Adrenergic β receptor activation reduces amyloid β1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP

Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ_1–42-induced impairment of LTP is due to Aβ_1–42-mediated Zn²⁺ toxicity, we postulated that adrenergic β receptor activation reduces Aβ_1–42-mediated intracellular Zn²⁺ toxicity followed by rescuing Aβ_1–42 toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ_1–42 injection into the dentate granule cell layer. Human Aβ_1–42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic β receptor agonist, but not by co-injection of phenylephrine, an adrenergic α₁ receptor agonist. Isoproterenol did not reduce Aβ_1–42 uptake into dentate granule cells, but reduced increase in intracellular Zn²⁺ in dentate granule cells induced by Aβ_1–42. In contrast, phenylephrine did not reduce both Aβ_1–42 uptake and increase in intracellular Zn²⁺ by Aβ_1–42. In the case of human Aβ₁₋₄₀ and rat Aβ_1–42, which do not increase intracellular Zn²⁺, human Aβ₁₋₄₀- and rat Aβ_1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic β receptor activation reduces Aβ_1–42-mediated increase in intracellular Zn²⁺ in dentate granule cells, resulting in rescuing Aβ_1–42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aβ_1–42-induced cognitive decline that is caused by intracellular Zn²⁺ dysregulation in the hippocampus.     

运动康复对脑梗死大鼠学习记忆能力和LTP的影响

目的　探讨运动康复对脑梗死大鼠学习记忆能力和习得性LTP的影响。方法　采用脑梗死动物模型 ,应用慢性埋植电极技术以电生理结合行为的方法 ,记录康复训练组和模型组大鼠Y 迷宫分辨学习前、60次训练及学会后在海马CA3 区的突触效应及其行为习得。结果　给予行为训练的康复组大鼠海马CA3区突触效应的习得性LTP的形成速度明显快于不给予任何训练的模型组 (P <0 .0 5 ) ,相应的Y 迷宫分辨学习的习得也明显强于模型组 (P <0 .0 5 )。结论　康复训练可加快海马CA3 区习得性LTP的形成 ,提高学习效率     

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis,neuropathology and glucocorticoid-based therapeutics

Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment

Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain‐derived neurotrophic factor (BDNF) supports hippocampal long‐term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus‐dependent learning that occurs following EE. In the absence of EE, LTP elicited by high‐frequency stimulation was equivalent in wildtype mice and heterozygous BDNF^+/? siblings. LTP elicited by theta‐burst stimulation in BDNF^+/? mice was less than in wildtypes. Long‐term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF^+/? mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

An interchangeable role for kainate and metabotropic glutamate receptors in the induction of rat hippocampal mossy fiber long‐term potentiation in vivo

The roles of both kainate receptors (KARs) and metabotropic glutamate receptors (mGluRs) in mossy fiber long‐term potentiation (MF‐LTP) have been extensively studied in hippocampal brain slices, but the findings are controversial. In this study, we have addressed the roles of both mGluRs and KARs in MF‐LTP in anesthetized rats. We found that MF‐LTP could be induced in the presence of either GluK1‐selective KAR antagonists or group I mGluR antagonists. However, LTP was inhibited when the group I mGluRs and the GluK1‐KARs were simultaneously inhibited. Either mGlu1 or mGlu5 receptor activation is sufficient to induce this form of LTP as selective inhibition of either subtype alone, together with the inhibition of KARs, did not inhibit MF‐LTP. These data suggest that mGlu1 receptors, mGlu5 receptors, and GluK1‐KARs are all engaged during high‐frequency stimulation, and that the activation of any one of these receptors alone is sufficient for the induction of MF‐LTP in vivo. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

ShcC proteins: Brain aging and beyond

To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging.     

Estradiol prevents Aβ25 35-inhibited long-term potentiation induction through enhancing survival of newborn neurons in the dentate gyrus

Aim and Methods: Estradiol (E2) is reported to attenuate β-amyloid (Aβ) accumulation and slow the progression of Alzheimer's disease (AD). This study explored the beneficial effect of E2 in AD using histological examination and electrophysiological recording technique in AD model mice created by intracerebroventricular injection of β-amyloid 25–35 (Aβ_25–35). Results: Infusion of Aβ_25–35 reduced the number of newborn neurons in the 2nd week after birth, a critical period for neurite growth, and impaired high-frequency stimulation-dependent long-term potentiation (LTP) induction in perforant path-granular synapses of hippocampal dentate gyrus (DG). Administration of E2 from the 2nd to 4th week after cell birth in Aβ_25–35-mice ameliorated the impairment of newborn neurons and LTP induction in DG. Acute application of E2 failed to increase the newborn neurons and rescue LTP induction in the DG of Aβ_25–35-mice. Conclusions: The effect of E2 in Aβ_25–35-impaired LTP induction depends on its neuroprotection improvement.     

Pretreatment with β‐adrenergic receptor agonists facilitates induction of LTP and sharp wave ripple complexes in rodent hippocampus

Norepinephrine, is involved in the enhancement of learning and memory formation by regulating synaptic mechanisms through its ability to activate pre‐ and post‐synaptic adrenergic receptors. Here we show that β‐agonists of norepinephrine facilitate the induction of both associational LTP and sharp wave ripples (SPW‐Rs) in acute slices of rat hippocampus in area CA3. Surprisingly, this facilitating effect persists when slices are only pretreated with β‐receptor agonists followed by wash out and application of the unspecific β‐adrenoreceptor (βAR) antagonist propranolol. During application of βAR agonists repeated stimulation resulted in facilitated induction of SPW‐Rs. Since SPW‐Rs are thought to be involved in memory replay we studied the effects of βAR‐agonists on spontaneous SPW‐Rs in murine hippocampus and found that amplitude and incidence of SPW‐Rs increased. These effects involve cyclic‐AMP and the activation of protein kinase A and suggest a supportive role in memory consolidation. © 2016 Wiley Periodicals, Inc.