Alzheimer's disease (AD), a neurodegenerative disorder with complex etiologies, manifests through a cascade of pathological changes before clinical symptoms become apparent. Among these early changes, alterations in the expression of non-coding RNAs (ncRNAs) have emerged as pivotal events. In this study, we focused on the aberrant expression of ncRNAs and revealed that Lamr1-ps1, a pseudogene of the laminin receptor, significantly exacerbates early spatial learning and memory deficits in APP/PS1 mice. Through a combination of bioinformatics prediction and experimental validation, we identified the miR-29c/Bace1 pathway as a potential regulatory mechanism by which Lamr1-ps1 influences AD pathology. Importantly, augmenting the miR-29c-3p levels in mice ameliorated memory deficits, underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention. This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for considering miR-29c as a viable therapeutic target, offering a novel avenue for AD research and treatment strategies.
Animals ; Alzheimer Disease/pathology* ; Pseudogenes/genetics* ; Mice ; Memory Disorders/metabolism* ; MicroRNAs/genetics* ; Disease Models, Animal ; Spatial Learning/physiology* ; Mice, Transgenic ; Presenilin-1/genetics* ; Male ; Amyloid Precursor Protein Secretases/metabolism* ; Mice, Inbred C57BL ; Aspartic Acid Endopeptidases/metabolism*

OBJECTIVE: To estimate the detrimental effects of shortwave exposure on rat hippocampal structure and function and explore the underlying mechanisms. METHODS: One hundred Wistar rats were randomly divided into four groups (25 rats per group) and exposed to 27 MHz continuous shortwave at a power density of 5, 10, or 30 mW/cm2 for 6 min once only or underwent sham exposure for the control. The spatial learning and memory, electroencephalogram (EEG), hippocampal structure and Nissl bodies were analysed. Furthermore, the expressions of N-methyl-D-aspartate receptor (NMDAR) subunits (NR1, NR2A, and NR2B), cAMP responsive element-binding protein (CREB) and phosphorylated CREB (p-CREB) in hippocampal tissue were analysed on 1, 7, and 14 days after exposure. RESULTS: The rats in the 10 and 30 mW/cm2 groups had poor learning and memory, disrupted EEG oscillations, and injured hippocampal structures, including hippocampal neurons degeneration, mitochondria cavitation and blood capillaries swelling. The Nissl body content was also reduced in the exposure groups. Moreover, the hippocampal tissue in the 30 mW/cm2 group had increased expressions of NR2A and NR2B and decreased levels of CREB and p-CREB. CONCLUSION Shortwave exposure (27 MHz, with an average power density of 10 and 30 mW/cm2) impaired rats' spatial learning and memory and caused a series of dose-dependent pathophysiological changes. Moreover, NMDAR-related CREB pathway suppression might be involved in shortwave-induced structural and functional impairments in the rat hippocampus.
Animals ; Cyclic AMP Response Element-Binding Protein ; genetics ; metabolism ; Dose-Response Relationship, Radiation ; Electroencephalography ; radiation effects ; Hippocampus ; radiation effects ; Male ; Memory ; radiation effects ; Nissl Bodies ; physiology ; radiation effects ; Radio Waves ; adverse effects ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; genetics ; metabolism ; Spatial Learning ; radiation effects

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.
Animals ; Brain ; drug effects ; metabolism ; pathology ; Cognitive Dysfunction ; drug therapy ; metabolism ; pathology ; Disease Models, Animal ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Hydrocarbons, Brominated ; Inflammasomes ; drug effects ; metabolism ; Male ; Maze Learning ; drug effects ; physiology ; Microglia ; drug effects ; metabolism ; pathology ; NLR Family, Pyrin Domain-Containing 3 Protein ; metabolism ; Neurons ; drug effects ; metabolism ; pathology ; Nootropic Agents ; pharmacology ; Random Allocation ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; metabolism ; Spatial Memory ; drug effects ; physiology ; Specific Pathogen-Free Organisms

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.
Alzheimer Disease ; metabolism ; pathology ; psychology ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; Disease Models, Animal ; Female ; Hippocampus ; metabolism ; pathology ; Humans ; Inflammation ; metabolism ; pathology ; psychology ; Male ; Maze Learning ; physiology ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurofibrillary Tangles ; metabolism ; pathology ; Plaque, Amyloid ; metabolism ; pathology ; psychology ; Presenilin-1 ; genetics ; metabolism ; Sex Characteristics ; Spatial Memory ; physiology ; p38 Mitogen-Activated Protein Kinases ; metabolism ; tau Proteins ; genetics ; metabolism

BACKGROUNDThe pain caused by orthodontic treatment has been considered as tough problems in orthodontic practice. There is substantial literature on pain which has exactly effected on learning and memory; orthodontic tooth movement affected the emotional status has been showed positive outcomes. Danggui-Shaoyao-San (DSS) is a Traditional Chinese Medicine prescription that has been used for pain treatment and analgesic effect for orthodontic pain via inhibiting the activations of neuron and glia. We raised the hypothesis that DSS could restore the impaired abilities of spatial learning and memory via regulating neuron or glia expression in the hippocampus.

METHODSA total of 36 rats were randomly divided into three groups: (1) Sham group (n = 12), rats underwent all the operation procedure except for the placement of orthodontic forces and received saline treatment; (2) experimental tooth movement (ETM) group (n = 12), rats received saline treatment and ETM; (3) DSS + ETM (DETM) group (n = 12), rats received DSS treatment and ETM. All DETM group animals were administered with DSS at a dose of 150 mg/kg. Morris water maze test was evaluated; immunofluorescent histochemistry was used to identify astrocytes activation, and immunofluorescent dendritic spine analysis was used to identify the dendritic spines morphological characteristics expression levels in hippocampus.

RESULTSMaze training sessions during the 5 successive days revealed that ETM significantly deficits in progressive learning in rats, DSS that was given from day 5 prior to ETM enhanced progressive learning. The ETM group rats took longer to cross target quadrant during the probe trial and got less times to cross-platform than DETM group. The spine density in hippocampus in ETM group was significantly decreased compared to the sham group. In addition, thin and mature spine density were decreased too. However, the DSS administration could reverse the dendritic shrinkage and increase the spine density compared to the ETM group. Astrocytes activation showed the opposite trend in hippocampus dentate gyrus (DG).

CONCLUSIONSTreatment with DSS could restore the impaired abilities on ETM-induced decrease of learning and memory behavior. The decreased spines density in the hippocampus and astrocytes activation in DG of hippocampus in the ETM group rats may be related with the decline of the ability of learning and memory. The ability to change the synaptic plasticity in hippocampus after DSS administration may be correlated with the alleviation of impairment of learn and memory after ETM treatment.

Animals ; Drugs, Chinese Herbal ; pharmacology ; Hippocampus ; drug effects ; physiology ; Male ; Memory ; drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spatial Learning ; drug effects ; Tooth Movement Techniques ; adverse effects

BACKGROUNDRecent clinical and preclinical studies have suggested that deep brain stimulation (DBS) can be used as a tool to enhance cognitive functions. The aim of the present study was to investigate the impact of DBS at three separate targets in the Papez circuit, including the anterior nucleus of thalamus (ANT), the entorhinal cortex (EC), and the fornix (FX), on cognitive behaviors in an Alzheimer's disease (AD) rat model.

METHODSForty-eight rats were subjected to an intrahippocampal injection of amyloid peptides 1-42 to induce an AD model. Rats were divided into six groups: DBS and sham DBS groups of ANT, EC, and FX. Spatial learning and memory were assessed by the Morris water maze (MWM). Recognition memory was investigated by the novel object recognition memory test (NORM). Locomotor and anxiety-related behaviors were detected by the open field test (OF). By using two-way analysis of variance (ANOVA), behavior differences between the six groups were analyzed.

RESULTSIn the MWM, the ANT, EC, and FX DBS groups performed differently in terms of the time spent in the platform zone (F(2,23) = 6.04, P < 0.01), the frequency of platform crossing (F(2,23) = 11.53, P < 0.001), and the percent time spent within the platform quadrant (F(2,23) = 6.29, P < 0.01). In the NORM, the EC and FX DBS groups spent more time with the novel object, although the ANT DBS group did not (F(2,23) = 10.03, P < 0.001). In the OF, all of the groups showed a similar total distance moved (F (1,42) = 1.14, P = 0.29) and relative time spent in the center (F(2,42) = 0.56, P = 0.58).

CONCLUSIONSOur results demonstrated that DBS of the EC and FX facilitated hippocampus-dependent spatial memory more prominently than ANT DBS. In addition, hippocampus-independent recognition memory was enhanced by EC and FX DBS. None of the targets showed side-effects of anxiety or locomotor behaviors.

Alzheimer Disease ; physiopathology ; therapy ; Animals ; Anterior Thalamic Nuclei ; physiology ; Deep Brain Stimulation ; methods ; Entorhinal Cortex ; physiology ; Fornix, Brain ; physiology ; Male ; Memory ; physiology ; Rats ; Rats, Sprague-Dawley ; Spatial Learning ; physiology

The purpose of the present study is to explore the relationship of spatial learning ability and specific electrical activities of neural oscillations in the rat. The fast and general avoidance response groups were selected on the basis of the animals' responses to the electric shock in Y type maze, and their local field potentials (LFPs) of hippocampal CA3 area were recorded by wireless telemetry before and after shock avoidance training, respectively. The components of neural oscillations related to spatial identifying and learning ability were analyzed. The results showed that, compared with the general avoidance response group, the fast avoidance response group did not show any differences of LFPs in hippocampal CA3 area before electric shock avoidance trial, but showed significantly increased percentages of 0-10 Hz and 30-40 Hz rhythm in right hippocampal CA3 area after the shock avoidance training (P < 0.01 or P < 0.05). Fast Fourier transform showed that percentage increase of 0-10 Hz band occurred mainly in θ (3-7 Hz) frequency, and 30-40 Hz frequency change was equivalent to the γ1 band. Furthermore, compared with those before training, only the percentages of β, β2 (20-30 Hz) and γ1 rhythm increased (P < 0.01 or P < 0.05) in fast avoidance response rats after training, while the θ rhythm percentage remained unchanged. In contrast, θ rhythm percentage and the large amplitude (intensity: +2.5 - -2.5 db) θ waves in right CA3 area of general avoidance response rats were significantly reduced after training (P < 0.01). These results suggest that the increased percentages of β2 and γ1 rhythm and high-level (unchanged) percentage of θ rhythm in the right hippocampus CA3 area might be related to strong spatial cognition ability of fast avoidance response rats.
Animals ; Avoidance Learning ; Beta Rhythm ; CA3 Region, Hippocampal ; physiology ; Electroshock ; Gamma Rhythm ; Rats ; Spatial Learning ; Theta Rhythm

Learning/memory impairment is one of the most serious problems induced by stress, and the underlying mechanisms remain unclear. Opiates and opioid receptors are implicated in multiple physiological functions including learning and memory. However, there is no clear evidence whether the endogenous opioid system is involved in the formation of the stress-induced spatial reference memory impairment. The aim of the present study was to evaluate the role of μ opioid receptor in the stress-induced spatial reference memory impairment by means of Morris water maze (MWM) test in a mouse elevated platform stress model. The mice were trained in the MWM for four trials a session for 4 consecutive days after receiving the elevated platform stress, and intracerebroventricular injection of μ opioid receptor agonist DAMGO, antagonist CTAP or saline. Retention of the spatial training was assessed 24 h after the last training session with a 60-s free-swim probe trial using a new starting position. The results showed that intracerebroventricular injection of μ opioid receptor agonist DAMGO but not antagonist CTAP before MWM training impaired the memory retrieval of mice. Elevated platform stress before MWM training also impaired memory retrieval, which could be reversed by pre-injection of CTAP, and aggravated by DAMGO. These results suggest that endogenous opioid system may play a crucial role in the formation of the stress-induced memory impairment.
Animals ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; pharmacology ; Maze Learning ; Memory Disorders ; Mice ; Receptors, Opioid, mu ; physiology ; Spatial Memory ; Stress, Physiological

OBJECTIVETo investigate the effect of GEPT extracts on spatial learning ability of the APPV717I transgenic mice at the early stage of dementia and its possible mechanism.

METHODThirty APPV717I transgenic mice were randomly divided into three GEPT groups by intragastric administration at doses of 0.075, 0.15, 0.3 g x kg(-1) x d(-1), and a donepezil group by intragastric administration of 0.92 mg x kg(-1) x d(-1), a APPV717I transgenic model group and a normal group by intragastric administration of distilled water. A four-month treatment regimen with GEPT extracts was administered to APPV717I transgenic mice. Results showed that Spatial memory ability was measured in Morris water maze. The total area covered by shank1 and integral optical density in CA1 subfield within the hippocampus were determined using immunohistochemical stains and Image-Pro plus analysis. The ultrastructure of synapses in the hippocampal CA1 region was observed by electronic microscope.

RESULTAfter a four-month of GEPT treatment regimen, the mean escape latency period were significantly shortened (P < 0.05), and the target quadrant search time were significantly increased (P < 0.05) compared to the APPV717I transgenic model mice. There was a significant higher level in the expression of shank1 detected in the hippocampal CA1 area of APPV717I transgenic mice associated with an increase in the number of synapses treated with GEPT than the levels in the APPV717I transgenic model mice alone. The total area of positive cells covered by shank1 and their integral optical density in the hippocampal CA1 area of the APPV717I transgenic mice treated with GEPT were significantly increased more than those of the APPV717I transgenic model mice.

CONCLUSIONGEPT extracts can obviously improve the spatial memory ability of APPV717I transgenic mice at the early stage of dementia through enhancing the number of synapses and the expression of shank1, and this might lead to development of novel treatment therapies for the memory loss associated with AD.

Animals ; Dementia ; prevention & control ; Disease Models, Animal ; Female ; Learning ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Panax ; chemistry ; Plant Extracts ; therapeutic use ; Space Perception ; drug effects ; physiology ; Spatial Behavior ; drug effects ; physiology

To investigate the effect of treadmill running on the ability of learning in young rats, male Sprague-Dawley rats (5 weeks of age) were used for the experiment. Animals were randomly divided into the control and running groups (n=15 in each group). The rats in running group were made run on a motor-driven treadmill for 1 week at a speed of 2 m/min for the first 5 min, at a speed of 5 m/min for the next 5 min, then at a speed of 8 m/min for the last 20 min. Then the Morris water maze was used to observe learning and memory ability of rats in both groups. The tests consisted of place navigation and spatial probe test. We found that, in place navigation training, the latency of rats in running group was less than that in control group (P<0.05); and from the third training session on, there was significant difference between the rats in control and running groups in swimming velocity (P<0.01); furthermore, it was observed that the rats in running group had stronger motivation and more exact orientation in searching for platform, which could be indicated by the index of turn angle and angular velocity. In spatial probe test, there was no significant difference between the two groups in swimming velocity, percentage of swimming distance and frequency of crossing platform in D quadrant, where the platform situated (P>0.05). These findings suggest that low speed treadmill running can enhance the ability of learning in young rats.
Age Factors ; Animals ; Male ; Maze Learning ; physiology ; Memory ; physiology ; Physical Conditioning, Animal ; physiology ; Rats ; Rats, Sprague-Dawley ; Spatial Behavior ; physiology ; Swimming ; physiology