Journal of Neuroscience最新文献

{"title":"A positive allosteric modulator of the SERCA pump rescues hippocampal neuronal circuits dysfunction and cognitive defects in a mouse model of Alzheimer's disease.","authors":"Evgenii Gerasimov,Anastasiya Rakovskaya,Ekaterina Pchitskaya,Olga Vlasova,Russell Dahl,Ilya Bezprozvanny","doi":"10.1523/jneurosci.2337-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2337-24.2025","url":null,"abstract":"Alzheimer's disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca²⁺) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump may help to stabilize cytosolic Ca2+ levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using an in vitro model of amyloid toxicity. Based on in vitro experiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer's disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statement Alzheimer's disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca²⁺ signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through an in vitro screening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"58 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural and Behavioral Markers of Negative Symptoms and Cognitive Impairment in Patients with Psychosis.","authors":"Raquel van Gool,Mariesa Cay,Hanne van der Heijden,Emma Golden,Amanda Cao,Boyu Ren,Joseph Gonzalez-Heydrich,Ann K Shinn,Jaymin Upadhyay","doi":"10.1523/jneurosci.0039-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0039-25.2025","url":null,"abstract":"Negative and cognitive symptoms impair functioning in patients with psychotic illnesses (i.e., schizophrenia spectrum disorders (SZ) and bipolar I disorder with psychotic features (BD)). Disruptions in mesocorticolimbic circuitry are hypothesized to underpin negative symptoms and cognitive impairment in patients with psychosis and may also facilitate reward-motivational deficits. In male and female patients with psychosis (N=44) and healthy controls (HC=27), we used neuroimaging to define gray matter morphology and white matter microstructure. We examined negative symptom severity with the Clinical Assessment Interview for Negative Symptoms (CAINS), effort allocation during reward processing with the Effort Expenditure for Rewards Task (EEfRT), and cognitive performance with the MATRICS Cognitive Consensus Battery (MCCB). Reduced nucleus accumbens volumes in patients with psychosis were associated to higher CAINS total and Motivation and Pleasure subscale scores as well as lower effort expenditure for medium (50%) and high (88%) reward probability conditions during the EEfRT. The fornix showed reduced fractional anisotropy in patients with psychosis. Negative associations were present between CAINS Motivation and Pleasure subscores and MCCB composite and subscale scores. Lower gray matter volume in cerebellar lobule VI corresponded with impaired effort allocation during medium and high reward probability conditions and lower cognitive performance. However, lobule VI was not correlated with CAINS scores. While nucleus accumbens volume may serve as marker of negative symptoms in psychotic illnesses, cerebellar lobule VI morphology may inform on cognitive impairment in patients with SZ and BD. The nucleus accumbens and lobule VI may each contribute to reduced effort allocation during reward processing.Significance Statement Improving negative symptoms and cognitive impairment in SZ and BD remains an unmet clinical need. This study reveals that, in SZ and BD, structural changes in the nucleus accumbens and cerebellar lobule VI are associated with negative symptoms and cognitive impairments, respectively. The current findings also suggest that reductions in nucleus accumbens and cerebellar lobule VI volume may also underpin impaired reduced effort allocation during reward processing. This study provides impetus for further probing supratentorial and cerebellar circuitry to further understand negative and cognitive symptoms experienced by patients with psychotic illness and their associations with reward-motivational deficits.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"141 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-tuning the details: post-encoding music differentially impacts general and detailed memory.","authors":"Kayla Clark,Stephanie L Leal","doi":"10.1523/jneurosci.0158-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0158-25.2025","url":null,"abstract":"Music can effectively induce emotional arousal, which is associated with the release of stress hormones that are important for the emotional modulation of memory. Thus, music may serve as a powerful modulator of memory and mood, making it a promising therapeutic tool for memory and mood disorders such as Alzheimer's disease or depression. However, music's impact on memory depends on its features, timing, and ability to elicit emotional arousal. In the current study, we manipulated various features of music played during post-encoding memory consolidation to elicit emotional arousal and impact subsequent memory in men and women. We found that larger increases and moderate decreases in post-encoding music-induced emotional arousal from baseline resulted in gist vs. detail trade-offs in memory, with improved general memory but impaired detailed memory, while moderate increases in arousal from baseline corresponded to improved detailed memory, but impaired general memory. Importantly, relative to controls, music-induced emotional arousal demonstrated unique impacts on detailed memory that are crucial in supporting episodic memory. These findings suggest that music intervention does not uniformly impact memory and has important implications in developing personalized music-related interventions for those with memory and mood impairments.Significance Statement Music may be a powerful tool for modulating memory and mood, offering therapeutic potential for disorders like Alzheimer's and depression. We found that individual differences in emotional arousal following music exposure influenced both general memory and detailed memory performance. Compared to controls, music specifically impacted memory for details, highlighting its potential to target specific memory aspects. These findings suggest that music interventions may not uniformly enhance memory, emphasizing the need for personalized approaches in treating memory and mood impairments.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"48 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse firing profiles of Crhbp-positive neurons in the dorsal pons suggestive of their pleiotropic roles in REM sleep regulation in mice.","authors":"Yoshifumi Arai,Mitsuaki Kashiwagi,Takeshi Kanda,Iyo Koyanagi,Masanori Sakaguchi,Masashi Yanagisawa,Yoshimasa Koyama,Yu Hayashi","doi":"10.1523/jneurosci.2365-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2365-24.2025","url":null,"abstract":"Rapid eye movement (REM) sleep is primarily regulated by the brainstem pons. In particular, the sublaterodorsal tegmentum (SubLDT) in the dorsal pons contains neurons whose activity is selective to REM sleep. Elucidation of the precise identities of these neurons and their roles in REM sleep regulation is challenging, however, due to the functional and molecular heterogeneity of the SubLDT. A recent study revealed that corticotropin-releasing hormone-binding protein (Crhbp)-positive neurons in the SubLDT projecting to the medulla play a crucial role in REM sleep regulation and that loss of these Crhbp-positive neurons underlies sleep deficits observed in Parkinson's disease. The firing patterns of these neurons during sleep/wake, however, remained unknown. Here, we used an opto-tagging method and conducted cell-type-specific recordings from Crhbp-positive neurons using a glass pipette microelectrode in unanesthetized male mice. We recorded 58 Crhbp-positive neurons and found that many of these neurons are REM sleep-active neurons (41.4%) and that the remaining neurons are mostly either wake-active, wake/REM sleep-active, or NREM sleep-active. In addition, projection-specific recordings revealed that the medulla-projecting Crhbp-positive neurons are mostly REM sleep-active neurons (75.0%). Based on clustering analysis and spike waveform analysis, REM sleep-active Crhbp-positive neurons can be further divided into different subtypes according to their electrophysiological properties, suggesting that Crhbp-positive neurons play diverse roles in REM sleep regulation.Significance statement Reduced REM sleep is a risk for dementia and mortality, suggesting it has critical roles in health. The mechanisms and functions of REM sleep, however, remain largely elusive. Classical electrophysiological studies identified neurons in the pons that are active during REM sleep, and a recent study revealed that Crhbp-positive neurons within the same area contribute to REM sleep regulation. The relationship between the neurons identified in each study, however, remained unknown. Loss of Crhbp-positive neurons underlies sleep deficits in Parkinson's disease, underscoring the importance of characterizing these neurons. Our study revealed that many of the Crhbp-positive neurons are REM sleep-active and comprise distinct subtypes in regard to firing patterns, suggesting their diverse roles in REM sleep regulation.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"6 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathic pain-like responses in a chronic CNS injury model are mediated by corticospinal-targeted spinal interneurons.","authors":"Xiaofei Guan,Yanjie Zhu,Jian Zhong,Edmund Hollis","doi":"10.1523/jneurosci.1264-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1264-24.2025","url":null,"abstract":"Chronic neuropathic pain is a persistent and debilitating outcome of traumatic central nervous system injury, affecting up to 80% of individuals. Post-injury pain is refractory to treatments due to the limited understanding of the brain-spinal cord circuits that underlie pain signal processing. The corticospinal tract (CST) plays critical roles in sensory modulation during skilled movements and tactile sensation; however, a direct role for the CST in injury-associated neuropathic pain is unclear. Here we show that complete, selective CST transection at the medullary pyramids leads to hyperexcitability within lumbar deep dorsal horn and hindlimb allodynia-like behavior in chronically injured adult male and female mice. Chemogenetic regulation of CST-targeted lumbar spinal interneurons demonstrates that dysregulation of activity in this circuit underlies the development of tactile allodynia in chronic injury. Our findings shed light on an unrecognized circuit mechanism implicated in CNS injury-induced neuropathic pain and provide a novel target for therapeutic intervention.Significance Statement CNS injury-induced neuropathic pain affects millions of people worldwide. A significant challenge in developing efficient therapeutics is the lack of suitable animal models that accurately replicate key features of human conditions, such as chronic onset of allodynia. We found a nuanced temporal evolution of sensory responses following a selective corticospinal tract (CST) lesion. Initially, there was a reduced tactile response, which later progressed to an exaggerated response characterized by increased mechanical hypersensitivity, a key feature of allodynia. We further identified a heterogenous population of CST-targeted spinal interneurons in the deep dorsal horn that modulate tactile sensory responses. These findings reveal a pivotal role for the CST in the development of CNS injury-induced chronic neuropathic pain.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"16 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Neural Dynamics in the Auditory Telencephalon of Crows using Functional Ultrasound Imaging.","authors":"Diana A Liao,Eva Schwarzbach,Andreas Nieder","doi":"10.1523/jneurosci.0016-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0016-25.2025","url":null,"abstract":"Crows, renowned for advanced cognitive abilities and vocal communication, rely on intricate auditory systems. While the neuroanatomy of corvid auditory pathways is partially explored, the underlying neurophysiological mechanisms are largely unknown. This study used functional ultrasound imaging (fUSi) to investigate sound-induced cerebral blood volume (CBV) changes in the field L complex of the auditory telencephalon in two female crows. FUSi revealed frequency-specific CBV responses, showing a tonotopic organization within the field L complex, with low frequencies in posterior dorsal region and high frequencies in the anterior ventral region. Machine learning analyses showed fUSi signals could be used to classify sound types accurately, in both awake and anesthetized states. Variable CBV responses to longer sound stimuli suggest a delineation of subregions within the field L complex. Together, these findings highlight the potential of fUSi for providing high-resolution insights into functional systems in corvids, enabling future exploration of experimental task-related cognitive dynamics.Significance Statement This study highlights the use of functional ultrasound imaging (fUSi) to explore auditory processing in crows, marking the first application of this technique in songbirds. By revealing the frequency map of the crow's auditory system and demonstrating the ability of fUSi to classify sound types, the research uncovers the neural dynamics supporting complex auditory functions. The findings suggest conserved auditory organization across avian species and provide insights into the evolution of audio-vocal behaviors in birds. This work paves the way for future studies on the neural underpinnings of cognition and communication in corvids, offering significant implications for comparative neuroscience and neuroethology.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"26 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC3 Serine 424 phospho-mimic and phospho-null mutants bidirectionally modulate long-term memory formation and synaptic plasticity in the adult and aging mouse brain.","authors":"Alyssa C Rodriguez,Emiko A Kramár,Agatha S Augustynski,Ashley A Keiser,Tri N Dong,Tamara S Jones,Shanya N Vakilian,Sasha T Patel,Jacob S Rounds,Carlene A Chinn,Janine L Kwapis,Dina P Matheos,Marcelo A Wood","doi":"10.1523/jneurosci.1619-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1619-24.2025","url":null,"abstract":"Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.Significance statement Histone deacetylase 3 (HDAC3) is a negative regulator of synaptic plasticity and memory. However, the mechanism that regulates HDAC3 activity remains poorly understood. This study demonstrates the pivotal nature of Serine 424 of HDAC3 to bidirectionally regulate long-term potentiation, a form of synaptic plasticity, and long-term memory formation. Serine 424 is a phosphorylation site, suggesting that phosphorylation of HDAC3 is a key regulatory mechanism controlling its regulation of gene expression required for long-term memory. Indeed, expression of a Serine 424 phospho-null in the aging brain ameliorated age-dependent long-term synaptic plasticity and long-term memory deficits in aging male and aging female mice. Thus, this study provides new insight into the regulation of HDAC3 activity involved in cognitive processes.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"640 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal Sharp-Wave Ripples Decrease during Physical Actions Including Consummatory Behavior in Immobile Rodents.","authors":"Tomomi Sakairi, Masanori Kawabata, Alain Rios, Yutaka Sakai, Yoshikazu Isomura","doi":"10.1523/JNEUROSCI.0080-25.2025","DOIUrl":"10.1523/JNEUROSCI.0080-25.2025","url":null,"abstract":"<p><p>Hippocampal sharp-wave ripples (SWRs) are intermittent, fast synchronous oscillations that play a pivotal role in memory formation. It has been well established that SWRs occur during \"consummatory behaviors,\" e.g., eating or drinking a reward for correct action. However, most of typical behavioral experiments using freely moving rodents have not rigorously distinguished between the act of eating/drinking (regardless of consummation or consumption) from stopping locomotion (immobility). Therefore, in this study, we investigated the occurrence of SWRs during a reward-seeking action and subsequent consummatory reward licking in constantly immobile rats (male and female) maintained under head fixation and body covering. Immobile rats performed a pedal hold-release action that was rewarded with water every other time (false and true consummation). Unexpectedly, the SWRs remarkably decreased during reward licking as well as pedal release action. Untrained rats also showed a similar SWR decrease during water licking. Conversely, SWRs gradually increased during the pedal hold period, which was enhanced by reward expectation. A cluster of hippocampal neurons responded to cue/pedal release and reward, as previously shown. Some other clusters exhibited spike activity changes similar to the SWR occurrence, i.e., decreasing during the pedal release action and reward licking, and enhanced by reward expectation during pedal hold period. These task event-responsive neurons and SWR-like neurons displayed stronger spiking synchrony with SWRs than task-unrelated neurons. These findings suggest that the hippocampus generates SWRs, which may associate action with outcome, in \"relative immobility\" (action pauses) rather than specific consummation or consumption.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Optogenetic Tool to Investigate the Role of Dopamine Signaling in the Basal Ganglia.","authors":"Gabriel S Rocha,Marco Aurelio M Freire","doi":"10.1523/jneurosci.0294-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0294-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"24 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Functional Anatomy of Nociception: Effective Connectivity in Chronic Pain and Placebo Response.","authors":"Sanjeev Nara, Marwan N Baliki, Karl J Friston, Dipanjan Ray","doi":"10.1523/JNEUROSCI.1447-24.2025","DOIUrl":"10.1523/JNEUROSCI.1447-24.2025","url":null,"abstract":"<p><p>Chronic pain presents a widespread and complex clinical puzzle, necessitating theoretical approaches. This study expands upon our evolving comprehension of the brain's top-down information processing, encompassing functions such as prediction, expectation, and attention. These processes are believed to play a substantial role in shaping both chronic pain and placebo responses. To examine hierarchical cortical processing in pain, we define a minimal cortical pain network comprising the lateral frontal pole, the primary somatosensory cortex, and posterior insula. Using spectral dynamic causal modeling on resting-state functional magnetic resonance imaging data, we compare effective connectivity among these regions in chronic osteoarthritic patients (<i>n</i> = 54) and healthy controls (<i>n</i> = 18), and further analyze differences in placebo responders and non-responders within the patient group. Our findings reveal distinct patterns of altered top-down, bottom-up, and recurrent (i.e., intrinsic) effective connectivity within the network in chronic pain and placebo response. Specifically, recurrent connectivity within the lateral frontal pole becomes more inhibitory, while backward connectivity (higher-to-lower cortical regions) decreases in both pain perceivers and placebo responders. Conversely, forward connections show opposite patterns: nociception is associated with more excitatory (disinhibited) connections, whereas placebo responses correspond to more inhibitory forward connections. The associated effect sizes were sufficiently large to survive a leave-one-out cross-validation analysis of predictive validity. The observed alterations are consistent with predictive processing accounts of placebo effects and chronic pain. Overall, effective extrinsic and intrinsic connectivity among cortical regions involved in pain processing emerge as potentially valuable and quantifiable markers of pain perception and placebo response.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}