Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region

The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.

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Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Neural Plasticity ◽

10.1155/2019/2158285 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Zhao-Hui Yao ◽

Xiao-li Yao ◽

Shao-feng Zhang ◽

Ji-chang Hu ◽

Yong Zhang

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

Learning And Memory ◽

Spatial Learning ◽

Long Term Potentiation ◽

Chronic Cerebral Hypoperfusion ◽

Synaptic Proteins ◽

Cerebral Hypoperfusion ◽

Spatial Learning And Memory ◽

Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

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Mfsd2a Reverses Spatial Learning and Memory Impairment Caused by Chronic Cerebral Hypoperfusion via Protection of the Blood–Brain Barrier

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00461 ◽

2020 ◽

Vol 14 ◽

Author(s):

Changhua Qu ◽

Hao Song ◽

Jun Shen ◽

Linling Xu ◽

Yaqing Li ◽

...

Keyword(s):

Learning And Memory ◽

Blood Brain Barrier ◽

Spatial Learning ◽

Memory Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Spatial Learning And Memory ◽

Blood Brain

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Time-Course Change of Redd1 Expressions in the Hippocampal CA1 Region Following Chronic Cerebral Hypoperfusion

Cellular and Molecular Neurobiology ◽

10.1007/s10571-016-0385-9 ◽

2016 ◽

Vol 37 (3) ◽

pp. 563-569 ◽

Cited By ~ 6

Author(s):

Jin-A Park ◽

Choong-Hyun Lee

Keyword(s):

Time Course ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1

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Targeted Reducing of Tauopathy Alleviates Epileptic Seizures and Spatial Memory Impairment in an Optogenetically Inducible Mouse Model of Epilepsy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.633725 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yang Gao ◽

Jie Zheng ◽

Tao Jiang ◽

Guilin Pi ◽

Fei Sun ◽

...

Keyword(s):

Spatial Memory ◽

Learning And Memory ◽

Spatial Learning ◽

Epileptic Seizures ◽

Neuronal Firing ◽

Spatial Learning And Memory ◽

Memory Impairments ◽

Optogenetic Stimulation ◽

Hippocampal Ca1 ◽

The Brain

Intracellular deposition of hyperphosphorylated tau has been reported in the brain of epilepsy patients, but its contribution to epileptic seizures and the association with spatial cognitive functions remain unclear. Here, we found that repeated optogenetic stimulation of the excitatory neurons in ventral hippocampal CA1 subset could induce a controllable epileptic seizure in mice. Simultaneously, the mice showed spatial learning and memory deficits with a prominently elevated total tau and phospho-tau levels in the brain. Importantly, selective facilitating tau degradation by using a novel designed proteolysis-targeting chimera named C4 could effectively ameliorate the epileptic seizures with remarkable restoration of neuronal firing activities and improvement of spatial learning and memory functions. These results confirm that abnormal tau accumulation plays a pivotal role in the epileptic seizures and the epilepsy-associated spatial memory impairments, which provides new molecular target for the therapeutics.

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