Effect of astrocyte on synchronization of thermosensitive neuron-astrocyte minimum system

Astrocytes have a regulatory function on the central nervous system (CNS), especially in the temperature sensitive hippocampal region. In order to explore the thermosensitive dynamic mechanism of astrocytes in CNS, we establish a neuron-astrocyte minimum system to analyze the synchronization change characteristics based on Hodgkin-Huxley model, in which a pyramidal cell and an interneuron are connected by an astrocyte. Besides, the temperature range set 0°C-40°C to juggle theoretical calculation and reality of brain environment. It is represented that the synchronization of thermosensitive neurons exhibits nonlinear behavior with change of astrocyte parameters. At temperature range of 0°C-18°C, the effects of astrocyte can provide tremendous influence to neurons in synchronization. We found existence of a value for inositol triphosphate (IP3) production rate and feedback intensities of astrocyte to neurons, which can ensure the weak synchronization of two neurons. In addition, it is revealed that the regulation of astrocyte to pyramidal cell is more sensitive than that to interneuron. Finally, it is shown that the synchronization and phase transition of neurons depend on the change of Ca2+ concentration at the temperature of weak synchronization. The results in this paper would provide some enlightenment in mechanism of cognitive dysfunction and neurological disorders with astrocytes.

Neuronal primary cilia regulate pyramidal cell positioning to the deep and superficial sublayers in the hippocampal CA1

It is well-recognized that primary cilia regulate embryonic neurodevelopment, but little is known about their roles in postnatal neurodevelopment. The striatum pyramidal (SP) of hippocampal CA1 consists of superficial and deep sublayers, however, it is not well understood how early- and late-born pyramidal neurons position to two sublayers postnatally. Here we show that neuronal primary cilia emerge after CA1 pyramidal cells have reached SP, but before final neuronal positioning. The axonemes of primary cilia of early-born neurons point to the stratum oriens (SO), whereas late-born neuronal cilia orient toward the stratum radiatum (SR), reflecting an inside-out lamination pattern. Neuronal primary cilia in SP undergo marked changes in morphology and orientation from postnatal day 5 (P5) to P14, concurrent with pyramidal cell positioning to the deep and superficial sublayers and with neuronal maturation. Transgenic overexpression of Arl13B, a protein regulating ciliogenesis, not only elongates primary cilia and promotes earlier cilia protrusion, but also affects centriole positioning and cilia orientation in SP. The centrioles of late-born neurons migrate excessively to cluster at SP bottom before primary cilia protrusion and a reverse movement back to the main SP. Similarly, this pull-back movement of centriole/cilia is also identified on late-born cortical pyramidal neurons, although early- and late-born cortical neurons display the same cilia orientation. Together, this study provides the first evidence demonstrating that late-born pyramidal neurons exhibit a reverse movement for cell positioning, and primary cilia regulate pyramidal neuronal positioning to the deep and superficial sublayers in the hippocampus.

Biocompatibility of Platinum Nanoparticles in Brain ex vivo Models in Physiological and Pathological Conditions

Platinum nanoparticles (PtNPs) have unique physico-chemical properties that led to their use in many branches of medicine. Recently, PtNPs gathered growing interest as delivery vectors for drugs, biosensors and as surface coating on chronically implanted biomedical devices for improving electrochemical properties. However, there are contradictory statements about their biocompatibility and impact on target organs such as the brain tissue, where these NPs are finding many applications. Furthermore, many of the reported studies are conducted in homeostasis conditions and, consequently, neglect the impact of the pathologic conditions on the tissue response. To expand our knowledge on the effects of PtNPs on neuronal and glial cells, we investigated the acute effects of monodisperse sodium citrate-coated PtNPs on rat organotypic hippocampal cultures in physiological or neuronal excitotoxic conditions induced by kainic acid (KA). The cellular responses of the PtNPs were evaluated through cytotoxic assays and confocal microscopy analysis. To mimic a pathologic scenario, 7-day organotypic hippocampal cultures were exposed to KA for 24 h. Subsequently, PtNPs were added to each slice. We show that incubation of the slices with PtNPs for 24 h, does not severely impact cell viability in normal conditions, with no significant differences when comparing the dentate gyrus (DG), as well as CA3 and CA1 pyramidal cell layers. Such effects are not exacerbated in KA-treated slices, where the presence of PtNPs does not cause additional neuronal propidium iodide (PI) uptake in CA3 and CA1 pyramidal cell layers. However, PtNPs cause microglial cell activation and morphological alterations in CA3 and DG regions indicating the establishment of an inflammatory reaction. Morphological analysis revealed that microglia acquire activated ameboid morphology with loss of ramifications, as a result of their response to PtNPs contact. Surprisingly, this effect is not increased in pathological conditions. Taken together, these results show that PtNPs cause microglia alterations in short-term studies. Additionally, there is no worsening of the tissue response in a neuropathological induced scenario. This work highlights the need of further research to allow for the safe use of PtNPs. Also, it supports the demand of the development of novel and more biocompatible NPs to be applied in the brain.

Disrupted-in-Schizophrenia-1 is required for proper pyramidal cell-interneuron communication and network dynamics in the prefrontal cortex

We interrogated prefrontal circuit function in mice lacking Disrupted-in-schizophrenia-1 (Disc1-mutant mice), a risk factor for psychiatric disorders. Single-unit recordings in awake mice revealed reduced average firing rates of fast-spiking interneurons (INTs), including optogenetically identified parvalbumin-positive cells, and a lower proportion of INTs phase-coupled to ongoing gamma oscillations. Moreover, we observed decreased spike transmission efficacy at local pyramidal cell (PYR)-INT connections in vivo, suggesting a reduced excitatory effect of local glutamatergic inputs as a potential mechanism of lower INT rates. On the network level, impaired INT function resulted in altered activation of PYR assemblies: While assembly activations were observed equally often, the expression strength of individual assembly patterns was significantly higher in Disc1-mutant mice. Our data thus reveal a role of Disc1 in shaping the properties of prefrontal assembly patterns by setting prefrontal INT responsiveness to glutamatergic drive.

Long-term potentiation at pyramidal cell to somatostatin interneuron synapses controls hippocampal network plasticity and memory

Hippocampal somatostatin (SOM) cells are dendrite-projecting inhibitory interneurons. CA1 SOM cells receive major excitatory inputs from pyramidal cells (PC-SOM synapses) which show mGluR1a- and mTORC1-mediated long-term potentiation (LTP). PC-SOM synapse LTP contributes to CA1 network metaplasticity and memory consolidation, but whether it is sufficient to regulate these processes remains unknown. Here we used optogenetic stimulation of CA1 pyramidal cells and whole cell recordings in slices to show that optogenetic theta burst stimulation (TBSopto) produces LTP at PC-SOM synapses. At the network level, we found that TBSopto differentially regulates metaplasticity of pyramidal cell inputs: enhancing LTP at Schaffer collateral synapses and depressing LTP at temporo-ammonic synapses. At the behavioral level, we uncovered that in vivo TBSopto regulates learning-induced LTP at PC-SOM synapses, as well as contextual fear memory. Thus, LTP of PC-SOM synapses is a long-term feedback mechanism controlling pyramidal cell synaptic plasticity, sufficient to regulate memory consolidation.

An astrocytic signaling loop for frequency-dependent control of dendritic integration and spatial learning

Dendrites of hippocampal CA1 pyramidal cells amplify clustered glutamatergic input by activation of voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). NMDAR activity depends on the presence of NMDAR co-agonists such as D-serine, but how co-agonists influence dendritic integration is not well understood. Using combinations of whole-cell patch clamp, iontophoretic glutamate application, two-photon excitation fluorescence microscopy and glutamate uncaging we found that exogenous D-serine reduces the threshold of dendritic spikes and increases their amplitude. Triggering an astrocytic mechanism controlling endogenous D-serine supply via endocannabinoid receptors (CBRs) also increased dendritic spiking. Unexpectedly, this pathway was activated by pyramidal cell activity primarily in the theta range, which required HCN channels and astrocytic CB1Rs. Therefore, astrocytes close a positive and frequency-dependent feedback loop between pyramidal cell activity and their integration of dendritic input. Its disruption led to an impairment of spatial memory, which demonstrates its behavioral relevance.

The Effects of Borax (NA2B4O710H2O) on Histopathology of Wistar Rats’ Cerebrum (Rattus norvegicus)

The present study aimed to determine the effects of borax (Na2B4O7.10H2O) addition on the changes of histological cerebrum imaging in the brains of white mice (Rattus norvegicus). The current research was an experimental study with randomization of 24 white mice that were divided into four treatment groups with five replications. Borax was dissolved for each treatment with a dose of 19 mg/mouse/day, 26 mg/mouse/day, and 37 mg/mouse/day, and it was administered orally for 14 days. Then, it was analyzed statistically using the Kruskal-Wallis test. The statistical analysis results suggested that there were significantly different results in each treatment group. The control treatment with an administration dose of 26 mg/rat/day had a significantly different result in the worst cloudy swelling degeneration of cerebrum in histopathology imaging on Wistar rats (Rattus norvegicus). Using the Mann-Whitney test, it was found that the dose of borax at 37 mg/rat/day led to significant difference, compared to the other treatment groups, which means that 37 mg/rat/day of borax caused the worst pyramidal cell necrosis in histopathology imaging of the cerebrum on white mice. Borax exposure on Wistar rats (Rattus norvegicus) can cause cloudy swelling at a dose of 26mg/head/day, and pyramidal cell necrosis at a dose of 37 mg/head/day.

Deciphering how interneuron specific 3 cells control oriens lacunosum-moleculare cells to contribute to circuit function

The wide diversity of inhibitory cells across the brain makes them suitable to contribute to network dynamics in specialized fashions. However, the contributions of a particular inhibitory cell type in a behaving animal are challenging to untangle as one needs to both record cellular activities and identify the cell type being recorded. Thus, using computational modeling and theory to predict and hypothesize cell-specific contributions is desirable. Here, we examine potential contributions of interneuron-specific 3 (I-S3) cells - an inhibitory interneuron found in CA1 hippocampus that only targets other inhibitory interneurons - during simulated theta rhythms. We use previously developed multi-compartment models of oriens lacunosum-moleculare (OLM) cells, the main target of I-S3 cells, and explore how I-S3 cell inputs during in vitro and in vivo scenarios contribute to theta. We find that I-S3 cells suppress OLM cell spiking, rather than engender its spiking via post-inhibitory rebound mechanisms, and contribute to theta frequency spike resonance during simulated in vivo scenarios. To elicit recruitment similar to in vitro experiments, inclusion of disinhibited pyramidal cell inputs is necessary, implying that I-S3 cell firing broadens the window for pyramidal cell disinhibition. Using in vivo virtual networks, we show that I-S3 cells contribute to a sharpening of OLM cell recruitment at theta frequencies. Further, shifting the timing of I-S3 cell spiking due to external modulation shifts the timing of the OLM cell firing and thus disinhibitory windows. We propose a specialized contribution of I-S3 cells to create temporally precise coordination of modulation pathways.

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

The medial prefrontal cortex (mPFC) plays an important role in regulating executive functions including reward seeking, task flexibility, and compulsivity. Studies in humans have demonstrated that drugs of abuse, including heroin, cocaine, methamphetamine, and alcohol, alter prefrontal function resulting in the consequential loss of inhibitory control and increased compulsive behaviors, including drug seeking. Within the mPFC, layer V pyramidal cells, which are delineated into two major subtypes (type I and type II, which project to subcortical or commissurally to other cortical regions, respectively), serve as the major output cells which integrate information from other cortical and subcortical regions and mediate executive control. Preclinical studies examining changes in cellular physiology in the mPFC in response to drugs of abuse, especially in regard to layer V pyramidal subtypes, are relatively sparse. In the present study, we aimed to explore how heroin, cocaine, methamphetamine, ethanol, and 3,4-methylenedioxypyrovalerone (MDPV) alter the baseline cellular physiology and excitability properties of layer V pyramidal cell subtypes. Specifically, animals were exposed to experimenter delivered [intraperitoneal (i.p.)] heroin, cocaine, the cocaine-like synthetic cathinone MDPV, methamphetamine, ethanol, or saline as a control once daily for five consecutive days. On the fifth day, whole-cell physiology recordings were conducted from type I and type II layer V pyramidal cells in the mPFC. Changes in cellular excitability, including rheobase (i.e., the amount of injected current required to elicit action potentials), changes in input/output curves, as well as spiking characteristics induced by each substance, were assessed. We found that heroin, cocaine, methamphetamine, and MDPV decreased the excitability of type II cells, whereas ethanol increased the excitability of type I pyramidal cells. Together, these results suggest that heroin, cocaine, MDPV, and methamphetamine reduce mPFC commissural output by reducing type II excitability, while ethanol increases the excitability of type I cells targeting subcortical structures. Thus, separate classes of abused drugs differentially affect layer V pyramidal subtypes in the mPFC, which may ultimately give rise to compulsivity and inappropriate synaptic plasticity underlying substance use disorders.