Pub Date : 2023-03-30eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1099598
Claudia Lodovichi, Gian Michele Ratto
Living organisms navigate through a cyclic world: activity, feeding, social interactions are all organized along the periodic succession of night and day. At the cellular level, periodic activity is controlled by the molecular machinery driving the circadian regulation of cellular homeostasis. This mechanism adapts cell function to the external environment and its crucial importance is underlined by its robustness and redundancy. The cell autonomous clock regulates cell function by the circadian modulation of mTOR, a master controller of protein synthesis. Importantly, mTOR integrates the circadian modulation with synaptic activity and extracellular signals through a complex signaling network that includes the RAS-ERK pathway. The relationship between mTOR and the circadian clock is bidirectional, since mTOR can feedback on the cellular clock to shift the cycle to maintain the alignment with the environmental conditions. The mTOR and ERK pathways are crucial determinants of synaptic plasticity and function and thus it is not surprising that alterations of the circadian clock cause defective responses to environmental challenges, as witnessed by the bi-directional relationship between brain disorders and impaired circadian regulation. In physiological conditions, the feedback between the intrinsic clock and the mTOR pathway suggests that also synaptic plasticity should undergo circadian regulation.
{"title":"Control of circadian rhythm on cortical excitability and synaptic plasticity.","authors":"Claudia Lodovichi, Gian Michele Ratto","doi":"10.3389/fncir.2023.1099598","DOIUrl":"10.3389/fncir.2023.1099598","url":null,"abstract":"<p><p>Living organisms navigate through a cyclic world: activity, feeding, social interactions are all organized along the periodic succession of night and day. At the cellular level, periodic activity is controlled by the molecular machinery driving the circadian regulation of cellular homeostasis. This mechanism adapts cell function to the external environment and its crucial importance is underlined by its robustness and redundancy. The cell autonomous clock regulates cell function by the circadian modulation of mTOR, a master controller of protein synthesis. Importantly, mTOR integrates the circadian modulation with synaptic activity and extracellular signals through a complex signaling network that includes the RAS-ERK pathway. The relationship between mTOR and the circadian clock is bidirectional, since mTOR can feedback on the cellular clock to shift the cycle to maintain the alignment with the environmental conditions. The mTOR and ERK pathways are crucial determinants of synaptic plasticity and function and thus it is not surprising that alterations of the circadian clock cause defective responses to environmental challenges, as witnessed by the bi-directional relationship between brain disorders and impaired circadian regulation. In physiological conditions, the feedback between the intrinsic clock and the mTOR pathway suggests that also synaptic plasticity should undergo circadian regulation.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10098176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713853","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 : 2023-03-24eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1113023
Ashraf Mahmud, Radu Gabriel Avramescu, Zhipeng Niu, Cecilia Flores
Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depression-like behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression.
{"title":"Awakening the dormant: Role of axonal guidance cues in stress-induced reorganization of the adult prefrontal cortex leading to depression-like behavior.","authors":"Ashraf Mahmud, Radu Gabriel Avramescu, Zhipeng Niu, Cecilia Flores","doi":"10.3389/fncir.2023.1113023","DOIUrl":"10.3389/fncir.2023.1113023","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depression-like behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9598468","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 : 2023-03-03eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1073537
Zhe Sage Chen
Predictive coding is a computational theory on describing how the brain perceives and acts, which has been widely adopted in sensory processing and motor control. Nociceptive and pain processing involves a large and distributed network of circuits. However, it is still unknown whether this distributed network is completely decentralized or requires networkwide coordination. Multiple lines of evidence from human and animal studies have suggested that the cingulate cortex and insula cortex (cingulate-insula network) are two major hubs in mediating information from sensory afferents and spinothalamic inputs, whereas subregions of cingulate and insula cortices have distinct projections and functional roles. In this mini-review, we propose an updated hierarchical predictive coding framework for pain perception and discuss its related computational, algorithmic, and implementation issues. We suggest active inference as a generalized predictive coding algorithm, and hierarchically organized traveling waves of independent neural oscillations as a plausible brain mechanism to integrate bottom-up and top-down information across distributed pain circuits.
{"title":"Hierarchical predictive coding in distributed pain circuits.","authors":"Zhe Sage Chen","doi":"10.3389/fncir.2023.1073537","DOIUrl":"10.3389/fncir.2023.1073537","url":null,"abstract":"<p><p>Predictive coding is a computational theory on describing how the brain perceives and acts, which has been widely adopted in sensory processing and motor control. Nociceptive and pain processing involves a large and distributed network of circuits. However, it is still unknown whether this distributed network is completely decentralized or requires networkwide coordination. Multiple lines of evidence from human and animal studies have suggested that the cingulate cortex and insula cortex (cingulate-insula network) are two major hubs in mediating information from sensory afferents and spinothalamic inputs, whereas subregions of cingulate and insula cortices have distinct projections and functional roles. In this mini-review, we propose an updated hierarchical predictive coding framework for pain perception and discuss its related computational, algorithmic, and implementation issues. We suggest active inference as a generalized predictive coding algorithm, and hierarchically organized traveling waves of independent neural oscillations as a plausible brain mechanism to integrate bottom-up and top-down information across distributed pain circuits.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9176278","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 : 2023-02-21eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1121049
Alicia N Vagnozzi, Matthew T Moore, Raquel López de Boer, Aambar Agarwal, Niccolò Zampieri, Lynn T Landmesser, Polyxeni Philippidou
Phrenic Motor Column (PMC) neurons are a specialized subset of motor neurons (MNs) that provide the only motor innervation to the diaphragm muscle and are therefore essential for survival. Despite their critical role, the mechanisms that control phrenic MN development and function are not well understood. Here, we show that catenin-mediated cadherin adhesive function is required for multiple aspects of phrenic MN development. Deletion of β- and γ-catenin from MN progenitors results in perinatal lethality and a severe reduction in phrenic MN bursting activity. In the absence of catenin signaling, phrenic MN topography is eroded, MN clustering is lost and phrenic axons and dendrites fail to grow appropriately. Despite the essential requirement for catenins in early phrenic MN development, they appear to be dispensable for phrenic MN maintenance, as catenin deletion from postmitotic MNs does not impact phrenic MN topography or function. Our data reveal a fundamental role for catenins in PMC development and suggest that distinct mechanisms are likely to control PMC maintenance.
{"title":"Catenin signaling controls phrenic motor neuron development and function during a narrow temporal window.","authors":"Alicia N Vagnozzi, Matthew T Moore, Raquel López de Boer, Aambar Agarwal, Niccolò Zampieri, Lynn T Landmesser, Polyxeni Philippidou","doi":"10.3389/fncir.2023.1121049","DOIUrl":"10.3389/fncir.2023.1121049","url":null,"abstract":"<p><p>Phrenic Motor Column (PMC) neurons are a specialized subset of motor neurons (MNs) that provide the only motor innervation to the diaphragm muscle and are therefore essential for survival. Despite their critical role, the mechanisms that control phrenic MN development and function are not well understood. Here, we show that catenin-mediated cadherin adhesive function is required for multiple aspects of phrenic MN development. Deletion of β- and γ-<i>catenin</i> from MN progenitors results in perinatal lethality and a severe reduction in phrenic MN bursting activity. In the absence of catenin signaling, phrenic MN topography is eroded, MN clustering is lost and phrenic axons and dendrites fail to grow appropriately. Despite the essential requirement for catenins in early phrenic MN development, they appear to be dispensable for phrenic MN maintenance, as catenin deletion from postmitotic MNs does not impact phrenic MN topography or function. Our data reveal a fundamental role for catenins in PMC development and suggest that distinct mechanisms are likely to control PMC maintenance.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705852","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}
Locomotion requires the complex involvement of the spinal and supraspinal systems. So far, the role of vestibular input in gait has been assessed mainly with respect to gait stability. The noninvasive technique of galvanic vestibular stimulation (GVS) has been reported to decrease gait variability and increase gait speed, but the extent of its effect on spatiotemporal gait parameters is not fully known. Objective: Characterize vestibular responses during gait and determine the influence of GVS on cycle duration in healthy young participants. Methods: Fifteen right-handed individuals participated in the study. Electromyography (EMG) recordings of the bilateral soleus (SOL) and tibialis anterior muscles (TA) were performed. First, to determine stimulation intensity, an accelerometer placed on the vertex recorded the amplitude of the head tilts evoked by the GVS (1-4 mA, 200 ms) to establish a motor threshold (T). Second, while participants walked on a treadmill, GVS was applied at the onset of the stance phase during the treadmill gait with an intensity of 1 and 1.5 T with the cathode behind the right (RCathode) or left ear (LCathode). EMG traces were rectified, averaged (n = 30 stimuli), and analyzed. Latency, duration, and amplitude of vestibular responses as well as the mean duration of the gait cycles were measured. Results: GVS mainly induced long-latency responses in the right SOL, right TA and left TA. Only short-latency responses were triggered in the left SOL. Responses in the right SOL, left SOL and left TA were polarity dependent, being facilitatory with RCathode and inhibitory with LCathode, whereas responses in the right TA remained facilitatory regardless of the polarity. With the RCathode configuration, the stimulated cycle was prolonged compared with the control cycle at both 1 and 1.5 T, due to prolonged left SOL and TA EMG bursts, but no change was observed in right SOL and TA. With LCathode, GVS did not modify the cycle duration. Conclusion: During gait, a brief, low-intensity GVS pulse delivered at the right stance onset induced mainly long-latency polarity-dependent responses. Furthermore, a RCathode configuration increased the duration of the stimulated gait cycle by prolonging EMG activity on the anodic side. A similar approach could be explored to influence gait symmetry in individuals with neurological impairment.
运动需要脊髓和脊髓上系统的复杂参与。迄今为止,对前庭输入在步态中作用的评估主要集中在步态稳定性方面。据报道,电刺激前庭(GVS)这一无创技术可降低步态变异性并提高步态速度,但其对步态时空参数的影响程度尚不完全清楚。研究目的描述健康年轻参与者在步态过程中的前庭反应,并确定 GVS 对周期持续时间的影响。方法15 名右撇子参加了研究。对双侧比目鱼肌(SOL)和胫骨前肌(TA)进行了肌电图(EMG)记录。首先,为了确定刺激强度,放置在顶点的加速度计记录了龙胆紫(1-4 mA,200 ms)诱发的头部倾斜幅度,以确定运动阈值(T)。其次,当参与者在跑步机上行走时,在跑步机步态的起始阶段施加强度为 1 和 1.5 T 的 GVS,阴极位于右耳(RCathode)或左耳(LCathode)后方。对 EMG 曲线进行整流、平均(n = 30 个刺激)和分析。测量前庭反应的延迟时间、持续时间和振幅以及步态周期的平均持续时间。结果显示GVS主要诱发右SOL、右TA和左TA的长时程反应。左侧 SOL 仅出现短时反应。右侧 SOL、左侧 SOL 和左侧 TA 的反应与极性有关,使用 RCathode 时为促进性,使用 LCathode 时为抑制性,而右侧 TA 的反应无论极性如何均为促进性。使用 RCathode 配置时,由于左侧 SOL 和 TA 肌电图猝发时间延长,在 1 T 和 1.5 T 条件下,刺激周期比对照周期延长,但右侧 SOL 和 TA 没有变化。使用 LCathode 时,GVS 不会改变周期持续时间。结论在步态过程中,在右侧站立开始时发出的短暂、低强度 GVS 脉冲主要诱发长周期极性依赖性反应。此外,RC 阴极配置通过延长阳极侧的肌电图活动,延长了刺激步态周期的持续时间。类似的方法也可用于影响神经系统受损患者的步态对称性。
{"title":"Effect of galvanic vestibular stimulation applied at the onset of stance on muscular activity and gait cycle duration in healthy individuals.","authors":"Faezeh Abbariki, Youstina Mikhail, Adjia Hamadjida, Jonathan Charron, Jean-Marc Mac-Thiong, Dorothy Barthélemy","doi":"10.3389/fncir.2022.1065647","DOIUrl":"10.3389/fncir.2022.1065647","url":null,"abstract":"<p><p>Locomotion requires the complex involvement of the spinal and supraspinal systems. So far, the role of vestibular input in gait has been assessed mainly with respect to gait stability. The noninvasive technique of galvanic vestibular stimulation (GVS) has been reported to decrease gait variability and increase gait speed, but the extent of its effect on spatiotemporal gait parameters is not fully known. <b>Objective:</b> Characterize vestibular responses during gait and determine the influence of GVS on cycle duration in healthy young participants. <b>Methods:</b> Fifteen right-handed individuals participated in the study. Electromyography (EMG) recordings of the bilateral soleus (SOL) and tibialis anterior muscles (TA) were performed. First, to determine stimulation intensity, an accelerometer placed on the vertex recorded the amplitude of the head tilts evoked by the GVS (1-4 mA, 200 ms) to establish a motor threshold (T). Second, while participants walked on a treadmill, GVS was applied at the onset of the stance phase during the treadmill gait with an intensity of 1 and 1.5 T with the cathode behind the right (RCathode) or left ear (LCathode). EMG traces were rectified, averaged (<i>n</i> = 30 stimuli), and analyzed. Latency, duration, and amplitude of vestibular responses as well as the mean duration of the gait cycles were measured. <b>Results:</b> GVS mainly induced long-latency responses in the right SOL, right TA and left TA. Only short-latency responses were triggered in the left SOL. Responses in the right SOL, left SOL and left TA were polarity dependent, being facilitatory with RCathode and inhibitory with LCathode, whereas responses in the right TA remained facilitatory regardless of the polarity. With the RCathode configuration, the stimulated cycle was prolonged compared with the control cycle at both 1 and 1.5 T, due to prolonged left SOL and TA EMG bursts, but no change was observed in right SOL and TA. With LCathode, GVS did not modify the cycle duration. <b>Conclusion:</b> During gait, a brief, low-intensity GVS pulse delivered at the right stance onset induced mainly long-latency polarity-dependent responses. Furthermore, a RCathode configuration increased the duration of the stimulated gait cycle by prolonging EMG activity on the anodic side. A similar approach could be explored to influence gait symmetry in individuals with neurological impairment.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9356978","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 : 2023-02-03eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1076761
Zhenyang Sun, David Crompton, Milad Lankarany, Frances K Skinner
Conductance-based models have played an important role in the development of modern neuroscience. These mathematical models are powerful "tools" that enable theoretical explorations in experimentally untenable situations, and can lead to the development of novel hypotheses and predictions. With advances in cell imaging and computational power, multi-compartment models with morphological accuracy are becoming common practice. However, as more biological details are added, they make extensive explorations and analyses more challenging largely due to their huge computational expense. Here, we focus on oriens-lacunosum/moleculare (OLM) cell models. OLM cells can contribute to functionally relevant theta rhythms in the hippocampus by virtue of their ability to express spiking resonance at theta frequencies, but what characteristics underlie this is far from clear. We converted a previously developed detailed multi-compartment OLM cell model into a reduced single compartment model that retained biophysical fidelity with its underlying ion currents. We showed that the reduced OLM cell model can capture complex output that includes spiking resonance in in vivo-like scenarios as previously obtained with the multi-compartment model. Using the reduced model, we were able to greatly expand our in vivo-like scenarios. Applying spike-triggered average analyses, we were able to to determine that it is a combination of hyperpolarization-activated cation and muscarinic type potassium currents that specifically allow OLM cells to exhibit spiking resonance at theta frequencies. Further, we developed a robust Kalman Filtering (KF) method to estimate parameters of the reduced model in real-time. We showed that it may be possible to directly estimate conductance parameters from experiments since this KF method can reliably extract parameter values from model voltage recordings. Overall, our work showcases how the contribution of cellular biophysical current details could be determined and assessed for spiking resonance. As well, our work shows that it may be possible to directly extract these parameters from current clamp voltage recordings.
{"title":"Reduced oriens-lacunosum/moleculare cell model identifies biophysical current balances for <i>in vivo</i> theta frequency spiking resonance.","authors":"Zhenyang Sun, David Crompton, Milad Lankarany, Frances K Skinner","doi":"10.3389/fncir.2023.1076761","DOIUrl":"10.3389/fncir.2023.1076761","url":null,"abstract":"<p><p>Conductance-based models have played an important role in the development of modern neuroscience. These mathematical models are powerful \"tools\" that enable theoretical explorations in experimentally untenable situations, and can lead to the development of novel hypotheses and predictions. With advances in cell imaging and computational power, multi-compartment models with morphological accuracy are becoming common practice. However, as more biological details are added, they make extensive explorations and analyses more challenging largely due to their huge computational expense. Here, we focus on oriens-lacunosum/moleculare (OLM) cell models. OLM cells can contribute to functionally relevant theta rhythms in the hippocampus by virtue of their ability to express spiking resonance at theta frequencies, but what characteristics underlie this is far from clear. We converted a previously developed detailed multi-compartment OLM cell model into a reduced single compartment model that retained biophysical fidelity with its underlying ion currents. We showed that the reduced OLM cell model can capture complex output that includes spiking resonance in <i>in vivo</i>-like scenarios as previously obtained with the multi-compartment model. Using the reduced model, we were able to greatly expand our <i>in vivo</i>-like scenarios. Applying spike-triggered average analyses, we were able to to determine that it is a combination of hyperpolarization-activated cation and muscarinic type potassium currents that specifically allow OLM cells to exhibit spiking resonance at theta frequencies. Further, we developed a robust Kalman Filtering (KF) method to estimate parameters of the reduced model in real-time. We showed that it may be possible to directly estimate conductance parameters from experiments since this KF method can reliably extract parameter values from model voltage recordings. Overall, our work showcases how the contribution of cellular biophysical current details could be determined and assessed for spiking resonance. As well, our work shows that it may be possible to directly extract these parameters from current clamp voltage recordings.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10828165","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 : 2023-02-02eCollection Date: 2023-01-01DOI: 10.3389/fncir.2023.1086053
Carina Soares-Cunha, Jasper A Heinsbroek
The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors. Significance: Research in the last decade has revealed a complex cell- and circuit-specific role for the VP in reward processing and the regulation of motivated behaviors. Novel insights obtained using cell- and circuit-specific interrogation strategies have led to a major shift in our understanding of this region. Here, we provide a comprehensive review of the VP in which we integrate novel findings with the existing literature and highlight the emerging role of the VP as a linchpin of the neural systems that regulate motivation, reward, and aversion. In addition, we discuss the dysfunction of the VP in animal models of neuropsychiatric disorders.
{"title":"Ventral pallidal regulation of motivated behaviors and reinforcement.","authors":"Carina Soares-Cunha, Jasper A Heinsbroek","doi":"10.3389/fncir.2023.1086053","DOIUrl":"10.3389/fncir.2023.1086053","url":null,"abstract":"<p><p>The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors. <b>Significance:</b> Research in the last decade has revealed a complex cell- and circuit-specific role for the VP in reward processing and the regulation of motivated behaviors. Novel insights obtained using cell- and circuit-specific interrogation strategies have led to a major shift in our understanding of this region. Here, we provide a comprehensive review of the VP in which we integrate novel findings with the existing literature and highlight the emerging role of the VP as a linchpin of the neural systems that regulate motivation, reward, and aversion. In addition, we discuss the dysfunction of the VP in animal models of neuropsychiatric disorders.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2023-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10819262","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 : 2023-01-06eCollection Date: 2022-01-01DOI: 10.3389/fncir.2022.1102051
Stefano Zucca, Adam C Puche, Serena Bovetti
{"title":"Editorial: The neural circuitry of mating behaviors.","authors":"Stefano Zucca, Adam C Puche, Serena Bovetti","doi":"10.3389/fncir.2022.1102051","DOIUrl":"10.3389/fncir.2022.1102051","url":null,"abstract":"","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579520","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}
Severe hypoxia induces seizures, which reduces ventilation and worsens the ictal state. It is a health threat to patients, particularly those with underlying hypoxic respiratory pathologies, which may be conducive to a sudden unexpected death in epilepsy (SUDEP). Recent studies provide evidence that brain microglia are involved with both respiratory and ictal processes. Here, we investigated the hypothesis that microglia could interact with hypoxia-induced seizures. To this end, we recorded electroencephalogram (EEG) and acute ventilatory responses to hypoxia (5% O2 in N2) in conscious, spontaneously breathing adult mice. We compared control vehicle pre-treated animals with those pre-treated with minocycline, an inhibitory modulator of microglial activation. First, we histologically confirmed that hypoxia activates microglia and that pre-treatment with minocycline blocks hypoxia-induced microglial activation. Then, we analyzed the effects of minocycline pre-treatment on ventilatory responses to hypoxia by plethysmography. Minocycline alone failed to affect respiratory variables in room air or the initial respiratory augmentation in hypoxia. The comparative results showed that hypoxia caused seizures, which were accompanied by the late phase ventilatory suppression in all but one minocycline pre-treated mouse. Compared to the vehicle pre-treated, the minocycline pre-treated mice showed a delayed occurrence of seizures. Further, minocycline pre-treated mice tended to resist post-ictal respiratory arrest. These results suggest that microglia are conducive to seizure activity in severe hypoxia. Thus, inhibition of microglial activation may help suppress or prevent hypoxia-induced ictal episodes.
{"title":"Minocycline prevents hypoxia-induced seizures.","authors":"Isato Fukushi, Keiko Ikeda, Kotaro Takeda, Masashi Yoshizawa, Yosuke Kono, Yohei Hasebe, Mieczyslaw Pokorski, Yasumasa Okada","doi":"10.3389/fncir.2023.1006424","DOIUrl":"https://doi.org/10.3389/fncir.2023.1006424","url":null,"abstract":"<p><p>Severe hypoxia induces seizures, which reduces ventilation and worsens the ictal state. It is a health threat to patients, particularly those with underlying hypoxic respiratory pathologies, which may be conducive to a sudden unexpected death in epilepsy (SUDEP). Recent studies provide evidence that brain microglia are involved with both respiratory and ictal processes. Here, we investigated the hypothesis that microglia could interact with hypoxia-induced seizures. To this end, we recorded electroencephalogram (EEG) and acute ventilatory responses to hypoxia (5% O<sub>2</sub> in N<sub>2</sub>) in conscious, spontaneously breathing adult mice. We compared control vehicle pre-treated animals with those pre-treated with minocycline, an inhibitory modulator of microglial activation. First, we histologically confirmed that hypoxia activates microglia and that pre-treatment with minocycline blocks hypoxia-induced microglial activation. Then, we analyzed the effects of minocycline pre-treatment on ventilatory responses to hypoxia by plethysmography. Minocycline alone failed to affect respiratory variables in room air or the initial respiratory augmentation in hypoxia. The comparative results showed that hypoxia caused seizures, which were accompanied by the late phase ventilatory suppression in all but one minocycline pre-treated mouse. Compared to the vehicle pre-treated, the minocycline pre-treated mice showed a delayed occurrence of seizures. Further, minocycline pre-treated mice tended to resist post-ictal respiratory arrest. These results suggest that microglia are conducive to seizure activity in severe hypoxia. Thus, inhibition of microglial activation may help suppress or prevent hypoxia-induced ictal episodes.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9272835","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 : 2023-01-01DOI: 10.3389/fncir.2023.1235181
Camila Chacon, Chioma V Nwachukwu, Narjes Shahsavani, Kristine C Cowley, Jeremy W Chopek
Although sympathetic autonomic systems are activated in parallel with locomotion, the neural mechanisms mediating this coordination are incompletely understood. Sympathetic preganglionic neurons (SPNs), primarily located in the intermediate laminae of thoracic and upper lumbar segments (T1-L2), increase activation of tissues and organs that provide homeostatic and metabolic support during movement and exercise. Recent evidence suggests integration between locomotor and autonomic nuclei occurs within the brainstem, initiating both descending locomotor and sympathetic activation commands. However, both locomotor and sympathetic autonomic spinal systems can be activated independent of supraspinal input, in part due to a distributed network involving propriospinal neurons. Whether an intraspinal mechanism exists to coordinate activation of these systems is unknown. We hypothesized that ascending spinal neurons located in the lumbar region provide synaptic input to thoracic SPNs. Here, we demonstrate that synaptic contacts from locomotor-related V3 interneurons (INs) are present in all thoracic laminae. Injection of an anterograde tracer into lumbar segments demonstrated that 8-20% of glutamatergic input onto SPNs originated from lumbar V3 INs and displayed a somatotopographical organization of synaptic input. Whole cell patch clamp recording in SPNs demonstrated prolonged depolarizations or action potentials in response to optical activation of either lumbar V3 INs in spinal cord preparations or in response to optical activation of V3 terminals in thoracic slice preparations. This work demonstrates a direct intraspinal connection between lumbar locomotor and thoracic sympathetic networks and suggests communication between motor and autonomic systems may be a general function of the spinal cord.
{"title":"Lumbar V3 interneurons provide direct excitatory synaptic input onto thoracic sympathetic preganglionic neurons, linking locomotor, and autonomic spinal systems.","authors":"Camila Chacon, Chioma V Nwachukwu, Narjes Shahsavani, Kristine C Cowley, Jeremy W Chopek","doi":"10.3389/fncir.2023.1235181","DOIUrl":"https://doi.org/10.3389/fncir.2023.1235181","url":null,"abstract":"<p><p>Although sympathetic autonomic systems are activated in parallel with locomotion, the neural mechanisms mediating this coordination are incompletely understood. Sympathetic preganglionic neurons (SPNs), primarily located in the intermediate laminae of thoracic and upper lumbar segments (T1-L2), increase activation of tissues and organs that provide homeostatic and metabolic support during movement and exercise. Recent evidence suggests integration between locomotor and autonomic nuclei occurs within the brainstem, initiating both descending locomotor and sympathetic activation commands. However, both locomotor and sympathetic autonomic spinal systems can be activated independent of supraspinal input, in part due to a distributed network involving propriospinal neurons. Whether an intraspinal mechanism exists to coordinate activation of these systems is unknown. We hypothesized that ascending spinal neurons located in the lumbar region provide synaptic input to thoracic SPNs. Here, we demonstrate that synaptic contacts from locomotor-related V3 interneurons (INs) are present in all thoracic laminae. Injection of an anterograde tracer into lumbar segments demonstrated that 8-20% of glutamatergic input onto SPNs originated from lumbar V3 INs and displayed a somatotopographical organization of synaptic input. Whole cell patch clamp recording in SPNs demonstrated prolonged depolarizations or action potentials in response to optical activation of either lumbar V3 INs in spinal cord preparations or in response to optical activation of V3 terminals in thoracic slice preparations. This work demonstrates a direct intraspinal connection between lumbar locomotor and thoracic sympathetic networks and suggests communication between motor and autonomic systems may be a general function of the spinal cord.</p>","PeriodicalId":12498,"journal":{"name":"Frontiers in Neural Circuits","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10493276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10244475","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}