pyramidal neurons of the CA1 and CA3 regions of the dorsal hippocampus in the Wistar rat exhibited changes in dendritic length in the metestrus phase of the estrous cycle. Together, these data are important when considering the use of these organisms in behavioral studies.

Temporal analysis of hippocampal CA3 gene coexpression networks in a rat model of febrile seizures.

Complex febrile seizures during infancy constitute an important risk factor for development of epilepsy. However, little is known about the alterations induced by febrile seizures that make the brain susceptible to epileptic activity. In this context, the use of animal models of hyperthermic seizures (HS) could allow the temporal analysis of brain molecular changes that arise after febrile seizures. Here, we investigated temporal changes in hippocampal gene coexpression networks during the development of rats submitted to HS. Total RNA samples were obtained from the ventral hippocampal CA3 region at four time points after HS at postnatal day (P) 11 and later used for gene expression profiling. Temporal endpoints were selected for investigating the acute (P12), latent (P30 and P60) and chronic (P120) stages of the HS model. A weighted gene coexpression network analysis was used to characterize modules of coexpressed genes, as these modules might contain genes with similar functions. The transcriptome analysis pipeline consisted of building gene coexpression networks, identifying network modules and hubs, performing gene-trait correlations and examining changes in module connectivity. Modules were functionally enriched to identify functions associated with HS. Our data showed that HS induce changes in developmental, cell adhesion and immune pathways, such as Wnt, Hippo, Notch, Jak-Stat and Mapk. Interestingly, modules involved in cell adhesion, neuronal differentiation and synaptic transmission were activated as early as 1 day after HS. These results suggest that HS trigger transcriptional alterations that could lead to persistent neurogenesis, tissue remodeling and inflammation in the CA3 hippocampus, making the brain prone to epileptic activity.