Differential effects of bilateral hippocampal CA3 damage on the implicit learning and recognition of complex event sequences.

Learning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.

Pharmacological characterization of the α2A-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.

The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α1, α2, and other receptor subtypes. Correlation and slope of unity were found for the α2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50) and relative efficacy (RE) were determined. Compared with NE (pEC50, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50, 7.94; RE, 37.9%), exhibited the highest potency (pEC50). In contrast, the catecholamines, EPI (pEC50, 6.95; RE, 120%) and α-methyl-NE (pEC50, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A-AR agonists that can cross the blood-brain barrier.

Effect of chronic sleep deprivation and sleep recovery on hippocampal CA3 neurons, spatial memory and anxiety-like behavior in rats.

Sleep deprivation-induced degenerative changes in the brain lead to the impairment of memory, anxiety, and quality of life. Several studies have reported the effects of sleep deprivation on CA1 and dentate gyrus regions of the hippocampus; in contrast, there is less known about the impact of chronic sleep deprivation (CSD) and sleep recovery on CA3 neurons and behavior. Hence, the present study aimed to understand the effect of CSD and sleep recovery on hippocampal CA3 neurons and spatial memory, and anxiety-like behavior in rats. Sixty male rats (Sprague Dawley) were grouped as control, environmental control (EC), CSD, 5 days sleep recovery (CSD + 5D SR), and 21 days sleep recovery (CSD + 21D SR). CSD, CSD + 5D SR and, CSD + 21D SR group rats were sleep deprived for 21 days (18 h/day). After CSD, the CSD + 5D SR and CSD + 21D SR rats were sleep recovered for 5- and 21-days respectively. Oxidative stress, dendritic arborization of CA3 neurons, spatial memory, and anxiety-like behavior was assessed. Spatial memory, basal, and apical dendritic branching points/intersections in hippocampal CA3 neurons were reduced, and anxiety-like behavior and oxidative stress increased significantly in the CSD group compared to control (p < 0.001). The CSD + 21D SR showed a significant improvement in spatial memory, reduction in anxiety-like behavior, and oxidative stress when compared to the CSD group (p < 0.05). The basal and apical dendritic branching points/intersections in hippocampal CA3 neurons were increased after CSD + 21D SR, however, it was not significant (p > 0.05). Even though the CSD + 21D SR showed a significant improvement in all the parameters, it did not reach the control level. There was an improvement in all the parameters after CSD + 5D SR but this was not significant compared to the CSD group (p > 0.05). Overall results indicate that the CSD-induced impairment of spatial memory and anxiety-like behavior was associated with oxidative stress and reduced dendritic arborization of hippocampal CA3 neurons. The CSD + 21D SR significantly reduced the damage caused by CSD, but it was not sufficient to reach the control level.

Quantitative analysis of size and regional distribution of corpora amylacea in the hippocampal formation of obstructive sleep apnoea patients.

Corpora amylacea (CoA) are spherical aggregates of glucose polymers and proteins within the periventricular, perivascular and subpial regions of the cerebral cortex and the hippocampal cornu ammonis (CA) subfields. The present study quantified the distribution of CoA in autopsied hippocampi of patients with obstructive sleep apnoea (OSA) using ethanolamine-induced fluorescence. CoA were observed in 29 of 30 patients (96.7%). They were most abundant in periventricular regions (wall of lateral ventricle, alveus, fimbria and CA4), rarely found in the CA3 and CA1, and undetectable in the CA2 or subiculum. A spatiotemporal sequence of CoA deposition was postulated, beginning in the fimbria and progressively spreading around the subpial layer until they extended medially to the wall of the lateral ventricle and laterally to the collateral sulcus. This ranked CoA sequence was positively correlated with CoA packing density (count and area fraction) and negatively correlated with CoA minimum diameters (p < 0.05). Although this sequence was not correlated with age or body mass index (BMI), age was positively correlated with the mean and maximum diameters of CoA. These findings support the view that the spatiotemporal sequence of CoA deposition is independent of age, and that CoA become larger due to the accretion of new material over time.

Hippocampal sub-networks exhibit distinct spatial representation deficits in Alzheimer's disease model mice.

Not much is known about how the dentate gyrus (DG) and hippocampal CA3 networks, critical for memory and spatial processing, malfunction in Alzheimer's disease (AD). While studies of associative memory deficits in AD have focused mainly on behavior, here, we directly measured neurophysiological network dysfunction. We asked what the pattern of deterioration of different networks is during disease progression. We investigated how the associative memory-processing capabilities in different hippocampal subfields are affected by familial AD (fAD) mutations leading to amyloid-ß dyshomeostasis. Specifically, we focused on the DG and CA3, which are known to be involved in pattern completion and separation and are susceptible to pathological alterations in AD. To identify AD-related deficits in neural-ensemble dynamics, we recorded single-unit activity in wild-type (WT) and fAD model mice (APPSwe+PSEN1/ΔE9) in a novel tactile morph task, which utilizes the extremely developed somatosensory modality of mice. As expected from the sub-network regional specialization, we found that tactile changes induced lower rate map correlations in the DG than in CA3 of WT mice. This reflects DG pattern separation and CA3 pattern completion. In contrast, in fAD model mice, we observed pattern separation deficits in the DG and pattern completion deficits in CA3. This demonstration of region-dependent impairments in fAD model mice contributes to understanding of brain networks deterioration during fAD progression. Furthermore, it implies that the deterioration cannot be studied generally throughout the hippocampus but must be researched at a finer resolution of microcircuits. This opens novel systems-level approaches for analyzing AD-related neural network deficits.

Neuroprotective Effects of Thymoquinone by the Modulation of ER Stress and Apoptotic Pathway in In Vitro Model of Excitotoxicity.

Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders' models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of the hippocampus. Thymoquinone (TQ) is the most important component of the essential oil obtained from black cumin (Nigella sativa L.) seeds. It has many pharmacological actions including antioxidant, anti-inflammatory, and anti-apoptotic effects. TQ was used in an in vitro experimental model of primary cultures where excitotoxicity was induced. Briefly, rat organotypic hippocampal slices were exposed to 5 µM KA for 24 h. Cell death in the CA3 subregions of slices was quantified by measuring propidium iodide fluorescence. The cross-talk between TQ, ER stress and apoptotic pathways was investigated by Western blot. In untreated slices TQ (10 µM) induced a significant increase on the PSD95 levels and it decreased the excitotoxic injury induced by KA. Additionally, TQ was able to ameliorate the KA-induced increase in unfolded proteins GRP78 and GRP94 expression. Finally, TQ was able to partially rescue the reduction of the KA-induced apoptotic pathway activation. Our results suggest that TQ modulates the processes leading to post-kainate neuronal death in the CA3 hippocampal area.

Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder.

Protocadherin-19 (PCDH19) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females (PCDH19HET♀ ) but not hemizygous males (PCDH19HEMI♂ ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET♀ but not Pcdh19HEMI♂ mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In Pcdh19HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.

Enriched environment ameliorates chronic temporal lobe epilepsy-induced behavioral hyperexcitability and restores synaptic plasticity in CA3-CA1 synapses in male Wistar rats.

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacoresistance and comorbidities pose significant challenges to its treatment necessitating the development of non-pharmacological approaches. In an earlier study, exposure to enriched environment (EE) reduced seizure frequency and duration and ameliorated chronic epilepsy-induced depression in rats. However, the cellular basis of beneficial effects of EE remains unknown. Accordingly, in the current study, we evaluated the effects of EE in chronic epilepsy-induced changes in behavioral hyperexcitability, synaptic transmission, synaptophysin (SYN), and calbindin (CB) expression, hippocampal subfield volumes and cell density in male Wistar rats. Epilepsy was induced by lithium-pilocarpine-induced status epilepticus. Chronic epilepsy resulted in behavioral hyperexcitability, decreased basal synaptic transmission, increased paired-pulse facilitation ratio, decreased hippocampal subfields volumes. Moreover, epileptic rats showed decreased synaptophysin and CB expression in the hippocampus. Six weeks post-SE, epileptic rats were exposed to EE for 2 weeks, 6 hr/day. EE significantly reduced the behavioral hyperexcitability and restored basal synaptic transmission correlating with increased expression of SYN and CB. Our results reaffirm the beneficial effects of EE on behavior in chronic epilepsy and establishes some of the putative cellular mechanisms. Since drug resistance and comorbidities are a major concern in TLE, we propose EE as a potent non-pharmacological treatment modality to mitigate these changes in chronic epilepsy.

Heat stress induced oxidative damage and perturbation in BDNF/ERK1/2/CREB axis in hippocampus impairs spatial memory.

Heat exposure is an environmental stress that causes diverse heat related pathophysiological changes under extreme conditions. The brain including hippocampal region which is associated with learning and memory is significantly affected by heat stress resulting in memory impairment. However, the effect of heat on the spatial memory remains unclear. The present study aimed to explore the effect of heat stress on hippocampus and spatial memory in rats. Rat model of acute heat stress was used which was divided into two groups, viz. moderate heat stress (MHS) and severe heat stress (SHS). Redox parameters evaluation revealed that MHS and SHS exposure markedly increase the production of malondialdehyde (MDA), oxidised glutathione (GSSG), reactive oxidative species (ROS), protein oxidation level and decrease the reduced glutathione (GSH) levels in the hippocampal tissue. Furthermore, Cresyl Violet (CV) staining of hippocampal region showed higher pyknosis in rats exposed to SHS. Pronounced increase of caspase3 expression and Fluoro Jade-C (FJ-C) positive cells were observed in SHS resulting in neuronal injury and apoptosis in CA3 region of hippocampus culminating in spatial memory deficit. Our data also suggest that heat stress induces phospho Extracellular signal-regulated kinases (pERK)1/2 activation induced by Brain-derived neurotrophic factor (BDNF) leading to further activation of phospho cAMP-response element binding protein (pCREB) under MHS. However, during SHS, BDNF and pCREB expression were completely dysregulated and not sufficient to rescue cognitive decline in rats. In conclusion, SHS induces pathological alterations that include oxidative damage and apoptosis of hippocampal neurons, disturbing BDNF/ERK1/2/CREB axis that may affect spatial memory.

Pannexin-1 Deficiency Decreases Epileptic Activity in Mice.

OBJECTIVE: Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models-(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion. RESULTS: Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta-gamma and delta-HF rhythms in the Panx1 knockout. SIGNIFICANCE: These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects.

Genetic Alzheimer's Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields.

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.

Human hippocampal CA3 damage disrupts both recent and remote episodic memories.

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.

Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice.

The hippocampus is a crucial part of the limbic system involved both in cognitive processing and in the regulation of responses to stress. Adverse experiences early in life can disrupt hippocampal development and lead to impairment of the hypothalamic-pituitary-adrenal axis response to subsequent stressors. In our study, two types of early-life stress were used: prolonged separation of pups from their mothers (for 3 hours/day, maternal separation, MS) and brief separation (for 15 minutes/day, handling, HD). In the first part of our study, we found that adult female mice (F0) who had experienced MS showed reduced locomotor activity and impairment of long-term spatial and recognition memory. Analysis of various hippocampal regions showed that MS reduced the number of mature neurons in CA3 of females, which is perhaps a crucial hippocampal region for learning and memory; however, neurogenesis remained unchanged. In the second part, we measured maternal care in female mice with a history of early-life stress (F0) as well as the behavior of their adult offspring (F1). Our results indicated that MS reduced the level of maternal care in adult females (F0) toward their own progeny and caused sex-specific changes in the social behavior of adult offspring (F1). In contrast to MS, HD had no influence on female behavior or hippocampal plasticity. Overall, our results suggest that prolonged MS early in life affects the adult behavior of F0 female mice and hippocampal neuronal plasticity, whereas the mothers' previous experience has effects on the behavior of their F1 offspring through disturbances of mother-infant interactions.

Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors.

Recent findings from in vivo-imaging and human post-mortem tissue studies in schizophrenic psychosis (SzP), have demonstrated functional and molecular changes in hippocampal subfields that can be associated with hippocampal hyperexcitability. In this study, we used a subfield-specific GluN1 knockout mouse with a disease-like molecular perturbation expressed only in hippocampal dentate gyrus (DG) and assessed its association with hippocampal physiology and psychosis-like behaviors. First, we used whole-cell patch-clamp recordings to measure the physiological changes in hippocampal subfields and cFos immunohistochemistry to examine cellular excitability. DG-GluN1 KO mice show CA3 cellular hyperactivity, detected using two approaches: (1) increased excitatory glutamate transmission at mossy fibers (MF)-CA3 synapses, and (2) an increased number of cFos-activated pyramidal neurons in CA3, an outcome that appears to project downstream to CA1 and basolateral amygdala (BLA). Furthermore, we examined psychosis-like behaviors and pathological memory processing; these show an increase in fear conditioning (FC), a reduction in prepulse inhibition (PPI) in the KO animal, along with a deterioration in memory accuracy with Morris Water Maze (MWM) and reduced social memory (SM). Moreover, with DREADD vectors, we demonstrate a remarkably similar behavioral profile when we induce CA3 hyperactivity. These hippocampal subfield changes could provide the basis for the observed increase in human hippocampal activity in SzP, based on the shared DG-specific GluN1 reduction. With further characterization, these animal model systems may serve as targets to test psychosis mechanisms related to hippocampus and assess potential hippocampus-directed treatments.

An Effect of Chronic Stress on Prospective Memory via Alteration of Resting-State Hippocampal Subregion Functional Connectivity.

The alteration of hippocampal function by chronic stress impairs higher order cognitive functions such as prospective memory (PM). However, how chronic stress affects hippocampal subregions related to PM remains largely unknown. In this study, the altered functional network of hippocampal subregions related to PM in chronic stress was explored. College students (N = 21) completed PM tasks and resting-state functional magnetic resonance imaging scans one month prior to (baseline) and during the final examination week (chronic stress). Hippocampal subregions' seed-based functional connectivity (FC) and PM were compared between baseline and chronic stress. PM performance declined in chronic stress. The FC of the cornu ammonis 2, 3 and dentate gyrus (CA23DG) with the bilateral caudate and precuneus was increased in chronic stress, while the FC of the subicular complex (SUBC) with the left middle frontal gyrus, the left inferior parietal gyrus and the right supramarginal gyrus was decreased. There was a negative correlation between PM performance and the FC of hippocampal subregions. We found chronic stress impairs PM by decreasing the FC of SUBC and increasing the FC of CA23DG. These findings suggest functional changes in hippocampal subregion networks as a mechanism underlying the impairment of PM in chronic stress.

Impaired Reliability and Precision of Spiking in Adults But Not Juveniles in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome, but our knowledge about intrinsic conductance changes is still limited. In this study, we show a differential effect of FMRP knockout in different subsections of hippocampus using whole-cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus, but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike numbers in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult mice (8 weeks) but not juvenile mice (4 weeks). This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium-activated potassium channels), but other currents involved in medium AHP, such as Ih and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single-cell correlate of the network observations of response variability and loss of synchronization, and suggest that the elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference.

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.

OBJECTIVE: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. METHODS: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. RESULTS: Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). INTERPRETATION: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728.

Retrieval of spatial representation on network level in hippocampal CA3 accompanied by overexpression and mixture of stored network patterns.

Retrieval of stored network activity pattern has been shown as a competitive transition from one attractor state to another, orchestrated by local theta oscillation. However, the fine nature of this process that is considered as substrate of memory recall is not clear. We found that hippocampal network recall is characterized by hyperactivity in the CA3 place cell population, associated with an "overexpression" of the retrieved network pattern. The overexpression was based on recruitment of cells from the same (recalled) spatial representation with low expected firing probability at the given position. We propose that increased place cell activation during state transitions might facilitate pattern completion towards the retrieved network state and stabilize its expression in the network. Furthermore, we observed frequent mixing of both activity patterns at the temporal level of a single theta cycle. On a sub-theta cycle scale, we found signs of segregation that might correspond to a gamma oscillation patterning, as well as occasional mixing at intervals of less than 5 milliseconds. Such short timescale coactivity might induce plasticity mechanisms, leading to associations across the two originally decorrelated network activity states.

Computer Modeling of Alzheimer's Disease-Simulations of Synaptic Plasticity and Memory in the CA3-CA1 Hippocampal Formation Microcircuit.

This paper aims to present computer modeling of synaptic plasticity and memory in the CA3-CA1 hippocampal formation microcircuit. The computer simulations showed a comparison of a pathological model in which Alzheimer's disease (AD) was simulated by synaptic degradation in the hippocampus and control model (healthy) of CA3-CA1 networks with modification of weights for the memory. There were statistically higher spike values of both CA1 and CA3 pyramidal cells in the control model than in the pathological model (p = 0.0042 for CA1 and p = 0.0033 for CA3). A similar outcome was achieved for frequency (p = 0.0002 for CA1 and p = 0.0001 for CA3). The entropy of pyramidal cells of the healthy CA3 network seemed to be significantly higher than that of AD (p = 0.0304). We need to study a lot of physiological parameters and their combinations of the CA3-CA1 hippocampal formation microcircuit to understand AD. High statistically correlations were obtained between memory, spikes and synaptic deletion in both CA1 and CA3 cells.

Early detonation by sprouted mossy fibers enables aberrant dentate network activity.

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, relatively large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an "early detonation" mode and an increased probability of release compared with mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release, thus facilitating reverberant circuit activity.