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

Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways. Increasing evidence suggests that imbalances in central nervous system function play an essential role in the progression of visceral pain, but the exact mechanisms underlying the neural circuitry and molecular targets remain largely unexplored. In the present study, the ventral tegmental area (VTA) was shown to mediate visceral pain in mice. Visceral pain stimulation increased c-Fos expression and Ca²⁺ activity of glutamatergic VTA neurons, and optogenetic modulation of glutamatergic VTA neurons altered visceral pain. In particular, the upregulation of NMDA receptor 2A (NR2A) subunits within the VTA resulted in visceral pain in mice. Administration of a selective NR2A inhibitor decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain. Pharmacology combined with chemogenetics further demonstrated that glutamatergic VTA neurons regulated visceral pain behaviors based on NR2A. In summary, our findings demonstrated that the upregulation of NR2A in glutamatergic VTA neurons plays a critical role in visceral pain. These insights provide a foundation for further comprehension of the neural circuits and molecular targets involved in chronic visceral pain and may pave the way for targeted therapies in chronic visceral pain.
Animals ; Male ; Visceral Pain/metabolism* ; Up-Regulation/physiology* ; Ventral Tegmental Area/metabolism* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Neurons/drug effects* ; Mice, Inbred C57BL ; Mice ; Proto-Oncogene Proteins c-fos/metabolism* ; Chronic Pain/metabolism* ; Glutamic Acid/metabolism*

At present, the problem of drug addiction treatment mainly lies in the high relapse rate of drug addicts. Addictive drugs will bring users a strong sense of euphoria and promote drug seeking. Once the drug is withdrawn, there will be withdrawal symptoms such as strong negative emotions and uncomfortable physical reactions. The recurrence of context-induced withdrawal memory is an important reason for drug relapse. Our previous study has shown increased c-Fos expression in prelimbic cortex (PrL) neurons projecting to paraventricular nucleus of the thalamus (PVT) (PrL^-PVT) during conditioned context-induced retrieval of morphine withdrawal memory. However, whether PrL^-PVT neurons are involved in withdrawal memory retrieval and the underlying molecular mechanisms remain unknown. In this study, we used conditioned place aversion (CPA) model combined with in vivo calcium signal recording, chemogenetics and nucleus drug injection methods to investigate the role and molecular mechanism of PrL^-PVT neurons in retrieval of morphine withdrawal memory. The results showed that the calcium signals of PrL^-PVT neurons were significantly enhanced by withdrawal-related context; Inhibition of PrL^-PVT neurons blocked the conditioned context-induced morphine withdrawal memory retrieval; Activation of PrL^-PVT neurons caused animals to escape from the context; After the inhibition of NMDA receptors in the PrL, withdrawal-related context failed to increase c-Fos and Arc expressions in PrL^-PVT neurons. The above results suggest that NMDA receptors in PrL^-PVT neurons are associated with retrieval of morphine withdrawal memory. This study is of great significance for further understanding the neural circuit mechanism of withdrawal memory retrieval as well as the intervention and prevention of drug relapse.
Animals ; Substance Withdrawal Syndrome/physiopathology* ; Morphine/adverse effects* ; Neurons/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Male ; Rats ; Paraventricular Hypothalamic Nucleus/metabolism* ; Memory ; Rats, Sprague-Dawley ; Morphine Dependence/physiopathology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/metabolism*

Social behaviors are fundamental and intricate functions in both humans and animals, governed by the interplay of social cognition and emotions. A noteworthy feature of several neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ), is a pronounced deficit in social functioning. Despite a burgeoning body of research on social behaviors, the precise neural circuit mechanisms underpinning these phenomena remain to be elucidated. In this paper, we review the pivotal role of the prefrontal cortex (PFC) in modulating social behaviors, as well as its functional alteration in social disorders in ASD or SCZ. We posit that PFC dysfunction may represent a critical hub in the pathogenesis of psychiatric disorders characterized by shared social deficits. Furthermore, we delve into the intricate connectivity of the medial PFC (mPFC) with other cortical areas and subcortical brain regions in rodents, which exerts a profound influence on social behaviors. Notably, a substantial body of evidence underscores the role of N-methyl-D-aspartate receptors (NMDARs) and the proper functioning of parvalbumin-positive interneurons within the mPFC for social regulation. Our overarching goal is to furnish a comprehensive understanding of these intricate circuits and thereby contribute to the enhancement of both research endeavors and clinical practices concerning social behavior deficits.
Prefrontal Cortex/physiopathology* ; Humans ; Social Behavior ; Animals ; Autism Spectrum Disorder/physiopathology* ; Schizophrenia/physiopathology* ; Receptors, N-Methyl-D-Aspartate/physiology* ; Interneurons/physiology*

Experimental autoimmune prostatitis (EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus (PVN). However, the mechanism has not yet been elucidated. Herein, we screened out the target prostate-derived inflammation cytokines (PDICs) by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid (CSF) between EAP rats and their controls. After identifying the target PDIC, qualified males in initial copulatory behavior testing (CBT) were subjected to implanting tubes onto bilateral PVN. Next, they were randomly divided into four subgroups (EAP-1, EAP-2, Control-1, and Control-2). After 1-week recovery, EAP-1 rats were microinjected with the target PDIC inhibitor, Control-1 rats were microinjected with the target PDIC, while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF (aCSF). Results showed that only interleukin-1β(IL-1β) had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls (P < 0.001) and significantly higher protein concentrations in both the serum (P = 0.001) and CSF (P < 0.001) of the EAP groups compared to the Control groups. Therefore, IL-1β was identified as the target PDIC which crosses the blood-brain barrier, thereby influencing the central nervous system. Moreover, the EAP-1 subgroup displayed a gradually prolonged ejaculation latency (EL) in the last three CBTs (all P < 0.01) and a significantly lower expression of NMDA NR1 subunit in the PVN (P = 0.043) compared to the respective control groups after a 10-day central administration of IL-1β inhibitors. However, the Control-1 subgroup showed a gradually shortened EL (P < 0.01) and a significantly higher NR1 expression (P = 0.004) after homochronous IL-1β administration. Therefore, we identified IL-1β as the primary PDIC which shortens EL in EAP rats. However, further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1β upregulates NMDA expression.
Animals ; Cytokines/metabolism* ; Disease Models, Animal ; Ejaculation/physiology* ; Interleukin-1beta/metabolism* ; Male ; N-Methylaspartate/metabolism* ; Prostate/metabolism* ; Prostatitis/metabolism* ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism*

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

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

OBJECTIVE: To investigate the effects of autophagy on N-methy-D-aspartate (NMDA) receptor and its subunit NR2B and behavioral test in a rat model of neuropathic pain (NP). METHODS: Male Sprague-Dawley (SD) rats were divided into sham group, NP group, autophagy inhibitor 3-methyladenine (3-MA) pretreatment group (3-MA+NP group) and autophagy inducer rapamyein (Rap) group (Rap+NP group) by random number table with 22 rats in each group. NP animal model was reproduced by ligating sciatic nerve, while sciatic nerve of the rats in the sham group were only exposed but not ligated. The rats in two pretreatment groups were intraperitoneally challenged with 3-MA 15 mg/kg or Rap 10 mg/kg injection 1 hour before operation. Mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured before and 1, 3, 7, 14 days after operation in each group. Spinal cord tissues were harvested at 1 day and 7 days after operation for autophagosome observation by electron microscope. The expressions of autophagy protein microtubule-associated protein 1 light chain 3-II (LC3-II), Beclin1, and NMDA, NR2B were determined by Western Blot. The positive expression of LC3 was detected by immunofluorescence. RESULTS: Compared with sham group, the MWT and TWL of rats in NP group were decreased gradually with the prolongation of operation time, the number of autophagosome, the expressions of LC3-II, Beclin1, NMDA, NR2B, and the positive expression of LC3 in spinal cord were significantly increased at 1 day after operation and till 7 days, which indicated that NP led to hyperpathia and autophagy activation. Compared with NP group, MWT was significantly further decreased, TWL was further shortened, the number of autophagosome was decreased, the expressions of LC3-II and Beclin1 in spinal cord were decreased, and NMDA and NR2B expressions were further increased after 3-MA pretreatment, with significant differences at 1 day after operation [MWT (g): 29.4±2.4 vs. 42.5±6.6, TWL (s): 7.2±1.0 vs. 8.8±1.1, LC3-II/β-actin: 0.38±0.03 vs. 0.52±0.07, Beclin1/β-actin: 0.29±0.06 vs. 0.59±0.05, NMDA/β-actin: 0.62±0.06 vs. 0.50±0.06, NR2B/β-actin: 0.57±0.03 vs. 0.46±0.03, all P < 0.05]. Immunofluorescence staining confirmed that the positive expression of LC3 was significantly decreased. Rap pretreatment could increase MWT, TWL and the number of autophagosome, increase LC3-II and Beclin1 expressions in spinal cord, and decrease NMDA and NR2B expressions in NP rats, and significant differences at 1 day after operation were found as compared with those in NP group [MWT (g): 49.4±4.4 vs. 42.5±6.6, TWL (s): 10.5±1.2 vs. 8.8±1.1, LC3-II/β-actin: 0.67±0.09 vs. 0.52±0.07, Beclin1/β-actin: 0.71±0.08 vs. 0.59±0.05, NMDA/β-actin: 0.40±0.05 vs. 0.50±0.06, NR2B/β-actin: 0.34±0.04 vs. 0.46±0.03, all P < 0.05], and immunofluorescence showed that the positive expression of LC3 was increased and lasted for 7 days. It indicated that Rap could increase the activity of autophagy, alleviate the occurrence of hyperalgesia, and reduce the expressions of NMDA receptor and its NR2B subunit. CONCLUSIONS NP could regulate the variety of NMDA/NR2B and hyperalgesia via increasing autophagy.
Animals ; Autophagy/physiology* ; Disease Models, Animal ; Hyperalgesia/metabolism* ; Male ; Neuralgia/metabolism* ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism*

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.
Animals ; Copulation ; Ejaculation/physiology* ; Female ; Male ; Neurons/physiology* ; Paraventricular Hypothalamic Nucleus/physiology* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Sexual Behavior, Animal/physiology* ; Splanchnic Nerves/physiology* ; Sympathetic Nervous System/physiology*