Pub Date : 2024-08-28Print Date: 2024-08-01DOI: 10.1523/ENEURO.0332-24.2024
Ashley N Plumb, Joseph B Lesnak, Louis J Kolling, Catherine A Marcinkiewcz, Kathleen A Sluka
Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ERs), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signaling alters GABA receptor and transporter expression, we examined if removal of testosterone in males would decrease mRNA expression of GABA receptor subunits and vesicular GABA transporter (VGAT). However, there were no differences in mRNA expression of GABA receptor subunits of VGAT between gonadectomized and sham control males. Lastly, we used RNAscope to determine expression of ER-α in the RVM and show expression in inhibitory (VGAT+), serotonergic (tryptophan hydroxylase 2+), and μ-opioid receptor expressing (MOR+) cells. In conclusion, testosterone protects males from development of widespread hyperalgesia through aromatization to estradiol and activation of ER-α which is widely expressed in multiple cell types in the RVM.
{"title":"Local Synthesis of Estradiol in the Rostral Ventromedial Medulla Protects against Widespread Muscle Pain in Male Mice.","authors":"Ashley N Plumb, Joseph B Lesnak, Louis J Kolling, Catherine A Marcinkiewcz, Kathleen A Sluka","doi":"10.1523/ENEURO.0332-24.2024","DOIUrl":"10.1523/ENEURO.0332-24.2024","url":null,"abstract":"<p><p>Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ERs), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signaling alters GABA receptor and transporter expression, we examined if removal of testosterone in males would decrease mRNA expression of GABA receptor subunits and vesicular GABA transporter (VGAT). However, there were no differences in mRNA expression of GABA receptor subunits of VGAT between gonadectomized and sham control males. Lastly, we used RNAscope to determine expression of ER-α in the RVM and show expression in inhibitory (VGAT+), serotonergic (tryptophan hydroxylase 2+), and μ-opioid receptor expressing (MOR+) cells. In conclusion, testosterone protects males from development of widespread hyperalgesia through aromatization to estradiol and activation of ER-α which is widely expressed in multiple cell types in the RVM.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28Print Date: 2024-08-01DOI: 10.1523/ENEURO.0454-23.2024
Xixiao Zhu, Chi Zhang, Yuxin Hu, Yifang Wang, Siqi Xiao, Yichen Zhu, Haiju Sun, Jing Sun, Chi Xu, Yunyun Xu, Yuerong Chen, Xiaofen He, Boyu Liu, Jinggen Liu, Junying Du, Yi Liang, Boyi Liu, Xiaoyu Li, Yongliang Jiang, Zui Shen, Xiaomei Shao, Jianqiao Fang
Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAGCamkIIα+ neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAGCamkIIα+ neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAGCamkIIα+ neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in alleviating these symptoms. Nevertheless, EA combined with chemogenetic activation failed to further relieve allodynia and anxiety-like behaviors. Artificial inhibition of vlPAGCamkIIα+ neurons abolished the analgesic and anxiolytic effects of EA. Overall, our study reveals a novel mechanism of neuropathic pain-induced anxiety and shows that EA may relieve comorbid chronic neuropathic pain and anxiety by activating vlPAGCamkIIα+ neurons.
慢性神经病理性疼痛和焦虑是一种常见疾病,也是一项重大的临床挑战。慢性神经病理性疼痛和焦虑的内在机制尚未完全明了,这限制了对有效治疗方法的探索。腹外侧uctal灰质(vlPAG)中的谷氨酸能神经元与疼痛的调节有关,但vlPAG在神经病理性疼痛诱发的焦虑中的潜在作用尚未得到研究。在本文中,全细胞记录和免疫荧光显示,在幸免神经损伤(SNI)的小鼠中,vlPAG中CamkIIα神经元(vlPAGCamkIIα+神经元)的兴奋性降低,而电针(EA)能激活这些神经元。我们还发现,对 vlPAGCamkIIα+ 神经元的化学抑制会导致天真小鼠出现异动症和焦虑样行为。此外,化学激活 vlPAGCamkIIα+ 神经元可减少 SNI 小鼠的焦虑样行为和异动症,而 EA 在缓解这些症状方面也有类似的效果。尽管如此,EA 与化学基因激活相结合也无法进一步缓解异动症和焦虑样行为。人工抑制 vlPAGCamkIIα+ 神经元可消除 EA 的镇痛和抗焦虑作用。总之,我们的研究揭示了神经病理性疼痛诱发焦虑的新机制,并表明 EA 可通过激活 vlPAGCamkIIα+ 神经元缓解慢性神经病理性疼痛和焦虑。腹外侧uctal灰质(vlPAG)中的谷氨酸能神经元和电针(EA)都具有镇痛作用。然而,这些干预措施在解决神经病理性疼痛及其伴随的焦虑方面的疗效还有待充分阐明。在小鼠神经损伤(SNI)模型中,我们观察到 vlPAG CamkIIα 神经元的兴奋性降低。值得注意的是,EA 治疗能显著增强这些神经元的兴奋性。此外,化学激活 vlPAGCamkIIα+ 神经元不仅能产生镇痛效果,还能减轻 SNI 小鼠的焦虑样行为,这与 EA 治疗所观察到的效果如出一辙。相反,抑制天真小鼠中 vlPAGCamkIIα+ 神经元的活性会降低疼痛阈值并诱发焦虑样行为,同时也会抵消 EA 的有益作用。这些发现为慢性神经病理性疼痛和焦虑之间的机理相互作用提供了新的见解,凸显了在这些情况下靶向 vlPAG 谷氨酸能神经元的治疗潜力。
{"title":"Modulation of Comorbid Chronic Neuropathic Pain and Anxiety-Like Behaviors by Glutamatergic Neurons in the Ventrolateral Periaqueductal Gray and the Analgesic and Anxiolytic Effects of Electroacupuncture.","authors":"Xixiao Zhu, Chi Zhang, Yuxin Hu, Yifang Wang, Siqi Xiao, Yichen Zhu, Haiju Sun, Jing Sun, Chi Xu, Yunyun Xu, Yuerong Chen, Xiaofen He, Boyu Liu, Jinggen Liu, Junying Du, Yi Liang, Boyi Liu, Xiaoyu Li, Yongliang Jiang, Zui Shen, Xiaomei Shao, Jianqiao Fang","doi":"10.1523/ENEURO.0454-23.2024","DOIUrl":"10.1523/ENEURO.0454-23.2024","url":null,"abstract":"<p><p>Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAG<sup>CamkIIα+</sup> neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAG<sup>CamkIIα+</sup> neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAG<sup>CamkIIα+</sup> neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in alleviating these symptoms. Nevertheless, EA combined with chemogenetic activation failed to further relieve allodynia and anxiety-like behaviors. Artificial inhibition of vlPAG<sup>CamkIIα+</sup> neurons abolished the analgesic and anxiolytic effects of EA. Overall, our study reveals a novel mechanism of neuropathic pain-induced anxiety and shows that EA may relieve comorbid chronic neuropathic pain and anxiety by activating vlPAG<sup>CamkIIα+</sup> neurons.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Print Date: 2024-08-01DOI: 10.1523/ENEURO.0021-23.2024
Bernard Marius 't Hart, Urooj Taqvi, Raphael Q Gastrock, Jennifer E Ruttle, Shanaathanan Modchalingam, Denise Y P Henriques
Moving effectively is essential for any animal. Thus, many different kinds of brain processes likely contribute to learning and adapting movement. How these contributions are combined is unknown. Nevertheless, the field of motor adaptation has been working under the assumption that measures of explicit and implicit motor adaptation can simply be added in total adaptation. While this has been tested, we show that these tests were insufficient. We put this additivity assumption to the test in various ways and find that measures of implicit and explicit adaptation are not additive. This means that future studies should measure both implicit and explicit adaptation directly. It also challenges us to disentangle how various motor adaptation processes do combine when producing movements and may have implications for our understanding of other kinds of learning as well (data and code: https://osf.io/3yhw5).
{"title":"Measures of Implicit and Explicit Adaptation Do Not Linearly Add.","authors":"Bernard Marius 't Hart, Urooj Taqvi, Raphael Q Gastrock, Jennifer E Ruttle, Shanaathanan Modchalingam, Denise Y P Henriques","doi":"10.1523/ENEURO.0021-23.2024","DOIUrl":"10.1523/ENEURO.0021-23.2024","url":null,"abstract":"<p><p>Moving effectively is essential for any animal. Thus, many different kinds of brain processes likely contribute to learning and adapting movement. How these contributions are combined is unknown. Nevertheless, the field of motor adaptation has been working under the assumption that measures of explicit and implicit motor adaptation can simply be added in total adaptation. While this has been tested, we show that these tests were insufficient. We put this additivity assumption to the test in various ways and find that measures of implicit and explicit adaptation are not additive. This means that future studies should measure both implicit and explicit adaptation directly. It also challenges us to disentangle how various motor adaptation processes do combine when producing movements and may have implications for our understanding of other kinds of learning as well (data and code: https://osf.io/3yhw5).</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Print Date: 2024-08-01DOI: 10.1523/ENEURO.0053-24.2024
Diana Rodrigues, Cátia Santa, Bruno Manadas, Patrícia Monteiro
The medial prefrontal cortex (mPFC) plays a pivotal role in regulating working memory, executive function, and self-regulatory behaviors. Dysfunction in the mPFC circuits is a characteristic feature of several neuropsychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder. Chronic stress (CS) is widely recognized as a major triggering factor for the onset of these disorders. Although evidence suggests synaptic dysfunction in mPFC circuits following CS exposure, it remains unclear how different neuronal populations in the infralimbic (IL) and prelimbic (PL) cortices are affected in terms of synaptic inhibition/excitation balance (I/E ratio). Here, using neuroproteomic analysis and whole-cell patch-clamp recordings in pyramidal neurons (PNs) and parvalbumin (PV) interneurons within the PL and IL cortices, we examined the synaptic changes after 21 d of chronic unpredictable stress, in male mice. Our results reveal distinct impacts of CS on PL and IL PNs, resulting in an increased I/E ratio in both subregions but through different mechanisms: CS increases inhibitory synaptic drive in the PL while decreasing excitatory synaptic drive in the IL. Notably, the I/E ratio and excitatory and inhibitory synaptic drive of PV interneurons remained unaffected in both PL and IL circuits following CS exposure. These findings offer novel mechanistic insights into the influence of CS on mPFC circuits and support the hypothesis of stress-induced mPFC hypofunction.
{"title":"Chronic Stress Alters Synaptic Inhibition/Excitation Balance of Pyramidal Neurons But Not PV Interneurons in the Infralimbic and Prelimbic Cortices of C57BL/6J Mice.","authors":"Diana Rodrigues, Cátia Santa, Bruno Manadas, Patrícia Monteiro","doi":"10.1523/ENEURO.0053-24.2024","DOIUrl":"10.1523/ENEURO.0053-24.2024","url":null,"abstract":"<p><p>The medial prefrontal cortex (mPFC) plays a pivotal role in regulating working memory, executive function, and self-regulatory behaviors. Dysfunction in the mPFC circuits is a characteristic feature of several neuropsychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder. Chronic stress (CS) is widely recognized as a major triggering factor for the onset of these disorders. Although evidence suggests synaptic dysfunction in mPFC circuits following CS exposure, it remains unclear how different neuronal populations in the infralimbic (IL) and prelimbic (PL) cortices are affected in terms of synaptic inhibition/excitation balance (<i>I</i>/<i>E</i> ratio). Here, using neuroproteomic analysis and whole-cell patch-clamp recordings in pyramidal neurons (PNs) and parvalbumin (PV) interneurons within the PL and IL cortices, we examined the synaptic changes after 21 d of chronic unpredictable stress, in male mice. Our results reveal distinct impacts of CS on PL and IL PNs, resulting in an increased <i>I</i>/<i>E</i> ratio in both subregions but through different mechanisms: CS increases inhibitory synaptic drive in the PL while decreasing excitatory synaptic drive in the IL. Notably, the <i>I</i>/<i>E</i> ratio and excitatory and inhibitory synaptic drive of PV interneurons remained unaffected in both PL and IL circuits following CS exposure. These findings offer novel mechanistic insights into the influence of CS on mPFC circuits and support the hypothesis of stress-induced mPFC hypofunction.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Print Date: 2024-08-01DOI: 10.1523/ENEURO.0207-24.2024
Lauren S Vaughn, Jinyoung Lee
{"title":"Neuronal Injury Model Divulges Differences in Dendrite and Axonal Function and Regeneration in Adults.","authors":"Lauren S Vaughn, Jinyoung Lee","doi":"10.1523/ENEURO.0207-24.2024","DOIUrl":"10.1523/ENEURO.0207-24.2024","url":null,"abstract":"","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Print Date: 2024-08-01DOI: 10.1523/ENEURO.0135-24.2024
Joshua P Kulasingham, Hamish Innes-Brown, Martin Enqvist, Emina Alickovic
The auditory brainstem response (ABR) is a measure of subcortical activity in response to auditory stimuli. The wave V peak of the ABR depends on the stimulus intensity level, and has been widely used for clinical hearing assessment. Conventional methods estimate the ABR average electroencephalography (EEG) responses to short unnatural stimuli such as clicks. Recent work has moved toward more ecologically relevant continuous speech stimuli using linear deconvolution models called temporal response functions (TRFs). Investigating whether the TRF waveform changes with stimulus intensity is a crucial step toward the use of natural speech stimuli for hearing assessments involving subcortical responses. Here, we develop methods to estimate level-dependent subcortical TRFs using EEG data collected from 21 participants listening to continuous speech presented at 4 different intensity levels. We find that level-dependent changes can be detected in the wave V peak of the subcortical TRF for almost all participants, and are consistent with level-dependent changes in click-ABR wave V. We also investigate the most suitable peripheral auditory model to generate predictors for level-dependent subcortical TRFs and find that simple gammatone filterbanks perform the best. Additionally, around 6 min of data may be sufficient for detecting level-dependent effects and wave V peaks above the noise floor for speech segments with higher intensity. Finally, we show a proof-of-concept that level-dependent subcortical TRFs can be detected even for the inherent intensity fluctuations in natural continuous speech.
听性脑干反应(ABR)是皮层下活动对听觉刺激反应的一种测量方法。ABR 的波峰 V 值取决于刺激强度水平,已被广泛用于临床听力评估。传统的 ABR 估算方法是将脑电图(EEG)反应平均到短的非自然刺激,如咔嗒声。最近的工作已转向使用称为时序响应函数(TRF)的线性解卷积模型来估算与生态逻辑更相关的连续语音刺激。调查 TRF 波形是否随刺激强度变化是使用自然语音刺激进行听力评估(涉及皮层下反应)的关键一步。在此,我们利用从 21 位聆听以 4 种不同强度水平呈现的连续语音的参与者处收集的脑电图数据,开发了估算皮层下 TRF 随强度变化的方法。我们发现,几乎所有参与者的皮层下 TRF 的 V 波峰值都能检测到电平依赖性变化,并且与点击-ABR V 波的电平依赖性变化一致。我们还研究了最适合生成预测电平依赖性皮层下 TRF 的外周听觉模型,并发现简单的伽马通滤波器库表现最佳。此外,大约 6 分钟的数据可能足以检测出电平依赖效应,以及强度较高的语音片段中高于噪声底限的 V 波峰值。最后,我们展示了一个概念证明,即即使是自然连续语音中固有的强度波动,也能检测到与电平相关的皮层下 TRF。 意义声明 皮层下脑电图对声音的反应取决于刺激强度水平,并为早期人类听觉通路提供了一个窗口。然而,目前的方法是使用非自然的瞬时刺激(如咔嗒声或啾啾声)来检测反应。我们开发的方法可检测对连续语音刺激的水平依赖性反应,这与生态学更加相关,而且与瞬时刺激相比可能具有一些优势。重要的是,我们在个体水平上发现了对连续语音的皮层下反应与水平相关的一致模式,这种模式可直接与对点击刺激的传统反应相媲美。我们的研究为将来在临床听力评估和听力辅助技术等应用中使用皮层下对自然语音刺激的反应奠定了基础。
{"title":"Level-Dependent Subcortical Electroencephalography Responses to Continuous Speech.","authors":"Joshua P Kulasingham, Hamish Innes-Brown, Martin Enqvist, Emina Alickovic","doi":"10.1523/ENEURO.0135-24.2024","DOIUrl":"10.1523/ENEURO.0135-24.2024","url":null,"abstract":"<p><p>The auditory brainstem response (ABR) is a measure of subcortical activity in response to auditory stimuli. The wave V peak of the ABR depends on the stimulus intensity level, and has been widely used for clinical hearing assessment. Conventional methods estimate the ABR average electroencephalography (EEG) responses to short unnatural stimuli such as clicks. Recent work has moved toward more ecologically relevant continuous speech stimuli using linear deconvolution models called temporal response functions (TRFs). Investigating whether the TRF waveform changes with stimulus intensity is a crucial step toward the use of natural speech stimuli for hearing assessments involving subcortical responses. Here, we develop methods to estimate level-dependent subcortical TRFs using EEG data collected from 21 participants listening to continuous speech presented at 4 different intensity levels. We find that level-dependent changes can be detected in the wave V peak of the subcortical TRF for almost all participants, and are consistent with level-dependent changes in click-ABR wave V. We also investigate the most suitable peripheral auditory model to generate predictors for level-dependent subcortical TRFs and find that simple gammatone filterbanks perform the best. Additionally, around 6 min of data may be sufficient for detecting level-dependent effects and wave V peaks above the noise floor for speech segments with higher intensity. Finally, we show a proof-of-concept that level-dependent subcortical TRFs can be detected even for the inherent intensity fluctuations in natural continuous speech.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1523/ENEURO.0111-24.2024
Yonghong Tan, Qiong Wang, Yubing Guo, Na Zhang, Yingyi Xu, Xue Bai, Jianhua Liu, Xiaobao Bi
Pyroptosis, an inflammatory Programmed cell death, has recently been found to play an important role in spinal cord injury (SCI). C-type lectin domain family 5 member A (CLEC5A), triggering receptor expressed on myeloid cells 1 (TREM1), and NLR-family CARD-containing protein 4 (NLRC4) have been reported to be associated with neuronal pyroptosis, but few studies have clarified their functions and regulatory mechanisms in SCI. In this study, CLEC5A, TREM1, and NLRC4 were highly expressed in lidocaine-induced SCI rat models, and their knockdown alleviated lidocaine-induced SCI. The elevation of proptosis related indicators LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β levels in SCI rats was attenuated after silencing of CLEC5A, TREM1, or NLRC4. Lidocaine-induced the decrease in cell viability and the elevation in cell death were partly reversed after CLEC5A, TREM1, or NLRC4 silencing. Lidocaine-mediated effects on the levels of LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β in lidocaine-induced PC-12 cells were weakened by downregulating CLEC5A, TREM1, or NLRC4. CLEC5A could interact with TREM1 to mediate NLRC4 expression, thus accelerating neuronal pyroptosis, ultimately leading to SCI exacerbation. In conclusions, CLEC5A interacted with TREM1 to increase NLRC4 expression, thus promoting neuronal pyroptosis in rat SCI models, providing new insights into the role of neuronal pyroptosis in SCI.Significance statement Pyroptosis has been reported to be involved in SCI. Higher levels of CLEC5A, TREM1, and NLRC4 associated with neuronal pyroptosis. However, the role and regulatory mechanism of CLEC5A, TREM1, and NLRC4 in SCI were not clear. Here, high expression of CLEC5A, TREM1, and NLRC4 was observed in lidocaine-induced SCI rat models. CLEC5A could interact with TREM1 to enhance the expression of NLRC4, thus accelerating neuronal pyroptosis in rat SCI models. These findings identify CLEC5A, TREM1, and NLRC4 as potential therapeutic targets for SCI.
{"title":"CLEC5A Promotes Neuronal Pyroptosis in Rat Spinal Cord Injury Models by Interacting with TREM1 and Elevating NLRC4 Expression.","authors":"Yonghong Tan, Qiong Wang, Yubing Guo, Na Zhang, Yingyi Xu, Xue Bai, Jianhua Liu, Xiaobao Bi","doi":"10.1523/ENEURO.0111-24.2024","DOIUrl":"https://doi.org/10.1523/ENEURO.0111-24.2024","url":null,"abstract":"<p><p>Pyroptosis, an inflammatory Programmed cell death, has recently been found to play an important role in spinal cord injury (SCI). C-type lectin domain family 5 member A (CLEC5A), triggering receptor expressed on myeloid cells 1 (TREM1), and NLR-family CARD-containing protein 4 (NLRC4) have been reported to be associated with neuronal pyroptosis, but few studies have clarified their functions and regulatory mechanisms in SCI. In this study, CLEC5A, TREM1, and NLRC4 were highly expressed in lidocaine-induced SCI rat models, and their knockdown alleviated lidocaine-induced SCI. The elevation of proptosis related indicators LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β levels in SCI rats was attenuated after silencing of CLEC5A, TREM1, or NLRC4. Lidocaine-induced the decrease in cell viability and the elevation in cell death were partly reversed after CLEC5A, TREM1, or NLRC4 silencing. Lidocaine-mediated effects on the levels of LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β in lidocaine-induced PC-12 cells were weakened by downregulating CLEC5A, TREM1, or NLRC4. CLEC5A could interact with TREM1 to mediate NLRC4 expression, thus accelerating neuronal pyroptosis, ultimately leading to SCI exacerbation. In conclusions, CLEC5A interacted with TREM1 to increase NLRC4 expression, thus promoting neuronal pyroptosis in rat SCI models, providing new insights into the role of neuronal pyroptosis in SCI.<b>Significance statement</b> Pyroptosis has been reported to be involved in SCI. Higher levels of CLEC5A, TREM1, and NLRC4 associated with neuronal pyroptosis. However, the role and regulatory mechanism of CLEC5A, TREM1, and NLRC4 in SCI were not clear. Here, high expression of CLEC5A, TREM1, and NLRC4 was observed in lidocaine-induced SCI rat models. CLEC5A could interact with TREM1 to enhance the expression of NLRC4, thus accelerating neuronal pyroptosis in rat SCI models. These findings identify CLEC5A, TREM1, and NLRC4 as potential therapeutic targets for SCI.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20Print Date: 2024-08-01DOI: 10.1523/ENEURO.0507-23.2024
Paul Iverson, Jieun Song
Adults heard recordings of two spatially separated speakers reading newspaper and magazine articles. They were asked to listen to one of them and ignore the other, and EEG was recorded to assess their neural processing. Machine learning extracted neural sources that tracked the target and distractor speakers at three levels: the acoustic envelope of speech (delta- and theta-band modulations), lexical frequency for individual words, and the contextual predictability of individual words estimated by GPT-4 and earlier lexical models. To provide a broader view of speech perception, half of the subjects completed a simultaneous visual task, and the listeners included both native and non-native English speakers. Distinct neural components were extracted for these levels of auditory and lexical processing, demonstrating that native English speakers had greater target-distractor separation compared with non-native English speakers on most measures, and that lexical processing was reduced by the visual task. Moreover, there was a novel interaction of lexical predictability and frequency with auditory processing; acoustic tracking was stronger for lexically harder words, suggesting that people listened harder to the acoustics when needed for lexical selection. This demonstrates that speech perception is not simply a feedforward process from acoustic processing to the lexicon. Rather, the adaptable context-sensitive processing long known to occur at a lexical level has broader consequences for perception, coupling with the acoustic tracking of individual speakers in noise.
{"title":"Neural Tracking of Speech Acoustics in Noise Is Coupled with Lexical Predictability as Estimated by Large Language Models.","authors":"Paul Iverson, Jieun Song","doi":"10.1523/ENEURO.0507-23.2024","DOIUrl":"10.1523/ENEURO.0507-23.2024","url":null,"abstract":"<p><p>Adults heard recordings of two spatially separated speakers reading newspaper and magazine articles. They were asked to listen to one of them and ignore the other, and EEG was recorded to assess their neural processing. Machine learning extracted neural sources that tracked the target and distractor speakers at three levels: the acoustic envelope of speech (delta- and theta-band modulations), lexical frequency for individual words, and the contextual predictability of individual words estimated by GPT-4 and earlier lexical models. To provide a broader view of speech perception, half of the subjects completed a simultaneous visual task, and the listeners included both native and non-native English speakers. Distinct neural components were extracted for these levels of auditory and lexical processing, demonstrating that native English speakers had greater target-distractor separation compared with non-native English speakers on most measures, and that lexical processing was reduced by the visual task. Moreover, there was a novel interaction of lexical predictability and frequency with auditory processing; acoustic tracking was stronger for lexically harder words, suggesting that people listened harder to the acoustics when needed for lexical selection. This demonstrates that speech perception is not simply a feedforward process from acoustic processing to the lexicon. Rather, the adaptable context-sensitive processing long known to occur at a lexical level has broader consequences for perception, coupling with the acoustic tracking of individual speakers in noise.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20Print Date: 2024-08-01DOI: 10.1523/ENEURO.0122-24.2024
Haydée G García-Lázaro, Santani Teng
Reverberation, a ubiquitous feature of real-world acoustic environments, exhibits statistical regularities that human listeners leverage to self-orient, facilitate auditory perception, and understand their environment. Despite the extensive research on sound source representation in the auditory system, it remains unclear how the brain represents real-world reverberant environments. Here, we characterized the neural response to reverberation of varying realism by applying multivariate pattern analysis to electroencephalographic (EEG) brain signals. Human listeners (12 males and 8 females) heard speech samples convolved with real-world and synthetic reverberant impulse responses and judged whether the speech samples were in a "real" or "fake" environment, focusing on the reverberant background rather than the properties of speech itself. Participants distinguished real from synthetic reverberation with ∼75% accuracy; EEG decoding reveals a multistage decoding time course, with dissociable components early in the stimulus presentation and later in the perioffset stage. The early component predominantly occurred in temporal electrode clusters, while the later component was prominent in centroparietal clusters. These findings suggest distinct neural stages in perceiving natural acoustic environments, likely reflecting sensory encoding and higher-level perceptual decision-making processes. Overall, our findings provide evidence that reverberation, rather than being largely suppressed as a noise-like signal, carries relevant environmental information and gains representation along the auditory system. This understanding also offers various applications; it provides insights for including reverberation as a cue to aid navigation for blind and visually impaired people. It also helps to enhance realism perception in immersive virtual reality settings, gaming, music, and film production.
{"title":"Sensory and Perceptual Decisional Processes Underlying the Perception of Reverberant Auditory Environments.","authors":"Haydée G García-Lázaro, Santani Teng","doi":"10.1523/ENEURO.0122-24.2024","DOIUrl":"10.1523/ENEURO.0122-24.2024","url":null,"abstract":"<p><p>Reverberation, a ubiquitous feature of real-world acoustic environments, exhibits statistical regularities that human listeners leverage to self-orient, facilitate auditory perception, and understand their environment. Despite the extensive research on sound source representation in the auditory system, it remains unclear how the brain represents real-world reverberant environments. Here, we characterized the neural response to reverberation of varying realism by applying multivariate pattern analysis to electroencephalographic (EEG) brain signals. Human listeners (12 males and 8 females) heard speech samples convolved with real-world and synthetic reverberant impulse responses and judged whether the speech samples were in a \"real\" or \"fake\" environment, focusing on the reverberant background rather than the properties of speech itself. Participants distinguished real from synthetic reverberation with ∼75% accuracy; EEG decoding reveals a multistage decoding time course, with dissociable components early in the stimulus presentation and later in the perioffset stage. The early component predominantly occurred in temporal electrode clusters, while the later component was prominent in centroparietal clusters. These findings suggest distinct neural stages in perceiving natural acoustic environments, likely reflecting sensory encoding and higher-level perceptual decision-making processes. Overall, our findings provide evidence that reverberation, rather than being largely suppressed as a noise-like signal, carries relevant environmental information and gains representation along the auditory system. This understanding also offers various applications; it provides insights for including reverberation as a cue to aid navigation for blind and visually impaired people. It also helps to enhance realism perception in immersive virtual reality settings, gaming, music, and film production.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19Print Date: 2024-08-01DOI: 10.1523/ENEURO.0115-24.2024
Thomas C Watson, Sam A Booker
The integration of spatial information in the mammalian dentate gyrus (DG) is critical to navigation. Indeed, DG granule cells (DGCs) rely upon finely balanced inhibitory neurotransmission in order to respond appropriately to specific spatial inputs. This inhibition arises from a heterogeneous population of local GABAergic interneurons (INs) that activate both fast, ionotropic GABAA receptors (GABAAR) and slow, metabotropic GABAB receptors (GABABR), respectively. GABABRs in turn inhibit pre- and postsynaptic neuronal compartments via temporally long-lasting G-protein-dependent mechanisms. The relative contribution of each IN subtype to network level GABABR signal setting remains unknown. However, within the DG, the somatostatin (SSt) expressing IN subtype is considered crucial in coordinating appropriate feedback inhibition on to DGCs. Therefore, we virally delivered channelrhodopsin 2 to the DG in order to obtain control of this specific SSt IN subpopulation in male and female adult mice. Using a combination of optogenetic activation and pharmacology, we show that SSt INs strongly recruit postsynaptic GABABRs to drive greater inhibition in DGCs than GABAARs at physiological membrane potentials. Furthermore, we show that in the adult mouse DG, postsynaptic GABABR signaling is predominantly regulated by neuronal GABA uptake and less so by astrocytic mechanisms. Finally, we confirm that activation of SSt INs can also recruit presynaptic GABABRs, as has been shown in neocortical circuits. Together, these data reveal that GABABR signaling allows SSt INs to control DG activity and may constitute a key mechanism for gating spatial information flow within hippocampal circuits.
{"title":"Somatostatin Interneurons Recruit Pre- and Postsynaptic GABA<sub>B</sub> Receptors in the Adult Mouse Dentate Gyrus.","authors":"Thomas C Watson, Sam A Booker","doi":"10.1523/ENEURO.0115-24.2024","DOIUrl":"10.1523/ENEURO.0115-24.2024","url":null,"abstract":"<p><p>The integration of spatial information in the mammalian dentate gyrus (DG) is critical to navigation. Indeed, DG granule cells (DGCs) rely upon finely balanced inhibitory neurotransmission in order to respond appropriately to specific spatial inputs. This inhibition arises from a heterogeneous population of local GABAergic interneurons (INs) that activate both fast, ionotropic GABA<sub>A</sub> receptors (GABA<sub>A</sub>R) and slow, metabotropic GABA<sub>B</sub> receptors (GABA<sub>B</sub>R), respectively. GABA<sub>B</sub>Rs in turn inhibit pre- and postsynaptic neuronal compartments via temporally long-lasting G-protein-dependent mechanisms. The relative contribution of each IN subtype to network level GABA<sub>B</sub>R signal setting remains unknown. However, within the DG, the somatostatin (SSt) expressing IN subtype is considered crucial in coordinating appropriate feedback inhibition on to DGCs. Therefore, we virally delivered channelrhodopsin 2 to the DG in order to obtain control of this specific SSt IN subpopulation in male and female adult mice. Using a combination of optogenetic activation and pharmacology, we show that SSt INs strongly recruit postsynaptic GABA<sub>B</sub>Rs to drive greater inhibition in DGCs than GABA<sub>A</sub>Rs at physiological membrane potentials. Furthermore, we show that in the adult mouse DG, postsynaptic GABA<sub>B</sub>R signaling is predominantly regulated by neuronal GABA uptake and less so by astrocytic mechanisms. Finally, we confirm that activation of SSt INs can also recruit presynaptic GABA<sub>B</sub>Rs, as has been shown in neocortical circuits. Together, these data reveal that GABA<sub>B</sub>R signaling allows SSt INs to control DG activity and may constitute a key mechanism for gating spatial information flow within hippocampal circuits.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}