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*

Within the prefrontal-cingulate cortex, abnormalities in coupling between neuronal networks can disturb the emotion-cognition interactions, contributing to the development of mental disorders such as depression. Despite this understanding, the neural circuit mechanisms underlying this phenomenon remain elusive. In this study, we present a biophysical computational model encompassing three crucial regions, including the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and ventromedial prefrontal cortex. The objective is to investigate the role of coupling relationships within the prefrontal-cingulate cortex networks in balancing emotions and cognitive processes. The numerical results confirm that coupled weights play a crucial role in the balance of emotional cognitive networks. Furthermore, our model predicts the pathogenic mechanism of depression resulting from abnormalities in the subgenual cortex, and network functionality was restored through intervention in the dorsolateral prefrontal cortex. This study utilizes computational modeling techniques to provide an insight explanation for the diagnosis and treatment of depression.
Prefrontal Cortex/physiology* ; Humans ; Emotions/physiology* ; Cognition/physiology* ; Gyrus Cinguli/physiology* ; Computer Simulation ; Models, Neurological ; Neural Pathways/physiology* ; Nerve Net/physiology*

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680^+/+) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680^+/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680^+/+ mice.
Animals ; Prefrontal Cortex/metabolism* ; Basolateral Nuclear Complex/metabolism* ; Mice ; Anxiety/metabolism* ; Nerve Tissue Proteins/genetics* ; Male ; Gene Knock-In Techniques ; Pyramidal Cells/physiology* ; Mice, Transgenic ; Neural Pathways/physiopathology* ; Mice, Inbred C57BL ; Microfilament Proteins

Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; alpha-Synuclein/metabolism* ; Male ; Prefrontal Cortex/drug effects* ; Rats, Sprague-Dawley ; Depression/metabolism* ; MAP Kinase Signaling System/drug effects* ; Rats ; Parkinson Disease/metabolism* ; Receptor, trkB/metabolism* ; Phosphorylation ; Disease Models, Animal ; Signal Transduction

While multiple step saccades (MSS) are occasionally reported in the healthy population, they are more evident in patients with Parkinson's disease (PD). Therefore, MSS has been suggested as a biological marker for the diagnosis of PD. However, the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic. We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades. Accordingly, brain regions involved in saccadic planning and execution might play a role in the generation of MSS. To test this hypothesis, we explored the role of the prefrontal (PFC) and posterior parietal cortex (PPC) in generating MSS by conducting two experiments: electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task. We found that the PFC and PPC are involved in the generation of MSS.
Humans ; Parietal Lobe/physiology* ; Saccades/physiology* ; Prefrontal Cortex/physiology* ; Male ; Transcranial Magnetic Stimulation ; Female ; Electroencephalography ; Adult ; Young Adult

In this study, we systematically tested the hypothesis that during the critical developmental period of adolescence, on a macro scale, the concentrations of major excitatory and inhibitory neurotransmitters (glutamate/glutamine and γ‑aminobutyric acid [GABA]) in the dorsal and ventral lateral prefrontal cortex are associated with the brain's functional connectivity and an individual's psychopathology. Neurotransmitters were measured via magnetic resonance spectroscopy while functional connectivity was measured with resting-state fMRI (n = 121). Seed-based and network-based analyses revealed associations of neurotransmitter concentrations and functional connectivities between regions/networks that are connected to prefrontal cortices via structural connections that are thought to be under dynamic development during adolescence. These regions tend to be boundary areas between functional networks. Furthermore, several connectivities were found to be associated with individual's levels of internalizing psychopathology. These findings provide insights into specific neurochemical mechanisms underlying the brain's macroscale functional organization, its development during adolescence, and its potential associations with symptoms associated with internalizing psychopathology.
Humans ; Adolescent ; Glutamic Acid/metabolism* ; Prefrontal Cortex/diagnostic imaging* ; Male ; Glutamine/metabolism* ; Female ; gamma-Aminobutyric Acid/metabolism* ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Nerve Net/metabolism* ; Neural Pathways ; Connectome

Humans and animals have a fundamental ability to use experiences and environmental information to organize behavior. It often happens that humans and animals make decisions and prepare actions under uncertain situations. Uncertainty would significantly affect the state of animals' minds, but may not be reflected in behavior. How to "read animals' mind state" under different situations is a challenge. Here, we report that neuronal activity in the medial prefrontal cortex (mPFC) of rats can reflect the environmental uncertainty when the task situation changes from certain to uncertain. Rats were trained to perform behavioral tasks under certain and uncertain situations. Under certain situations, rats were required to simply repeat two nose-poking actions that each triggered short auditory tone feedback (single-task situation). Whereas under the uncertain situation, the feedback could randomly be either the previous tone or a short musical rhythm. No additional action was required upon the music feedback, and the same secondary nose-poking action was required upon the tone feedback (dual-task situation); therefore, the coming task was uncertain before action initiation. We recorded single-unit activity from the mPFC when the rats were performing the tasks. We found that in the dual task, when uncertainty was introduced, many mPFC neurons were actively engaged in dealing with the uncertainty before the task initiation, suggesting that the rats could be aware of the task situation change and encode the information in the mPFC before the action of task initiation.
Animals ; Prefrontal Cortex/cytology* ; Uncertainty ; Neurons/physiology* ; Male ; Rats ; Rats, Long-Evans ; Action Potentials/physiology* ; Acoustic Stimulation

OBJECTIVE: To elucidate the specific mechanisms by which electroacupuncture (EA) alleviates anxiety and fear behaviors associated with posttraumatic stress disorder (PTSD), focusing on the role of lipocalin-2 (Lcn2). METHODS: The PTSD mouse model was subjected to single prolonged stress and shock (SPS&S), and the animals received 15 min sessions of EA at Shenmen acupoint (HT7). Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear. Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex (PFC). Additionally, the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology. RESULTS: Mice subjected to SPS&S presented increased anxiety- and fear-like behaviors. Lcn2 expression in the PFC was significantly upregulated following SPS&S, leading to increased expression of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and suppression of PFC neuronal activity. However, EA at HT7 inhibited Lcn2 release, reducing neuroinflammation and hypoexcitability in the PFC. Lcn2 overexpression mitigated the effects of EA at HT7, resulting in anxiety- and fear-like behaviors. CONCLUSION EA at HT7 can ameliorate PTSD-associated anxiety and fear, and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC. Please cite this article as: Yang YD, Zhong W, Chen M, Tang QC, Li Y, Yao LL, et al. Electroacupuncture alleviates behaviors associated with posttraumatic stress disorder by modulating lipocalin-2-mediated neuroinflammation and neuronal activity in the prefrontal cortex. J Integr Med. 2025; 23(5):537-547.
Electroacupuncture ; Stress Disorders, Post-Traumatic/metabolism* ; Animals ; Lipocalin-2/metabolism* ; Prefrontal Cortex/physiopathology* ; Male ; Mice ; Neurons/physiology* ; Disease Models, Animal ; Fear ; Behavior, Animal ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/metabolism* ; Anxiety/therapy* ; Acupuncture Points

OBJECTIVE: To explore the improvement effect of electroacupuncture (EA) based on Xingnao Kaiqiao acupuncture (acupuncture for regaining consciousness and opening orifices) on cognitive impairment in mice with Parkinson's disease (PD), and to explore its regulatory mechanisms on the kinesin family member 5A (KIF5A)/mitochondrial Rho GTPase 1 (Miro1) pathway and mitophagy in prefrontal cortical neurons. METHODS: A total of 70 male C57BL/6J mice of clean grade were randomly divided into a normal group (12 mice), a sham operation group (12 mice), and a model pre-screening group (46 mice). Unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle was adopted to establish the PD model in the model pre-screening group. Twenty-four mice after successful modeling were randomly selected and divided into a model group and an EA group, 12 mice in each one. In the EA group, acupuncture was applied at "Shuigou" (GV26) and bilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6), ipsilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6) were connected to EA respectively, with disperse-dense wave, 5 Hz/20 Hz in frequency, 0.5 mA in current intensity, 20 min a time, 6 times a week for 30 days. Cognitive function was assessed by Y-maze and Morris water maze tests; morphology of prefrontal cortex was observed by H.E. staining; reactive oxygen species (ROS) level in prefrontal cortex was detected by fluorescence probe method; mitochondrial morphology and autophagosome ultrastructure were observed by transmission electron microscopy; the mRNA expression of tyrosine hydroxylase (TH) was detected by quantitative real-time PCR; the protein expression of TH, KIF5A, Miro1, p62, Parkin and PTEN induced kinase 1 (PINK1) was detected by Western blot. RESULTS: Compared with the sham operation group, both the model group and the EA group exhibited increased rotation number of per minute (P<0.001). Compared with the sham operation group, in the model group, the novel arm exploration time of Y-maze test was shortened (P<0.001), the escape latency of Morris water maze test was prolonged (P<0.05) and the platform crossing number of Morris water maze test was reduced (P<0.01); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was increased (P<0.001), and mitochondrial autophagosomes could be observed; in the prefrontal cortex, the relative expression of ROS was increased (P<0.001), the protein and mRNA expression of TH was decreased (P<0.001), the protein expression of Miro1, PINK1, Parkin was increased (P<0.001, P<0.01), the protein expression of KIF5A and p62 was decreased (P<0.001). Compared with the model group, in the EA group, the novel arm exploration time of Y-maze test was prolonged (P<0.01), the escape latency of Morris water maze test was shortened (P<0.05) and the platform crossing number of Morris water maze test was increased (P<0.05); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was decreased (P<0.001), and the number of mitochondrial autophagosomes reduced and the mitochondrial morphology was improved; in the prefrontal cortex, the relative expression of ROS was decreased (P<0.01), the protein and mRNA expression of TH was increased (P<0.001, P<0.01), the protein expression of Miro1, PINK1, Parkin was decreased (P<0.001, P<0.01, P<0.05), the protein expression of KIF5A and p62 was increased (P<0.01, P<0.05). CONCLUSION Xingnao Kaiqiao electroacupuncture effectively alleviates cognitive impairment and damage of neuronal function in PD mice, its mechanism may be related to the regulation of KIF5A/Miro1 pathway, hence reducing the mitophagy in prefrontal cortical neurons.
Animals ; Electroacupuncture ; Male ; Mice ; Parkinson Disease/physiopathology* ; Cognitive Dysfunction/psychology* ; Kinesins/genetics* ; Humans ; Mitophagy ; Mice, Inbred C57BL ; rho GTP-Binding Proteins/genetics* ; Mitochondria/genetics* ; Prefrontal Cortex/metabolism*

Fatigue driving is one of the leading causes of traffic accidents, posing a significant threat to drivers and road safety. Most existing methods focus on studying whole-brain multi-channel electroencephalogram (EEG) signals, which involve a large number of channels, complex data processing, and cumbersome wearable devices. To address this issue, this paper proposes a fatigue detection method based on frontal EEG signals and constructs a fatigue driving detection model using an asymptotic hierarchical fusion network. The model employed a hierarchical fusion strategy, integrating an attention mechanism module into the multi-level convolutional module. By utilizing both cross-attention and self-attention mechanisms, it effectively fused the hierarchical semantic features of power spectral density (PSD) and differential entropy (DE), enhancing the learning of feature dependencies and interactions. Experimental validation was conducted on the public SEED-VIG dataset. The proposed model achieved an accuracy of 89.80% using only four frontal EEG channels. Comparative experiments with existing methods demonstrate that the proposed model achieves high accuracy and superior practicality, providing valuable technical support for fatigue driving monitoring and prevention.
Humans ; Electroencephalography/methods* ; Automobile Driving ; Fatigue/diagnosis* ; Accidents, Traffic/prevention & control* ; Signal Processing, Computer-Assisted ; Neural Networks, Computer ; Algorithms ; Prefrontal Cortex/physiology*