The intricate link between brain functional connectivity (FC) and structural connectivity (SC) is explored through models performing diffusion on SC to derive FC, using varied methodologies from single to multiple graph diffusion kernels. However, existing studies have not correlated diffusion scales with specific brain regions of interest (RoIs), limiting the applicability of graph diffusion. We propose a novel approach using graph heat diffusion wavelets to learn the appropriate diffusion scale for each RoI to accurately estimate the SC-FC mapping. Using the open HCP dataset, we achieve an average Pearson's correlation value of 0.833, surpassing the state-of-the-art methods for prediction of FC. It is important to note that the proposed architecture is entirely linear, computationally efficient, and notably demonstrates the power-law distribution of diffusion scales. Our results show that the bilateral frontal pole, by virtue of it having large diffusion scale, forms a large community structure. The finding is in line with the current literature on the role of the frontal pole in resting-state networks. Overall, the results underscore the potential of graph diffusion wavelet framework for understanding how the brain structure leads to functional connectivity.
大脑功能连通性（FC）和结构连通性（SC）之间存在着错综复杂的联系，通过对结构连通性（SC）进行扩散以推导出功能连通性（FC）的模型，采用了从单图扩散核到多图扩散核的各种方法。然而，现有研究并未将扩散尺度与特定的大脑感兴趣区（RoIs）相关联，从而限制了图扩散的适用性。我们提出了一种新方法，利用图热扩散小波来学习每个感兴趣区的适当扩散尺度，从而准确估计 SC-FC 映射。利用开放的 HCP 数据集，我们实现了 0.833 的平均皮尔逊相关值，超越了预测 FC 的最先进方法。值得注意的是，所提出的架构完全是线性的，计算效率高，并显著显示了扩散尺度的幂律分布。我们的研究结果表明，由于双侧额极具有较大的扩散尺度，因此形成了一个较大的群落结构。这一发现与目前有关额极在静息态网络中的作用的文献一致。总之，研究结果强调了图扩散小波框架在理解大脑结构如何导致功能连接方面的潜力。
{"title":"Diffusion Wavelets on Connectome: Localizing the Sources of Diffusion Mediating Structure-Function Mapping Using Graph Diffusion Wavelets","authors":"Chirag Shantilal Jain, Sravanthi Upadrasta Naga Sita, Avinash Sharma, Surampudi Bapi Raju","doi":"10.1101/2024.09.07.611772","DOIUrl":"https://doi.org/10.1101/2024.09.07.611772","url":null,"abstract":"The intricate link between brain functional connectivity (FC) and structural connectivity (SC) is explored through models performing diffusion on SC to derive FC, using varied methodologies from single to multiple graph diffusion kernels. However, existing studies have not correlated diffusion scales with specific brain regions of interest (RoIs), limiting the applicability of graph diffusion. We propose a novel approach using graph heat diffusion wavelets to learn the appropriate diffusion scale for each RoI to accurately estimate the SC-FC mapping. Using the open HCP dataset, we achieve an average Pearson's correlation value of 0.833, surpassing the state-of-the-art methods for prediction of FC. It is important to note that the proposed architecture is entirely linear, computationally efficient, and notably demonstrates the power-law distribution of diffusion scales. Our results show that the bilateral frontal pole, by virtue of it having large diffusion scale, forms a large community structure. The finding is in line with the current literature on the role of the frontal pole in resting-state networks. Overall, the results underscore the potential of graph diffusion wavelet framework for understanding how the brain structure leads to functional connectivity.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.04.23.590862
Malin Ramne, Jon Sensinger
Pain perception is influenced not only by sensory input from afferent neurons but also by cognitive factors such as prior expectations. It has been suggested that overly precise priors may be a key contributing factor to chronic pain states such as neuropathic pain. However, it remains an open question how overly precise priors in favor of pain might arise. Here, we first verify that a Bayesian approach can describe how statistical integration of prior expectations and sensory input results in pain phenomena such as placebo hypoalgesia, nocebo hyperalgesia, chronic pain, and spontaneous neuropathic pain. Our results indicate that the value of the prior, which is determined by the internal model parameters, may be a key contributor to these phenomena. Next, we apply a hierarchical Bayesian approach to update the parameters of the internal model based on the difference between the predicted and the perceived pain, to reflect that people integrate prior experiences in their future expectations. In contrast with simpler approaches, this hierarchical model structure is able to show for placebo hypoalgesia and nocebo hyperalgesia how these phenomena can arise from prior experiences in the form of a classical conditioning procedure. We also demonstrate the phenomenon of offset analgesia, in which a disproportionally large pain decrease is obtained following a minor reduction in noxious stimulus intensity. Finally, we turn to simulations of neuropathic pain, where our hierarchical model corroborates that persistent non-neuropathic pain is a risk factor for developing neuropathic pain following denervation, and additionally offers an interesting prediction that complete absence of informative painful experiences could be a similar risk factor. Taken together, these results provide insight to how prior experiences may contribute to pain perception, in both experimental and neuropathic pain, which in turn might be informative for improving strategies of pain prevention and relief.
{"title":"A Computational Framework for Understanding the Impact of Prior Experiences on Pain Perception and Neuropathic Pain","authors":"Malin Ramne, Jon Sensinger","doi":"10.1101/2024.04.23.590862","DOIUrl":"https://doi.org/10.1101/2024.04.23.590862","url":null,"abstract":"Pain perception is influenced not only by sensory input from afferent neurons but also by cognitive factors such as prior expectations. It has been suggested that overly precise priors may be a key contributing factor to chronic pain states such as neuropathic pain. However, it remains an open question how overly precise priors in favor of pain might arise. Here, we first verify that a Bayesian approach can describe how statistical integration of prior expectations and sensory input results in pain phenomena such as placebo hypoalgesia, nocebo hyperalgesia, chronic pain, and spontaneous neuropathic pain. Our results indicate that the value of the prior, which is determined by the internal model parameters, may be a key contributor to these phenomena. Next, we apply a hierarchical Bayesian approach to update the parameters of the internal model based on the difference between the predicted and the perceived pain, to reflect that people integrate prior experiences in their future expectations. In contrast with simpler approaches, this hierarchical model structure is able to show for placebo hypoalgesia and nocebo hyperalgesia how these phenomena can arise from prior experiences in the form of a classical conditioning procedure. We also demonstrate the phenomenon of offset analgesia, in which a disproportionally large pain decrease is obtained following a minor reduction in noxious stimulus intensity. Finally, we turn to simulations of neuropathic pain, where our hierarchical model corroborates that persistent non-neuropathic pain is a risk factor for developing neuropathic pain following denervation, and additionally offers an interesting prediction that complete absence of informative painful experiences could be a similar risk factor. Taken together, these results provide insight to how prior experiences may contribute to pain perception, in both experimental and neuropathic pain, which in turn might be informative for improving strategies of pain prevention and relief.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.12.612710
Melise M. Edwards, Ha K. Nguyen, Andrew D. Dodson, Adam J. Herbertson, Mackenzie K. Honeycutt, Jared D. Slattery, June R. Rambousek, Edison Tsui, Tami Wolden-Hanson, Tomasz A. Wietecha, James L. Graham, Geronimo P. Tapia, Carl L. Sikkema, Kevin D. O'Brien, Thomas O. Mundinger, Elaine R. Peskind, Vitaly Ryu, Peter J. Havel, Arshad M. Khan, Gerald J. Tabosky, James Ernest Blevins
Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by −7.2 ± 9.6 g and −14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.
最近的研究表明，中枢注射催产素（OT）可通过减少能量摄入和增加能量消耗（EE）来降低高脂饮食诱发肥胖（DIO）啮齿动物的体重（BW）。我们实验室以前的研究表明，在第四脑室（4V；后脑）注射 OT 会导致 DIO 大鼠体重下降并刺激肩胛间棕色脂肪组织温度（TIBAT）。我们假设，OT 引起的交感神经系统（SNS）对 IBAT 的激活刺激有助于其激活 DIO 大鼠的棕色脂肪组织并降低体重。为了验证这一点，我们确定了中断交感神经系统对 IBAT 的激活对 OT 引起的 TIBAT 刺激和 DIO 大鼠体重下降的影响。我们首先确认了对 IBAT 的双侧 SNS 神经支配手术是成功的，因为 DIO 大鼠 IBAT 去甲肾上腺素（NE）含量降低了≥ 60%。去神经支配后 1 周、6 周和 7 周，IBAT 中的 NE 含量分别选择性地减少了 94.7 ± 2.7%、96.8 ± 1.8% 和 85.9 ± 6.1%（P<0.05），而肝脏或腹股沟白色脂肪组织中的 NE 含量则没有变化。然后，我们测量了双侧手术去神经传导系统 IBAT 对急性 4V OT（1、5 μg）刺激 DIO 大鼠 TIBAT 能力的影响。我们发现，高剂量 4V OT（5 μg）对假大鼠和去神经支配大鼠的 TIBAT 刺激作用相似（P=NS），而且 4V OT 刺激 TIBAT 的作用不需要 beta-3 肾上腺素能受体信号传导。随后，我们测量了双侧 IBAT 手术去神经支配对长期输注 4V OT（16 毫摩尔/天）或载体以减少 DIO 大鼠体重、脂肪和能量摄入的影响。慢性 4V OT 可使假大鼠和去神经支配大鼠的体重增加分别减少 -7.2 ± 9.6 克和 -14.1 ± 8.8 克（P<0.05 vs 车辆处理），且不同组间的效果相似（P=NS）。这些影响与脂肪和能量摄入的减少有关（P<0.05）。总之，这些研究结果支持这样一个假设，即中枢 OT 增加 BAT 产热并减少雄性 DIO 大鼠体重增加和脂肪含量并不需要 IBAT 的交感神经支配。
{"title":"Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats","authors":"Melise M. Edwards, Ha K. Nguyen, Andrew D. Dodson, Adam J. Herbertson, Mackenzie K. Honeycutt, Jared D. Slattery, June R. Rambousek, Edison Tsui, Tami Wolden-Hanson, Tomasz A. Wietecha, James L. Graham, Geronimo P. Tapia, Carl L. Sikkema, Kevin D. O'Brien, Thomas O. Mundinger, Elaine R. Peskind, Vitaly Ryu, Peter J. Havel, Arshad M. Khan, Gerald J. Tabosky, James Ernest Blevins","doi":"10.1101/2024.09.12.612710","DOIUrl":"https://doi.org/10.1101/2024.09.12.612710","url":null,"abstract":"Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by −7.2 ± 9.6 g and −14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.07.611793
Takuma Morimoto, Luna Wang, Kinjiro Amano, David H. Foster, Sérgio M. C. Nascimento
Our visual experience does not merely reflect a static view of the world but is a dynamic consequence of our actions, most notably our continuously shifting gaze. These shifts determine the spectral diet of any individual cone photoreceptor. The aim of this study was to characterize that diet and its relationship to scene adaptation. Gaze shifts were recorded from observers freely viewing scenes outdoors for five minutes. Hyperspectral images of the scenes were also recorded from the eye position of observers. As a control, gaze shifts were also recorded from observers viewing the images on a computer-controlled display in the laboratory. From the hyperspectral data, spatially local histograms of estimated excitations in long-, medium-, and short-wavelength-sensitive cones were accumulated over time at different retinal locations. A global illuminant change was then introduced to test how well local retinal adaptation discounted its effects. The results suggest that over short periods individual cones tend to experience the statistics of full scenes, with local adaptation compensating for illumination changes almost as well as global adaptation. This compensation may help to maintain our stable local perception of scene colour despite changes in scene illumination.
{"title":"Single cone photoreceptors experience global image statistics through gaze shifts","authors":"Takuma Morimoto, Luna Wang, Kinjiro Amano, David H. Foster, Sérgio M. C. Nascimento","doi":"10.1101/2024.09.07.611793","DOIUrl":"https://doi.org/10.1101/2024.09.07.611793","url":null,"abstract":"Our visual experience does not merely reflect a static view of the world but is a dynamic consequence of our actions, most notably our continuously shifting gaze. These shifts determine the spectral diet of any individual cone photoreceptor. The aim of this study was to characterize that diet and its relationship to scene adaptation. Gaze shifts were recorded from observers freely viewing scenes outdoors for five minutes. Hyperspectral images of the scenes were also recorded from the eye position of observers. As a control, gaze shifts were also recorded from observers viewing the images on a computer-controlled display in the laboratory. From the hyperspectral data, spatially local histograms of estimated excitations in long-, medium-, and short-wavelength-sensitive cones were accumulated over time at different retinal locations. A global illuminant change was then introduced to test how well local retinal adaptation discounted its effects. The results suggest that over short periods individual cones tend to experience the statistics of full scenes, with local adaptation compensating for illumination changes almost as well as global adaptation. This compensation may help to maintain our stable local perception of scene colour despite changes in scene illumination.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.10.612183
Jiajie Shao, Jana Liewald, Wagner Costa, Christiane Ruse, Jens Gruber, Mohammad Djamshedzad, Wulf Gebhardt, Alexander Gottschalk
Chemical synaptic transmission at the neuromuscular junction (NMJ) is regulated by electrical activity of the motor circuit, but may also be affected by neuromodulation. Here, we assess the role of neuropeptide signaling in the plasticity of NMJ function in Caenorhabditis elegans. We show that the CAPS (Ca2+-dependent activator protein for secretion) ortholog UNC-31, which regulates the exocytosis of dense core vesicles (DCVs), affects both pre- and post-synaptic functional properties, as well as NMJ-mediated locomotion. Despite reduced evoked acetylcholine transmission, the loss of unc-31 results in a more vigorous response to presynaptic stimulation, i.e., enhanced muscle contraction and Ca2+ transients. Based on expression profiles, we identified neuropeptides involved in both cholinergic (FLP-6, NLP-9, NLP-21 and NLP-38) and GABAergic motor neurons (FLP-15, NLP-15), that mediate normal transmission at the NMJ. In the absence of these peptides, neurons fail to upregulate their transmitter output in response to increased cAMP signaling. We also identified proprotein convertases encoded by aex-5/kpc-3 and egl-3/kpc-2 that act synergistically to generate these neuropeptides. We propose that postsynaptic homeostatic scaling, mediated by increased muscle excitability, could compensate for the reduced cholinergic transmission in mutants affected for neuropeptide signaling, thus maintaining net synaptic strength. We show that in the absence of UNC-31 muscle excitability is modulated by upregulating the expression of the muscular L-type voltage-gated Ca2+ channel EGL-19 (CaV1). Collectively, our results unveil a role for neuropeptidergic regulation in synaptic plasticity, linking changes in presynaptic transmission to compensatory changes in muscle excitability.
{"title":"Loss of neuropeptidergic regulation of cholinergic transmission induces CaV1-mediated homeostatic compensation in muscle cells","authors":"Jiajie Shao, Jana Liewald, Wagner Costa, Christiane Ruse, Jens Gruber, Mohammad Djamshedzad, Wulf Gebhardt, Alexander Gottschalk","doi":"10.1101/2024.09.10.612183","DOIUrl":"https://doi.org/10.1101/2024.09.10.612183","url":null,"abstract":"Chemical synaptic transmission at the neuromuscular junction (NMJ) is regulated by electrical activity of the motor circuit, but may also be affected by neuromodulation. Here, we assess the role of neuropeptide signaling in the plasticity of NMJ function in Caenorhabditis elegans. We show that the CAPS (Ca2+-dependent activator protein for secretion) ortholog UNC-31, which regulates the exocytosis of dense core vesicles (DCVs), affects both pre- and post-synaptic functional properties, as well as NMJ-mediated locomotion. Despite reduced evoked acetylcholine transmission, the loss of unc-31 results in a more vigorous response to presynaptic stimulation, i.e., enhanced muscle contraction and Ca2+ transients. Based on expression profiles, we identified neuropeptides involved in both cholinergic (FLP-6, NLP-9, NLP-21 and NLP-38) and GABAergic motor neurons (FLP-15, NLP-15), that mediate normal transmission at the NMJ. In the absence of these peptides, neurons fail to upregulate their transmitter output in response to increased cAMP signaling. We also identified proprotein convertases encoded by aex-5/kpc-3 and egl-3/kpc-2 that act synergistically to generate these neuropeptides. We propose that postsynaptic homeostatic scaling, mediated by increased muscle excitability, could compensate for the reduced cholinergic transmission in mutants affected for neuropeptide signaling, thus maintaining net synaptic strength. We show that in the absence of UNC-31 muscle excitability is modulated by upregulating the expression of the muscular L-type voltage-gated Ca2+ channel EGL-19 (CaV1). Collectively, our results unveil a role for neuropeptidergic regulation in synaptic plasticity, linking changes in presynaptic transmission to compensatory changes in muscle excitability.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.12.612741
Lydia J Borjon, Luana C de Assis Ferreira, Jonathan C Trinidad, Suncica Sasic, Andrea G Hohmann, W Daniel Tracey
Evolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as "Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand." The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds. The venom's low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels. We found that velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk/Bba. Drosophila Ppk/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs). However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ant's defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.
{"title":"Multiple mechanisms of action of an extremely painful venom","authors":"Lydia J Borjon, Luana C de Assis Ferreira, Jonathan C Trinidad, Suncica Sasic, Andrea G Hohmann, W Daniel Tracey","doi":"10.1101/2024.09.12.612741","DOIUrl":"https://doi.org/10.1101/2024.09.12.612741","url":null,"abstract":"Evolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as \"Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand.\" The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds. The venom's low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels. We found that velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk/Bba. Drosophila Ppk/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs). However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ant's defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.08.28.610055
Eleni Samara, Tabea Schilling, Inês M. A. Ribeiro, Juergen Haag, Maria-Bianca Leonte, Alexander Borst
Several nicotinic and muscarinic acetylcholine receptors (AChRs) are expressed in the brain of Drosophila melanogaster. However, the contribution of different AChRs to visual information processing remains poorly understood. T5 cells are the primary motion-sensing neurons in the OFF pathway and receive input from four different columnar cholinergic neurons, Tm1, Tm2, Tm4 and Tm9. We reasoned that different AChRs in T5 postsynaptic sites might contribute to direction selectivity, a central feature of motion detection. We show that the nicotinic nAChRα1, nAChRα4, nAChRα5 and nAChRα7 subunits localize on T5 dendrites. By targeting synaptic markers specifically to each cholinergic input neuron, we find a prevalence of the nAChRα5 in Tm1-, Tm2- and Tm4-to-T5 synapses and of nAChRα7 in Tm9-to-T5 synapses. Knock-down of nAChRα4, nAChRα5, nAChRα7, or mAChR-B individually in T5 cells alters the optomotor response and reduces T5 directional selectivity. Our findings indicate a differential contribution of postsynaptic receptors to input visual processing and, thus, to the computation of motion direction in T5 cells.
{"title":"Columnar cholinergic neurotransmission onto T5 cells of Drosophila","authors":"Eleni Samara, Tabea Schilling, Inês M. A. Ribeiro, Juergen Haag, Maria-Bianca Leonte, Alexander Borst","doi":"10.1101/2024.08.28.610055","DOIUrl":"https://doi.org/10.1101/2024.08.28.610055","url":null,"abstract":"Several nicotinic and muscarinic acetylcholine receptors (AChRs) are expressed in the brain of <em>Drosophila melanogaster</em>. However, the contribution of different AChRs to visual information processing remains poorly understood. T5 cells are the primary motion-sensing neurons in the OFF pathway and receive input from four different columnar cholinergic neurons, Tm1, Tm2, Tm4 and Tm9. We reasoned that different AChRs in T5 postsynaptic sites might contribute to direction selectivity, a central feature of motion detection. We show that the nicotinic nAChRα1, nAChRα4, nAChRα5 and nAChRα7 subunits localize on T5 dendrites. By targeting synaptic markers specifically to each cholinergic input neuron, we find a prevalence of the nAChRα5 in Tm1-, Tm2- and Tm4-to-T5 synapses and of nAChRα7 in Tm9-to-T5 synapses. Knock-down of nAChRα4, nAChRα5, nAChRα7, or mAChR-B individually in T5 cells alters the optomotor response and reduces T5 directional selectivity. Our findings indicate a differential contribution of postsynaptic receptors to input visual processing and, thus, to the computation of motion direction in T5 cells.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.11.612196
Lola Beerendonk, Jorge F. Mejias, Stijn A. Nuiten, Jan Willem de Gee, Jasper B Zantvoord, Johannes Jacobus Fahrenfort, Simon van Gaal
Performance typically peaks at moderate arousal levels, consistent with the Yerkes-Dodson law, as confirmed by recent human and mouse pupillometry studies. Arousal states are influenced by neuromodulators like catecholamines (noradrenaline; NA and dopamine; DA) and acetylcholine (ACh). To explore their causal roles in this law, we pharmacologically enhanced arousal while measuring human decision-making and spontaneous arousal fluctuations via pupil size. The catecholaminergic agent atomoxetine (ATX) increased overall arousal and shifted the entire arousal-performance curve, suggesting a relative arousal mechanism where performance adapts to arousal fluctuations within arousal states. In contrast, the cholinergic agent donepezil (DNP) did not affect arousal or the curve. We modeled these findings in a neurobiologically plausible computational framework, showing how catecholaminergic modulation alters a disinhibitory neural circuit that encodes sensory evidence for decision-making. This work suggests that performance adapts flexibly to arousal fluctuations, ensuring optimal performance in each and every arousal state.
{"title":"Adaptive arousal regulation: Pharmacologically shifting the peak of the Yerkes-Dodson curve by catecholaminergic enhancement of arousal","authors":"Lola Beerendonk, Jorge F. Mejias, Stijn A. Nuiten, Jan Willem de Gee, Jasper B Zantvoord, Johannes Jacobus Fahrenfort, Simon van Gaal","doi":"10.1101/2024.09.11.612196","DOIUrl":"https://doi.org/10.1101/2024.09.11.612196","url":null,"abstract":"Performance typically peaks at moderate arousal levels, consistent with the Yerkes-Dodson law, as confirmed by recent human and mouse pupillometry studies. Arousal states are influenced by neuromodulators like catecholamines (noradrenaline; NA and dopamine; DA) and acetylcholine (ACh). To explore their causal roles in this law, we pharmacologically enhanced arousal while measuring human decision-making and spontaneous arousal fluctuations via pupil size. The catecholaminergic agent atomoxetine (ATX) increased overall arousal and shifted the entire arousal-performance curve, suggesting a relative arousal mechanism where performance adapts to arousal fluctuations within arousal states. In contrast, the cholinergic agent donepezil (DNP) did not affect arousal or the curve. We modeled these findings in a neurobiologically plausible computational framework, showing how catecholaminergic modulation alters a disinhibitory neural circuit that encodes sensory evidence for decision-making. This work suggests that performance adapts flexibly to arousal fluctuations, ensuring optimal performance in each and every arousal state.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.11.612562
Krisha Aghi, Ryan Schultz, Zachary L. Newman, Philipe Mendonca, Dariya Bakshinska, Ehud Y. Isacoff
Basal synaptic strength can vary greatly between synapses formed by an individual neuron because of diverse probabilities of action potential (AP) evoked transmitter release (Pr). Optical quantal analysis on large numbers of identified Drosophila larval glutamatergic synapses shows that short-term plasticity (STP) also varies greatly between synapses made by an individual type I motor neuron (MN) onto a single body wall muscle. Synapses with high and low Pr and different forms and level of STP have a random spatial distribution in the MN nerve terminal, and ones with very different properties can be located within 200 nm of one other. While synapses start off with widely diverse basal Pr at low MN AP firing frequency and change Pr differentially when MN firing frequency increases, the overall distribution of Pr remains remarkably constant due to a balance between the numbers of synapses that facilitate and depress as well as their degree of change and basal synaptic weights. This constancy in transmitter release can ensure robustness across changing behavioral conditions.
{"title":"Synapse-to-synapse plasticity variability balanced to generate input-wide constancy of transmitter release","authors":"Krisha Aghi, Ryan Schultz, Zachary L. Newman, Philipe Mendonca, Dariya Bakshinska, Ehud Y. Isacoff","doi":"10.1101/2024.09.11.612562","DOIUrl":"https://doi.org/10.1101/2024.09.11.612562","url":null,"abstract":"Basal synaptic strength can vary greatly between synapses formed by an individual neuron because of diverse probabilities of action potential (AP) evoked transmitter release (Pr). Optical quantal analysis on large numbers of identified Drosophila larval glutamatergic synapses shows that short-term plasticity (STP) also varies greatly between synapses made by an individual type I motor neuron (MN) onto a single body wall muscle. Synapses with high and low Pr and different forms and level of STP have a random spatial distribution in the MN nerve terminal, and ones with very different properties can be located within 200 nm of one other. While synapses start off with widely diverse basal Pr at low MN AP firing frequency and change Pr differentially when MN firing frequency increases, the overall distribution of Pr remains remarkably constant due to a balance between the numbers of synapses that facilitate and depress as well as their degree of change and basal synaptic weights. This constancy in transmitter release can ensure robustness across changing behavioral conditions.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.06.611764
Niels Meijns, Max Blokker, Sander Idema, Bert A t' Hart, Mitko Veta, Loes Ettema, Juliet van Iersel, Zhiqing Zhang, Geert Schenk, Marloes Groot, Antonio Luchicchi
Myelin pathology is known to play a central role in disorders such as multiple sclerosis (MS) among others. Despite this, the pathological mechanisms underlying these conditions are often difficult to unravel. Conventional techniques like immunohistochemistry or dye-based approaches, do not provide a temporal characterization of the pathophysiological aberrations responsible for myelin changes in human specimens. Here, to circumvent this curb, we present a label-free, live-cell imaging approach of myelin using recent advancements in nonlinear harmonic generation microscopy applied to physiologically viable human brain tissue from post-mortem donors. Gray and white matter brain tissue from epilepsy surgery and post-mortem donors was excised. To sustain viability of the specimens for several hours, they were subjected to either acute or organotypic slice culture protocols in artificial cerebral spinal fluid. Imaging was performed using a femtosecond pulsed 1060 nm laser to generate second harmonic generation (SHG) and third harmonic generation (THG) signals directly from myelin and axon-like structures without the need to add any labels. Experiments on acute human brain slices and post-mortem human slice cultures reveal that myelin, along with lipid bodies, are the prime sources of THG signal. We show that tissue viability is maintained over extended periods during THG microscopy, and that prolonged THG imaging is able to detect experimentally induced subtle alterations in myelin morphology. Finally, we provide practical evidence that live-cell imaging of myelin with THG microscopy is a sensitive tool to investigate subtle changes in white matter of neurological donors. Overall, our findings support that nonlinear live-cell imaging is a suitable setup for researching myelin morphology in neurological conditions like MS.
{"title":"Dynamic imaging of myelin pathology in physiologically preserved human brain tissue using third harmonic generation microscopy","authors":"Niels Meijns, Max Blokker, Sander Idema, Bert A t' Hart, Mitko Veta, Loes Ettema, Juliet van Iersel, Zhiqing Zhang, Geert Schenk, Marloes Groot, Antonio Luchicchi","doi":"10.1101/2024.09.06.611764","DOIUrl":"https://doi.org/10.1101/2024.09.06.611764","url":null,"abstract":"Myelin pathology is known to play a central role in disorders such as multiple sclerosis (MS) among others. Despite this, the pathological mechanisms underlying these conditions are often difficult to unravel. Conventional techniques like immunohistochemistry or dye-based approaches, do not provide a temporal characterization of the pathophysiological aberrations responsible for myelin changes in human specimens. Here, to circumvent this curb, we present a label-free, live-cell imaging approach of myelin using recent advancements in nonlinear harmonic generation microscopy applied to physiologically viable human brain tissue from post-mortem donors. Gray and white matter brain tissue from epilepsy surgery and post-mortem donors was excised. To sustain viability of the specimens for several hours, they were subjected to either acute or organotypic slice culture protocols in artificial cerebral spinal fluid. Imaging was performed using a femtosecond pulsed 1060 nm laser to generate second harmonic generation (SHG) and third harmonic generation (THG) signals directly from myelin and axon-like structures without the need to add any labels. Experiments on acute human brain slices and post-mortem human slice cultures reveal that myelin, along with lipid bodies, are the prime sources of THG signal. We show that tissue viability is maintained over extended periods during THG microscopy, and that prolonged THG imaging is able to detect experimentally induced subtle alterations in myelin morphology. Finally, we provide practical evidence that live-cell imaging of myelin with THG microscopy is a sensitive tool to investigate subtle changes in white matter of neurological donors. Overall, our findings support that nonlinear live-cell imaging is a suitable setup for researching myelin morphology in neurological conditions like MS.","PeriodicalId":501581,"journal":{"name":"bioRxiv - Neuroscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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