Yuhao Sun, Wantong Liao, Jinhao Li, Xinche Zhang, Guan Wang, Zhiyuan Ma, Sen Song
{"title":"Reward-optimizing learning using stochastic release plasticity.","authors":"Yuhao Sun, Wantong Liao, Jinhao Li, Xinche Zhang, Guan Wang, Zhiyuan Ma, Sen Song","doi":"10.3389/fncir.2025.1618506","DOIUrl":"10.3389/fncir.2025.1618506","url":null,"abstract":"<p><p>Synaptic plasticity underlies adaptive learning in neural systems, offering a biologically plausible framework for reward-driven learning. However, a question remains: how can plasticity rules achieve robustness and effectiveness comparable to error backpropagation? In this study, we introduce Reward-Optimized Stochastic Release Plasticity (RSRP), a learning framework where synaptic release is modeled as a parameterized distribution. Utilizing natural gradient estimation, we derive a synaptic plasticity learning rule that effectively adapts to maximize reward signals. Our approach achieves competitive performance and demonstrates stability in reinforcement learning, comparable to Proximal Policy Optimization (PPO), while attaining accuracy comparable with error backpropagation in digit classification. Additionally, we identify reward regularization as a key stabilizing mechanism and validate our method in biologically plausible networks. Our findings suggest that RSRP offers a robust and effective plasticity learning rule, especially in a discontinuous reinforcement learning paradigm, with potential implications for both artificial intelligence and experimental neuroscience.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1618506"},"PeriodicalIF":3.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12390965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144949864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryusei Abo, Mei Ishikawa, Rio Shinohara, Takayuki Michikawa, Itaru Imayoshi
{"title":"Volitional and forced running ability in mice lacking intact primary motor cortex.","authors":"Ryusei Abo, Mei Ishikawa, Rio Shinohara, Takayuki Michikawa, Itaru Imayoshi","doi":"10.3389/fncir.2025.1630932","DOIUrl":"10.3389/fncir.2025.1630932","url":null,"abstract":"<p><p>The coordination of various brain regions achieves both volitional and forced motor control, but the role of the primary motor cortex in proficient running motor control remains unclear. This study trained mice to run at high performance (>10,000 rotations per day or >2,700 rotations per hour) using a running wheel, and then assessed the effects of the removal of bilateral cortical areas including the primary motor cortex on volitional (self-initiated) and forced (externally driven) running locomotion. The control sham-operated group revealed a quick recovery of volitional running, reaching half of the maximum daily rotation in 3.9 ± 2.6 days (<i>n</i> = 10). In contrast, the cortical injury group took a significantly longer period (7.0 ± 3.3 days, <i>n</i> = 15, <i>p</i> < 0.05) to reach half of the maximum volitional daily rotation, but recovered to preoperative levels in about two weeks. Furthermore, even 3 days after surgery to remove cortical regions, the running time on a treadmill moving at 35.3 cm/s, which is difficult for naïve mice to run on, was not significantly different from that in the sham-operated group. These results suggest that the intact primary motor cortex is not necessarily required to execute trained fast-running locomotion, but rather contributes to the spontaneity of running in mice.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1630932"},"PeriodicalIF":3.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144949785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effective training procedure for a simultaneous bimanual movement task in head-fixed mice.","authors":"Kotaro Tezuka, Hironobu Osaki, Kaneyasu Nishimura, Shin-Ichiro Terada, Masanori Matsuzaki, Yoshito Masamizu","doi":"10.3389/fncir.2025.1633843","DOIUrl":"https://doi.org/10.3389/fncir.2025.1633843","url":null,"abstract":"<p><p>Bimanual movements consist of simultaneous and nonsimultaneous movements. The neural mechanisms of unimanual and nonsimultaneous bimanual movements have been explored in rodent studies through electrophysiological recordings and calcium imaging techniques. However, the neural bases of simultaneous bimanual movements remain poorly understood because of a lack of effective training procedures for such movements in head-fixed rodents. To address this issue, we developed a task in which mice simultaneously pull right and left levers with their forelimbs in a head-fixed condition. Here, we conducted sessions with the link plate in which both levers were mechanically linked to help mice learn the importance of simultaneous bimanual movements. These sessions with the link plate enabled the mice to maintain high success rates even during independent sessions, where the right and left levers could move independently. In these independent sessions, mice were not required to pull both levers at the same time, but rather simply to hold levers simultaneously for a specific period. The mice that experienced sessions with the link plate showed a significantly higher ratio of simultaneous (i.e., lag < 20 ms) than nonsimultaneous lever pulls. In contrast, mice without experience in sessions with the link plate showed no significant increase in simultaneous over nonsimultaneous pulls. This study demonstrates the efficacy of our new task in facilitating repetitive simultaneous forelimb movements in rodents and provides a basis for understanding the neural mechanisms underlying bimanual movements.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1633843"},"PeriodicalIF":3.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144949835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Localization and connections of the tail of caudate and caudal putamen in mouse brain.","authors":"Run-Zhe Ma, Sheng-Qiang Chen, Ge Zhu, Hui-Ru Cai, Jin-Yuan Zhang, Yi-Min Peng, Dian Lian, Song-Lin Ding","doi":"10.3389/fncir.2025.1611199","DOIUrl":"10.3389/fncir.2025.1611199","url":null,"abstract":"<p><p>The neural circuits of the striatum (caudate and putamen) constitute a crucial component of the extrapyramidal motor system, and dysfunction in these circuits is correlated with significant neurological disorders including Parkinson's disease and Huntington's disease. Many previous studies in rodents revealed the neural connections of the rostral and intermediate parts of the striatum, but relatively fewer studies focused on the caudal striatum, which likely contains both the tail of caudate (CaT) and caudal putamen (PuC). In this study, we investigate the gene markers for the CaT and PuC and brain-wide afferent and efferent projections of the caudal striatum in mice using both anterograde and retrograde neural tracing methods. Some genes such as <i>prodynorphin</i>, <i>otoferlin</i>, and <i>Wolfram syndrome 1 homolog</i> are strongly expressed in CaT and PuC while some others such as neurotensin are almost exclusively expressed in CaT. The major afferent projections of the CaT originate from the substantia nigra (SN), ventral tegmental area, basolateral amygdala, parafascicular nucleus, and visual, somatosensory, auditory and parietal association cortices. The PuC receives its main inputs from the posterior intralaminar nucleus, ventroposterior medial nucleus (VPM), medial geniculate nucleus, and entorhinal, motor and auditory cortices. Both CaT and PuC neurons (including dopamine receptor 1 expressing ones) project in a rough topographical manner to the external and internal divisions of globus pallidus (GP) and SN. However, dopamine receptor 2 expressing neurons in nearly all striatal regions (including CaT and PuC) exclusively target the external GP. In conclusion, the present study has identified the mouse equivalent of the primate CaT and revealed detailed brain-wide connections of the CaT and PuC in rodent. These findings would offer new insights into the functional correlation and disease-related neural circuits related to the caudal striatum.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1611199"},"PeriodicalIF":3.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Differentiation between bipolar disorder and major depressive disorder based on AMPA receptor distribution.","authors":"Sakiko Tsugawa, Yuichi Kimura, Junichi Chikazoe, Hiroki Abe, Tetsu Arisawa, Mai Hatano, Waki Nakajima, Hiroyuki Uchida, Tomoyuki Miyazaki, Yuuki Takada, Akane Sano, Kotaro Nakano, Tsuyoshi Eiro, Akira Suda, Takeshi Asami, Akitoyo Hishimoto, Hideaki Tani, Nobuhiro Nagai, Teruki Koizumi, Shinichiro Nakajima, Shunya Kurokawa, Yohei Ohtani, Kie Takahashi, Yuhei Kikuchi, Taisuke Yatomi, Ryo Mitoma, Shunsuke Tamura, Shingo Baba, Osamu Togao, Yoji Hirano, Hirotaka Kosaka, Hidehiko Okazawa, Masaru Mimura, Takuya Takahashi","doi":"10.3389/fncir.2025.1624179","DOIUrl":"10.3389/fncir.2025.1624179","url":null,"abstract":"<p><p>An accurate diagnostic method using biological indicators is critically needed for bipolar disorder (BD) and major depressive disorder (MDD). The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a crucial regulator of synaptic function, and its dysregulation may play a central role in the pathophysiology of psychiatric disorders. Our recently developed positron emission tomography (PET) tracer, [<sup>11</sup>C]K-2, enables the quantitative visualization of AMPAR distribution and is considered useful for characterizing synaptic phenotypes in patients with psychiatric disorders. This study aimed to develop a machine learning-based method to differentiate bipolar disorder from major depressive disorder using AMPAR density. Sixteen patients with BD and 27 patients with MDD, all in depressive episodes, underwent PET scans with [<sup>11</sup>C]K-2 and structural magnetic resonance imaging. AMPAR density was estimated using the standardized uptake value ratio from 30 to 50 min after tracer injection, normalized to whole brain radioactivity. A partial least squares model was trained to predict diagnoses based on AMPAR density, and its performance was evaluated using a leave-one-pair-out cross-validation. Significant differences in AMPAR density were observed in the parietal lobe, cerebellum, and frontal lobe, notably the dorsolateral prefrontal cortex between patients with BD and patients with MDD during a depressive episode. The model achieved an area under the curve of 0.80, sensitivity of 75.0%, and specificity of 77.8%. These findings suggest that AMPAR density measured with [<sup>11</sup>C]K-2 can effectively distinguish BD from MDD and may aid diagnosis, especially in patients with ambiguous symptoms or incomplete clinical presentation.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1624179"},"PeriodicalIF":3.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NMDA receptor antagonist induced c-Fos expression in the medial entorhinal cortex during postnatal development.","authors":"Feng Liang, Hong Wang, Robert Konrad Naumann","doi":"10.3389/fncir.2025.1619534","DOIUrl":"10.3389/fncir.2025.1619534","url":null,"abstract":"<p><p><i>N</i>-methyl-D-aspartate receptor (NMDAR) antagonists, including ketamine, phencyclidine (PCP), and dizocilpine (MK-801), are an important class of drugs that can produce antidepressant, hallucinogenic, dissociative, psychotomimetic, and anesthetic effects in humans and animal models. To understand the effects of NMDAR antagonists on the brain, it is essential to map their actions at cellular resolution. We quantified c-Fos expressing cells in the mouse telencephalon after systemic injection of the potent NMDAR antagonist MK-801 and found a 10-fold higher density of c-Fos in the medial entorhinal cortex (MEC) compared to other regions of the telencephalon. c-Fos density was high in layer 3 of the dorsal MEC but low in other parts of the MEC. Since previous studies have shown that parvalbumin (PV) staining shows a strong dorsal-ventral gradient in the MEC, we investigated the spatial correlation between c-Fos and PV staining. We classified PV neurons based on their level of immunoreactivity and found that high and medium PV neurons were positively correlated with c-Fos density, while low PV neurons were negatively correlated. To understand the temporal correlation of c-Fos and PV staining, we examined their expression patterns after MK-801 injections during postnatal development. PV expression emerged on postnatal day 12, preceding c-Fos expression, which emerged on postnatal day 16. Our results suggest that local circuits comprising specific subtypes of inhibitory and excitatory neurons are critical for generating a sustained neuronal response to NMDAR antagonists. Furthermore, a high density of PV neuron input may be a prerequisite for the induction of c-Fos expression observed in MEC principal neurons. This study contributes to our understanding of how the brain responds to NMDAR antagonists in the developing and adult brain and reveals cell types in the dorsal MEC that are highly sensitive to this class of drugs.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1619534"},"PeriodicalIF":3.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12339504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Vagus nerve stimulation modulates information representation of sustained activity in layer specific manner in the rat auditory cortex.","authors":"Tomoyo Isoguchi Shiramatsu, Kenji Ibayashi, Kensuke Kawai, Hirokazu Takahashi","doi":"10.3389/fncir.2025.1569158","DOIUrl":"10.3389/fncir.2025.1569158","url":null,"abstract":"<p><p>Understanding how vagus nerve stimulation (VNS) modulates cortical information processing is essential to developing sustainable, adaptive artificial intelligence inspired by biological systems. This study presents the first evidence that VNS alters the representation of auditory information in a manner that is both layer- and frequency band-specific within the rat auditory cortex. Using a microelectrode array, we meticulously mapped the band-specific power and phase-locking value of sustained activities in layers 2/3, 4, and 5/6, of the rat auditory cortex. We used sparse logistic regression to decode the test frequency from these neural characteristics and compared the decoding accuracy before and after applying VNS. Our results showed that VNS impairs high-gamma band representation in deeper layers (layers 5/6), enhances theta band representation in those layers, and slightly improves high-gamma representation in superficial layers (layers 2/3 and 4), demonstrating the layer-specific and frequency band-specific effect of VNS. These findings suggest that VNS modulates the balance between feed-forward and feed-back pathways in the auditory cortex, providing novel insights into the mechanisms of neuromodulation and its potential applications in brain-inspired computing and therapeutic interventions.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1569158"},"PeriodicalIF":3.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bayesian estimation of orientation and direction tuning captures parameter uncertainty.","authors":"Zongting Wu, Stephen D Van Hooser","doi":"10.3389/fncir.2025.1542332","DOIUrl":"10.3389/fncir.2025.1542332","url":null,"abstract":"<p><p>This study explores the efficacy of Bayesian estimation in modeling the orientation and direction selectivity of neurons in the primary visual cortex (V1). Unlike traditional methods such as least squares, Bayesian estimation adeptly handles the probabilistic nature of neuronal responses, offering robust analysis even with limited data and weak selectivity. Through the analysis of both simulated and experimental data, we demonstrate that Bayesian estimation not only accurately fits the neuronal tuning curves but also effectively captures parameter certainty or uncertainty of both strongly and weakly selective neurons. Our results affirm the complex interdependencies among response parameters and highlight the variability in neuronal behavior under varied stimulus conditions. Our findings provide guidance as to how many response samples are necessary for Bayesian parameter estimation to achieve reliable fitting, making it particularly suitable for studies with constraints on data availability.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1542332"},"PeriodicalIF":3.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12319010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rishi R Dhingra, Peter M MacFarlane, Peter J Thomas, Julian F R Paton, Mathias Dutschmann
{"title":"Asymmetric neuromodulation in the respiratory network contributes to rhythm and pattern generation.","authors":"Rishi R Dhingra, Peter M MacFarlane, Peter J Thomas, Julian F R Paton, Mathias Dutschmann","doi":"10.3389/fncir.2025.1532401","DOIUrl":"10.3389/fncir.2025.1532401","url":null,"abstract":"<p><p>Like other brain circuits, the brainstem respiratory network is continually modulated by neurotransmitters that activate slow metabotropic receptors. In many cases, activation of these receptors only subtly modulates the respiratory motor pattern. However, activation of some receptor types evokes the arrest of the respiratory motor pattern as can occur following the activation of μ-opioid receptors. We propose that the varied effects of neuromodulation on the respiratory motor pattern depend on the pattern of neuromodulator receptor expression and their influence on the excitability of their post-synaptic targets. Because a comprehensive characterization of these cellular properties across the respiratory network remains challenging, we test our hypothesis by combining computational modeling with ensemble electrophysiologic recording in the pre-Bötzinger complex (pre-BötC) using high-density multi-electrode arrays (MEA). Our computational model encapsulates the hypothesis that neuromodulatory transmission is organized asymmetrically across the respiratory network to promote rhythm and pattern generation. To test this hypothesis, we increased the strength of subsets of neuromodulatory connections in the model and used selective agonists <i>in situ</i> while monitoring pre-BötC ensemble activities. The <i>in silico</i> simulations of increasing slow inhibition were consistent with experiments examining the effect of systemic administration of the 5HT1aR agonist 8-OH-DPAT. Similarly, the effects of increasing slow excitation in the model were experimentally confirmed in pre-BötC ensemble activities before and after systemic administration of the <i>μ</i>-opioid receptor agonist fentanyl. We conclude that asymmetric neuromodulation can contribute to respiratory rhythm and pattern generation and accounts for its varied effects on breathing.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1532401"},"PeriodicalIF":3.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neonatal testosterone exposure alleviates female-specific severity of formalin-induced inflammatory pain in mice.","authors":"Moeko Kanaya, Yoshifumi Ueta, Makiko Mochizuki-Kashio, Ayako Nakamura-Ishizu, Mariko Miyata","doi":"10.3389/fncir.2025.1593443","DOIUrl":"10.3389/fncir.2025.1593443","url":null,"abstract":"<p><p>Gonadal hormones may influence higher pain sensitivity in females than males by transiently activating the central pain pathway and organizing sexually dimorphic neuronal circuits during development. The latter effects of gonadal hormones, called organizational effects, are critical for establishing sex-specific reproductive functions and transforming them postnatally. However, it remains unclear whether the organizational effects determine sex-specific pain severity in adulthood. In this study, testosterone administration to female mice on day of birth alleviated intraplantar formalin injection-induced inflammatory pain in adulthood, resulting in comparable severity to males. In contrast, intense pain persisted in females with adult testosterone administration. We found no sex differences in thermal pain responses and spinal reflexes. Formalin injection similarly increased c-Fos activity in the spinal dorsal horn in both sexes, suggesting the involvement of supraspinal mechanisms and/or immune responses in sex-specific inflammatory pain. In the periaqueductal gray (PAG) region related to the descending pain modulation pathway, formalin increased c-Fos-positive cells in the lateral region of males but not females. In the bed nucleus of the stria terminalis (BNST) related to affective pain responses, formalin increased c-Fos-positive cells in females. Notably, in common with these regions, testosterone administration to neonatal females changed formalin-induced c-Fos activity from the female to the male type. We further examined the involvement of immune cells. Systemic microglial ablation using PLX3397 suppressed formalin-induced pain in a sex-independent manner. Although formalin injection changed T lymphocyte subsets in the peripheral blood in females, it was independent from neonatal testosterone administration. Therefore, the organizational effects of testosterone determine the male characteristic of formalin-induced inflammatory pain, possibly via sexually dimorphic PAG and BNST functions.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":"19 ","pages":"1593443"},"PeriodicalIF":3.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}