Journal of Physiology-London最新文献

{"title":"Pannexin 1 and pannexin 3 differentially regulate the cancer cell properties of cutaneous squamous cell carcinoma.","authors":"Brooke L O'Donnell, Danielle Johnston, Ayushi Bhatt, Zahra Kardan, Dan Stefan, Andrew Bysice, Samar Sayedyahossein, Lina Dagnino, Matthew Cecchini, Sampath Kumar Loganathan, Kathryn Roth, Silvia Penuela","doi":"10.1113/JP286172","DOIUrl":"https://doi.org/10.1113/JP286172","url":null,"abstract":"<p><p>Pannexin (PANX) channels are present in skin and facilitate the movement of signalling molecules during cellular communication. PANX1 and PANX3 function in skin homeostasis and keratinocyte differentiation but were previously reduced in a small cohort of human cutaneous squamous cell carcinoma (cSCC) tumours compared to normal epidermis. In our study we used SCC-13 cells, limited publicly available RNA-seq data and a larger cohort of cSCC patient-matched samples to analyse PANX1 and PANX3 expression and determine the association between their dysregulation and the malignant properties of cSCC. In a bioinformatics analysis, PANX1 transcripts were increased in cSCC and head and neck SCC tumours compared to normal tissues, but PANX3 mRNA showed no differences. However, in our own cohort PANX3 transcripts were decreased in cSCC compared to patient-matched aged skin, whereas PANX1 protein was upregulated in cSCC. PANX1 localized to all regions within the cSCC tumour microenvironment, and increased levels were associated with larger tumour dimensions. To investigate PANX1 function in SCC-13 cells, we deleted PANX1 via CRISPR/Cas9 and treated with PANX1 inhibitors, which markedly reduced cell growth and migration. To assess PANX3 function in cutaneous carcinogenesis, we employed the 7,12-dimethylbenz(a)anthracene/12-otetradecanoylphorbol-13-acetate (DMBA/TPA) model using our global Panx3 knockout (KO) mice, where 60% of wild-type and 100% of KO mice formed precancerous papillomas. Average papilloma volumes at endpoint were significantly increased in KO mice and showed moderate evidence of increases in KO mice over time. Collectively, these findings suggest PANX1 and PANX3 dysregulation may have potential tumour-promoting and tumour-suppressive effects for keratinocyte transformation, respectively. KEY POINTS: Pannexin 1 (PANX1) and pannexin 3 (PANX3) are channel-forming proteins which are critical in the normal maintenance and function of keratinocytes in the skin but may become altered in cutaneous squamous cell carcinoma (cSCC) tumours. In this study we used a combination of culture models, mouse models and patient-derived tissues. We found PANX1 levels are increased in cSCC tumours and present in all tumour regions, functioning to promote cSCC cell growth and migration. Conversely, PANX3 levels are decreased in cSCC tumours, and this protein reduces the incidence and growth of precancerous lesions. Taken together our data indicate that in cSCC these pannexin family members seem to have opposite effects, in either promoting or restricting cancer cell properties. These results help us to better understand the mechanisms of malignant transformation of keratinocytes and offer a new potential therapeutic target for the treatment of advanced cSCC.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669945","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":"Purkinje cell ablation and Purkinje cell-specific deletion of Tsc1 in the developing cerebellum strengthen cerebellothalamic synapses.","authors":"Hiroshi Nishiyama, Naoko Nishiyama, Boris V Zemelman","doi":"10.1113/JP285887","DOIUrl":"https://doi.org/10.1113/JP285887","url":null,"abstract":"<p><p>Cerebellar damage early in life often causes long-lasting motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviours. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is a major direct target of the cerebellar nuclei, conveying cerebellar signals to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The ablation of Purkinje cells in the developing cerebellum strengthened cerebellothalamic synapses and enhanced thalamic suprathreshold activities. Purkinje-cell specific deletion of tuberous sclerosis complex subunit 1 (Tsc1), an autism-associated gene for which the protein product negatively regulates the mammalian target of rapamycin, also strengthened cerebellothalamic synapses. However, this strengthening occurred only in homozygous deletion, whereas both homozygous and hemizygous deletion are known to cause autism-like behaviours. These results suggest that, although the cerebellothalamic projection is vulnerable to disturbances in the developing cerebellar cortex, other changes may also drive the behavioural consequences of early cerebellar perturbation. KEY POINTS: Cerebellar damage early in life often causes motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. Recent studies focus on how the developing cerebellum affects the formation and function of the cerebral cortex, the higher-order centre for all behaviours. However, the cerebellum does not directly connect to the cerebral cortex. Here, we studied the consequences of early cerebellar perturbation on the thalamus because it is a direct postsynaptic target of the cerebellum, sending cerebellar signals to the cerebral cortex. Loss of cerebellar Purkinje cells, which are commonly associated with various neurological disorders, strengthened cerebellothalamic synapses, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum. Purkinje cell-specific loss of tuberous sclerosis complex-1, a negative regulator of mammalian target of rapamycin, is an established mouse model of autism. This mouse model also showed strengthened cerebellothalamic synapses.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669948","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":"Bioelectronic block of stellate ganglia mitigates pacing-induced heterogeneous release of catecholamine and neuropeptide Y in the infarcted pig heart.","authors":"Tina Vrabec, Shane Bender, Shyue-An Chan, Steven Cha, Sahil Haridas, Peter Hanna, Olujimi A Ajijola, Kalyanam Shivkumar, Corey Smith, Jeffrey L Ardell","doi":"10.1113/JP286924","DOIUrl":"https://doi.org/10.1113/JP286924","url":null,"abstract":"<p><p>The sympathetic nervous system modulates cardiac contractile and electrophysiological function and contributes to adverse remodelling following myocardial infarction (MI). Axonal modulation therapy (AMT), directed at the sympathetic chain, blocks efferent sympathetic outflow to the heart and is a strategy to transiently and controllably mitigate chronic MI-associated sympatho-excitation. In porcine models, we evaluated scalable AMT, directed at the paravertebral chain, in blocking reflex-mediated pacing-induced sympatho-excitation post-MI. The level of sympatho-excitation was assessed by dynamic interstitial measurement of noradrenaline (NA) and neuropeptide Y (NPY). In anaesthetized normal (n = 5) and age-matched pigs 6 weeks post-MI induction (n = 10), we electrically stimulated the right sympathetic chain and determined levels of direct current block applied at the T1-T2 level sufficient to reduce the evoked changes in heart rate and/or contractility by 25-75%. Reflex-mediated neural release of NA and NPY into the interstitial space during programmed pacing (PP) was assessed using fast-scanning cyclic voltammetry and capacitive immunoprobes. Normal animals demonstrated homogeneous NA and NPY release profiles during PP. In contrast, for MI animals PP evoked differential NA and NPY release in remote and MI border zones of the left ventricle. Right-sided AMT mitigated NA and NPY pacing-induced release in the remote left ventricle with a positive correlation to increasing AMT levels. Pacing-induced NA and NPY release in the MI border zone was not mitigated by AMT. Differential effects of AMT on NA and NPY may underlie the anti-arrhythmic effects of partial stellate ganglion block in the setting of chronic MI. KEY POINTS: Programmed cardiac pacing evokes homogeneous noradrenaline (NA) and neuropeptide Y (NPY) release in equivalent areas (e.g. medial and lateral aspects) of the normal left ventricle. Programmed cardiac pacing evokes differential NA and NPY release in remote and border zones of the infarcted left ventricle. Axonal modulation therapy (AMT), using a graded direct current block applied to the stellate ganglia, can proportionally modulate cardiac sympathetic reflexes. Unilateral AMT mitigates NA and NPY release in remote left ventricular tissue, with release negatively correlated to increasing AMT levels. Heterogeneities in NA and NPY between the border and remote tissues are reduced by progressive AMT.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669943","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":"Interleukin-1 type 1 receptor blockade attenuates the exaggerated exercise pressor reflex in male UC Davis type 2 diabetic mellitus rats.","authors":"Yu Huo, Milena Samora, Richard K McCuller, Kimber L Stanhope, Peter J Havel, Michelle L Harrison, Audrey J Stone","doi":"10.1113/JP287120","DOIUrl":"https://doi.org/10.1113/JP287120","url":null,"abstract":"<p><p>An exaggerated exercise pressor reflex and peripheral neuropathy are both evoked by the same type of thinly myelinated afferents and are present in patients with type 2 diabetes mellitus (T2DM). Although it is known that the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to peripheral neuropathy, the effects of IL-1β on the exercise pressor reflex in T2DM are not known. Therefore, we aimed to determine the effect of IL-1 receptors on the exercise pressor reflex in T2DM. We compared changes in peak pressor (mean arterial pressure; ΔMAP), blood pressure index (ΔBPi), heart rate (ΔHR) and heart rate index (ΔHRi) responses to static and intermittent contractions and tendon stretch before and after peripheral IL-1 type 1 receptor blockade (anakinra, Kineret^®) in T2DM and healthy male rats and IL-1 receptor activation (IL-1β) in healthy rats. Blocking IL-1 receptors significantly attenuated the ΔMAP and ΔBPi to static contraction in T2DM rats. Furthermore, blocking IL-1 receptors significantly attenuated the ΔMAP, ΔBPi and ΔHRi to intermittent contraction, and ΔMAP to tendon stretch in T2DM rats (all P < 0.05). In addition, IL-1 receptor activation significantly exaggerated the ΔMAP and ΔBPi to static contraction and ΔMAP, ΔBPi and ΔHR to intermittent contraction in healthy rats, all P < 0.05. Furthermore, circulating IL-1β serum concentrations were significantly greater in T2DM rats than in healthy rats (P < 0.05). We conclude that IL-1 signalling contributes to the exaggerated exercise pressor reflex in T2DM, suggesting for the first time that inflammatory cytokines play a critical role in exaggerated blood pressure responses to exercise in those with T2DM. KEY POINTS: Chronic inflammation, a complication of type 2 diabetes mellitus (T2DM), causes increased production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor-α. IL-1β has been shown to sensitize muscle afferents that conduct the exercise pressor reflex. We found blocking of IL-1 receptors by anakinra (Kineret^®), an IL-1 type 1 receptor antagonist, significantly attenuated the exaggerated exercise pressor reflex in T2DM rats, but not in healthy rats. In addition, activating IL-1 receptors with IL-1β significantly augmented the exercise pressor reflex in healthy rats. Our findings suggest that IL-1 receptors, by mediating IL-1β signalling, play a role in exaggerating the exercise pressor reflex in T2DM. These results highlight the complex interplay between inflammation and the autonomic nervous system in regulating cardiovascular function, and the potential for using an FDA-approved IL-1 receptor antagonist, Kineret^®, as a therapeutic approach to reduce adverse cardiovascular events during physical activity in those with T2DM.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669944","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":"Prospective in silico trials identify combined SK and K₂P channel block as an effective strategy for atrial fibrillation cardioversion.","authors":"Albert Dasí, Lucas Arantes Berg, Hector Martinez-Navarro, Alfonso Bueno-Orovio, Blanca Rodriguez","doi":"10.1113/JP287124","DOIUrl":"https://doi.org/10.1113/JP287124","url":null,"abstract":"<p><p>Virtual evaluation of medical therapy through human-based modelling and simulation can accelerate and augment clinical investigations. Treatment of the most common cardiac arrhythmia, atrial fibrillation (AF), requires novel approaches. This study prospectively evaluates and mechanistically explains three novel pharmacological therapies for AF through in silico trials, including single and combined SK and K₂P channel block. AF and pharmacological action were assessed in a large cohort of 1000 virtual patients, through 2962 multiscale simulations. Extensive calibration and validation with experimental and clinical data support their credibility. Sustained AF was observed in 654 virtual patients. In this cohort, cardioversion efficacy increased to 82% (535 of 654) through combined SK+K₂P channel block, from 33% (213 of 654) and 43% (278 of 654) for single SK and K₂P blocks, respectively. Drug-induced prolongation of tissue refractoriness, dependent on the virtual patient's ionic current profile, explained cardioversion efficacy (atrial refractory period increase: 133.0 ± 48.4 ms for combined vs. 45.2 ± 43.0 and 71.0 ± 55.3 ms for single SK and K₂P block, respectively). Virtual patients cardioverted by SK channel block presented lower K₂P densities, while lower SK densities favoured the success of K₂P channel inhibition. Both ionic currents had a crucial role on atrial repolarization, and thus a synergism resulted from the multichannel block. All three strategies, including the multichannel block, preserved atrial electrophysiological function (i.e. conduction velocity and calcium transient dynamics) and thus its contractile properties (safety). In silico trials identify key factors determining treatment success and the combined SK+K₂P channel block as a promising strategy for AF management. KEY POINTS: This is a large-scale in silico trial study involving 2962 multiscale simulations. A population of 1000 virtual patients underwent three treatments for atrial fibrillation. Single and combined SK+K₂P channel block were assessed prospectively. The multi-ion channel inhibition resulted in 82% cardioversion efficacy. In silico trials have broad implications for precision medicine.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669947","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":"Load-dependence of the activation of myosin filaments in heart muscle.","authors":"Yanhong Wang, Luca Fusi, Jesus G Ovejero, Cameron Hill, Samina Juma, Flair Paradine Cullup, Andrea Ghisleni, So-Jin Park-Holohan, Weikang Ma, Thomas Irving, Theyencheri Narayanan, Malcolm Irving, Elisabetta Brunello","doi":"10.1113/JP287434","DOIUrl":"https://doi.org/10.1113/JP287434","url":null,"abstract":"<p><p>Contraction of heart muscle requires activation of both the actin and myosin filaments. The mechanism of myosin filament activation is unknown, but the leading candidate hypothesis is direct mechano-sensing by the filaments. Here, we tested this hypothesis by activating intact trabeculae from rat heart by electrical stimulation under different loads and measuring myosin filament activation by X-ray diffraction. Unexpectedly, we found that the distinct structural changes in the myosin filament associated with activation had different dependences on the load. In early activation, all the structural changes indicated faster activation at higher load, as expected from the mechano-sensing hypothesis, but, at later times, the helical order of the myosin motors characteristic of the inactivated state was lost even at very low load. We conclude that mechano-sensing does operate in heart muscle, but it is supplemented by a previously undescribed mechanism that links myosin filament activation to actin filament activation. KEY POINTS: Myosin filament activation controls the strength and speed of contraction in heart muscle. Early activation of the myosin filament is determined by the filament load. At later times, myosin filament activation is controlled by a load independent pathway. This load independent pathway provides new targets and assays for drug development.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649005","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":"Late-gestation maternal undernutrition induces circulatory redistribution while preserving uteroplacental function independent of fetal glycaemic state.","authors":"Steven K S Cho, Jack R T Darby, Brahmdeep S Saini, Stacey L Holman, Mitchell C Lock, Sunthara Rajan Perumal, Georgia K Williams, Christopher K Macgowan, Mike Seed, Janna L Morrison","doi":"10.1113/JP287171","DOIUrl":"https://doi.org/10.1113/JP287171","url":null,"abstract":"<p><p>Programming effects of maternal undernutrition on fetal metabolic and cardiovascular systems are well elucidated, yet a detailed characterization of maternal haemodynamics is not available. This study used comprehensive cardiovascular magnetic resonance (CMR) imaging to quantify maternal haemodynamics after 29 days (111-140 days) of late-gestation undernutrition (LGUN) in pregnant sheep. Control ewes received 100% of metabolizable energy requirements (MERs, n = 15), whereas LGUN ewes were globally nutrient restricted to 50% MER (n = 18), with a subset of fetuses undergoing continuous glucose infusion (LGUN + G, n = 6/18). Ewes underwent CMR (138-140 days' gestation), and placental tissue was collected the next day. Ewes in both LGUN groups had reduced body weight and mean blood glucose concentration across gestation. Ventricular dimensions were lower in both LGUN groups. Uterine artery blood flow (QUtA) was elevated in the LGUN group compared with controls, whereas peripheral blood flow was reduced and further diminished in LGUN + G. Maternal weight change correlated with all haemodynamic parameters across all groups. Uteroplacental oxygen and glucose delivery were increased in LGUN compared to control ewes, whereas uteroplacental oxygen consumption was preserved. LGUN did not impact placental or fetal weight, and markers of brain-sparing physiology were absent. Placental expression of insulin-like growth factors (IGF-1 and IGF-2) and their receptors, glucose, fatty acid (FA) or amino acid transporters and markers of angiogenesis was not impacted. FA transporter expression was positively correlated with QUtA, and FA binding protein correlated negatively with maternal weight change. Maternal cardiovascular adaptations in response to LGUN manifest as preservation of placental growth and function, thereby preserving fetal growth. KEY POINTS: Maternal undernutrition during pregnancy alters fetal metabolic and cardiovascular physiology, but little is known about alterations in maternal haemodynamics. Late-gestation undernutrition (LGUN) and LGUN + G redirected maternal blood flow from the periphery to the uteroplacental unit, concomitantly increasing the delivery of glucose and oxygen to the uteroplacental unit. Substrate transporter expression and uteroplacental oxygen consumption were preserved in LGUN and LGUN + G, suggesting prioritization of the placenta. This study is the first to report detailed maternal haemodynamics in the setting of maternal undernutrition, where placental growth and function were maintained, ultimately preserving fetal oxygen metabolism and growth.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645035","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":"Terrar Opinion supplement.","authors":"Derek A Terrar","doi":"10.1113/JP287947","DOIUrl":"https://doi.org/10.1113/JP287947","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645040","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":"Motor unit discharge rates and acute intermittent hypoxia: the other half of the force equation.","authors":"Quinn McCallion, Madelyn Weidner, Sri Vyshnavi Gayathri Punukollu, Heather Adams","doi":"10.1113/JP287570","DOIUrl":"https://doi.org/10.1113/JP287570","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645037","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":"Orbitofrontal control of the olfactory cortex regulates olfactory discrimination learning.","authors":"Ding Wang, Ying Zhang, Shan Li, Penglai Liu, Xiang Li, Zhiqiu Liu, Anan Li, Dejuan Wang","doi":"10.1113/JP286606","DOIUrl":"https://doi.org/10.1113/JP286606","url":null,"abstract":"<p><p>Serving as an integral node for cognitive processing and value-based decision-making, the orbitofrontal cortex (OFC) plays a multifaceted role in associative learning and reward-driven behaviours through its widespread synaptic integration with both subcortical structures and sensory cortices. Despite the OFC's robust innervation of the olfactory cortex, the functional implications and underlying mechanisms of this top-down influence remain largely unexplored. In this study, we demonstrated that the OFC formed both direct excitatory and indirect inhibitory synaptic connections with pyramidal neurons in the anterior piriform cortex (aPC). OFC projection predominantly regulated spontaneous and odour-evoked excitatory activity in the aPC of awake mice. Importantly, suppression of this OFC-aPC projection disrupted olfactory discrimination learning, potentially due to a consequent decrease in the excitability of aPC principal output neurons following inhibition of this projection. Whole-cell recordings revealed that olfactory learning increased the intrinsic excitability of aPC neurons while concurrently decreasing OFC input to these neurons. These findings underscore the pivotal influence of orbitofrontal modulation over the olfactory cortex in the context of olfactory learning and provide insight into the associated neurophysiological mechanisms. KEY POINTS: The orbitofrontal cortex (OFC) densely innervates the anterior piriform cortex (aPC) through direct excitatory synaptic connections. The OFC regulates both spontaneous and odour-evoked excitatory activities in the aPC of awake mice. Inhibition of OFC projections disrupts olfactory discrimination learning, probably due to reduced excitability of aPC main output neurons. Following olfactory learning, the intrinsic excitability of aPC neurons increases while the OFC-aPC input decreases, highlighting the importance of adaptable OFC input for olfactory learning. These results provide new perspectives on how the OFC's top-down control modulates sensory integration and associative learning.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645038","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}