CA1 Field Research Articles

The level of apoptosis in the cells of the neocortex and hippocampus of white rats after mild traumatic brain injury with the introduction of glyproline

Glyprolines have a wide range of pharmacological effects, including antioxidant effects. This can be used to correct functional and morphological disorders of the brain after traumatic brain injury (TBI) by inhibiting secondary damage, the prevention of which is the main way to improve TBI outcomes. The aim of the study was to investigate the level of apoptosis in the cells of the proper parietal lobe (PPL) and the CA1 field of the hippocampus of mature male Wistar rats after mild TBI and a course of glyproline RPGP (Arg-Pro-Gly-Pro). Material and methods. Rat brain tissues (n = 38) were used in the experiment. Mild TBI was modeled by free fall of a load. After the injury, the animals received intraperitoneal RPGP peptide at a dose of 0.1 mg/kg, dissolved in 0.9% NaCl solution or NaCl solution. The level of apoptosis in brain tissues was assessed by the expression of p53 antigen using immunohistochemistry. Results. On the 22st day after TBI, the number of glial cells that entered into apoptosis in layer II of the proper parietal lobe (PPL) of the Wistar rat brain increases. In animals subjected to simulated TBI and receiving RPGP intraperitoneally at a dose of 0.1 mg/kg for 21 days, the level of apoptosis did not increase. Conclusion. It was found that after a course of RPGP administration against the background of TBI, the level of apoptosis in neuroglial cells decreases.

Comparison of the effects of three glyprolines after five days of intraperitoneal administration

To date, about 70 drugs based on regulatory peptides have been registered, including proline-containing ones, such as the nootropics Semax and Selank. Further study of the properties of glyproline peptide sequences is relevant in order to describe their neuroprotective properties and the possible development of new drugs based on them. The purpose of the study was to compare the effects of three glyproline peptides on the morphometric characteristics and proliferative activity of brain cells in albino rats. Material and methods. Sexually mature Wistar male rats were intraperitoneally injected with the peptides Thy-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP), Arg-Pro-Gly-Pro (RPGP) and Pro-Gly-Pro-Leu (PGPL) at a dose of 0.1 mg/kg for 5 days. The intact animals that received 0.9 % sodium chloride solution in equivolume served as controls. Morphocytometry was performed on preparations of the right hemisphere of the brain after staining with hematoxylin and eosin. The dimensional (area of bodies, nuclei, and nucleoli) and numerical (number of nucleoli) characteristics of cells were assessed. We examined the parameters of neurons and gliocytes in five localizations (the second and fifth layers of the anterior parietal lobe, the second and fifth layers of the proprietal lobe, field CA1 of the hippocampus). Using immunohistochemical staining, the proliferation intensity was determined (marker Ki-67, clone MIB1). Results. The TKPRPGP peptide changed the morphometric parameters of nervous tissue cells and the gliocyte proliferation index to a greater extent than RPGP and PGPL. In our experiment, the proliferative activity of neurons is maximally influenced by glyproline PGPL. The arginine-containing compound RPGP activates the proliferative activity of gliocytes. Leucine-containing PGPL, to a greater extent, changes the morphometric parameters of neurons. Conclusions. Both studied tetrapeptides affect the morphometric characteristics and proliferative activity of nervous tissue cells when administered five times intraperitoneally at a dose of 0.1 mg/kg. When comparing glyprolines, a more pronounced effect was observed after the administration of PGPL.

Elevated IRS‐1 pS616 Pathology in Human Hippocampal Area CA1 as a Biomarker of Preclinical and Alzheimer's Disease Dementia

AbstractBackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease whose risk can be assessed in the AT(N) framework based on brain levels of Aβ and pathological tau with or without neuronal injury. This helps determine if a cognitively normal or mildly cognitively impaired (MCI) person has clear signs of AD pathogenesis. The AT(N) framework might be enhanced by also considering brain insulin resistance (BIR), which is a common feature in AD dementia (ADd). However, a clear biomarker for brain insulin resistance has yet to be identified. Some studies have identified elevated insulin receptor substrate‐1 phosphorylated at S616 (IRS‐1pS616) in ADd, with conflicting results in other studies. Here, we observed IRS‐1pS616 is mostly limited to cell nuclei in hippocampal field CA1 of normal cases but becomes prominent in neuronal cytoplasm in ADd cases, quantifying this pathological feature using artificial intelligence‐based analysis.MethodsWe performed quantitative immunohistochemical studies on fixed hippocampal sections from 217 age‐ and sex‐matched cases: 68 non‐cognitively impaired (NCI), 13 preclinical (PrCl; i.e., NCI but A+T+), 24 non‐amnestic MCI (naMCI), 32 amnestic MCI (aMCI), and 80 ADd from 3 brain banks (University of Pennsylvania [UPenn], Rush University, and the Banner Research Institute) for β‐amyloid (NAB228), phospho‐tau (AT8), and IRS‐1pS616 (44‐550G). Immunoreactive cells and plaques were quantified using supervised deep‐learning U‐Net neural networks with additional morphology‐based criterions.ResultsDemographical characteristics of study participants are presented in Table 1. The density of CA1 neurons with IRS‐1pS616 pathology was significantly elevated in ADd cases across all cohorts, in PrCl cases from some cohorts, but not in MCI cases (Figure 1). Significant associations were found between IRS‐1pS616, β‐amyloid, and phospho‐tau pathologies in regression analyses, which were weak between IRS‐1pS616 cells and β‐amyloid plaques (Figure 2). No significant differences in IRS‐1pS616 pathology were found between APOE genotypes.ConclusionThese results suggest that elevated IRS‐1pS616 pathology in hippocampal field CA1 is a potential biomarker for BIR in preclinical and ADd, which may be treatable with antidiabetics in the class of incretin receptor agonists shown to reduce BIR in ex vivo preparations of the hippocampus from MCI and ADd cases (see Abstract 89821).

Representation of spatial information in the CA1 field

Information in the brain is encoded by large populations of neurons – neural ensembles. The place cells in the hippocampal CA1 field have become an experimental model for the study of neural ensembles of the brain due to the convenience of research. This review is devoted to the latest studies of place cells in the CA1 field. We consider the principles of encoding space by place cells, mechanisms for controlling the activity of place cells, anatomical and physiological features of place cells in different parts of the CA1 field. Key points: 1. There are rate and phase coding; 2. Dense local connections between pyramidal neurons can provide information processing; 3. Interneurons are involved in the formation of both the rate and phase code of place cells; 4. Pyramidal neurons are anatomically and functionally divided into deep and superficial; 5. Along the dorsoventral axis, the spatial and non-spatial component of information is generalized. The CA1 field has extensive capabilities for signal processing and can implement a computationally complex operation in the cognitive processes of the brain.

Activation of BDNF-TrkB Signaling in Specific Structures of the Sheep Brain by Kynurenic Acid.

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentrations in the cerebroventricular circulation on the expression of BDNF and its high-affinity tropomyosin-related kinase receptor B (TrkB) in specific structures of the sheep brain. Intracerebroventricularly cannulated anestrous sheep were subjected to a series of four 30 min infusions of KYNA: 4 × 5 μg/60 μL/30 min (KYNA20, n = 6) and 4 × 25 μg/60 μL/30 min (KYNA100, n = 6) or a control infusion (n = 6), at 30 min intervals. Sections of the hippocampal CA3 field, amygdala (AMG), prefrontal cortex (PCx), and the hypothalamic medial-basal (MBH) and preoptic (POA) areas were dissected from the brain immediately after the experiment. The highest concentration of BDNF protein was found in the CA3 field (p < 0.001), which was 8-fold higher than in the AMG and 12-fold higher than that in the PCx (MBH and POA were not analyzed). The most pronounced BDNF mRNA expression was observed in the MBH, followed by the PCx, POA, AMG and CA3, while the highest abundance of TrkB mRNA was recorded in the AMG, followed by the MBH, PCx, CA3, and POA. KYNA increased (p < 0.05-p < 0.01) BDNF protein levels and the expression of its gene in the brain structures were examined, with the effect varying by dose and brain region. KYNA, particularly at the KYNA100 dose, also increased (p < 0.01) TrkB gene expression, except for the AMG, where the lower KYNA20 dose was more effective (p < 0.01). These findings suggest a positive relationship between KYNA levels in the cerebroventricular circulation and BDNF-TrkB expression in specific brain regions in a sheep model. This indicates that a transient increase in the CSF KYNA concentration can potentially restore BDNF production, for which deficiency underlies numerous neurological disorders.

Metabotropic NMDAR Signaling Contributes to Sex Differences in Synaptic Plasticity and Episodic Memory.

NMDA receptor (NMDAR)-mediated calcium influx triggers the induction and initial expression of long-term potentiation (LTP). Here we report that in male rodents, ion flux-independent (metabotropic) NMDAR signaling is critical for a third step in the production of enduring LTP, i.e., cytoskeletal changes that stabilize the activity-induced synaptic modifications. Surprisingly, females rely upon estrogen receptor alpha (ERα) for the metabotropic NMDAR operations used by males. Blocking NMDAR channels with MK-801 eliminated LTP expression in hippocampal field CA1 of both sexes but left intact theta burst stimulation (TBS)-induced actin polymerization within dendritic spines. A selective antagonist (Ro25-6981) of the NMDAR GluN2B subunit had minimal effects on synaptic responses but blocked actin polymerization and LTP consolidation in males only. Conversely, an ERα antagonist thoroughly disrupted TBS-induced actin polymerization and LTP in females while having no evident effect in males. In an episodic memory paradigm, Ro25-6981 prevented acquisition of spatial locations by males but not females, whereas an ERα antagonist blocked acquisition in females but not males. Sex differences in LTP consolidation were accompanied by pronounced differences in episodic memory in tasks involving minimal (for learning) cue sampling. Males did better on acquisition of spatial information whereas females had much higher scores than males on tests for acquisition of the identity of cues (episodic "what") and the order in which the cues were sampled (episodic "when"). We propose that sex differences in synaptic processes used to stabilize LTP result in differential encoding of the basic elements of episodic memory.

Kynurenic Acid Modulates the Expression of Genes and the Activity of Cellular Antioxidant Enzymes in the Hypothalamus and Hippocampus in Sheep.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 μg/60 μL/30 min, KYNA20) and higher (4 × 25 μg/60 μL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

Selective disruption of synaptic NMDA receptors of the hippocampal trisynaptic circuit in Aβ pathology

Synaptic dysfunction is an early feature in Alzheimer’s disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aβ pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

Recurrence quantification analysis of rs-fMRI data: A method to detect subtle changes in the TgF344-AD rat model

Background and objectiveAlzheimer's disease (AD) is one of the leading causes of dementia, affecting the world's population at a growing rate. The preclinical stage of AD lasts over a decade, hence understanding AD-related early neuropathological effects on brain function at this stage facilitates early detection of the disease. MethodsResting-state functional magnetic resonance imaging (rs-fMRI) has been a powerful tool for understanding brain function, and it has been widely used in AD research. In this study, we apply Recurrence Quantification Analysis (RQA) on rs-fMRI images of 4-months (4 m) and 6-months-old (6 m) TgF344-AD rats and WT littermates to identify changes related to the AD phenotype and aging. RQA has been focused on areas of the default mode-like network (DMLN) and was performed based on Recurrence Plots (RP). RP is a mathematical representation of any dynamical system that evolves over time as a set of its state recurrences. In this paper, RPs were extracted in order to identify the affected regions of the DMLN at very early stages of AD. ResultsUsing the RQA approach, we identified significant changes related to the AD phenotype at 4 m and/or 6 m in several areas of the rat DMLN including the BFB, Hippocampal fields CA1 and CA3, CG1, CG2, PrL, PtA, RSC, TeA, V1, V2. In addition, with age, brain activity of WT rats showed less predictability, while the AD rats presented reduced decline of predictability. ConclusionsThe results of this study demonstrate that RQA of rs-fMRI data is a potent approach that can detect subtle changes which might be missed by other methodologies due to the brain's non-linear dynamics. Moreover, this study provides helpful information about specific areas involved in AD pathology at very early stages of the disease in a very promising rat model of AD. Our results provide valuable information for the development of early detection methods and novel diagnosis tools for AD.

Effect of kynurenic acid on enzymatic activity of the DNA base excision repair pathway in specific areas of the sheep brain

Relatively low levels of antioxidant enzymes coupled with high oxygen metabolism result in the formation of numerous oxidative DNA damages in the tissues of the central nervous system. Recently, kynurenic acid (KYNA), knowns for its neuroprotective properties, has gained increasing attention in this context. Therefore, our hypothesis assumed that increased KYNA levels in the brain would positively influence mRNA expression of selected enzymes of the base excision repair pathway as well as enhance their efficiency in excising damaged nucleobases in specific areas of the sheep brain. The study was conducted on adult anestrous sheep (n = 18), in which two different doses of KYNA (20 and 100 μg/day) were infused into the third brain ventricle for three days. Molecular and biochemical analysis included the hypothalamus (preoptic and mediol-basal areas), hippocampus (CA3 field) and amygdala (central amygdaloid nucleus), dissected from the brain of sheep euthanized immediately after the last infusion. The results revealed a significant increase P < 0.001) in the relative mRNA abundance of N-methylpurine DNA glycosylase (MPG) following administration of both dose of KYNA across all examined tissues. The transcription of thymine-DNA glycosylase (TDG) increased significantly (P < 0.001) in all tissues in response to the lower KYNA dose compared to the control group. Moreover, 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1) mRNA levels were also higher in both animal groups (P < 0.001). In addition, in the hypothalamus, hippocampus and amygdala, AP endonuclease 1 (APE1) mRNA expression increased under both doses of KYNA. Moreover, the both dose of KYNA significantly stimulated the efficiency of 8-oxoG excision in hypothalamus and amygdala (P < 0.05–0.001). The lower and higher doses of KYNA significantly influenced the effectiveness of εA and εC in all structures (P < 0.01–0.001). In conclusion, the favorable effect of KYNA in the brain may include the protection of genetic material in nerve and glial cells by stimulating the expression and efficiency of BER pathway enzymes.

Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Recruitment of hippocampal and thalamic pathways to the central amygdala in the control of feeding behavior under novelty.

It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating can become maladaptive. Currently, the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance.

MORPHOLOGICAL CHANGES IN THE HIPPOCAMPUS OF THE RAT BRAIN IN ISCHEMIA AND IN CONDITIONS OF COMBINED PRECONDITIONING

BACKGROUND: Preconditioning is an effective method of increasing the body's resistance to hypoxia/ischemia.&#x0D; AIM: The aim is to evaluate morphological changes in the most hypoxia-sensitive fields of the hippocampus CA1 and CA3 in cerebral ischemia in rats and under conditions of combined preconditioning.&#x0D; MATERIALS AND METHODS. Cerebral ischemia was simulated in rats under anesthesia (8% chloral hydrate solution 400 mg/kg) by bilateral ligation of the common carotid arteries. The combined preconditioning method (CPreC) included the alternate use of two preconditional factors – pharmacological (amtisol at a dose of 25 mg /kg) and hypoxic (hypobaric hypoxia, 410 mmHg, exposure time 60 min). Morphometric assessment of brain damage was performed a day after modeling ischemia in the CA1 and CA3 fields of the hippocampus.&#x0D; RESULTS. KPreK has a positive effect on the morphometric parameters of the brain during its ischemia, increasing the survival of neurons in the early and late periods of ischemia modeling, preventing the formation of necrotically and apoptotically altered neurons, hyperactivation of microglial cells and contributing to the preservation of endotheliocytes. &#x0D; CONCLUSION. KPreK (amtisol + hypobaric hypoxia) has a neuroprotective effect in cerebral ischemia.

Electrophysiological Properties of the Medial Mammillary Bodies across the Sleep-Wake Cycle.

The medial mammillary bodies (MBs) play an important role in the formation of spatial memories; their dense inputs from hippocampal and brainstem regions makes them well placed to integrate movement-related and spatial information, which is then extended to the anterior thalamic nuclei and beyond to the cortex. While the anatomical connectivity of the medial MBs has been well studied, much less is known about their physiological properties, particularly in freely moving animals. We therefore carried out a comprehensive characterization of medial MB electrophysiology across arousal states by concurrently recording from the medial MB and the CA1 field of the hippocampus in male rats. In agreement with previous studies, we found medial MB neurons to have firing rates modulated by running speed and angular head velocity, as well as theta-entrained firing. We extended the characterization of MB neuron electrophysiology in three key ways: (1) we identified a subset of neurons (25%) that exhibit dominant bursting activity; (2) we showed that ∼30% of theta-entrained neurons exhibit robust theta cycle skipping, a firing characteristic that implicates them in a network for prospective coding of position; and (3) a considerable proportion of medial MB units showed sharp-wave ripple (SWR) responsive firing (∼37%). The functional heterogeneity of MB electrophysiology reinforces their role as an integrative node for mnemonic processing and identifies potential roles for the MBs in memory consolidation through propagation of SWR-responsive activity to the anterior thalamus and prospective coding in the form of theta cycle skipping.

Inhibition of fatty acid amide hydrolase reverses aberrant prefrontal gamma oscillations in the sub-chronic PCP model for schizophrenia.

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5mg/kg, twice daily for 7days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.

Immunohistochemical Analysis of Mitochondrial Dynamics in Different Zones of the Hippocampus during Experimental Modeling of Alzheimer's Disease.

We performed a comparative assessment of the immunohistochemical distribution of markers of mitochondrial fission (Drp-1), mitochondrial fusion (Mfn-2), and mitochondrial biogenesis (PGC-1α) in pyramidal neurons of different zones of the hippocampus in mice with intrahippocampal administration of β-amyloid peptide 25-35. The most pronounced changes in the dynamics associated with a decrease in the amount of the fission marker and an increase in the amount of the fusion marker were observed in the CA3 field on day 38 after peptide administration. In the CA1 field, a significant decrease in the marker of mitochondrial biogenesis PGC-1α was found on day 38, which can indicate a decrease in the intensity of mitochondrial biogenesis. Early mitochondrial changes can play an important role in the pathogenesis of all types of memory impairment in Alzheimer's disease.

α7 nicotinic acetylcholine receptors induce long-term synaptic enhancement in the dorsal but not ventral hippocampus.

Agents that positively modulate the activity of α7nAChRs are used as cognitive enhancers and for the treatment of hippocampus-dependent functionaldecline. However, it is not known whether the expression and the effects of α7nAChRs apply to the entire longitudinal axis of the hippocampus equally. Given that cholinergic system-involving hippocampal functions are not equally distributed along the hippocampus, we comparatively examined the expression and the effects of α7nAChRs on excitatory synaptic transmission between the dorsal and the ventral hippocampal slices from adult rats. We found that α7nAChRs are equally expressed in the CA1 field of the two segments of the hippocampus. However, activation of α7nAChRs by their highly selective agonist PNU 282987 induced a gradually developing increase in field excitatory postsynaptic potential only in the dorsal hippocampus. This long-term potentiation was not reversed upon application of nonselective nicotinic receptor antagonist mecamylamine, but the induction of potentiation was prevented by prior blockade of α7nAChRs by their antagonist MG 624. In contrast to the long-term synaptic plasticity, we found that α7nAChRs did not modulate short-term synaptic plasticity in either the dorsal or the ventral hippocampus. These results may have implications for the role that α7nAChRs play in specifically modulating functions that depend on the normal function of the dorsal hippocampus. We propose that hippocampal functions that rely on a direct α7 nAChR-mediated persistent enhancement of glutamatergic synaptic transmission are preferably supported by dorsal but not ventral hippocampal synapses.

Activity of hippocampal CA1 field neurons during aversive memory formation and reactivation in mice &lt;i&gt;in vivo&lt;/i&gt;

Activity of hippocampal CA1 field neurons during aversive memory formation and reactivation in mice &lt;i&gt;in vivo&lt;/i&gt;

Dynamics of space coding by mouse hippocampal CA1 field neurons in a free navigation task in different environments

The development of persistent cognitive adaptations in neurons is a key area of focus in contemporary neuroscience. A significant illustration of such adaptations occurs through spatial specializations in place cells with one or more receptive fields that are sensitive to spatial cues (place fields) [1]. In prior research, we extensively examined the dynamics of place field formation in granular layer neurons of the CA1 field in the hippocampus of mice during arbitrary free navigation in a circular track [2]. As the primary factor for maintaining stability in the spatial specialization of place cells, we have introduced dynamic selectivity. This approach enables us to monitor the latency of each place field’s formation and the selectivity dynamics of place cells to their respective fields throughout one or multiple shooting sessions. However, in one-dimensional settings, like the circular track referenced previously, place fields can demonstrate direction-specificity with regards to animal movement [3]. This factor considerably complicates the analysis for arbitrary movement trajectories of animals. In this study, additional experiments were conducted to capture the neural activity of mice in two-dimensional environments. The experiments were conducted in both a rectangular field with objects and a circular arena with a varying number of obstacles. In this paper, we conduct a comparative analysis to examine the critical parameters governing the development of spatial specializations in a one-dimensional circle track and two-dimensional arenas. These parameters include specialization latency, average dynamic selectivity, initial increase in selectivity, and the proportion of “immediate” place fields that remain stable from the first animal visit. The study discovered that the mean selectivity of the place fields escalated in each session, with higher rates observed in subsequent sessions versus the initial session in a novel setting. Additionally, there was a significant occurrence of “immediate” place fields, representing 11% of all place fields in the rounded arena with obstacles, and 25% of all place fields in the circular track. Additionally, a population analysis of neural activity was performed on the first session in a circular track and a round arena with obstacles. Using Laplace eigenmaps for the dimension reduction of population vectors, the trajectory of animals was reconstructed, and the accuracy of this reconstruction agreed with the average dynamic selectivity for each animal included in the analysis. Thus, dynamic selectivity was verified as a measure of the spatial coding quality of the entire registered population of neurons.

Febrile seizures cause a decrease in calcium-permeable AMPA receptors at synapses of rat cortical and hippocampal pyramidal neurons

Febrile seizures (FS) are a prevalent childhood neurological disorder that can result in lasting functional alterations in neural networks, contributing to the onset of epilepsy and cognitive impairment [1]. Higher levels of calcium-permeable AMPA receptors (CP-AMPARs), which lack the GluA2 subunit, are detected in the hippocampus and cortex at an early age. CP-AMPARs are involved in various plastic changes within the central nervous system (CNS), including regular physiological processes (synaptic plasticity) and various pathological conditions. Such changes occur when these receptors are included in the neurons’ membrane, where they are not typically expressed. CP-AMPARs were demonstrated to incorporate into synapses during seizures [2]. The effect of FSs on CP-AMPAR expression is uncertain, and the resultant alterations in neuronal network function are unclear. The aim of this study was to determine whether the proportion of CP-AMPARs at synapses of pyramidal neurons in the rat entorhinal cortex and hippocampus alters immediately (at 15 min) and 48 h post FS. Ten-day-old rats were exposed to a stream of warm air (46 °C) for 30 minutes to induce hyperthermia, resulting in the development of FS. Only animals with FS that lasted for a minimum of 15 minutes were included in the study. The control group was comprised of littermates removed from the dam for an equivalent period but kept at room temperature. Isolated pyramidal neurons were used to determine the proportion of CP-AMPARs in the hippocampus. AMPAR-mediated currents were induced by application of 100 μM kainate. Excitatory postsynaptic currents (EPSCs) were evoked by extracellular stimulation in the entorhinal cortex. The antagonist IEM-1460 was used to selectively block CP-AMPARs. The rectification index of AMPA-mediated EPSCs was calculated to better assess the contribution of CP-AMPARs. Neurons expressing CP-AMPARs were visualized using the kainate-induced cobalt uptake method. Brain slices were stimulated with kainate while AR-5 and TTX were present. The DNQX blocker was used for the determination that the influx of Co2+ was mediated by AMPARs. Basal synaptic transmission was assessed by recording field postsynaptic responses in the hippocampus stimulated by Shaffer collaterals at different current strengths. FS induced a rapid decrease in the levels of CP-AMPARs on the membranes of pyramidal neurons in the hippocampus. As a result, 15 min after FS, IEM-1460 caused significantly less blockade of kainate-evoked current in neurons isolated from rat hippocampus compared to control (22% vs. 14%, p 0.05). A similar finding was observed for EPSCs evoked extracellularly in the entorhinal cortex, with a frequency of 10% in the FS group compared to 3% in the control group (p 0.05). Furthermore, the FS group’s neurons exhibited a significantly greater rectification index of EPSCs compared to the control group’s neurons. However, two days post-FS, no significant differences existed between the two groups. This observation may be attributed to the rapid decrease in the proportion of CP-AMPARs in pyramidal neurons at this stage. The cobalt uptake method supported electrophysiological findings, revealing higher staining levels in the CA1 field of the hippocampus and entorhinal cortex of control rats compared to FS rats. The observed effect surfaced 15 minutes after FS, and no divergences emerged between the groups after two days. Although the proportion of CP-AMPARs was reduced, basal neurotransmission levels in brain slices obtained from rats that underwent FS did not differ from control values. In summary, the expression of CP-AMPARs in entorhinal cortex and hippocampal pyramidal neurons in young rats decreases significantly with FS. These alterations do not impact the characteristics of basal synaptic transmission in the hippocampus.