Effect of Donepezil on Vascular Dementia in Rats via PI3K/AKT Pathway

Background: Previous studies have shown that Donepezil has therapeutic effects on vascular dementia (VD). PI3K/AKT involves in oxidative stress injury and cell apoptosis. This study investigated whether Donepezil affects the neurological function and apoptosis of VD mice via PI3K/AKT signaling. Methods: Mice were assigned into Sham group, VD group, VD+Donepezil groupfollowed by analysis of mice learning and memory ability by Water maze test, p-AKT expression by Western blot, Caspase-3 activity, MDA content, SOD activity and GSH-Px in hippocampus. HT22 cells were cultured and separated into control group, I-R group and I-R+Donepezil group followed by measuring p-AKT level, ROS content and apoptosis. Results: Learning and memory abilities of VD group mice were significantly decreased, Caspase-3 activity and MDA in brain tissue were significantly increased, along with decreased SOD activity, GSH-Px and p-AKT level. Donepezil treatment can significantly improve VD mice learning and memory ability, reduce Caspase-3 activity and MDA in brain tissue, increase SOD activity, GSH-Px and p-AKT level. In vitro, I-R treatment significantly induced apoptosis of HT22 cells, increased ROS production and decreased p-AKT level. Donepezil treatment could up-regulate p-AKT in HT22 cells and reduce apoptosis and ROS production in HT22 cells. Conclusion: Donepezil improves the function of brain nerve in VD mice through regulating PI3K/AKT pathway, thus reducing oxidative stress injury and apoptosis of brain nerve cells.

Minocycline improves learning and memory functions in ischemic stroke rats via reduction of cerebral ischemia-induced neuroinflammation and apoptosis

Purpose: To study the effect minocycline on learning and memory functions in ischemic stroke rats, and the underlying mechanism. Methods: 60 adult male SD rats were randomly divided into control group, ischemic brain damage (6 and 24 h MACO) groups; and 6 and 24 h minocycline groups, with 12 rats in each group. The volume of cerebral infarction, neuronal cell apoptosis, NF-κB protein expression, learning and memory ability, and the number of Iba-1+CD206-positive cells, and CD206/CD68 mRNA expressions in sham group, 6 h MACO group and 6 h minocycline group were determined and compared. Results: The number of iba-1 +CD206-positive cells, expression level of CD206 mRNA, frequency of platform crossing, and percentage of third quadrant route in 6 h minocycline group were significantly higher than the corresponding values in 6 h MACO group. However, the cerebral infarction volume, number of Nini-positive cells, and the NF- B protein expression levels were markedly reduced, relative to corresponding values in 6 h MACO rats. The number of iba-1+CD206-positive cells was significantly lower in 6 h MACO rats than in sham rats, while the expression level of CD68 mRNA was significantly higher (p < 0.05). The number of TUNEL-positive cells in 6 and 24 h minocycline groups were markedly lower than that in 6 h MACO group (p < 0.05). Conclusion: Minocycline improves learning and memory of ischemic stroke rats by relieving the neuroinflammation induced by cerebral ischemia and cell apoptosis. Thus, the compound can be further developed for management learning and memory deficits in stroke patients.

The Effects of Intraoperative Hypothermia on Postoperative Cognitive Function in the Rat Hippocampus and Its Possible Mechanisms

Intraoperative hypothermia is a common complication during operations and is associated with several adverse events. Postoperative cognitive dysfunction (POCD) and its adverse consequences have drawn increasing attention in recent years. There are currently no relevant studies investigating the correlation between intraoperative hypothermia and POCD. The aim of this study was to assess the effects of intraoperative hypothermia on postoperative cognitive function in rats undergoing exploratory laparotomies and to investigate the possible related mechanisms. We used the Y-maze and Morris Water Maze (MWM) tests to assess the rats’ postoperative spatial working memory, spatial learning, and memory. The morphological changes in hippocampal neurons were examined by haematoxylin-eosin (HE) staining and hippocampal synaptic plasticity-related protein expression. Activity-regulated cytoskeletal-associated protein (Arc), cyclic adenosine monophosphate-response element-binding protein (CREB), S133-phosphorylated CREB (p-CREB [S133]), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1 (AMPAR1), and S831-phosphorylated AMPAR1 (p-AMPAR1 [S831]) were evaluated by Western blotting. Our results suggest a correlation between intraoperative hypothermia and POCD in rats and that intraoperative hypothermia may lead to POCD regarding impairments in spatial working memory, spatial learning, and memory. POCD induced by intraoperative hypothermia might be due to hippocampal neurons damage and decreased expression of synaptic plasticity-related proteins Arc, p-CREB (S133), and p-AMPAR1 (S831).

Prenatal Exposure to Classical Music Improves Learning and Memory in Adult Rats

Background: Exposure to music during pregnancy enhances brain development and improves learning in neonatal rats. Methods: In these experiments, we examined the effects of exposure to silence, hard rock, classical, and rap music in utero plus 60 days postpartum on learning and memory in adult Wistar rats. Passive avoidance learning (PAL) was assessed at age 60 days, and a retention test was done 24 hours after training. Elevated plus maze (EPM) was also used as a standard behavioral task for assessing the effects of music therapy on anxiety. Furthermore, we measured serum corticosterone levels and adrenal weight at the end of experiments to show the possible effect of stress on the rats’ behavior. Results: Hard rock music impaired acquisition, increasing the number of trials to acquisition in PAL task. Hard rock music also impaired the retrieval process by decreasing step-through latency and increasing time spent in the dark compartment during the retention trial. Further, in the hard rock group, there were increases in serum corticosterone and adrenal weight of rats. Classical music, in turn, improved acquisition learning and retention memory and decreased serum corticosterone levels compared to the silence group. Rats’ exposure to rap music did not show any significant change in acquisition and retrieval processes compared to the silence group. In the EPM task, classical music exposure had anxiolytic-like effects revealed in an increase in the number of entries into open arms and time spent in the open arms. However, in this task, hard rock music induced an anxiogenic effect. Conclusions: Prenatal and postnatal exposure to music improves PAL and memory in adult rats. The effects of music therapy with classical music might be related to stress reduction by lowering corticosterone as a stress biomarker or anxiolytic effects; this deserves further examination.

Effects of the Combination of High-intensity Interval Training and Ecdysterone on Learning and Memory Abilities, Antioxidant Enzymes Activities, and Neuronal Population in an Amyloid-beta-induced Rat Model of Alzheimer’s Disease

Aims: Oxidative stress and neuronal death are the primary reasons for the progression of amyloid-beta (Aβ) deposition and cognitive deficits in Alzheimer’s disease (AD). Ecdysterone (Ecdy), a common derivative of ecdysteroids, possesses free radical scavenging and cognitive-improving effects. High-intensity interval training (HIIT) may be a therapeutic strategy for improving cognitive decline and oxidative stress. The present study was aimed to evaluate the effect of HIIT alone and its combination with Ecdysterone on the changes in learning and memory functions, hippocampal antioxidant enzymes activities, and neuronal population after AD induced by Aβ in male rats.Materials and methods: Following ten days of Aβ-injection, HIIT exercise and Ecdysterone treatment (10 mg/kg/day; P.O.) were initiated and continued for eight consecutive weeks in rats. At the end of the treatment period, rat’s learning and memory functions were assessed using water-maze and passive-avoidance tests. Moreover, the activity of superoxide dismutase (SOD), catalase (CAT), Glutathione Peroxidase (GPx), Glutathione Reductase (GRx) and neuronal population were evaluated in rat’s brains.Results: The results indicated that Aβ injection disrupted spatial/passive avoidance learning and memory in both water-maze and passive-avoidance paradigms, accompanied by a decrease in the superoxide dismutase and catalase (as endogenous antioxidants) in rat hippocampus. Additionally, Aβ injection resulted in neuronal loss in the cerebral cortex and hippocampus. Although consumption of Ecdysterone separately improved spatial/passive avoidance learning and memory impairments, recovered hippocampal activity of SOD, CAT, GRx, GRx and prevented the hippocampal neuronal loss, its combination with HIIT resulted in a more powerful and effective amelioration in all the above-mentioned Aβ-neuropathological changes.Conclusion: The current work's data confirms that a combination of HIIT exercise and Ecdysterone treatment could be a promising potential therapeutic agent against AD-associated cognitive decline, owing to their free radical scavenging and neuroprotective properties.

Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Alzheimer’s disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

A New Player in the Hippocampus: A Review on VGLUT3+ Neurons and Their Role in the Regulation of Hippocampal Activity and Behaviour

Glutamate is the most abundant excitatory amino acid in the central nervous system. Neurons using glutamate as a neurotransmitter can be characterised by vesicular glutamate transporters (VGLUTs). Among the three subtypes, VGLUT3 is unique, co-localising with other “classical” neurotransmitters, such as the inhibitory GABA. Glutamate, manipulated by VGLUT3, can modulate the packaging as well as the release of other neurotransmitters and serve as a retrograde signal through its release from the somata and dendrites. Its contribution to sensory processes (including seeing, hearing, and mechanosensation) is well characterised. However, its involvement in learning and memory can only be assumed based on its prominent hippocampal presence. Although VGLUT3-expressing neurons are detectable in the hippocampus, most of the hippocampal VGLUT3 positivity can be found on nerve terminals, presumably coming from the median raphe. This hippocampal glutamatergic network plays a pivotal role in several important processes (e.g., learning and memory, emotions, epilepsy, cardiovascular regulation). Indirect information from anatomical studies and KO mice strains suggests the contribution of local VGLUT3-positive hippocampal neurons as well as afferentations in these events. However, further studies making use of more specific tools (e.g., Cre-mice, opto- and chemogenetics) are needed to confirm these assumptions.

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.