OBJECTIVES: To investigate the neural mechanisms of rhythmic activity in the hippocampal CA1 region and orbitofrontal cortex (OFC) during a spatial goal-directed task. METHODS: Four long-Evans rats were trained to perform a spatial goal-directed task in a land-based water maze (Cheese-board maze). The task was divided into 5 periods: Pre-test, Pre-sleep, Learning, Post-sleep, and Post-test. During the Learning phase, the task was split into two goal navigation and two reward acquisition processes with a total of 8 learning stages. Local field potentials (LFP) from the CA1 and the OFC were recorded, and power spectral density analysis was performed on Theta (6-12 Hz), Beta (15-30 Hz), Low gamma (30-60 Hz), and High gamma (60-90 Hz) bands. Coherence, phase-locking value (PLV), and phase-amplitude cross coupling (PAC) were used to assess the interactions between the CA1 and the OFC during learning and memory. RESULTS: During the task training, the rats showed consistent rhythms of OFC neural activity across the task states (P>0.05) while exhibiting significant changes in Beta and High gamma rhythms in the CA1 region (P<0.05). Coherence and PLV between the CA1 and the OFC were higher during goal navigation, especially in the stable learning phase (Stage 8 vs Stage 1, P<0.01). The rats showed stronger cross-frequency coupling between CA1-Theta and OFC-Low gamma in the Post-test phase than in the Pre-test phase (P<0.05). CONCLUSIONS Learning and memory consolidation in goal-directed tasks involve synchronized activity between the CA1 region and the OFC, and cross-frequency coupling plays a key role in maintaining short-term memory of reward locations in rats.
Animals ; Rats ; Rats, Long-Evans ; CA1 Region, Hippocampal/physiology* ; Memory Consolidation/physiology* ; Prefrontal Cortex/physiology* ; Maze Learning/physiology* ; Goals ; Male ; Memory/physiology* ; Learning/physiology*

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
Animals ; Female ; Mice ; CA1 Region, Hippocampal/metabolism* ; Cell Adhesion Molecules/metabolism* ; CRF Receptor, Type 1/metabolism* ; Memory Disorders/etiology* ; Mice, Inbred C57BL ; Nectins/genetics* ; Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors* ; Recognition, Psychology/physiology* ; Stress, Psychological/complications*

Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording; this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.
Animals ; CA1 Region, Hippocampal/physiology* ; Male ; Association Learning/physiology* ; Neuronal Plasticity/physiology* ; Cues ; Memory/physiology* ; Synapses/physiology* ; Conditioning, Classical/physiology* ; Excitatory Postsynaptic Potentials/physiology* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Rats ; Optogenetics

Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.
Animals ; Male ; Neuralgia/metabolism* ; Rats ; Down-Regulation/physiology* ; Ubiquitination/physiology* ; Neuronal Plasticity/physiology* ; Rats, Sprague-Dawley ; CA1 Region, Hippocampal/metabolism* ; Cognitive Dysfunction/metabolism* ; RNA-Binding Proteins/metabolism* ; Receptors, AMPA/metabolism*

The retrosplenial cortex has been implicated in processing sensory information and spatial learning, with abnormal neural activity reported in association with psychedelics and in mouse and non-human primate models of autism spectrum disorders (ASDs). The direct role of the retrosplenial cortex in regulating social behaviors remains unclear. In this work, we reveal that neural activity in the retrosplenial agranular cortex (RSA), a subregion of the retrosplenial cortex, is initially activated, then quickly suppressed upon social contact. This up-down phase of RSA neurons is crucial for normal social behaviors. Parvalbumin-positive GABAergic neurons in the hippocampal CA1 region were found to send inhibitory projections to the RSA. Blocking these CA1-RSA inhibitory inputs significantly impaired social behavior. Notably, enhancing the CA1-RSA inhibitory input rescued the social behavior defects in an ASD mouse model. This work suggests a neural mechanism for the salience processing of social behavior and identifies a potential target for ASD intervention using neural modulation approaches.
Animals ; Social Behavior ; CA1 Region, Hippocampal/physiology* ; Mice ; Male ; Autism Spectrum Disorder/physiopathology* ; Mice, Inbred C57BL ; GABAergic Neurons/drug effects* ; Neural Inhibition/drug effects* ; Parvalbumins/metabolism* ; Neural Pathways/physiology* ; Cerebral Cortex/physiology*

The aim of this paper was to investigate the effect of total saponins from Panax japonicus( SPJ) on cognitive decline of natural aging rats and its mechanism. Thirty male SD rats of eighteen month old were randomly divided into three groups: aged group,10 mg·kg~(-1) SPJ-treated group and 30 mg·kg~(-1) SPJ-treated group. The SPJ-treated groups were given SPJ at the dosages of 10 mg·kg~(-1) and 30 mg·kg~(-1),respectively,from the age of 18 to 24 months. Aged group were lavaged the same amount of saline,10 six-month-old rats were used as control group,with 10 rats in each group. The open field test,novel object recognition and Morris water maze were performed to detect the changes of cognitive function in each group. The changes of synaptic transmission of long-term potentiation( LTP) in hippocampal CA1 region were detected by field potential recording. Western blot was used to detect the protein levels of NLRP3,ASC,caspase-1 and the changes of Glu A1,Glu A2,CAMKⅡ,CREB and phosphorylation of CAMKⅡ,CREB in each group.The results showed that SPJ could improve the decline of cognitive function in aging rats,reduce the damage of LTP in the hippocampal CA1 region of aged rats,and decrease the expression of NLRP3,ASC,caspase-1 in aging rats. At the same time,SPJ could enhance the membrane expression of AMPA receptor( Glu A1 and Glu A2),and increase the expression of p-CAMKⅡand p-CREB in aging rats.SPJ could improve cognitive decline of natural aging rats,and its mechanism may be related to regulating NLRP3 inflammasome,thus regulating the membrane expression of AMPA receptor,and enhancing the expression phosphorylation of CAMKⅡ and CREB.
Aging ; Animals ; CA1 Region, Hippocampal ; physiology ; Cognition ; drug effects ; Inflammasomes ; metabolism ; Long-Term Potentiation ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein ; metabolism ; Panax ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Saponins ; pharmacology

The aim of this study was to investigate whether G protein-coupled estrogen receptor (GPER) could alleviate hippocampal neuron injury under cerebral ischemia-reperfusion injury (CIRI) by acting on endoplasmic reticulum stress (ERS). The CIRI animal model was established by middle cerebral artery occlusion (MCAO). Female ovariectomized (OVX) Sprague-Dawley (SD) female rats were randomly divided into 4 groups: control, ischemia-reperfusion injury (MCAO), vehicle (MCAO+DMSO), and GPER-specific agonist G1 (MCAO+G1) groups. The neurobehavioral score was assessed by the Longa score method, the morphological changes of the neurons were observed by the Nissl staining, the cerebral infarction was detected by the TTC staining, and the neural apoptosis in the hippocampal CA1 region was detected by TUNEL staining. The distribution and expression of GRP78 (78 kDa glucose-regulated protein 78) in the hippocampal CA1 region were observed by immunofluorescent staining. The protein expression levels of GRP78, Caspase-12, CHOP and Caspase-3 were detected by Western blot, and the mRNA expression levels of GRP78, Caspase-12, and CHOP were detected by the real-time PCR. The results showed that the neurobehavioral score, cerebral infarct volume, cellular apoptosis index, as well as GRP78, Caspase-12 and CHOP protein and mRNA expression levels in the MCAO group were significantly higher than those of control group. And G1 reversed the above-mentioned changes in the MCAO+G1 group. These results suggest that the activation of GPER can decrease the apoptosis of hippocampal neurons and relieve CIRI, and its mechanism may involve the inhibition of ERS.
Animals ; Apoptosis ; Brain Ischemia ; CA1 Region, Hippocampal ; cytology ; Caspase 12 ; metabolism ; Caspase 3 ; metabolism ; Endoplasmic Reticulum Stress ; Female ; Heat-Shock Proteins ; metabolism ; Neurons ; cytology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Estrogen ; physiology ; Receptors, G-Protein-Coupled ; agonists ; Reperfusion Injury ; Transcription Factor CHOP ; metabolism

Deep brain stimulation (DBS), which usually utilizes high frequency stimulation (HFS) of electrical pulses, is effective for treating many brain disorders in clinic. Studying the dynamic response of downstream neurons to HFS and its time relationship with stimulus pulses can reveal important mechanisms of DBS and advance the development of new stimulation modes (e.g., closed-loop DBS). To exhibit the dynamic neuronal firing and its relationship with stimuli, we designed a two-dimensional raster plot to visualize neuronal activity during HFS (especially in the initial stage of HFS). Additionally, the influence of plot resolution on the visualization effect was investigated. The method was then validated by investigating the neuronal responses to the axonal HFS in the hippocampal CA1 region of rats. Results show that the new design of raster plot is able to illustrate the dynamics of indexes (such as phase-locked relationship and latency) of single unit activity (i.e., spikes) during periodic pulse stimulations. Furthermore, the plots can intuitively show changes of neuronal firing from the baseline before stimulation to the onset dynamics during stimulation, as well as other information including the silent period of spikes immediately following the end of HFS. In addition, by adjusting resolution, the raster plot can be adapted to a large range of firing rates for clear illustration of neuronal activity. The new raster plot can illustrate more information with a clearer image than a regular raster plot, and thereby provides a useful tool for studying neuronal behaviors during high-frequency stimulations in brain.
Action Potentials ; Animals ; Axons ; physiology ; CA1 Region, Hippocampal ; physiology ; Deep Brain Stimulation ; Neurons ; physiology ; Rats

OBJECTIVETo determine 5-lipoxygenase (5-LOX) expression and the effect of zileuton, a selective 5-LOX inhibitor,on hippocampal neuron injury induced by global cerebral ischemia in rats.

METHODSGlobal cerebral ischemia was induced by bilateral common carotid artery occlusion combined with hypotension in rats. 5-LOX expression was detected by Western blot analyses and 5-LOX localization was visualized by immunohistochemistry and double immunofluorescence methods. The 5-LOX inhibitor zileuton (10, 30, 50 mg/kg) was orally administered for 3 d after ischemia.

RESULTSThe 5-LOX expression was increased in the ischemic hippocampus on d1-7 (peaked at d3), and 5-LOX protein was primarily localized in neurons and translocated to the nuclei in the hippocampal CA1 region after ischemia. The 5-LOX inhibitor zileuton (30, 50 mg/kg) reduced ischemia-induced hippocampal neurons death 3d after ischemia.

CONCLUSION5-LOX is involved in global cerebral ischemic damage in rats, and the 5-LOX inhibitor zileuton has a protective effect on neuronal damage in the rat hippocampus following global cerebral ischemia.

Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; physiology ; Brain Ischemia ; metabolism ; pathology ; CA1 Region, Hippocampal ; metabolism ; pathology ; Disease Models, Animal ; Hydroxyurea ; analogs & derivatives ; pharmacology ; Lipoxygenase Inhibitors ; pharmacology ; Male ; Neurons ; drug effects ; pathology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effects of beta-amyloid (Aβ) and apolipoprotein E4(apoE4) on choline acetyl transferase (ChAT) in hippocampus and to explore possible the synergistic effect of both Aβ and apoE4.

METHODSMale Wistar rats were divided into four groups: control group, Aβ group, apoE4 group and Aβ + apoE4 group. Rats in different group received injection of normal saline, Aβ1-40, apoE4 and Aβ1-40 + apoE4, respectively, into bilateral hippocampus CA1 regions under the control of a brain stereotaxic apparatus. The learning-memory ability with the escape latency and the times of passing platform and the expression of ChAT in hippocampus CA1 regions were documented.

RESULTSThe escape latency at fifth day and the times of passing platform and ChAT mRNA PU values were obtained for the control group (10.75 s ± 2.44 s, 4.13 ± 0.64, and 28.90 ± 4.43), apoE4 group (23.88 s ± 4.32 s, 2.38 ± 0.52, and 20.85 ± 3.98), Aβ group (43.50 s ± 9.78 s, 1.38 ± 0.52, and 16.96 ± 2.53), and Aβ + apoE4 group (70.63 s ± 10.04 s, 0.75 ± 0.71, and 13.01 ± 2.21). Through 5 days of training all animals acquired learning-memory ability with the gradually shortened escape latency, although injection of Aβ1-40 and apoE4 all induced learning-memory damage, due to a significantly prolonged the escape latency at fifth day (P < 0.01) and markedly decreased the times of passing platform (P < 0.01) in both Aβ and apoE4 group than in control group. An interaction between Aβ and apoE4 also was observed, with further prolonged escape latency(P < 0.01). ChAT mRNA PU values were significantly lower in the Aβ group and apoE4 group than in the control group (P < 0.01). Aβ and apoE4 demonstrated interaction in lowering ChAT mRNA level(P < 0.05).

CONCLUSIONSBoth Aβ and apoE4 induce an injury to hippocampal cholinergic system and its learning-memory ability, in which Aβ and apoE4 have a synergistic effect in the initiation of such injury.

Alzheimer Disease ; enzymology ; physiopathology ; Amyloid beta-Peptides ; toxicity ; Animals ; Apolipoprotein E4 ; toxicity ; CA1 Region, Hippocampal ; enzymology ; physiology ; Choline O-Acetyltransferase ; genetics ; metabolism ; Drug Synergism ; Escape Reaction ; drug effects ; Learning ; drug effects ; Male ; Memory ; drug effects ; RNA, Messenger ; metabolism ; Random Allocation ; Rats ; Rats, Wistar