Pub Date : 2024-10-22DOI: 10.1016/j.ynstr.2024.100683
E. Bączyńska , M. Zaręba-Kozioł , B. Ruszczycki , A. Krzystyniak , T. Wójtowicz , K. Bijata , B. Pochwat , M. Magnowska , M. Roszkowska , I. Figiel , J. Masternak , A. Pytyś , J. Dzwonek , R. Worch , K.H. Olszyński , A.D. Wardak , P. Szymczak , J. Labus , K. Radwańska , P. Jahołkowski , J. Włodarczyk
Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subregion of the hippocampus.
{"title":"Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses","authors":"E. Bączyńska , M. Zaręba-Kozioł , B. Ruszczycki , A. Krzystyniak , T. Wójtowicz , K. Bijata , B. Pochwat , M. Magnowska , M. Roszkowska , I. Figiel , J. Masternak , A. Pytyś , J. Dzwonek , R. Worch , K.H. Olszyński , A.D. Wardak , P. Szymczak , J. Labus , K. Radwańska , P. Jahołkowski , J. Włodarczyk","doi":"10.1016/j.ynstr.2024.100683","DOIUrl":"10.1016/j.ynstr.2024.100683","url":null,"abstract":"<div><div>Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subregion of the hippocampus.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100683"},"PeriodicalIF":4.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.ynstr.2024.100682
Zihan Tang , Yadong Liu , Xiaolin Zhao , Weiyu Hu , Mengning Zhang , Yipeng Ren , Zhenni Wei , Juan Yang
Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (r = -0.268, p = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [-0.036, -0.001], p = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.
{"title":"Stress-induced cortisol response predicts empathy for pain: The role of task-based connectivity between the insula and sensorimotor cortex during acute stress","authors":"Zihan Tang , Yadong Liu , Xiaolin Zhao , Weiyu Hu , Mengning Zhang , Yipeng Ren , Zhenni Wei , Juan Yang","doi":"10.1016/j.ynstr.2024.100682","DOIUrl":"10.1016/j.ynstr.2024.100682","url":null,"abstract":"<div><div>Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (<em>r</em> = -0.268, <em>p</em> = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [-0.036, -0.001], <em>p</em> = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100682"},"PeriodicalIF":4.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.ynstr.2024.100681
Rinki Saha , Lisa-Sophie Wüstner , Darpan Chakraborty , Rachel Anunu , Silvia Mandel , Joyeeta Dutta Hazra , Martin Kriebel , Hansjuergen Volkmer , Hanoch Kaphzan , Gal Richter-Levin
The basolateral amygdala (BLA) is a dynamic brain region involved in emotional experiences and subject to long-term plasticity. The BLA also modulates activity, plasticity, and related behaviors associated with other brain regions, including the mPFC and hippocampus. Accordingly, intra-BLA plasticity can be expected to alter both BLA-dependent behaviors and behaviors mediated by other brain regions. Lasting intra-BLA plasticity may be considered a form of metaplasticity, since it will affect subsequent plasticity and response to challenges later on. Activity within the BLA is tightly modulated by GABAergic interneurons, and thus inducing lasting alteration of GABAergic modulation of principal neurons may have an impactful metaplastic effect on BLA functioning. Previously, we demonstrated that intra-BLA knockdown (KD) of neurofascin (NF) reduced GABAergic synapses exclusively at the axon initial segment (AIS). Here, by reducing the expression of the tyrosine kinase receptor ephrin A7 (EphA7), we selectively impaired the modulatory function of a different subpopulation of interneurons, specifically targeting the soma and proximal dendrites of principal neurons. This perturbation induced an expected reduction in the spontaneous inhibitory synaptic input and an increase in the excitatory spontaneous synaptic activity, most probably due to the reduction of inhibitory tone. Moreover, this increased synaptic activity was followed by a reduction in intrinsic excitability. While intra-BLA NF-KD resulted in impaired extinction learning, without increased symptoms of anxiety, intra-BLA reduction of EphA7 expression resulted in increased symptoms of anxiety, as measured in the elevated plus maze, but without affecting fear conditioning or extinction learning. These results confirm the role of the BLA and intra-BLA metaplasticity in stress-induced increased anxiety symptoms and in impaired fear extinction learning but reveals a difference in intra-BLA mechanisms involved. The results also confirm the contribution of GABAergic interneurons to these effects but indicate selective roles for different subpopulations of intra-BLA interneurons.
{"title":"Intra-BLA alteration of interneurons’ modulation of activity in rats, reveals a dissociation between effects on anxiety symptoms and extinction learning","authors":"Rinki Saha , Lisa-Sophie Wüstner , Darpan Chakraborty , Rachel Anunu , Silvia Mandel , Joyeeta Dutta Hazra , Martin Kriebel , Hansjuergen Volkmer , Hanoch Kaphzan , Gal Richter-Levin","doi":"10.1016/j.ynstr.2024.100681","DOIUrl":"10.1016/j.ynstr.2024.100681","url":null,"abstract":"<div><div>The basolateral amygdala (BLA) is a dynamic brain region involved in emotional experiences and subject to long-term plasticity. The BLA also modulates activity, plasticity, and related behaviors associated with other brain regions, including the mPFC and hippocampus. Accordingly, intra-BLA plasticity can be expected to alter both BLA-dependent behaviors and behaviors mediated by other brain regions. Lasting intra-BLA plasticity may be considered a form of metaplasticity, since it will affect subsequent plasticity and response to challenges later on. Activity within the BLA is tightly modulated by GABAergic interneurons, and thus inducing lasting alteration of GABAergic modulation of principal neurons may have an impactful metaplastic effect on BLA functioning. Previously, we demonstrated that intra-BLA knockdown (KD) of neurofascin (NF) reduced GABAergic synapses exclusively at the axon initial segment (AIS). Here, by reducing the expression of the tyrosine kinase receptor ephrin A7 (EphA7), we selectively impaired the modulatory function of a different subpopulation of interneurons, specifically targeting the soma and proximal dendrites of principal neurons. This perturbation induced an expected reduction in the spontaneous inhibitory synaptic input and an increase in the excitatory spontaneous synaptic activity, most probably due to the reduction of inhibitory tone. Moreover, this increased synaptic activity was followed by a reduction in intrinsic excitability. While intra-BLA NF-KD resulted in impaired extinction learning, without increased symptoms of anxiety, intra-BLA reduction of EphA7 expression resulted in increased symptoms of anxiety, as measured in the elevated plus maze, but without affecting fear conditioning or extinction learning. These results confirm the role of the BLA and intra-BLA metaplasticity in stress-induced increased anxiety symptoms and in impaired fear extinction learning but reveals a difference in intra-BLA mechanisms involved. The results also confirm the contribution of GABAergic interneurons to these effects but indicate selective roles for different subpopulations of intra-BLA interneurons.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100681"},"PeriodicalIF":4.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.ynstr.2024.100679
Jen-Yin Goh , Patricia Rueda , Joy Taylor , Alex Rathbone , Daniel Scott , Christopher J. Langmead , Kevin C.F. Fone , Gregory D. Stewart , Madeleine V. King
Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.
{"title":"Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation – Relevance to psychiatric and neurodevelopmental illness, and implications for treatment","authors":"Jen-Yin Goh , Patricia Rueda , Joy Taylor , Alex Rathbone , Daniel Scott , Christopher J. Langmead , Kevin C.F. Fone , Gregory D. Stewart , Madeleine V. King","doi":"10.1016/j.ynstr.2024.100679","DOIUrl":"10.1016/j.ynstr.2024.100679","url":null,"abstract":"<div><div>Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (<em>Hrh3</em>, <em>Snca</em> and <em>Sod1</em>) and agonists or activators for products of six of these down-regulated DEGs (<em>Chrm4</em>, <em>Klf2</em>, <em>Lrrk2</em>, <em>Nr4a1</em>, <em>Nr4a3</em> and <em>Prkca</em>). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to <em>Hrh3</em>, <em>Sod1</em>, <em>Chrm4</em>, <em>Lrrk2</em>, <em>Nr4a1</em> and <em>Prkca</em> were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100679"},"PeriodicalIF":4.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.ynstr.2024.100680
Wei Fang , Xi Chen , Jufang He
The basolateral amygdala (BLA) hyperactivity has been implicated in the pathophysiology of anxiety disorders. We recently found that enhancing inhibitory transmission in BLA by chemo-genetic activation of local interneurons (INs) can reduce stress-induced anxiety-like behaviors in mice. Cholecystokinin interneurons (CCK-INs) are a major part of INs in BLA. It remains unknown whether CCK-INs modulated inhibition in BLA can mediate anxiety. In the present study, we found that BLA CCK-INs project extensively to most local excitatory neurons. Activating these CCK-INs using chemo-genetics and optogenetics can both effectively suppress electrical-induced neuronal activity within the BLA. Additionally, we observed that direct and sustained activation of CCK-INs within the BLA via chemo-genetics can mitigate stress-induced anxiety-like behaviors in mice and reduce stress-induced hyperactivity within the BLA itself. Furthermore, augmenting inhibitory plasticity within the BLA through a brief, 10-min high-frequency laser stimulation (HFLS) of CCK-INs also reduce stress-induced anxiety-like behaviors in mice. Collectively, these findings underscore the pivotal role of BLA CCK-IN-mediated inhibitory transmission and plasticity in modulating anxiety.
杏仁基底外侧（BLA）的过度活跃与焦虑症的病理生理学有关。我们最近发现，通过化学基因激活局部中间神经元（INs）来增强杏仁基底外侧的抑制性传导，可以减少小鼠由压力诱发的焦虑样行为。胆囊收缩素中间神经元（CCK-INs）是BLA中INs的主要组成部分。CCK-INs调节BLA中的抑制作用是否能介导焦虑仍是一个未知数。在本研究中，我们发现 BLA CCK-INs 广泛投射到大多数局部兴奋性神经元。利用化学遗传学和光遗传学激活这些 CCK-INs 都能有效抑制 BLA 内电诱导的神经元活动。此外，我们还观察到，通过化学遗传学直接、持续地激活 BLA 内的 CCK-INs 可以减轻应激诱导的小鼠焦虑样行为，并降低应激诱导的 BLA 自身的过度活跃性。此外，通过对CCK-INs进行10分钟的短暂高频激光刺激（HFLS）来增强BLA内的抑制可塑性，也能减少小鼠应激诱发的焦虑样行为。总之，这些发现强调了BLA CCK-IN介导的抑制性传递和可塑性在调节焦虑中的关键作用。
{"title":"Cholecystokinin-expressing interneurons mediated inhibitory transmission and plasticity in basolateral amygdala modulate stress-induced anxiety-like behaviors in mice","authors":"Wei Fang , Xi Chen , Jufang He","doi":"10.1016/j.ynstr.2024.100680","DOIUrl":"10.1016/j.ynstr.2024.100680","url":null,"abstract":"<div><div>The basolateral amygdala (BLA) hyperactivity has been implicated in the pathophysiology of anxiety disorders. We recently found that enhancing inhibitory transmission in BLA by chemo-genetic activation of local interneurons (INs) can reduce stress-induced anxiety-like behaviors in mice. Cholecystokinin interneurons (CCK-INs) are a major part of INs in BLA. It remains unknown whether CCK-INs modulated inhibition in BLA can mediate anxiety. In the present study, we found that BLA CCK-INs project extensively to most local excitatory neurons. Activating these CCK-INs using chemo-genetics and optogenetics can both effectively suppress electrical-induced neuronal activity within the BLA. Additionally, we observed that direct and sustained activation of CCK-INs within the BLA via chemo-genetics can mitigate stress-induced anxiety-like behaviors in mice and reduce stress-induced hyperactivity within the BLA itself. Furthermore, augmenting inhibitory plasticity within the BLA through a brief, 10-min high-frequency laser stimulation (HFLS) of CCK-INs also reduce stress-induced anxiety-like behaviors in mice. Collectively, these findings underscore the pivotal role of BLA CCK-IN-mediated inhibitory transmission and plasticity in modulating anxiety.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100680"},"PeriodicalIF":4.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.ynstr.2024.100678
Renaud C. Gom , Antis G. George , Sydney A. Harris , Pasindu Wickramarachchi , Dhyey Bhatt , Shaona Acharjee , Quentin J. Pittman , Matthew N. Hill , Roberto Colangeli , G. Campbell Teskey
People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy.
We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity.
Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses.
Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.
{"title":"Emotional comorbidities in epilepsy result from seizure-induced corticosterone activity","authors":"Renaud C. Gom , Antis G. George , Sydney A. Harris , Pasindu Wickramarachchi , Dhyey Bhatt , Shaona Acharjee , Quentin J. Pittman , Matthew N. Hill , Roberto Colangeli , G. Campbell Teskey","doi":"10.1016/j.ynstr.2024.100678","DOIUrl":"10.1016/j.ynstr.2024.100678","url":null,"abstract":"<div><div>People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy.</div><div>We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity.</div><div>Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses.</div><div>Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100678"},"PeriodicalIF":4.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142526669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.ynstr.2024.100677
Jing Lyu , Jiayue Li , Rui Ding , Hui Zhao , Chao Liu , Shaozheng Qin
Fear learning is pivotal for organismal survival, ensuring the ability to avoid potential threats through learning based on experiencing minimal fear information. In reality, fear learning requires to form a structured representation of fear experiences from multiple dimensions in order to support flexible use in ever-changing environment. Yet, the underlying neural mechanisms of constructing dimensional fear space remain elusive. Here we set up an innovative approach with two-dimensional fear learning, by utilizing the probability (uncertainty) and subjective pain intensity of threatening mild electric shock with five levels of each dimension. Behaviorally, individuals constructed a two-dimensional fear space after learning phase, as evidenced by significant changes in participant's fearful ratings for each cue associated with a five-by-five grid after (relative to before) learning phase. Analysis of neuroimaging data revealed that the medial temporal lobe, in conjunction with the amygdala, the insula, the anterior cingulate cortex (ACC), the hippocampus, and the dorsolateral prefrontal cortex (dlPFC), collectively contribute to the construction of a two-dimensional fear space consisting of uncertainty and intensity. Activation in the parahippocampal gyrus, insula, and dlPFC was associated with mental navigation within two-dimensional fear space, whereas the engagement of insula, ACC, amygdala, the hippocampus, the dlPFC was associated with a unified fearful scoring cross uncertainty and intensity dimensions after fear learning. Our findings suggest a neurocognitive model through which emotional salience network underlies the construction of a structured representation of fear experiences from multiple dimensions.
{"title":"Emotional salience network involved in constructing two-dimensional fear space in humans","authors":"Jing Lyu , Jiayue Li , Rui Ding , Hui Zhao , Chao Liu , Shaozheng Qin","doi":"10.1016/j.ynstr.2024.100677","DOIUrl":"10.1016/j.ynstr.2024.100677","url":null,"abstract":"<div><div>Fear learning is pivotal for organismal survival, ensuring the ability to avoid potential threats through learning based on experiencing minimal fear information. In reality, fear learning requires to form a structured representation of fear experiences from multiple dimensions in order to support flexible use in ever-changing environment. Yet, the underlying neural mechanisms of constructing dimensional fear space remain elusive. Here we set up an innovative approach with two-dimensional fear learning, by utilizing the probability (uncertainty) and subjective pain intensity of threatening mild electric shock with five levels of each dimension. Behaviorally, individuals constructed a two-dimensional fear space after learning phase, as evidenced by significant changes in participant's fearful ratings for each cue associated with a five-by-five grid after (relative to before) learning phase. Analysis of neuroimaging data revealed that the medial temporal lobe, in conjunction with the amygdala, the insula, the anterior cingulate cortex (ACC), the hippocampus, and the dorsolateral prefrontal cortex (dlPFC), collectively contribute to the construction of a two-dimensional fear space consisting of uncertainty and intensity. Activation in the parahippocampal gyrus, insula, and dlPFC was associated with mental navigation within two-dimensional fear space, whereas the engagement of insula, ACC, amygdala, the hippocampus, the dlPFC was associated with a unified fearful scoring cross uncertainty and intensity dimensions after fear learning. Our findings suggest a neurocognitive model through which emotional salience network underlies the construction of a structured representation of fear experiences from multiple dimensions.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"34 ","pages":"Article 100677"},"PeriodicalIF":4.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1016/j.ynstr.2024.100676
Ai-Mei Wu , Jing-Ya Zhang , Wei-Zhong Lun , Zhi Geng , Ye Yang , Jun-Cang Wu , Gui-Hai Chen
Astrocytes play significant roles in regulating the central stress response. Chronic stress impairs the structure and function of astrocytes in many brain regions such as media prefrontal cortex (mPFC) in multiple neuropsychiatric conditions, but the astrocytic dynamics on the timescale of behavior remains unclear. Here, we recorded mPFC astrocytic activity in freely behaving mice and found that astrocytes are activated immediately by different aversive stimuli. Astrocyte specific GCaMP6s calcium indicator were virally expressed in mPFC astrocytes and fiber photometry experiments revealed that astrocytes are activated by tail-restraint (TRT), foot shock (FS), open arm exploration, stressor of height, predator odor and social defeat (SD) stress. ΔF/F analyses demonstrated that an unpredictable stimulus such as elevated platform stress (EPS) at the initial encounter induced the most intense and rapid changes in astrocytic calcium activity, while a predictable 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) stimulus resulted in the weakest response with a longer peak latency. In TRT, FS or SD test, a somatic stimulus led to higher average calcium activity level and faster average peak latency in repeated trails. Similar to TMT stimulus, astrocytic calcium activity in elevated plus maze (EPM) test exhibited a smaller average change in amplitude and the longest peak latency during open arm exploration. Moreover, astrocytic calcium activity exhibited different changes across behavioral states in SD tests. Our findings show that mPFC astrocytes exhibit distinct patterns of calcium activity in response to various negative stimuli, indicating that the dynamic activity of astrocytes may reflect the stress-related behavioral state under different stimulus conditions.
{"title":"Dynamic changes of media prefrontal cortex astrocytic activity in response to negative stimuli in male mice","authors":"Ai-Mei Wu , Jing-Ya Zhang , Wei-Zhong Lun , Zhi Geng , Ye Yang , Jun-Cang Wu , Gui-Hai Chen","doi":"10.1016/j.ynstr.2024.100676","DOIUrl":"10.1016/j.ynstr.2024.100676","url":null,"abstract":"<div><div>Astrocytes play significant roles in regulating the central stress response. Chronic stress impairs the structure and function of astrocytes in many brain regions such as media prefrontal cortex (mPFC) in multiple neuropsychiatric conditions, but the astrocytic dynamics on the timescale of behavior remains unclear. Here, we recorded mPFC astrocytic activity in freely behaving mice and found that astrocytes are activated immediately by different aversive stimuli. Astrocyte specific GCaMP6s calcium indicator were virally expressed in mPFC astrocytes and fiber photometry experiments revealed that astrocytes are activated by tail-restraint (TRT), foot shock (FS), open arm exploration, stressor of height, predator odor and social defeat (SD) stress. ΔF/F analyses demonstrated that an unpredictable stimulus such as elevated platform stress (EPS) at the initial encounter induced the most intense and rapid changes in astrocytic calcium activity, while a predictable 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) stimulus resulted in the weakest response with a longer peak latency. In TRT, FS or SD test, a somatic stimulus led to higher average calcium activity level and faster average peak latency in repeated trails. Similar to TMT stimulus, astrocytic calcium activity in elevated plus maze (EPM) test exhibited a smaller average change in amplitude and the longest peak latency during open arm exploration. Moreover, astrocytic calcium activity exhibited different changes across behavioral states in SD tests. Our findings show that mPFC astrocytes exhibit distinct patterns of calcium activity in response to various negative stimuli, indicating that the dynamic activity of astrocytes may reflect the stress-related behavioral state under different stimulus conditions.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100676"},"PeriodicalIF":4.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142420393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.ynstr.2024.100675
Julia R. Mitchell , Lindsay Vincelette , Samantha Tuberman , Vivika Sheppard , Emmett Bergeron , Roberto Calitri , Rose Clark , Caitlyn Cody , Akshara Kannan , Jack Keith , Abigail Parakoyi , MaryClare Pikus , Victoria Vance , Leena Ziane , Heather Brenhouse , Mikaela A. Laine , Rebecca M. Shansky
Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.
{"title":"Behavioral and neural correlates of diverse conditioned fear responses in male and female rats","authors":"Julia R. Mitchell , Lindsay Vincelette , Samantha Tuberman , Vivika Sheppard , Emmett Bergeron , Roberto Calitri , Rose Clark , Caitlyn Cody , Akshara Kannan , Jack Keith , Abigail Parakoyi , MaryClare Pikus , Victoria Vance , Leena Ziane , Heather Brenhouse , Mikaela A. Laine , Rebecca M. Shansky","doi":"10.1016/j.ynstr.2024.100675","DOIUrl":"10.1016/j.ynstr.2024.100675","url":null,"abstract":"<div><div>Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100675"},"PeriodicalIF":4.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000717/pdfft?md5=4b62059f360b89745fab62771589e0b0&pid=1-s2.0-S2352289524000717-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142312606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1016/j.ynstr.2024.100674
Savannah Brannan, Lauren Garbe, Ben D. Richardson
Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risk. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of adolescence being a female-specific sensitive period. To understand the underlying neuronal mechanisms potentially responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine signaling-associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention deficits (5-choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female-specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC.
{"title":"Early life stress induced sex-specific changes in behavior is paralleled by altered locus coeruleus physiology in BALB/cJ mice","authors":"Savannah Brannan, Lauren Garbe, Ben D. Richardson","doi":"10.1016/j.ynstr.2024.100674","DOIUrl":"10.1016/j.ynstr.2024.100674","url":null,"abstract":"<div><div>Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risk. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of adolescence being a female-specific sensitive period. To understand the underlying neuronal mechanisms potentially responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine signaling-associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention deficits (5-choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female-specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"33 ","pages":"Article 100674"},"PeriodicalIF":4.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000705/pdfft?md5=619d3e35ab97587f0de791597ebd7efb&pid=1-s2.0-S2352289524000705-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142316279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号