Does ( −)-epigallocatechin-3-gallate protects the neurotoxicity induced by bisphenol A in vivo?

Bisphenol A (BPA) is one of the chemicals that is firmly accompanied by hippocampal neuronal injury. As oxidative stress appears to be a major contributor to neurotoxicity induced by BPA, antioxidants with remarkable neuroprotective effects can play a valuable protective role. Around the world, ( −)-epigallocatechin-3-gallate (EGCG) was one of the most popular antioxidants that could exert a beneficial neuroprotective role. Here, we examined the potential efficiency of EGCG against neurotoxicity induced by BPA in the hippocampal CA3 region of the rat model. This study revealed that EGCG was unable to abrogate the significant decrease in circulating adiponectin level and hippocampal superoxide dismutase activity as well as an increase in hippocampal levels of nitric oxide and malondialdehyde. Notably, EGCG failed to antagonize the oxidative inhibitory effect of BPA on hippocampal neurotransmission and its associated cognitive deficits. In addition, the histopathological examination with immunohistochemical detection of caspase-3 and NF-kB/p65 emphasized that EGCG failed to protect hippocampal CA3 neurons from apoptotic and necrotic effects induced by BPA. Our study revealed that EGCG showed no protective role against the neurotoxic effect caused by BPA, which may be attributed to its failure to counteract the BPA-induced oxidative stress in vivo. The controversial effect is probably related to EGCG’s ability to impede BPA glucuronidation and thus, its detoxification. That inference requires further additional experimental and clinical studies. Graphical abstract

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal CA3 circuit

Homeostatic plasticity of intrinsic excitability goes hand in hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging, and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2 to 3 d induces an up-regulation of both synaptic transmission at CA3–CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3–CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Effects of Sevoflurane at Different Concentrations on ApoE in Hippocampus of Aged Rats With Hypercholesterolemia

Objective: To observe the behavioral changes of aged rats with hypercholesterolemia after inhalation of 1.0 MAC and 1.3MAC sevoflurane , the levels of hippocampal ApoE3, ApoE4 and Aβ1-42, as well as the changes of Aβ1-42 levels of optical density in hippocampal CA3 and CA1 regions, and to investigate the effects of different concentrations of sevoflurane on cognitive function in aged rats with hypercholesterolemia.Method: The 15-month-old male SD rats were fed a high-fat diet for 9 months. Rats successfully modeled (N=54) were randomly divided into three groups:control group (Con group, n=18), low concentration sevoflurane group ( Sev1.0 group, n=18), high concentration sevoflurane group (Sev1.3 group, n=18). Rats in the three groups inhaled aero mixed gas(1L/min O2+1L/min Air), 1.0MAC sevoflurane and 1.3MAC sevoflurane for 2h respectively.1 day, 30 days and 90 days after sevoflurane treatment were defined as T1, T30 and T90 experimental periods, respectively. In the three experiments, 6 rats were randomly selected from Con group, Sev1.0 group and Sev1.3 group to complete the behavior experiment in Morris water maze.Subsequently, the levels of ApoE3, ApoE4 and Aβ1-42 in the left hippocampus were detected by Western Blot.Expression of Aβ1-42 in the right hippocampal CA3 and CA1 regions of rats in each group was detected by frozen immunofluorescence assay.Result: 1. No behavioral changes were found in T1, T30 and T90 experiments.2. At T1 and T30, ApoE4 and Aβ1-42 in Sev1.3 group was significantly different from that in Con group. At T90, there was no difference in the levels of ApoE4 and Aβ1-42 between groups. ApoE3 expression was not statistically significant in the three experimental periods. 3. At T1 and T30, the average optical density of Aβ1-42 in CA3 and CA1 region, Sev1.3 group was significantly different from that in Con group. At T90, there was no significant difference between groups.Conclusion: After inhalation of 1.3MAC sevoflurane in aged SD hypercholesterolemia rats, the levels of ApoE4 and Aβ1-42 were increased in hippocampus at early and middle stage, and the average optical density of Aβ1-42 was increased in CA3 and CA1 area. The change trend of the two ones was consistent, but not enough to cause behavioral changes.

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory–Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

Astrocytic Based Controller Shifts Epileptic Activity to the Chaotic State

Investigating effective controller to shift hippocampal epileptic periodicity to normal chaotic behavior will be new hope for epilepsy treatment. Astrocytes nourish and protect neurons as well as maintaining synaptic transmission and network activity. Therefore, this study explores the ameliorating effect of astrocyte computational model on epileptic periodicity. Modified Morris-Lecar equations were used to model hippocampal CA3 network. Network inhibitory parameters were employed to generate oscillation induced epileptiform periodicity. The astrocyte controller was based on a functional dynamic mathematical model of brain astrocytic cells. Results demonstrated that synchronization of two neural networks shifted the brain chaotic state to periodicity. Applying astrocytic controller to the synchronized networks returned the system to the desynchronized chaotic state. It is concluded that astrocytes are probably a good model in controlling epileptic periodicity. However, more research efforts are needed to delineate the effect.