CA1 Neurons Research Articles

Unique potential of immature adult-born neurons for the remodeling of CA3 spatial maps

Mammalian hippocampal circuits undergo extensive remodeling through adult neurogenesis. While this process has been widely studied, the specific contribution of adult-born granule cells (aGCs) to spatial operations in the hippocampus remains unknown. Here, we show that optogenetic activation of 4-week-old (young) aGCs in free-foraging mice produces a non-reversible reconfiguration of spatial maps in proximal CA3 while rarely evoking neural activity. Stimulation of the same neuronal cohort on subsequent days recruits CA3 neurons with increased efficacy but fails to induce further remapping. In contrast, stimulation of 8-week-old (mature) aGCs can reliably activate CA3 cells but produces no alterations in spatial maps. Our results reveal a unique role of young aGCs in remodeling CA3 representations, a potential that can be depleted and is lost with maturation. This ability could contribute to generate orthogonalized downstream codes supporting pattern separation.

Toll-Like Receptor 4 Deficiency Ameliorates Propofol-Induced Impairments of Cognitive Function and Synaptic Plasticity in Young Mice.

Propofol is one of the most used intravenous anesthetic agents, which is widely used in clinical anesthesia induction and maintenance of pediatric patients. Exposure of the developing brain to propofol has been reported to lead to adverse brain changes, which in turn can induce persistent behavioral abnormalities in adulthood. However, the mechanisms by which propofol exposure in the developing brain induces cognitive impairment remain unclear. Here we report that repeated propofol exposure during the second postnatal week impairs spatial learning and memory in young mice. The reduced excitatory synaptic function and synaptogenesis in hippocampal CA1 neurons underlie this cognitive impairment. Propofol exposure specifically activates Toll-like receptor 4 (TLR4)-myeloid differentiation primary response protein 88 (MyD88)-NF-κB signaling pathway. TLR4 deficiency recues propofol exposure-induced synaptic function and cognitive deficits in young mice. Thus, we provide evidence that the activation of the TLR4-mediated pathway by propofol exposure may serve as a crucial trigger for the cognitive impairment in young adulthood caused by repeated exposure to propofol in the developing brain.

Effects of aerobic exercise on depression-like behavior and TLR4/NLRP3 pathway in hippocampus CA1 region of CUMS-depressed mice

Background and purposeThe paper observes regulation of the expression levels of NLRP3 and TLR4 in hippocampal CA1 neurons in CUMS mice by aerobic exercise with constructing CUMS depression mouse model, in order to explore the neuroprotective mechanism of aerobic exercise on the hippocampus of depressed mice. Study design and method24 healthy male 8-week-old C57BL/6 mice were randomly divided into CG, MG and ME. Thirteen stress-stimulating factors were randomly formulated into a CUMS stress-stimulating program. The mice were underwent 28 days of CUMS depression model, referenced clinical means for experimental research. The study was approved by the Ethics Committee of Yichun University (YCUEC IRB number LSK NO.2022.18). After model preparation, ME mice were subjected to moderate-intensity treadmill exercise training for 8 weeks. TST, FST and SPT were used to detect the depression-like behaviors of the mice in each group. Nissl staining was used to compare the cell morphology in the CA1 region of the mouse hippocampus. Immunohistochemical staining and western blot were used to detect the changes in the expression levels of NLRP3, TLR4 and other proteins in the CA1 region of the mouse hippocampus. ResultsThe results of neurobehavioral assessment showed that, the immobility time of TST and FST were significantly increased, and SPT index was significantly decreased of MG mice. Compared with MG, ME mice significantly improved depression-like behaviors such as TST, FST and SPT index. Nissl staining showed that the morphology of neurons in CA1 region of hippocampus of MG mice were mostly vacuolar-like, with severe nuclear pyknosis. Abnormal morphological changes such as vacuolar-like and pyknotic pyknosis of neurons in the hippocampal CA1 region of ME mice were significantly reduced. Protein expression test showed that the number of NLRP3, TLR4, IL-1β and IL-10 positive neurons in hippocampal CA1 region of MG mice increased significantly compared with CG, and the proportion of positive cells increased significantly, while NLRP3 and TLR4 positive neurons in the hippocampal CA1 region of ME mice were significantly reduced, the proportion of TLR4 positive cells was significantly reduced. ConclusionSystematic moderate-intensity exercise can effectively improve the depression-like behavior of CUMS depressed mice through the expression of TLR4/NLRP3 inflammatory signaling pathway, and provide an effective experimental basis for the clinical rehabilitation treatment of depression.

Dorsal-Ventral Gradient of Activin Regulates Strength of GABAergic Inhibition along Longitudinal Axis of Mouse Hippocampus in an Activity-Dependent Fashion.

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this difference is effected by the dorsal-ventral gradient of activin A, a member of the transforming growth factor-β family, which is increasingly recognized for its modulatory role in brain regions involved in cognitive functions and affective behavior. Lending credence to this hypothesis, we found that in slices from transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), inhibitory transmission was enhanced only in CA1 neurons of the dorsal hippocampus, where the basal activin A level is much higher than in the ventral hippocampus. We next asked how a rise in endogenous activin A would affect GABAergic inhibition along the longitudinal axis of the hippocampus. We performed ex vivo recordings in wild-type and dnActRIB mice after overnight exposure to an enriched environment (EE), which engenders a robust increase in activin A levels in both dorsal and ventral hippocampi. Compared to control mice from standard cages, the behaviorally induced surge in activin A produced a decline in ventral inhibition, an effect that was absent in slices from dnActRIB mice. Underscoring the essential role of activin in the EE-associated modulation of ventral inhibition, this effect was mimicked by acute application of recombinant activin A in control slices. In summary, both genetic and behavioral manipulations of activin receptor signaling affected the dorsal-ventral difference in synaptic inhibition, suggesting that activin A regulates the strength of GABAergic inhibition in a region-specific fashion.

Simulations predict differing phase responses to excitation vs. inhibition in theta-resonant pyramidal neurons.

Rhythmic activity is ubiquitous in neural systems, with theta-resonant pyramidal neurons integrating rhythmic inputs in many cortical structures. Impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs, but it assumes that the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms (voltage-gated ion channels). The goals of this work were to 1) develop an analysis method to evaluate membrane responses in this nonlinear domain and 2) explore phase relationships between rhythmic stimuli and subthreshold and spiking membrane potential (Vmemb) responses in models of theta-resonant pyramidal neurons. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold theta-rhythmic stimuli produced nonstationary Vmemb responses. Sinusoidal inputs produced "phase retreat": action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Sinusoidal current with increasing amplitude over cycles produced "phase advance": action potentials occurred progressively earlier. Phase retreat, phase advance, and subthreshold phase shifts were modulated by multiple ion channel conductances. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, also observed in hippocampal CA1 neurons.NEW & NOTEWORTHY We augmented electrical impedance analysis to characterize phase shifts between large-amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation vs. inhibition, as well as shifts in spike timing over multiple input cycles, in theta-resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena such as phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.

Autoimmune processes in neurological patients are much more common than presently suspected

Autoimmune encephalitides are seldom diseases. How rare they actually are, however, is not known. The low incidence combined with the problematic identification may dampen efforts of neurologists, to identify patients with unclear symptoms as suffering from autoimmune encephalitis. Here, we aim to obtain a better estimate, how many patients with autoimmune disorders should be expected among 100 inpatients in a conventional neurological department. From a total number of 2603 non-stroke patients attended in a 2-year period (2018–2019) 460 CSFs were obtained. From this collection 187 samples (40.7%, > 500 sections) could be analyzed with our immunocytochemical technique. Autoreactive antibodies were detected in 102 (55%) of these 187 CSF samples. Certainly, the presence of autoreactive antibodies does not necessarily indicate that the patient suffers from an autoimmune disease. Our data indicate that from roughly 2000 patients during 1 year about 125 patients with autoreactive CSF antibodies should be expected in a conventional neurological department. This represents the about 35-fold value of what is generally expected at present. Being aware of this high incidence may intensify the efforts of neurologist to identify patients with any type of autoimmune encephalitis. This will be beneficial for patients, because they often profit from immunomodulatory therapy. Interestingly, some CFSs from our patients react with the CA2 subdivision of the hippocampus. While long neglected, recent research places this area into an important position to influence hippocampal network physiology. Autoreactive antibodies in the CSF may disturb the function of CA2 neurons, thereby explaining some neuropsychiatric symptoms in patients with autoimmune encephalitides.

The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus.

We studied changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus. Rats under urethane anesthesia were implanted with stimulating electrodes in the ventral hippocampal commissure and dMSA and a recording electrode in the CA1 area of the hippocampus. We found that high-frequency stimulation (HFS) of the dMSA led to the induction of long-term potentiation in the synapses formed by the ventral hippocampal commissure on the hippocampal CA1 neurons. One hour after dMSA HFS, we collected the dorsal and ventral hippocampi on both the ipsilateral (damaged by the implanted electrode) and contralateral (intact) sides and analyzed the expression of genes by qPCR. The dMSA HFS led to an increase in the expression of bdnf and cyr61 in the ipsilateral hippocampi and egr1 in the ventral contralateral hippocampus. Thus, dMSA HFS under the conditions of degeneration of the cholinergic neurons in the medial septal area prevented the described increase in gene expression. The changes in cyr61 expression appeared to be dependent on the muscarinic M1 receptors. Our data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.

Effects of thymoquinone and memantine alone and in combination on memory and hippocampal morphology in rats with streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model. Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg for 2 weeks. Group 2 (sham group): In addition to ICV STZ, 9% NaCl, 1 mL/day i.p. for 2 weeks of injection, was applied. Group 3 (TQ group): In addition to ICV STZ, rats received TQ 10 mg/kg i.p. for 2 weeks. Group 4 (MEM group): In addition to ICV STZ, rats were given MEM at a dose of 5 mg/kg for two weeks. Group 5 (TQ+MEM group): In addition to ICV STZ, this group was given TQ (10 mg/kg/day, i.p.) and MEM (5 mg/kg/day, i.p.) for 2 weeks. On the 15th day, passive avoidance learning (PAL) was applied to all groups. Then, rats were sacrificed, neurons in the hippocampal CA1, CA2, CA3 regions were evaluated. Groups 3, 4, 5 had longer latency periods than groups 1 and 2. The neuron density in the CA1, CA2, CA3 regions had decreased in groups 1 and 2 compared to groups 3, 4, 5. There were significantly more neurons in groups 3, 4, 5 than in groups 1 and 2. We found that TQ alone and in combination with MEM showed ameliorative effects on memory and hippocampal morphology. TQ may offer a promising treatment strategy for AD.

Exendin-4 increases the firing activity of hippocampal CA1 neurons through TRPC4/5 channels

The central neuropeptide GLP-1 is synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed in central nervous system. Hippocampus is a key component of the limbic system which is involved in learning, memory, and cognition. Previous studies have shown that overexpression of GLP-1 receptors in the hippocampus could improve the process of learning and memory. However, up to now, the direct electrophysiological effects and possible molecular mechanisms of GLP-1 in hippocampal CAl neurons remain unexplored. The present study aims to evaluate the effects and mechanisms of GLP-1 on the spontaneous firing activity of hippocampal CAl neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micro-pressure administration of GLP-1 receptor agonist, exendin-4, significantly increased the spontaneous firing rate of hippocampal CA1 neurons in rats. Furthermore, application of the specific GLP-1 receptor antagonist, exendin(9−39), alone significantly decreased the firing rate of CA1 neurons, suggesting that endogenous GLP-1 modulates the firing activity of CA1 neurons. Co-application of exendin(9−39) completely blocked exendin-4-induced excitation of hippocampal CA1 neurons. Finally, the present study demonstrated for the first time that the transient receptor potential canonical 4 (TRPC4)/TRPC5 channels may be involved in exendin-4-induced excitation. The present studies may provide a rationale for further investigation of the modulation of GLP-1 on learning and memory as well as its possible involvement in Alzheimer's disease.

Quantitative analysis of the optogenetic excitability of CA1 neurons.

Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Employing state-of-the-art computational models coupled with Monte Carlo simulated light propagation, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitable. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.

Effect of WiFi signal exposure in utero and early life on neurodevelopment and behaviors of rats.

The aim of this study is to examine the long-term effects of prenatal and early-life WIFI signal exposure on neurodevelopment and behaviors as well as biochemical alterations of Wistar rats. On the first day of pregnancy (E0), expectant rats were allocated into two groups: the control group (n = 12) and the WiFi-exposed group (WiFi group, n = 12). WiFi group was exposed to turn on WiFi for 24h/day from E0 to postnatal day (PND) 42. The control group was exposed to turn-off WiFi at the same time. On PND7-42, we evaluated the development and behavior of the offspring, including body weight, pain threshold, and swimming ability, spatial learning, and memory among others. Also, levels of proteins involved in apoptosis were analyzed histologically in the hippocampus in response to oxidative stress. The results showed that WiFi signal exposure in utero and early life (1) increased the body weight of WiFi + M (WiFi + male) group; (2) no change in neuro-behavioral development was observed in WiFi group; (3) increased learning and memory function in WiFi + M group; (4) enhanced comparative levels of BDNF and p-CREB proteins in the hippocampus of WiFi + M group; (5) no neuronal loss or degeneration was detected, and neuronal numbers in hippocampal CA1 were no evidently differences in each group; (6) no change in the apoptosis-related proteins (caspase-3 and Bax) levels; and (7) no difference in GSH-PX and SOD activities in the hippocampus. Prenatal WiFi exposure has no effects on hippocampal CA1 neurons, oxidative equilibrium in brain, and neurodevelopment of rats. Some effects of prenatal WiFi exposure are sex dependent. Prenatal WiFi exposure increased the body weight, improved the spatial memory and learning function, and induced behavioral hyperactivity of male rats.

Progressive development of synchronous activity in the hippocampal neuronal network is modulated by GluK1 kainate receptors

Kainate receptors are potent modulators of circuit excitability and have been repeatedly implicated in pathophysiological synchronization of limbic networks. While the role of aberrant GluK2 subunit containing KARs in generation of epileptiform hypersynchronous activity is well described, the contribution of other KAR subtypes, including GluK1 subunit containing KARs remain less well understood. To investigate the contribution of GluK1 KARs in developmental and pathological synchronization of the hippocampal neural network, we used multielectrode array recordings on organotypic hippocampal slices that display first multi-unit activity and later spontaneous population discharges resembling ictal-like epileptiform activity (IEA). Chronic blockage of GluK1 activity using selective antagonist ACET or lentivirally delivered shRNA significantly delayed developmental synchronization of the hippocampal CA3 network and generation of IEA. GluK1 overexpression, on the other hand, had no significant effect on occurrence of IEA, but enhanced the size of the neuron population participating in the population discharges. Correlation analysis indicated that local knockdown of GluK1 locally in the CA3 neurons reduced their functional connectivity, while GluK1 overexpression increased the connectivity to both CA1 and DG. These data suggest that GluK1 KARs regulate functional connectivity between the excitatory neurons, possibly via morphological changes in glutamatergic circuit, affecting synchronization of neuronal populations. The significant effects of GluK1 manipulations on network activity call for further research on GluK1 KAR as potential targets for antiepileptic treatments, particularly during the early postnatal development when GluK1 KARs are strongly expressed in the limbic neural networks.

Local autocrine plasticity signaling in single dendritic spines by insulin-like growth factors.

The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.

Na+/HCO3- Co-transporters Inhibitor S0859 Attenuates Global Cerebral Ischemia-reperfusion Injury of the CA1 Neurons in the Gerbil's Hippocampus.

Metabolic acidosis plays a key role in transient global cerebral ischemiareperfusion (I/R) induced delayed neuronal death (DND) of the hippocampal CA1 region of gerbils. Na+ coupled HCO3 - transporters (NBCs) mediated Na+/HCO3- - co-transportation can be activated by the pH gradient of intracellular and extracellular environments induced by acidosis. However, whether NBCs are activated and involved in I/R-induced neuronal injury is unknown. In this work, we studied neuronal apoptosis, astrocyte activation, and hippocampusdependent memory task using a well-established transient global cerebral I/R model of gerbils and investigated whether the specific NBCs inhibitor S0859 could reverse this injury. To explore the role of S0859 in I/R-induced DND, we established a transient global cerebral I/R model of Mongolian gerbils and studied neuronal apoptosis by using Nissl stain and TUNEL assay. The excitability and NBCs current were analyzed by whole-cell patch-clamp, while the cognitive function was evaluated by Barnes maze. We found that I/R increased the NBCs current, inhibited the excitability of CA1 neurons, and led to apoptosis in CA1 neurons. Selective NBCs inhibitor S0859 protected CA1 neurons from I/R induced neuronal cell death, astrocyte accumulation, and spatial memory impairment. These findings indicate that NBCs mediate transient global cerebral I/R induced DND of CA1 neurons, and NBCs inhibitors could be a promising target to protect neuronal functions after I/R.

Theta and gamma rhythmic coding through two spike output modes in the hippocampus during spatial navigation

Hippocampal CA1 neurons generate single spikes and stereotyped bursts of spikes. However, it is unclear how individual neurons dynamically switch between these output modes and whether these two spiking outputs relay distinct information. We performed extracellular recordings in spatially navigating rats and cellular voltage imaging and optogenetics in awake mice. We found that spike bursts are preferentially linked to cellular and network theta rhythms (3-12Hz) and encode an animal's position via theta phase precession, particularly as animals are entering a place field. In contrast, single spikes exhibit additional coupling to gamma rhythms (30-100Hz), particularly as animals leave a place field. Biophysical modeling suggests that intracellular properties alone are sufficient to explain the observed input frequency-dependent spike coding. Thus, hippocampal neurons regulate the generation of bursts and single spikes according to frequency-specific network and intracellular dynamics, suggesting that these spiking modes perform distinct computations to support spatial behavior.

Comparative effects of the alcoholic extract of Terminalia chebula and crocin on stress‑induced anxiety‑like behavior and memory impairment in male rats.

Crocin and Terminalia chebula (T. chebula) were proven to have neuroprotective effects. In this study, we evaluated the preventive effects of crocin and alcoholic extract of the T. chebula alone and in combination to examine their efficacy against chronic restraint stress (CRS)‑induced cognitive impairment, anxiety‑like behaviors, hippocampal synaptic plasticity deficit as well as neuronal arborization damage in the hippocampal CA1 neurons. Over 14 consecutive days, animals received crocin, T. chebula, or their combination (5 min before CRS). The elevated plus‑maze results showed that crocin and T. chebula alone and in combination treatment significantly increased the time spent in open arms, percentage of open arm entries, and head dipping as compared with the CRS group. Barnes maze results showed that administration of crocin and T. chebula alone and their combination significantly improves spatial memory indicators such as distance traveled, latency time to achieving the target hole, and the number of errors when compared to the CRS group. These learning deficits in CRS animals correlated with a reduction of long-term potentiation (LTP) in hippocampal CA1 synapses, which both T. chebula and crocin treatment improved field excitatory postsynaptic potentials (fEPSP) amplitude and fEPSP slope reduction induced by CRS. Golgi‑Cox staining showed that T. chebula and crocin treatment increased the number of dendrites and soma arbors in the CA1 neurons compared with the CRS group. Our results suggest that both T. chebula and crocin attenuated CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons. We found no significant difference between single treatments of T. chebula or crocin and their combination in protecting CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons.

Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1−/− mice

Mutations of the GABA-A receptor subunit β1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1-/- mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABAAR-currents in the CA1 neurons were detected in Gabrb1-/- mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1-/- mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

Learning-prolonged maintenance of stimulus information in CA1 and subiculum during trace fear conditioning

Temporal associative learning binds discontiguous conditional stimuli (CSs) and unconditional stimuli (USs), possibly by maintaining CS information in the hippocampus after its offset. Yet, how learning regulates such maintenance of CS information in hippocampal circuits remains largely unclear. Using the auditory trace fear conditioning (TFC) paradigm, we identify a projection from the CA1 to the subiculum critical for TFC. Deep-brain calcium imaging shows that the peak of trace activity in the CA1 and subiculum is extended toward the US and that the CS representation during the trace period is enhanced during learning. Interestingly, such plasticity is consolidated only in the CA1, not the subiculum, after training. Moreover, CA1 neurons, but not subiculum neurons, increasingly become active during CS-and-trace and shock periods, respectively, and correlate with CS-evoked fear retrieval afterward. These results indicate that learning dynamically enhances stimulus information maintenance in the CA1-subiculum circuit during learning while storing CS and US memories primarily in the CA1 area.

Hippocampal place cell remapping occurs with memory storage of aversive experiences.

Aversive stimuli can cause hippocampal place cells to remap their firing fields, but it is not known whether remapping plays a role in storing memories of aversive experiences. Here we addressed this question by performing in-vivo calcium imaging of CA1 place cells in freely behaving rats (n=14). Rats were first trained to prefer a short path over a long path for obtaining food reward, then trained to avoid the short path by delivering a mild footshock. Remapping was assessed by comparing place cell population vector similarity before acquisition versus after extinction of avoidance. Some rats received shock after systemic injections of the amnestic drug scopolamine at a dose (1 mg/kg) that impaired avoidance learning but spared spatial tuning and shock-evoked responses of CA1 neurons. Place cells remapped significantly more following remembered than forgotten shocks (drug-free versus scopolamine conditions); shock-induced remapping did not cause place fields to migrate toward or away from the shocked location and was similarly prevalent in cells that were responsive versus non-responsive to shocks. When rats were exposed to a neutral barrier rather than aversive shock, place cells remapped significantly less in response to the barrier. We conclude that place cell remapping occurs in response to events that are remembered rather than merely perceived and forgotten, suggesting that reorganization of hippocampal population codes may play a role in storing memories for aversive events.

Pinostrobin mitigates neurodegeneration through an up-regulation of antioxidants and GDNF in a rat model of Parkinson’s disease

Background: One of the most common neurodegenerative diseases is Parkinson’s disease (PD); PD is characterized by a reduction of neurons containing dopamine in the substantia nigra (SN), which leads to a lack of dopamine (DA) in nigrostriatal pathways, resulting in motor function disorders. Oxidative stress is considered as one of the etiologies involved in dopaminergic neuronal loss. Thus, we aimed to investigate the neuroprotective effects of pinostrobin (PB), a bioflavonoid extracted from Boesenbergia rotunda with antioxidative activity in PD. Methods: Rats were treated with 40 mg/kg of PB for seven consecutive days before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. After completing the experiment, the brains including SN and striatum were used for histological studies and biochemical assays. Results: PB treatment demonstrated a reduction of free radicals in the SN as indicated by significantly decreased MDA levels, whereas the antioxidative enzymes (SOD and GSH) were significantly increased. Furthermore, PB treatment significantly increased glial cell line-derived neurotrophic factor (GDNF) immunolabelling which has neurotrophic and neuroprotective effects on the survival of dopaminergic neurons. Furthermore, PB treatment was shown to protect CA1 and CA3 neurons in the hippocampus and dopaminergic neurons in the SN. DA levels in the SN were increased after PB treatment, leading to the improvement of motor function of PD rats. Conclusions: These results imply that PB prevents MPTP-induced neurotoxicity via its antioxidant activities and increases GDNF levels, which may contribute to the therapeutic strategy for PD.