CA1 Field Of Hippocampus Research Articles

Aluminium chloride-induced hippocampal damage: CA3 hippocampal subfield involvement and the neuroprotective role of Buchholzia coriacea ethanolic seed extract

Early signs of neurodegenerative events of Alzheimer's disease manifest within the hippocampus and presents as cognitive and memory impairment. Aluminium-chloride (AlCl 3 ), a neurotoxicant interferes with the structure and functions of the hippocampus as well as its neurogenesis, thereby causing cognitive and memory impairment. Buchholzia coriacea (BC), a plant of nutraceutical value is traditionally reputed to boost memory and cognitive functions. This study elucidated the neuroprotective role of Buchholzia coriacea seed extract on AlCl 3 -induced hippocampal neuronal damage in Wistar rat model by examining the biochemical, histological, immunohistochemical, and neurobehavioural changes. Twenty-five male Wistar rats were randomly assigned into five groups A-E (n = 5). Group A served as the control, groups B-E were given 200 mg/kg of AlCl 3 for 14 days and then received 2 mLs/kg distilled water, 50mg/kg BC, 100mg/kg BC and 2.5mg/kg donepezil respectively for 14 days orally. Glutathione and neurotransmitters (Glutamate, dopamine, and acetylcholine) levels, G6PDH and neurobehavioral activities, as well as histological (H and E, LFB and Cresyl violet stains) and immunohistochemical (ionized calcium-binding adapter molecule 1, Iba-1) changes were evaluated AlCl 3 impaired spatial working memory with observable improvements in the treated groups. Enzymatic activity and neurotransmitter levels were augmented in the group treated with the highest dose of BC compared to the control. Histological assessment showed that BC high-dose mitigated neurodegenerative changes in the CA3 hippocampal subfield. Taken together, BC exhibited neuroprotective ability on AlCl 3 -induced CA3 hippocampal field neuronal damage and demonstrated memory impairment reversing ability.

Combined Preconditioning Reduces the Negative Influence of Cerebral Ischemia on the Morphofunctional Condition of CNS

We studied the influence of combined preconditioning (compound pQ-4 and moderate hypoxia) on morphometrical parameters of neuronal populations in hippocampal fields CA1 and CA3 in rats after bilateral ligation of the common carotid artery. Preconditioning produced a neuroprotective effect, improved survival of pyramidal neurons in the early and delayed periods of modeled ischemia, prevented the formation of necrotic and apoptotic neurons and hyperactivation of microglia, and protected endotheliocytes. The positive influence of preconditioning factors on the morphometric parameters of the brain under ischemic conditions agrees with the results of behavioral tests (open field and elevated plus maze) that demonstrated increased locomotor activity and exploratory behavior of animals.

The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy.

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

The Rapid Place Field Tuning in Mice Exploring a Novel Environment

Hippocampal place cells are a well-known object of plenty of studies about learning and memory. Their firing patterns, or place fields, constitute cognitive maps that support animal's navigation in space. However, most of the place cell studies used rewarded models, where animals were pre-trained to run back and forth for food or water reward. Thereby a question is still unclear about the speed of formation of such cognitive maps in a novel context, i.e., which time is required for place cells to tune on a special piece of the environment. To address this question and to exclude the influence of explicitly reinforced behavior, we developed a reward-free model where animals can explore a novel environment (custom made circular O-shaped track with visual cues on surrounding curtains, see Fig. 1А). Then we recorded the neural activity from the hippocampal field CA1 of mice with a head-mounted Inscopix nVista HD miniature microscope (see Fig. 1B), while the animals were placed in the track, which was a completely novel environment for them. We aligned these data with trajectories of mice and determined place cells as neurons that have a preferential activation zone (putative place field) and that activated in most of the moments the animal visited the field (i.e., more than in 50% of such cases). As expected, place fields were distributed uniformly across the track, without significant gaps and clusters which might be caused by the proximity of visual cues (Fig. 1C-1D). Then, we estimated the time which is required for each individual cell to begin firing with respect to its place field. The majority of cells got tuned within the first three minutes of context exploration, the distribution of times of first in-field activation can be seen on Fig. 1E. However, different animals demonstrate different exploration dynamics, so we re-calculated this distribution in terms of full laps along the circular track. More than 1/3 of cells got tuned within the first lap, while more than 60% of cells do that within the first three laps. Taken together, these data suggest that a cognitive map is mainly formed while an animal makes it first laps in a novel environment, which is consistent with previous findings in rats. Also, the obtained data should serve as a base for searching for possible behavior or intrinsic triggers for cognitive map formation in a novel environment.

Benincasa hispida alleviates amyloid pathology by inhibition of Keap1/Nrf2-axis: Emphasis on oxidative and inflammatory stress involved in Alzheimer's disease model

ObjectivesAlzheimer's disease is a progressive neurodegenerative disorder with cognitive and memory impairment. Benincasa hispida is being used in the treatment of various neurological diseases in Ayurveda system of medicine. The objective of the study was to investigate the effect of Benincasa hispida fruit extract in the Alzheimer's disease rats. MethodsBenincasa hispida fruits extract was administered orally for 16 weeks at doses of 250 and 500-mg/kg/day. The cognitive deficits were examined by behavioural tests like Morris water maze test, Y-maze and rota-rod test. Biochemical and neurochemical analysis of Acetylcholine, dopamine, serotonin levels and anti-oxidant, anti-inflammatory markers were evaluated and the mRNA expression of Keap/Nrf2 axis was analysed by RT-PCR. ResultsAluminum chloride (AlCl3) induction altered the behavioural profile and produced significant alterations in the cortical and hippocampal regions of the brain and the treatment with Benincasa hispida extract at doses of 250-mg/kg/day (p<0.05) and 500mg/kg/day (p<0.05) alleviated the acetylcholine, dopamine and serotonin neurotransmitter levels. The antioxidant enzyme markers such as superoxide dismutase (SOD), Catalase (CAT), glutathione (GSH) were increased and the oxidative stress marker malondialdehyde(MDA) was decreased. The inflammatory cytokine levels of TNF-α, IL-1β were decreased in Alzheimer's disease induced rats. We further estimated Keap/Nrf2/HO-1 genes these anti-oxidant genes were upregulated(p < 0.001) in treatment groups. Further, the neuroprotective activity of Benincasa was further confirmed by histopathological studies of hippocampal CA3 fields. ConclusionsThe findings of the current study indicates Benincasa hispida as a possible neuroprotective alternative for Alzheimer's disease.

Structural differences in the hippocampus and amygdala of behaviorally inhibited macaque monkeys.

Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in the hippocampus and amygdala. However, few studies have investigated the structural differences that may underlie these functional abnormalities. In this exploratory study, we evaluated rhesus monkeys exhibiting a phenotype consistent with human behavioral inhibition. We performed quantitative neuroanatomical analyses that cannot be performed in humans including estimates of the volume and neuron number of distinct hippocampal regions and amygdala nuclei in behaviorally inhibited and control rhesus monkeys. Behaviorally inhibited monkeys had larger volumes of the rostral third of the hippocampal field CA3, smaller volumes of the rostral third of CA2, and smaller volumes of the accessory basal nucleus of the amygdala. Furthermore, behaviorally inhibited monkeys had fewer neurons in the rostral third of CA2. These structural differences may contribute to the functional abnormalities in the hippocampus and amygdala of behaviorally inhibited individuals. These structural findings in monkeys are consistent with a reduced modulation of amygdala activity via prefrontal cortex projections to the accessory basal nucleus. Given the putative roles of the amygdala in affective processing, CA3 in associative learning and CA2 in social memory, increased amygdala and CA3 activity, and diminished CA2 structure and function, may be associated with increased social anxiety and the heritability of behavioral inhibition. The findings from this exploratory study compel follow-up investigations with larger sample sizes and additional analyses to provide greater insight and more definitive answers regarding the neurobiological bases of behavioral inhibition.

The Effect Of Halothane On Number Of The Gad65/67 Positive Cells In Rat Hippocampus At The Midazolam Premedication

The experimental results of halothane effect on GAD65/67 positive cells, number in ÑÀ1 and ÑÀ1 fields of white rat hippocampus are presented in the proposed work. It has been shown, that the number of GAD65/67 positive cells are decreased in CA3 field of hippocampus after 24 hours of halothane anesthesia. Simultaneously the number of the same cells are increased in CA1 field of hippocampus. Midazolam premedication promotes normalization of activity of GAD65/67 which is substantiated by increased number of GAD65/67 positive cells in CA3 field of rat hippocampus after 24 hours.

Electrophysiological Activity and Survival Rate of Rats Nervous Tissue Cells Depends on D/H Isotopic Composition of Medium.

The deuterium content modification in an organism has a neuroprotective effect during the hypoxia model, affecting anxiety, memory and stress resistance. The aim of this work was to elucidate the possible mechanisms of the medium D/H composition modification on nerve cells. We studied the effect of an incubation medium with a 50 ppm deuterium content compared to a medium with 150 ppm on: (1) the activity of Wistar rats’ hippocampus CA1 field neurons, (2) the level of cultured cerebellar neuron death during glucose deprivation and temperature stress, (3) mitochondrial membrane potential (MMP) and the generation of reactive oxygen species in cultures of cerebellar neurons. The results of the analysis showed that the incubation of hippocampal sections in a medium with a 50 ppm deuterium reduced the amplitude of the pop-spike. The restoration of neuron activity was observed when sections were returned to the incubation medium with a 150 ppm deuterium content. An environment with a 50 ppm deuterium did not significantly affect the level of reactive oxygen species in neuron cultures, while MMP decreased by 16–20%. In experiments with glucose deprivation and temperature stress, the medium with 50 ppm increased the death of neurons. Thus, a short exposure of nerve cells in the medium with 50 ppm deuterium acts as an additional stressful factor, which is possibly associated with the violation of the cell energy balance. The decrease in the mitochondrial membrane potential, which is known to be associated with ATP synthesis, indicates that this effect may be associated with the cell energy imbalance. The decrease in the activity of the CA1 field hippocampal neurons may reflect reversible adaptive changes in the operation of fast-reacting ion channels.

Frequency-dependent layer-specific differences in short-term synaptic plasticity in the dorsal and ventral CA1 hippocampal field.

Information from the entorhinal cortex arrives to the hippocampal CA1 microcircuit directly through the temporoammonic path (TA) that terminates in the stratum lacunosum-moleculare (SLM), and indirectly through Schaffer collateral pathway (SC) that terminates in the stratum radiatum (SR). By virtue of this input convergence, CA1 circuitry may act to compare and integrate incoming cortical information. Although a remarkable dorsal-ventral difference in short-term plasticity (STP) has been recently described at SC-CA1 synapses, the corresponding properties at TA-CA1 synapses have not been examined. Here, we report that stimulation of TA in the dorsal hippocampus produces significant facilitation of all conditioned responses evoked by 1-30Hz, peaking at 20-30Hz, and significant depression of steady-state responses to 50-100Hz. Dorsal SC-CA1 synapses display a similar pattern of responses, yet, facilitation peaked at 10Hz and depression (at 75-100Hz) is weaker. Strikingly, stimulation of TA in the ventral hippocampus produces facilitation of steady-state responses to 1-30Hz and highly contrasts with the depression of SC-CA1 synapses. Steady-state responses to 40-100Hz in the ventral hippocampus depress in both layers similarly. High-frequency TA input (40-100Hz) to the dorsal hippocampus depresses more in proximal than in distal SLM, while low-frequency (1-3Hz) TA input to the ventral hippocampus facilitates more in distal than in proximal SLM. The present evidence suggests that direct and indirect entorhinal cortical inputs across the septotemporal extent of hippocampal CA1 field display frequency selectivity both in the radial and transverse axes, and that a rapid information processing may take place through direct ventral hippocampal CA1-EC circuit interactions independently of trisynaptic circuit.

Pentylenetetrazol-induced seizures in adult rats are associated with plastic changes to the dendritic spines on hippocampal CA1 pyramidal neurons

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1−3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.

Long-Term Sequelae of Traumatic Brain Injury in Rats: A Morphological, Behavioral, and Electrophysiological Study

The long-term sequelae of traumatic brain injury (TBI) in humans are linked with the development of convulsions and cognitive and emotional disorders and are also associated with acceleration of brain aging processes and the formation of hippocampal sclerosis (HS). The mechanisms of these complications remain incompletely understood and treatment is extremely difficult. Existing data obtained using experimental models in animals do not provide a clear assessment of these mechanisms. The present study clarifies the long-term histological, behavioral, and electrophysiological sequelae of TBI in rats. Six months after lateral hydrodynamic blows, animals displayed severe asymmetrical gliosis in hippocampal field CA3 and the dental gyrus in the form of fibrillary astrogliosis, with an increase in the number of glial cells and depletion of the pyramidal layer of field CA3 in the ipsilateral hemisphere (corresponding to type 3 HS in humans); sham-operated animals displayed only symmetrical gliosis (isolated gliosis in the human HS classification). The behavior of the rats six months after TBI and the sham procedure was characterized by decreases in motor activity, which some signs of increased anxiety. Behavioral impairments were more severe in rats after TBI, mainly due to decreases in exploratory activity. The long-term period of TBI was characterized on ECoG by prolonged spike-wave discharges in the cortex and asymmetry of epileptiform spikes in the hippocampus. Two rats in the late period demonstrated epileptic seizures. Intense brain aging processes in rats with TBI and the development of neurodegenerative changes in the hippocampus may be linked with chronic remote neuroinflammation, which plays an important role in the development of posttraumatic epilepsy and dementia.

CD200 Change Is Involved in Neuronal Death in Gerbil Hippocampal CA1 Field Following Transient Forebrain Ischemia and Postischemic Treatment with Risperidone Displays Neuroprotection without CD200 Change.

It has been reported that CD200 (Cluster of Differentiation 200), expressed in neurons, regulates microglial activation in the central nervous system, and a decrease in CD200 expression causes an increase in microglial activation and neuronal loss. The aim of this study was to investigate time-dependent changes in CD200 expression in the hippocampus proper (CA1, 2, and 3 fields) after transient forebrain ischemia for 5 min in gerbils. In this study, 5-min ischemia evoked neuronal death (loss) of pyramidal neurons in the CA1 field, but not in the CA2/3 fields, at 5 days postischemia. In the sham group, CD200 expression was found in pyramidal neurons of the CA1 field, and the immunoreactivity in the group with ischemia was decreased at 6 h postischemia, dramatically increased at 12 h postischemia, decreased (to level found at 6 h postischemia) at 1 and 2 days postischemia, and significantly increased again at 5 days postischemia. At 5 days postischemia, CD200 immunoreactivity was strongly expressed in microglia and GABAergic neurons. However, in the CA3 field, the change in CD200 immunoreactivity in pyramidal neurons was markedly weaker than that in the CA1 field, showing there was no expression of CD 200 in microglia and GABAergic neurons. In addition, treatment of 10 mg/kg risperidone (an atypical antipsychotic drug) after the ischemia hardly changed CD200 immunoreactivity in the CA1 field, showing that CA1 pyramidal neurons were protected from the ischemic injury. These results indicate that the transient ischemia-induced change in CD200 expression may be associated with specific and selective neuronal death in the hippocampal CA1 field following transient forebrain ischemia.

Three-dimensional analysis of synaptic organization in the hippocampal CA1field in Alzheimer's disease.

Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-β peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-β and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer’s disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer’s disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer’s disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer’s disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer’s disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer’s disease cases.

Prenatal Introduction of Dexamethasone Causes Disruption of Glucocorticoid Feedback Associated with a Change in the Amount of Corticosteroid Receptors in Extrahypothalamic Brain Structures of Adult Rats

As are other artificial glucocorticoids, dexamethasone is widely used in everyday obstetric practice. The threat of termination of pregnancy is an indication for the use of glucocorticoids. However, there is evidence that the introduction of glucocorticoids during pregnancy can lead to impaired brain development and behavior of offspring that can be caused by a change in the activity of the hypothalamic–pituitary–adrenocortical system (HPAS) due to past effects. The aim of the present work was to study the effect of the introduction of synthetic hormone dexamethasone at the 14th–16th (DM14–16) and 17th–19th (DM17–19) days of prenatal ontogenesis on the stress reactivity of the HPAS in adult 3-month-old rats, as well as on the level of gluco- (GR) and mineralocorticoid (MR) receptors in the most vulnerable areas of the brain (hippocampus and neocortex). Significant intergroup differences in the dynamics of a change in the level of corticosterone in the blood of adult rats in response to a weak stress effect (rapid stress reactivity test) were detected. Using the immunohistochemical method, changes in the expression (the amount of immunopositive cells) of GR and MR were studied in CA1 field and dentate gyrus (DG) of the hippocampus, as well as in second and fifth neocortex layers in adult male rats. In animals of the DM14–16 group, a significant decrease in the number of cells intensively stained using antibodies to GR in CA1 field, hippocampus DG, and neocortex layer V (to 24.5, 32.4, and 5.5%, respectively) as compared with the control were observed. The introduction of dexamethasone at the 17th–19th day of gestation also led to a decrease in the amount of intensively stained GR-immunopositive cells in the hippocampus CA1 field and neocortex layer V (to 31.9 and 35.7%, respectively), but to a lesser degree than in animals from the group DM14–16. A trend toward a decrease in the number of GR-positive cells is accompanied by an increase in immunoreactivity of the cells to MR. Thus, the introduction of dexamethasone at different periods of prenatal ontogenesis modifies the work of gluco- and mineralocorticoid receptors; however, the degree, localization, and direction of these changes differ depending on the time of the effect.

Rhythmic Activity in the Hippocampus and Entorhinal Cortex is Impaired in a Model of Kainate Neurotoxicity in Rats in Free Behavior

The hippocampus and medial entorhinal cortex (MEC) interact by means of bidirectional connections and play an important role in the processing, memorization, and reproduction of information. Data obtained in healthy animals show that the θ and γ oscillations are critical activities necessary for the interaction of the hippocampus and the MEC in signal processing. At the same time, these structures are among the most vulnerable parts of the brain to hyperactivation leading to excitotoxic damage and neuron death. In the present study toxicity was provoked by systemic administration of kainic acid (KA), inducing the development of status epilepticus. In control rats given physiological saline and rats given injections of KA, local field potentials were recorded simultaneously in hippocampal field CA1 and the MEC during exploratory behavior in an open field. A clearly apparent θ rhythm (4–10 Hz) was observed, along with a slow γ rhythm (25–50 Hz) and a fast γ rhythm (55–100 Hz) in the hippocampus and MEC of animals of both groups. Movement of control animals to the center of the open field was accompanied by an increase in the frequency of the θ rhythm and a decrease in the frequency of the fast γ rhythm in the hippocampus; the MEC showed a decrease in the power of the slow γ rhythm. This was not seen in rats given KA. This group also showed impairment to the phase-amplitude modulation of MEC activity by the hippocampal θ rhythm: changes in this modulation on movement of animals from the peripheral zones to the center of the open field were significantly less marked than in controls. There was also a significant increase in θ coherence between the hippocampus and MEC for all locations of the animal in the open field. Changes in the characteristics of rhythms in hippocampus-entorhinal interactions are potential biomarkers for impairments to the coding of spatial information and its retrieval from memory due to status epilepticus and often leading to the development of a convulsive focus in the temporal structures of the brain.

Involvement of Pannexin-1 in the Mechanism of Deprivation Potentiation of Population Spikes of Neurons in Rat Hippocampal Field CA1

Testing of the connections of Schaffer collaterals with field CA1 neurons in living slices of rat hippocampus was used to study the mechanism of deprivation potentiation (DeP) of population spikes developing as a result of a 60-min pause in stimulation (deprivation). Previous studies have shown that DeP has the property of input specificity and the ability to persist for prolonged periods; it consists of two components with independent mechanisms of induction: an initial short-term “peak” of presynaptic origin and a long-lasting “plateau” with a Ca2+-dependent postsynaptic mechanism mediated by P2 purine receptors. Studies of the properties of the input specificity of DeP were run using stimulation of two different populations of Schaffer collaterals and recording of pop-spikes in the general population of neurons in field CA1. These experiments showed that changes in synaptic efficiency in the deprived input depend only on a presynaptic mechanism responsible for the development of the short-term component of DeP. Studies of the postsynaptic mechanism of induction of the long-term component of DeP demonstrated that the function of the adenosine triphosphate (ATP) source required for activation of P2 purine receptors is mediated by pannexin-1, which forms ATP-conducting channels on the postsynapse. A working model of the cyclic mechanism of induction of the long-term component of DeP is presented.

Activation of p38 MAPK participates in the sulbactam-induced cerebral ischemic tolerance mediated by glial glutamate transporter-1 upregulation in rats

Our previous studies have shown that sulbactam can play a neuroprotection role in hippocampal neurons by upregulating the expression and function of glial glutamate transporter-1 (GLT-1) during ischemic insult. Here, using rat global cerebral ischemia model, we studied in vivo the role of p38 mitogen-activated protein kinases (MAPK) in the sulbactam-induced GLT-1 upregulation and neuroprotection against ischemia. The hippocampal CA1 field was selected as observing target. The expressions of phosphorylated-p38 MAPK and GLT-1 were assayed with western blot analysis and immunohistochemistry. The condition of delayed neuronal death (DND) was assayed with neuropathological evaluation under thionin staining. It was shown that administration of sulbactam protected CA1 hippocampal neurons against ischemic insult accompanied with significantly upregulation in the expressions of phosphorylated-p38 MAPK and GLT-1. The time course analysis showed that sulbactam activated p38 MAPK before the GLT-1 upregulation in either normal or global cerebral ischemic rats. Furthermore, inhibiting p38 MAPK activation by SB203580 blocked the GLT-1 upregulation and neuroprotection induced by sulbactam. The above results suggested that p38 MAPK, at least partly, participated in the sulbactam-induced brain tolerance to ischemia mediated by GLT-1 upregulation in rats.

Formation and Retrieval of Associative Memory for a Complex Signal in Mice: Specific Involvement of Hippocampal Field CA1 Neurons

Most important events in the environment are complex in sensory terms. Integration of multimodal information relating to such complex signals by the brain is regarded by many investigators as a biological function of very early forms of consciousness. We report here use of a model of associative learning in mice in which electrocutaneous stimulation was combined with a complex conditioned signal consisting of simultaneous presentation of light and sound stimuli. These studies showed that mice successfully learned and formed long-term memory in a task consisting of conditioned reflex freezing in response to a complex conditioned stimulus. Immunohistochemical mapping of the neuronal expression of the c-fos gene in the hippocampus and associative retrosplenial cortex was performed to study the neural substrates of this memory. We found that only hippocampal field CA1 and not other areas of the hippocampus or the retrosplenial cortex underwent activation on retrieval of the associative memory for the complex conditioned signal, while its components produced no hippocampal activation. In addition, field CA1 showed a strong positive correlation between the level of freezing on retrieval of the memory and the number of neurons activated by retrieval of the memory. Thus, it can be suggested that hippocampal field CA1 is specifically involved in forming and retrieving associative memory for complex signals in the natural environment.

The Effect of Allopregnanolone on Enzymatic Activity of the DNA Base Excision Repair Pathway in the Sheep Hippocampus and Amygdala under Natural and Stressful Conditions.

The neurosteroid allopregnanolone (AL) has many beneficial functions in the brain. This study tested the hypothesis that AL administered for three days into the third brain ventricle would affect the enzymatic activity of the DNA base excision repair (BER) pathway in the hippocampal CA1 and CA3 fields and the central amygdala in luteal-phase sheep under both natural and stressful conditions. Acute stressful stimuli, including isolation and partial movement restriction, were used on the last day of infusion. The results showed that stressful stimuli increased N-methylpurine DNA glycosylase (MPG), thymine DNA glycosylase (TDG), 8-oxoguanine glycosylase (OGG1), and AP-endonuclease 1 (APE1) mRNA expression, as well as repair activities for 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC), and 8-oxoguanine (8-oxoG) compared to controls. The stimulated events were lower in stressed and AL-treated sheep compared to sheep that were only stressed (except MPG mRNA expression in the CA1 and amygdala, as well as TDG mRNA expression in the CA1). AL alone reduced mRNA expression of all DNA repair enzymes (except TDG in the amygdala) relative to controls and other groups. DNA repair activities varied depending on the tissue—AL alone stimulated the excision of εA in the amygdala, εC in the CA3 and amygdala, and 8-oxoG in all tissues studied compared to controls. However, the excision efficiency of lesioned bases in the AL group was lower than in the stressed and stressed and AL-treated groups, with the exception of εA in the amygdala. In conclusion, the presented modulating effect of AL on the synthesis of BER pathway enzymes and their repair capacity, both under natural and stressful conditions, indicates another functional role of this neurosteroid in brain structures.

Effects of Homocysteine and its Derivatives on Spontaneous Network Activity in the Hippocampus of Neonatal Rat Pups

Homocysteine is a sulfur-containing amino acid, which at high concentrations has neurotoxic effects and induces impairments to the development of the nervous system. Homocysteine is rapidly oxidized in the plasma, forming disulfide bonds with proteins and other low molecular weight thiols; it also undergoes transformation into the into homocysteine thiolactone. On chronic exposure, the neurotoxicity of homocysteine is therefore mediated mainly by its derivatives. The aim of the present work was to investigate the effects of homocysteine and its derivatives – homocystine and homocysteine thiolactone – on spontaneous network activity in the hippocampus of rats in the first week after birth. Giant depolarizing potentials (GDP) and multiple action potentials (MAP) were recorded using an extracellular electrode in hippocampal field CA3. All three study compounds were found to induce increases in the frequency of GDP and MAP at concentrations of 100 and 500 μM, homocystine producing the most significant increase in neuron network activity. The effects of homocysteine, homocystine, and homocysteine thiolactone on the spontaneous network activity of neurons were completely eliminated on blockade of NMDA and AMPA receptors. Thus, homocysteine and its derivatives lead to increased spontaneous network activity of hippocampal neurons in neonatal rats, which can induce impairments to the formation of the neural networks of the hippocampus in conditions of chronic hyperhomocysteinemia, and could also induce hyperexcitability and the risk of developing epilepsy in the postnatal period.