Neurons In Hippocampal Formation Research Articles

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer's Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss.

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon’s horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

Keel bone fractures induce a depressive-like state in laying hens

In commercial flocks of laying hens, keel bone fractures (KBFs) are prevalent and associated with behavioural indicators of pain. However, whether their impact is severe enough to induce a depressive-like state of chronic stress is unknown. As chronic stress downregulates adult hippocampal neurogenesis (AHN) in mammals and birds, we employ this measure as a neural biomarker of subjective welfare state. Radiographs obtained longitudinally from Lohmann Brown laying hens housed in a commercial multi-tier aviary were used to score the severity of naturally-occurring KBFs between the ages of 21–62 weeks. Individual birds’ transitions between aviary zones were also recorded. Focal hens with severe KBFs at 3–4 weeks prior to sampling (n = 15) had lower densities of immature doublecortin-positive (DCX+) multipolar and bipolar neurons in the hippocampal formation than focal hens with minimal fractures (n = 9). KBF severity scores at this time also negatively predicted DCX+ cell numbers on an individual level, while hens that acquired fractures earlier in their lives had fewer DCX+ neurons in the caudal hippocampal formation. Activity levels 3–4 weeks prior to sampling were not associated with AHN. KBFs thus lead to a negative affective state lasting at least 3–4 weeks, and management steps to reduce their occurrence are likely to have significant welfare benefits.

Neuropeptide S Displays as a Key Neuromodulator in Olfactory Spatial Memory.

Neuropeptide S (NPS) is an endogenous peptide recently recognized to be presented in the brainstem and believed to play an important role in maintaining memory. The deletion of NPS or NPS receptor (NPSR) in mice shows a deficit in memory formation. Our recent studies have demonstrated that central administration of NPS facilitates olfactory function and ameliorates olfactory spatial memory impairment induced by muscarinic cholinergic receptor antagonist and N-methyl-D-aspartate receptor antagonist. However, it remains to be determined if endogenous NPS is an indispensable neuromodulator in the control of the olfactory spatial memory. In this study, we examined the effects of NPSR peptidergic antagonist [D-Val5]NPS (10 and 20 nmol, intracerebroventricular) and nonpeptidergic antagonist SHA 68 (10 and 50 mg/kg, intraperitoneal) on the olfactory spatial memory using computer-assisted 4-hole-board olfactory spatial memory test in mice. Furthermore, immunofluorescence was employed to identify the distributions of c-Fos and NPSR immunoreactive (-ir) neurons in olfactory system and hippocampal formation known to closely relate to the olfactory spatial memory. [D-Val5]NPS dosing at 20 nmol and SHA 68 dosing at 50 mg/kg significantly decreased the number of visits to the 2 odorants interchanged spatially, switched odorants, in recall trial, and simultaneously reduced the percentage of Fos-ir in NPSR-ir neurons, which were densely distributed in the anterior olfactory nucleus, piriform cortex, subiculum, presubiculum, and parasubiculum. These findings suggest that endogenous NPS is a key neuromodulator in olfactory spatial memory.

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain.

Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II–VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II–VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

Self-Organized Attractor Dynamics in the Developing Head Direction Circuit

SummaryHead direction (HD) cells are neurons found in an extended cortical and subcortical network that signal the orientation of an animal’s head relative to its environment [1, 2, 3]. They are a fundamental component of the wider circuit of spatially responsive hippocampal formation neurons that make up the neural cognitive map of space [4]. During post-natal development, HD cells are the first among spatially modulated neurons in the hippocampal circuit to exhibit mature firing properties [5, 6], but before eye opening, HD cell responses in rat pups have low directional information and are directionally unstable [7, 8]. Using Bayesian decoding of HD cell ensemble activity recorded in the anterodorsal thalamic nucleus (ADN), we characterize this instability and identify its source: under-signaling of angular head velocity, which incompletely shifts the directional signal in proportion to head turns. We find evidence that geometric cues (the corners of a square environment) can be used to mitigate this under-signaling and, thereby, stabilize the directional signal even before eye opening. Crucially, even when directional firing cannot be stabilized, ensembles of unstable HD cells show short-timescale (1–10 s) temporal and spatial couplings consistent with an adult-like HD network. The HD network is widely modeled as a continuous attractor whose output is one coherent activity peak, updated during movement by angular head velocity signals and anchored by landmark cues [9, 10, 11]. Our findings present strong evidence for this model, and they demonstrate that the required network circuitry is in place and functional early during development, independent of reference to landmark information.

Experience-Related Changes in Place Cell Responses to New Sensory Configuration That Does Not Occur in the Natural Environment in the Rat Hippocampus.

The hippocampal formation (HF) is implicated in a comparator that detects sensory conflict (mismatch) among convergent inputs. This suggests that new place cells encoding the new configuration with sensory mismatch develop after the HF learns to accept the new configuration as a match. To investigate this issue, HF CA1 place cell activity in rats was analyzed after the adaptation of the rats to the same sensory mismatch condition. The rats were placed on a treadmill on a stage that was translocated in a figure 8-shaped pathway. We recorded HF neuronal activities under three conditions; (1) an initial control session, in which both the stage and the treadmill moved forward, (2) a backward (mismatch) session, in which the stage was translocated backward while the rats locomoted forward on the treadmill, and (3) the second control session. Of the 161 HF neurons, 56 place-differential activities were recorded from the HF CA1 subfield. These place-differential activities were categorized into four types; forward-related, backward-related, both-translocation-related, and session-dependent. Forward-related activities showed predominant spatial firings in the forward sessions, while backward-related activities showed predominant spatial firings in the backward sessions. Both-translocation-related activities showed consistent spatial firings in both the forward and backward conditions. On the other hand, session-dependent activities showed different spatial firings across the sessions. Detailed analyses of the place fields indicated that mean place field sizes were larger in the forward-related, backward-related, and both-translocation-related activities than in the session-dependent activities. Furthermore, firing rate distributions in the place fields were negatively skewed and asymmetric, which is similar to place field changes that occur after repeated experience. These results demonstrate that the HF encodes a naturally impossible new configuration of sensory inputs after adaptation, suggesting that the HF is capable of updating its stored memory to accept a new configuration as a match by repeated experience.

Evaluation of histomorphometric and neurochemical changes in the aluminium treated hippocampus following treatment with Huperzine A

Event Abstract Back to Event Evaluation of histomorphometric and neurochemical changes in the aluminium treated hippocampus following treatment with Huperzine A Nilesh K. Mitra1* 1 Taylor's University, Department of Anatomy, School of Medicine, Malaysia Aluminium (Al) is used in cooking utensils, as adjuvant in vaccines and is found in drinking water as a flocculent. The neurotoxic symptoms of aluminium exposure include speech disturbances, tremors, psychosis, partial memory loss and cognitive deficits, some of which mimic neurodegenerative diseases like Alzheimer’s and Parkinson’s Diseases. Huperzine A, a lycopodium alkaloid and acetylcholinesterase (AChE) inhibitor has been used as a neuroprotective agent in traditional Chinese medicine. The objective of this study was to determine the effect of Huperzine A on brain AChE and MAO activity and histomorphometry of hippocampal neurons in albino mice pre-treated with Aluminium Chloride. Female ICR mice (22 weeks, n=6) were treated intraperitoneally with Al (30mg/kg) for 14 days followed by post-treatment with saline, Huperzine A (0.5mg/kg), Huperzine A (0.2mg/kg) and Huperzine A (0.1mg/kg)(Al-Hup 0.1) for further 14 days. A control group was treated with saline. AChE and MAO levels were estimated using spectroflurometric methods from blood and brain samples. Thionin stained coronal serial sections (8 µ) of brain samples were used to estimate neuronal density of neurons of hippocampus using NIS Elements Software. Al treated mice showed decrease in serum AChE and increase in brain AChE. Al-Hup 0.1 group showed significant decrease in brain AChE activity. Brain MAO activity was increased by Al treatment, whereas, Huperzine A post–treatment decreased MAO activity significantly. The neuronal density in CA1, CA2 and CA3 areas of hippocampus following Al treatment showed significant reduction (p<0.001). All Huperzine A post-treatment groups showed increase in neuronal density significantly (p<0.001) in the 3 areas compared to Al-saline group. It can be concluded that although Al has a biphasic effect on serum and brain AChE, it has a persistent toxic effect on neurons of hippocampal formation. Huperzine A has neuro-protective effect on Al induced neurotoxicity in hippocampus. Keywords: in vivo, metal, Huperzine A (HupA), Neuroprotection, Hippocampus, Neurotoxin Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Mitra NK (2016). Evaluation of histomorphometric and neurochemical changes in the aluminium treated hippocampus following treatment with Huperzine A. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00110 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Prof. Nilesh K Mitra, Taylor's University, Department of Anatomy, School of Medicine, Subang Jaya, Selangor, Malaysia, NileshKumar.Mitra@taylors.edu.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nilesh K Mitra Google Nilesh K Mitra Google Scholar Nilesh K Mitra PubMed Nilesh K Mitra Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

5-HT2A Serotonin Receptor Density in Adult Male Rats' Hippocampus after Morphine-based Conditioned Place Preference.

Introduction:A close interaction exists between the brain opioid and serotonin (5-HT) neurotransmitter systems. Brain neurotransmitter 5-HT plays an important role in the regulation of reward-related processing. However, a few studies have investigated the potential role of 5-HT2A receptors in this behavior. Therefore, the aim of the present study was to assess the influence of morphine and Conditioned Place Preference (CPP) on the density of 5-HT2A receptor in neurons of rat hippocampal formation.Methods:Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method.Results:Our data showed that the maximum response was obtained with 2.5 mg/kg of morphine. The density of 5-HT2A receptor in different areas of the hippocampus increased significantly at sham-morphine and CPP groups (P<0.05). On the other hand, the CPP groups had more 5-HT2A receptors than sham-morphine groups and also the sham-morphine groups had more 5-HT2A receptors than the control groups.Conclusion:We concluded that the phenomenon of conditioned place preference induced by morphine can cause a significant increase in the number of serotonin 5-HT2A receptors in neurons of all areas of hippocampus.

Neuronal and Astrocytic Metabolism in a Transgenic Rat Model of Alzheimer's Disease

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer's disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using (1)H- and (13)C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate-glutamine cycle were found in McGill-R-Thy1-APP rats.

Place-related neuronal activity in the monkey parahippocampal gyrus and hippocampal formation during virtual navigation

Neuropsychological data in primates demonstrated a pivotal role of the hippocampal formation (HF) and parahippocampal gyrus (PH) in navigation and episodic memory. To investigate the role of HF and PH neurons in environmental scaling in primates, we recorded neuronal activities in the monkey HF and PH during virtual navigation (VN) and pointer translocation (PT) tasks. The monkeys had to navigate within three differently sized virtual spaces with the same spatial cues (VN task) or move a pointer on a screen (PT task) by manipulating a joystick to receive a reward. Of the 234 recorded neurons, 170 and 61 neurons displayed place-related activities in the VN and PT tasks, respectively. Significant differences were observed between the HF and PH neurons. The spatial similarity of place fields between the two different virtual spaces was lower in PH than in HF, while specificities of the neuronal responses to distal spatial cues were higher in PH than in HF. Spatial view information was predominately processed in posterior PH. The spatial scales (place field sizes) of the HF and PH neurons were reduced in the reduced virtual space, as shown in rodent place cells. These results suggest the complementary roles of HF (allocentric representation of landmarks) and PH (representation of the spatial layout of landmarks) in the recognition of a location during navigation.

Abstract 197: The Calcium Sensitizer Levosimendan Improves Long-Term Neurological Outcome After Experimental Cardiac Arrest

Introduction: Neurological disorder after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is common in human survivors. Impaired cerebral blood flow (CBF) and myocardial dysfunction after successful CPR possibly affect neurological outcome. Levosimendan (Orion Corporation, Finland) improves myocardial function and enhances CBF after experimental CA and CPR. The present study investigated the effect of levosimendan on mortality and neurological outcome 7 d after experimental CA and CPR in rats. Methods: After governmental animal care committee approval (Koblenz, Germany) 80 male Sprague-Dawley rats (330 - 390 g) were included. In 64 animals asphyxial CA and CPR was achieved, randomized to a group with levosimendan treatment (Levo, n = 32, bolus [12 µg/kg] and infusion for 3 h [0.3 µg/min/kg]), or normal saline treatment (Vehicle, n = 32, bolus and infusion for 3 h [equivalent fluid volume]). For technical control 16 animals received surgical intervention and treatment without CA and CPR (sLevo, n = 8; sVehicle, n = 8). After 9 min of asphyxia and CA, CPR was initiated and experimental treatment was started. Survival, neurological assessment (neuro-deficit-score, NDS) and motor function were evaluated over a 7-d-observation period. Histopathological neuronal injury was assessed using HE-staining (expressed as numbers of viable neurons in cortex and hippocampal formation). Results: Survival showed no differences between the CA-groups after 7 d (Levo vs. Vehicle: 25 vs. 28 animals, p = 0.5092). All animals survived in sham-groups. NDS (Group comparison Levo vs. Vehicle: p = 0.003; day 7 of observation period: 13.4 ± 0.6 vs. 14.2 ± 1.4 [mean ± SD]) and cortical neuronal injury (Levo vs. Vehicle: 401 ± 87 vs. 343 ± 57 viable neurons, p = 0.007) were reduced in the Levo-group compared to Vehicle-group. Improved motor function was detected in animals treated with levosimendan (Group comparison Levo vs. Vehicle: p = 0.0091). Conclusion: In this model of CA and CPR treatment with levosimendan reduced cortical neuronal injury and ameliorated neurological performance after 7 d of survival. Based on previously demonstrated findings, the improvement of myocardial function and cerebral blood flow during reperfusion by levosimendan may cause this result.

Hippocampal neuronal responses during signaled licking of gustatory stimuli in different contexts

Neuroanatomical studies suggest that hippocampal formation (HF) receives information from all sensory modalities including taste via the parahippocampal cortices. To date, however, no neurophysiological study has reported that HF neurons encode taste information. In the present study, we recorded CA1 HF neurons from freely behaving rats during performance of a visually-guided licking task in two different triangular chambers. When a cue lamp came on, the rats were required to press a bar to trigger a tube to protrude into the chambers for 3 s. During this period, the rats could lick one of six sapid solutions: [0.1M NaCl (salty), 0.3M sucrose (sweet), 0.01 M citric acid (sour), 0.0001 M quinine HCl (bitter), 0.01 M monosodium L-glutamate (MSG, umami), and a mixture of MSG and 0.001 M disodium-5'-inosinate (IMP) (MSG+IMP)], and distilled water. Of a total 285 pyramidal and interneurons, the activity of 173 was correlated with at least one of the events in the task-illumination of cue lamps, bar pressing, or licking the solution. Of these, 137 neurons responded during licking, and responses of 62 of these cells were greater to sapid solutions than to water (taste neurons). Multivariate analyses of the taste neurons suggested that, in the HF, taste quality might be encoded based on hedonic value. Furthermore, the activity of most taste neurons was chamber-specific. These results implicate the HF in guiding appetitive behaviors such as conditioned place preference.

Trial Outcome and Associative Learning Signals in the Monkey Hippocampus

In tasks of associative learning, animals establish new links between unrelated items by using information about trial outcome to strengthen correct/rewarded associations and modify incorrect/unrewarded ones. To study how hippocampal neurons convey information about reward and trial outcome during new associative learning, we recorded hippocampal neurons as monkeys learned novel object-place associations. A large population of hippocampal neurons (50%) signaled trial outcome by differentiating between correct and error trials during the period after the behavioral response. About half these cells increased their activity following correct trials (correct up cells) while the remaining half fired more following error trials (error up cells). Moreover, correct up cells, but not error up cells, conveyed information about learning by increasing their stimulus-selective response properties with behavioral learning. These findings suggest that information about successful trial outcome conveyed by correct up cells may influence new associative learning through changes in the cell's stimulus-selective response properties.

Response properties of avian hippocampal formation cells in an environment with unstable goal locations

The response properties of 48 right (n=24) and left (n=24) hippocampal formation (HF) cells were examined by recording from freely moving homing pigeons as they foraged in an open-field environment with unstable goal locations. Compared to previous results based on HF recordings from environments with stable goal locations, the spatial signal of the HF neurons recorded in the present study was substantially diminished; there was little indication of PATH cells found in previous HF recordings and nothing resembling place cells routinely recorded in rat hippocampus under similar conditions. However, lateralized response properties were detected. Right HF cells dramatically reduced their firing rates during a foraging session, resulting in very low reliability scores. By contrast, left HF cells maintained firing rates throughout sessions and displayed modestly higher reliability scores compared to right HF neurons. Notable was one striking group of cells (n=13), predominantly found in the right HF, that displayed rate maps characterized by numerous, discrete areas of above baseline firing rates, overall very low firing rates and higher specificity than other cells recorded in this study. Overall, the data emphasize the importance of stable goal locations in shaping the spatial response profile of homing pigeon HF neurons and demonstrate the persistence of lateralized response properties under conditions when space explains little of the temporal variation in firing rate.

Glycoprotein M6a is present in glutamatergic axons in adult rat forebrain and cerebellum

Glycoprotein M6a is a neuronally expressed member of the proteolipid protein (PLP) family of tetraspans. In vitro studies suggested a potential role in neurite outgrowth and spine formation and previous investigations have identified M6a as a stress-regulated gene. To investigate whether the distribution of M6a correlates with neuronal structures susceptible to alterations in response to stress, we localized M6a expression in neurons of hippocampal formation, prefrontal cortex and cerebellum using in situ hybridization and confocal immunofluorescence microscopy. In situ hybridization confirmed that M6a is expressed in dentate gyrus and cerebellar granule neurons and in hippocampal and cortical pyramidal neurons. Confocal microscopy localized M6a immunoreactivity to distinct sites within axonal membranes, but not in dendrites or neuronal somata. Moreover, M6a colocalized with synaptic markers of glutamatergic, but not GABAergic nerve terminals. M6a expression in the adult brain is particularly strong in unmyelinated axonal fibers, i.e. cerebellar parallel and hippocampal mossy fibers. In contrast, myelinated axons exhibit only minimal M6a immunoreactivity localized exclusively to terminal regions. The present neuroanatomical data demonstrate that M6a is an axonal component of glutamatergic neurons and that it is localized to distinct sites of the axonal plasma membrane of pyramidal and granule cells.

Reduced Spike-Timing Reliability Correlates with the Emergence of Fast Ripples in the Rat Epileptic Hippocampus

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.

Oral Administration of Avocado Soybean Unsaponifiables (ASU) Reduces Ischemic Damage in the Rat Hippocampus

The beneficial effects of avocado/soybean unsaponifiables (ASU) are known as an antiarthritic agent. This experimental study presents the effects of ASU on oxidant/antioxidant systems and the number of apoptotic neurons of hippocampal formation after ischemia and reperfusion. Eighteen rats were divided into three equal groups: group I rats were used as controls; group II rats were fed with standard diet and group III rats were fed with standard diet plus ASU pills for 10 days. One day after electrocauterization of bilateral vertebral arteries for groups II and III, bilateral common carotid arteries were occluded for 30 min and then reperfused for 30 min. After these procedures, rats of all groups were sacrificed. The levels of malondialdehyde (MDA) and nitric oxide (NO) and activities of superoxide dismutase (SOD) and catalase (CAT) were measured in the left hippocampus. The number of apoptotic neurons was counted by Tunel method in histological samples of right hippocampus. MDA and NO levels increased in group II compared with group I rats (p = 0.002, p = 0.015). In group III, MDA and NO levels decreased as compared to group II (p = 0.041, p = 0.002). SOD and CAT activities increased in group III as compared to group II rats (p = 0.002, p = 0.002). The number of apoptotic neurons was lower in group III as compared to group II rats. The present findings suggest that ASU could decrease oxidative stress and apoptotic changes in ischemic rat hippocampus. Dietary supplementation of ASU may be beneficial to prevent or ameliorate ischemic cerebral vascular disease.

Increased expression of phosphate-activated glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy

Patients with mesial temporal lobe epilepsy (MTLE) have increased basal concentrations of extracellular glutamate in the epileptogenic versus the non-epileptogenic hippocampus. Such elevated glutamate levels have been proposed to underlie the initiation and maintenance of recurrent seizures, and a key question is what causes the elevation of glutamate in MTLE. Here, we explore the possibility that neurons in the hippocampal formation contain higher levels of the glutamate synthesizing enzyme phosphate-activated glutaminase (PAG) in patients with MTLE versus patients with other forms of temporal lobe epilepsy (non-MTLE). Increased PAG immunoreactivity was recorded in subpopulations of surviving neurons in the MTLE hippocampal formation, particularly in CA1 and CA3 and in the polymorphic layer of the dentate gyrus. Immunogold analysis revealed that PAG was concentrated in mitochondria. Double-labeling experiments indicated a positive correlation between the mitochondrial contents of PAG protein and glutamate, as well as between PAG enzyme activity and PAG protein as determined by Western blots. These data suggest that the antibodies recognize an enzymatically active pool of PAG. Western blots and enzyme activity assays of hippocampal homogenates revealed no change in PAG between MTLE and non-MTLE, despite a greatly (>50%) reduced number of neurons in the MTLE hippocampal formation compared to non-MTLE. Thus, the MTLE hippocampal formation contains an increased concentration and activity of PAG per neuron compared to non-MTLE. This increase suggests an enhanced capacity for glutamate synthesis-a finding that might contribute to the disrupted glutamate homeostasis in MTLE.

Neuronal Implementation of Hippocampal-Mediated Spatial Behavior: A Comparative Evolutionary Perspective

The hippocampal formation (HF) of mammals and birds plays a strikingly similar role in the representation of space. This evolutionarily conserved property, however, belies the contrasting spatial ecology of animals such as rats and homing pigeons, differing spatial ecologies that should have promoted the evolution of group-specific adaptations to the HF representation of space. However, the spatial response properties of pigeon and rat HF neurons reveal surprising similarity in the contribution of position, direction, and trajectory toward explaining spatial variation in firing rate. By contrast, the asymmetrical distribution of neuronal response properties in the left and right HF of homing pigeons, but not rats, indicates a difference in network organization. The authors propose that hippocampal evolution may be characterized by inertia with respect to changes in the basic spatial elements that determine the response properties of neurons but considerable plasticity in how the neuronal response elements are organized into functional networks.

The effects of a changing ambient magnetic field on single-unit activity in the homing pigeon hippocampus

The central representation of geomagnetic information in the avian brain continues to challenge researchers. Although the homing pigeon hippocampal formation primarily participates in the map-like representation of landmarks, some suggestive data indicate that it may also participate in spatial behavior guided by geomagnetic information. Forty-four isolated neurons were recorded from the hippocampal formation of homing pigeons trained to shuttle between two goal locations under changing (direction and intensity, and direction only) magnetic field conditions. Of the 37 slow-firing cells sampled (<14 spikes/s), none displayed a change in firing rate at the time of magnetic field transitions or during different ambient magnetic field conditions. By contrast, three of seven fast firing cells (>17 spikes/s) clearly displayed a phasic increase in firing during at least one of the magnetic field transitions used. The results are consistent with the hypothesis that a subset of hippocampal formation neurons receives information regarding changes in the earth's magnetic field that may be used to guide behavior.