Pub Date : 2024-06-05DOI: 10.1016/j.bpsgos.2024.100340
Hannah C. Smith , Zhe Yu , Laxmi Iyer , Paul J. Marvar
Background
The renin-angiotensin system has been identified as a potential therapeutic target for posttraumatic stress disorder, although its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. Therefore, we used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R–expressing neurons in fear and stess related behavior.
Methods
To characterize mPFC-AT2R–expressing neurons in the mPFC, AT2R-Cre/tdTomato male and female mice were used for immunohistochemistry. mPFC brain sections were stained with glutamatergic or interneuron markers, and density of AT2R+ cells and colocalization with each marker were quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using a Cre-expressing adeno-associated virus. Mice then underwent Pavlovian auditory fear conditioning, elevated plus maze, and open field testing.
Results
Immunohistochemistry results revealed that AT2R was densely expressed throughout the mPFC and primarily expressed in somatostatin interneurons in a sex-dependent manner. Following fear conditioning, mPFC-AT2R Cre-lox deletion impaired extinction and increased exploratory behavior in female but not male mice, while locomotion was unaltered by mPFC-AT2R deletion in both sexes.
Conclusions
These results identify mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons and reveal their role in regulating fear learning in a sex-dependent manner, potentially offering insights into novel therapeutic targets for posttraumatic stress disorder.
背景肾素-血管紧张素系统已被确定为创伤后应激障碍的潜在治疗靶点,但其作用机制尚不十分清楚。脑血管紧张素 2 型受体(AT2Rs)是血管紧张素 II 受体的一种亚型,位于包括内侧前额叶皮层(mPFC)在内的应激和焦虑相关区域,但其在 mPFC 中的功能和机制仍有待探索。因此,我们综合使用成像、cre/lox和行为学方法研究了mPFC-AT2R表达神经元在恐惧和焦虑相关行为中的作用。用谷氨酸能或中间神经元标记物染色mPFC脑切片,量化AT2R+细胞的密度以及与每种标记物的共定位。为了评估AT2R-flox小鼠的恐惧相关行为,我们使用Cre表达的腺相关病毒选择性地从mPFC神经元中删除了AT2R。结果免疫组化结果显示,AT2R在整个mPFC中密集表达,并且主要以性别依赖的方式在体司他丁中间神经元中表达。结论这些结果确定了mPFC-AT2R+神经元是体生长激素中间神经元的一个新亚群,并揭示了它们以性别依赖的方式在调节恐惧学习中的作用,有可能为创伤后应激障碍的新治疗靶点提供启示。
{"title":"Sex-Dependent Effects of Angiotensin Type 2 Receptor–Expressing Medial Prefrontal Cortex Interneurons in Fear Extinction Learning","authors":"Hannah C. Smith , Zhe Yu , Laxmi Iyer , Paul J. Marvar","doi":"10.1016/j.bpsgos.2024.100340","DOIUrl":"10.1016/j.bpsgos.2024.100340","url":null,"abstract":"<div><h3>Background</h3><p>The renin-angiotensin system has been identified as a potential therapeutic target for posttraumatic stress disorder, although its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. Therefore, we used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R–expressing neurons in fear and stess related behavior.</p></div><div><h3>Methods</h3><p>To characterize mPFC-AT2R–expressing neurons in the mPFC, AT2R-Cre/tdTomato male and female mice were used for immunohistochemistry. mPFC brain sections were stained with glutamatergic or interneuron markers, and density of AT2R+ cells and colocalization with each marker were quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using a Cre-expressing adeno-associated virus. Mice then underwent Pavlovian auditory fear conditioning, elevated plus maze, and open field testing.</p></div><div><h3>Results</h3><p>Immunohistochemistry results revealed that AT2R was densely expressed throughout the mPFC and primarily expressed in somatostatin interneurons in a sex-dependent manner. Following fear conditioning, mPFC-AT2R Cre-lox deletion impaired extinction and increased exploratory behavior in female but not male mice, while locomotion was unaltered by mPFC-AT2R deletion in both sexes.</p></div><div><h3>Conclusions</h3><p>These results identify mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons and reveal their role in regulating fear learning in a sex-dependent manner, potentially offering insights into novel therapeutic targets for posttraumatic stress disorder.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100340"},"PeriodicalIF":4.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000533/pdfft?md5=a11f43510692df10c19232a6191c181c&pid=1-s2.0-S2667174324000533-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141960385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1016/j.bpsgos.2024.100342
Background
The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively.
Methods
We studied healthy older adult participants (N = 21, ages 48–79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task.
Results
Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation.
Conclusions
The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.
{"title":"Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults","authors":"","doi":"10.1016/j.bpsgos.2024.100342","DOIUrl":"10.1016/j.bpsgos.2024.100342","url":null,"abstract":"<div><h3>Background</h3><p>The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively.</p></div><div><h3>Methods</h3><p>We studied healthy older adult participants (<em>N</em> = 21, ages 48–79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task.</p></div><div><h3>Results</h3><p>Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation.</p></div><div><h3>Conclusions</h3><p>The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100342"},"PeriodicalIF":4.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000557/pdfft?md5=4d325151d7bc5d44ca7f036cda2204df&pid=1-s2.0-S2667174324000557-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1016/j.bpsgos.2024.100343
Adam Pavlinek , Dwaipayan Adhya , Alex Tsompanidis , Varun Warrier
Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell–derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome–linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
性别差异广泛存在于神经发育过程中,并在自闭症等神经精神疾病中发挥作用,而自闭症在男性中的发病率高于女性。在人类中,男性的脑容量比女性大,海马体和杏仁核的发育显示出显著的性别差异。从机理上讲,性类固醇和性染色体推动了大脑发育的这些差异,这些差异似乎在产前和青春期阶段达到高峰。动物模型在理解性别差异方面发挥了至关重要的作用,但人类性别差异的研究需要一个能再现复杂遗传特征的实验模型。为了填补这一空白,人类诱导多能干细胞衍生的脑器官现在被用来研究复杂的遗传特征如何影响产前大脑发育。例如,来自自闭症患者和与X染色体相关的雷特综合征和脆性X综合征患者的脑器官组织显示了产前细胞增殖差异、脑容量差异和兴奋抑制失衡。脑器官组织也显示,由于雄激素的作用,兴奋性神经元的神经发生增加。然而,尽管人们对使用脑器官组织的兴趣与日俱增,但仍有几个关键挑战影响着其作为模型系统的有效性。在这篇综述中,我们将讨论性类固醇和性染色体如何各自导致大脑发育的性别差异。然后,我们将探讨 X 染色体失活作为性别差异驱动因素的作用。最后,我们讨论了在研究性别差异时需要考虑的 X 染色体失活建模的综合挑战和脑器官模型的局限性。
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Pub Date : 2024-06-03DOI: 10.1016/j.bpsgos.2024.100341
Cathy Spatz Widom , Hang (Heather) Do , Quincy C. Miller , Magda Javakhishvili , Claire Eckstein Indik , Daniel W. Belsky
Background
Childhood maltreatment and psychiatric morbidity have each been associated with accelerated biological aging primarily through cross-sectional studies. Using data from a prospective longitudinal study of individuals with histories of childhood maltreatment and control participants followed into midlife, we tested 2 hypotheses examining whether 1) psychiatric symptoms mediate the relationship between childhood maltreatment and biological aging and 2) psychiatric symptoms of anxiety, depression, or posttraumatic stress disorder (PTSD) act in conjunction with childhood maltreatment to exacerbate the association of child maltreatment to aging.
Methods
Children (ages 0–11 years) with documented histories of maltreatment and demographically matched control children were followed into adulthood (N = 607) and interviewed over several waves of the study. Depression, anxiety, and PTSD symptoms were assessed at mean ages of 29 (interview 1) and 40 (interview 2) years. Biological age was measured from blood chemistries collected later (mean age = 41 years) using the Klemera-Doubal method. Hypotheses were tested using linear regressions and path analyses.
Results
Adults with documented histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety at both interviews and more advanced biological aging, compared with control participants. PTSD symptoms at both interviews and depression and anxiety symptoms only at interview 2 predicted accelerated biological aging. There was no evidence of mediation; however, anxiety and depression moderated the relationship between childhood maltreatment and biological aging.
Conclusions
These new findings reveal the shorter- and longer-term longitudinal impact of PTSD on biological aging and the amplifying effect of anxiety and depression on the relationship between child maltreatment and biological aging.
{"title":"Childhood Maltreatment and Biological Aging in Middle Adulthood: The Role of Psychiatric Symptoms","authors":"Cathy Spatz Widom , Hang (Heather) Do , Quincy C. Miller , Magda Javakhishvili , Claire Eckstein Indik , Daniel W. Belsky","doi":"10.1016/j.bpsgos.2024.100341","DOIUrl":"10.1016/j.bpsgos.2024.100341","url":null,"abstract":"<div><h3>Background</h3><p>Childhood maltreatment and psychiatric morbidity have each been associated with accelerated biological aging primarily through cross-sectional studies. Using data from a prospective longitudinal study of individuals with histories of childhood maltreatment and control participants followed into midlife, we tested 2 hypotheses examining whether 1) psychiatric symptoms mediate the relationship between childhood maltreatment and biological aging and 2) psychiatric symptoms of anxiety, depression, or posttraumatic stress disorder (PTSD) act in conjunction with childhood maltreatment to exacerbate the association of child maltreatment to aging.</p></div><div><h3>Methods</h3><p>Children (ages 0–11 years) with documented histories of maltreatment and demographically matched control children were followed into adulthood (<em>N</em> = 607) and interviewed over several waves of the study. Depression, anxiety, and PTSD symptoms were assessed at mean ages of 29 (interview 1) and 40 (interview 2) years. Biological age was measured from blood chemistries collected later (mean age = 41 years) using the Klemera-Doubal method. Hypotheses were tested using linear regressions and path analyses.</p></div><div><h3>Results</h3><p>Adults with documented histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety at both interviews and more advanced biological aging, compared with control participants. PTSD symptoms at both interviews and depression and anxiety symptoms only at interview 2 predicted accelerated biological aging. There was no evidence of mediation; however, anxiety and depression moderated the relationship between childhood maltreatment and biological aging.</p></div><div><h3>Conclusions</h3><p>These new findings reveal the shorter- and longer-term longitudinal impact of PTSD on biological aging and the amplifying effect of anxiety and depression on the relationship between child maltreatment and biological aging.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100341"},"PeriodicalIF":4.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000545/pdfft?md5=1e155e23809e6af54b49f2883ae9e2b9&pid=1-s2.0-S2667174324000545-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141274278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fetal brain development requires increased maternal protein intake to ensure that offspring reach their optimal cognitive potential in infancy and adulthood. While protein deficiency remains a prevalent issue in developing countries, it is also reemerging in Western societies due to the growing adoption of plant-based diets, some of which are monotonous and may fail to provide sufficient amino acids crucial for the brain’s critical developmental phase. Confounding variables in human nutritional research have impeded our understanding of the precise impact of protein deficiency on fetal neurodevelopment, as well as its implications for childhood neurocognitive performance. Moreover, it remains unclear whether such deficiency could predispose to mental health problems in adulthood, mirroring observations in individuals exposed to prenatal famine. In this review, we sought to evaluate mechanistic data derived from rodent models, placing special emphasis on the involvement of neuroendocrine axes, the influence of sex and timing, epigenetic modifications, and cellular metabolism. Despite notable progress, critical knowledge gaps remain, including understanding the long-term reversibility of effects due to fetal protein restriction and the interplay between genetic predisposition and environmental factors. Enhancing our understanding of the precise mechanisms that connect prenatal nutrition to brain development in future research endeavors can be significantly advanced by integrating multiomics approaches and utilizing additional alternative models such as nonhuman primates. Furthermore, it is crucial to investigate potential interventions aimed at alleviating adverse outcomes. Ultimately, this research has profound implications for guiding public health strategies aimed at raising awareness about the crucial role of optimal maternal nutrition in supporting fetal neurodevelopment.
{"title":"Unraveling the Molecular Mechanisms of the Neurodevelopmental Consequences of Fetal Protein Deficiency: Insights From Rodent Models and Public Health Implications","authors":"Pieter Vancamp , Morgane Frapin , Patricia Parnet , Valérie Amarger","doi":"10.1016/j.bpsgos.2024.100339","DOIUrl":"10.1016/j.bpsgos.2024.100339","url":null,"abstract":"<div><p>Fetal brain development requires increased maternal protein intake to ensure that offspring reach their optimal cognitive potential in infancy and adulthood. While protein deficiency remains a prevalent issue in developing countries, it is also reemerging in Western societies due to the growing adoption of plant-based diets, some of which are monotonous and may fail to provide sufficient amino acids crucial for the brain’s critical developmental phase. Confounding variables in human nutritional research have impeded our understanding of the precise impact of protein deficiency on fetal neurodevelopment, as well as its implications for childhood neurocognitive performance. Moreover, it remains unclear whether such deficiency could predispose to mental health problems in adulthood, mirroring observations in individuals exposed to prenatal famine. In this review, we sought to evaluate mechanistic data derived from rodent models, placing special emphasis on the involvement of neuroendocrine axes, the influence of sex and timing, epigenetic modifications, and cellular metabolism. Despite notable progress, critical knowledge gaps remain, including understanding the long-term reversibility of effects due to fetal protein restriction and the interplay between genetic predisposition and environmental factors. Enhancing our understanding of the precise mechanisms that connect prenatal nutrition to brain development in future research endeavors can be significantly advanced by integrating multiomics approaches and utilizing additional alternative models such as nonhuman primates. Furthermore, it is crucial to investigate potential interventions aimed at alleviating adverse outcomes. Ultimately, this research has profound implications for guiding public health strategies aimed at raising awareness about the crucial role of optimal maternal nutrition in supporting fetal neurodevelopment.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100339"},"PeriodicalIF":4.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000521/pdfft?md5=4dd6047aa08132b56864d0198c989f52&pid=1-s2.0-S2667174324000521-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141276416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-31DOI: 10.1016/j.bpsgos.2024.100338
Débora A.E. Colodete , Anthony A. Grace , Francisco S. Guimarães , Felipe V. Gomes
Background
Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility.
Methods
Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress.
Results
Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress.
Conclusions
Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.
{"title":"Degradation of Perineuronal Nets in the Ventral Hippocampus of Adult Rats Recreates an Adolescent-Like Phenotype of Stress Susceptibility","authors":"Débora A.E. Colodete , Anthony A. Grace , Francisco S. Guimarães , Felipe V. Gomes","doi":"10.1016/j.bpsgos.2024.100338","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100338","url":null,"abstract":"<div><h3>Background</h3><p>Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility.</p></div><div><h3>Methods</h3><p>Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV<sup>+</sup> and PNN<sup>+</sup> cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress.</p></div><div><h3>Results</h3><p>Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV<sup>+</sup> and PNN<sup>+</sup> cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress.</p></div><div><h3>Conclusions</h3><p>Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100338"},"PeriodicalIF":4.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266717432400051X/pdfft?md5=3d359dd3e171957c8c07928256546504&pid=1-s2.0-S266717432400051X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1016/j.bpsgos.2024.100337
Emily M. Hicks , Maria Niarchou , Slavina Goleva , Dia Kabir , Jessica Johnson , Keira J.A. Johnston , Julia Ciarcia , Gita A. Pathak , Jordan W. Smoller , Lea K. Davis , Caroline M. Nievergelt , Karestan C. Koenen , Laura M. Huckins , Karmel W. Choi , PGC/PsycheMERGE PTSD & Trauma EHR Working Group
Background
Previous epidemiological research has linked posttraumatic stress disorder (PTSD) with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records provide an opportunity to overcome clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex.
Methods
PTSD was defined among biobank participants (N = 145,959) in 3 major healthcare systems using 2 ICD code-based definitions: broad (≥1 PTSD or acute stress codes vs. 0; ncases = 16,706) and narrow (≥2 PTSD codes vs. 0; ncases = 3325). Using a phenome-wide association study design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified phenome-wide association study analyses including a sex × diagnosis interaction term in each logistic regression.
Results
A substantial number of phecodes were significantly associated with PTSDNarrow (61%) and PTSDBroad (83%). While the strongest associations were shared between the 2 definitions, PTSDBroad captured 334 additional phecodes not significantly associated with PTSDNarrow and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed in that PTSDBroad was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients.
Conclusions
This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using electronic health records.
{"title":"Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome","authors":"Emily M. Hicks , Maria Niarchou , Slavina Goleva , Dia Kabir , Jessica Johnson , Keira J.A. Johnston , Julia Ciarcia , Gita A. Pathak , Jordan W. Smoller , Lea K. Davis , Caroline M. Nievergelt , Karestan C. Koenen , Laura M. Huckins , Karmel W. Choi , PGC/PsycheMERGE PTSD & Trauma EHR Working Group","doi":"10.1016/j.bpsgos.2024.100337","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100337","url":null,"abstract":"<div><h3>Background</h3><p>Previous epidemiological research has linked posttraumatic stress disorder (PTSD) with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records provide an opportunity to overcome clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex.</p></div><div><h3>Methods</h3><p>PTSD was defined among biobank participants (<em>N</em> = 145,959) in 3 major healthcare systems using 2 ICD code-based definitions: broad (≥1 PTSD or acute stress codes vs. 0; <em>n</em><sub>cases</sub> = 16,706) and narrow (≥2 PTSD codes vs. 0; <em>n</em><sub>cases</sub> = 3325). Using a phenome-wide association study design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified phenome-wide association study analyses including a sex × diagnosis interaction term in each logistic regression.</p></div><div><h3>Results</h3><p>A substantial number of phecodes were significantly associated with PTSD<sub>Narrow</sub> (61%) and PTSD<sub>Broad</sub> (83%). While the strongest associations were shared between the 2 definitions, PTSD<sub>Broad</sub> captured 334 additional phecodes not significantly associated with PTSD<sub>Narrow</sub> and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed in that PTSD<sub>Broad</sub> was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients.</p></div><div><h3>Conclusions</h3><p>This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using electronic health records.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100337"},"PeriodicalIF":4.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000508/pdfft?md5=2b533b65c5a7d3328c7604a2ad768c02&pid=1-s2.0-S2667174324000508-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141543372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-28DOI: 10.1016/j.bpsgos.2024.100336
Simon R. Poortman , Marjolein E.A. Barendse , Nikita Setiaman , Martijn P. van den Heuvel , Siemon C. de Lange , Manon H.J. Hillegers , Neeltje E.M. van Haren
Background
Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at elevated risk of developing psychiatric illness owing to both genetic predisposition and increased burden of environmental stress. Emerging evidence indicates a disruption of brain network connectivity in young offspring of patients with bipolar disorder and schizophrenia, but the age trajectories of these brain networks in this high-familial-risk population remain to be elucidated.
Methods
A total of 271 T1-weighted and diffusion-weighted scans were obtained from 174 offspring of at least 1 parent diagnosed with bipolar disorder (n = 74) or schizophrenia (n = 51) and offspring of parents without severe mental illness (n = 49). The age range was 8 to 23 years; 97 offspring underwent 2 scans. Anatomical brain networks were reconstructed into structural connectivity matrices. Network analysis was performed to investigate anatomical brain connectivity.
Results
Offspring of parents with schizophrenia had differential trajectories of connectivity strength and clustering compared with offspring of parents with bipolar disorder and parents without severe mental illness, of global efficiency compared with offspring of parents without severe mental illness, and of local connectivity compared with offspring of parents with bipolar disorder.
Conclusions
The findings of this study suggest that familial high risk of schizophrenia is related to deviations in age trajectories of global structural connectome properties and local connectivity strength.
{"title":"Age Trajectories of the Structural Connectome in Child and Adolescent Offspring of Individuals With Bipolar Disorder or Schizophrenia","authors":"Simon R. Poortman , Marjolein E.A. Barendse , Nikita Setiaman , Martijn P. van den Heuvel , Siemon C. de Lange , Manon H.J. Hillegers , Neeltje E.M. van Haren","doi":"10.1016/j.bpsgos.2024.100336","DOIUrl":"https://doi.org/10.1016/j.bpsgos.2024.100336","url":null,"abstract":"<div><h3>Background</h3><p>Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at elevated risk of developing psychiatric illness owing to both genetic predisposition and increased burden of environmental stress. Emerging evidence indicates a disruption of brain network connectivity in young offspring of patients with bipolar disorder and schizophrenia, but the age trajectories of these brain networks in this high-familial-risk population remain to be elucidated.</p></div><div><h3>Methods</h3><p>A total of 271 T1-weighted and diffusion-weighted scans were obtained from 174 offspring of at least 1 parent diagnosed with bipolar disorder (<em>n</em> = 74) or schizophrenia (<em>n</em> = 51) and offspring of parents without severe mental illness (<em>n</em> = 49). The age range was 8 to 23 years; 97 offspring underwent 2 scans. Anatomical brain networks were reconstructed into structural connectivity matrices. Network analysis was performed to investigate anatomical brain connectivity.</p></div><div><h3>Results</h3><p>Offspring of parents with schizophrenia had differential trajectories of connectivity strength and clustering compared with offspring of parents with bipolar disorder and parents without severe mental illness, of global efficiency compared with offspring of parents without severe mental illness, and of local connectivity compared with offspring of parents with bipolar disorder.</p></div><div><h3>Conclusions</h3><p>The findings of this study suggest that familial high risk of schizophrenia is related to deviations in age trajectories of global structural connectome properties and local connectivity strength.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100336"},"PeriodicalIF":4.0,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000491/pdfft?md5=32f3b37b2f0bfe33307b66cdfec14a5a&pid=1-s2.0-S2667174324000491-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141481894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1016/j.bpsgos.2024.100334
Rie Ryoke, Teruo Hashimoto, Ryuta Kawashima
Background
Traumatic events can cause long-lasting and uncontrollable fear and anxiety. Posttraumatic stress disorder is an intractable mental disorder, and neurobiological mechanisms using animal models are expected to help development of posttraumatic stress disorder treatment. In this study, we combined multiple stress (MS) and longitudinal in vivo magnetic resonance imaging to reveal the effects of long-lasting anxiety-like behaviors on adult male rat brains.
Methods
Twelve male Wistar rats (8 weeks old) were exposed to the MS of 1-mA footshocks and forced swimming, while 12 control rats were placed in a plastic cage. Contextual fear conditioning with 0.1-mA footshocks in a context different from the MS was conducted 15 days after the MS for both groups. Three retention tests were administered after 24 hours and 9 and 16 days. Two magnetic resonance imaging scans were conducted, one on the day before MS induction and one the day after the third retention test, with a 32-day interval.
Results
The MS group showed greater freezing responses than the control group in all retention tests. Whole-brain voxel-based morphometry analyses revealed reduced gray matter volume in the anterior amygdalohippocampal area in MS group rats compared with control rats. These volume changes were negatively associated with freezing time in the third retention test in the MS group.
Conclusions
These results suggest that individual variability in the amygdalohippocampal area may be related to long-lasting fear responses after severe stress.
背景创伤事件会导致长期无法控制的恐惧和焦虑。创伤后应激障碍是一种难治性精神障碍,利用动物模型研究神经生物学机制有望有助于创伤后应激障碍治疗的发展。在这项研究中,我们将多重应激(MS)和纵向体内磁共振成像相结合,揭示了长期焦虑样行为对成年雄性大鼠大脑的影响。方法将12只雄性Wistar大鼠(8周大)置于1毫安脚震和强迫游泳的MS中,同时将12只对照组大鼠置于塑料笼中。两组大鼠均在接触 MS 15 天后,在不同于 MS 的情境中进行 0.1 毫安脚震的情境恐惧条件反射。分别在 24 小时、9 天和 16 天后进行了三次保持测试。进行了两次磁共振成像扫描,一次是在诱导 MS 的前一天,另一次是在第三次保持测试的第二天,间隔时间为 32 天。基于体素的全脑形态计量分析显示,与对照组大鼠相比,MS 组大鼠杏仁核海马前区灰质体积减少。这些结果表明,杏仁海马区的个体差异可能与严重应激后的持久恐惧反应有关。
{"title":"Multiple Stressors Induce Amygdalohippocampal Volume Reduction in Adult Male Rats as Detected by Longitudinal Structural Magnetic Resonance Imaging","authors":"Rie Ryoke, Teruo Hashimoto, Ryuta Kawashima","doi":"10.1016/j.bpsgos.2024.100334","DOIUrl":"10.1016/j.bpsgos.2024.100334","url":null,"abstract":"<div><h3>Background</h3><p>Traumatic events can cause long-lasting and uncontrollable fear and anxiety. Posttraumatic stress disorder is an intractable mental disorder, and neurobiological mechanisms using animal models are expected to help development of posttraumatic stress disorder treatment. In this study, we combined multiple stress (MS) and longitudinal in vivo magnetic resonance imaging to reveal the effects of long-lasting anxiety-like behaviors on adult male rat brains.</p></div><div><h3>Methods</h3><p>Twelve male Wistar rats (8 weeks old) were exposed to the MS of 1-mA footshocks and forced swimming, while 12 control rats were placed in a plastic cage. Contextual fear conditioning with 0.1-mA footshocks in a context different from the MS was conducted 15 days after the MS for both groups. Three retention tests were administered after 24 hours and 9 and 16 days. Two magnetic resonance imaging scans were conducted, one on the day before MS induction and one the day after the third retention test, with a 32-day interval.</p></div><div><h3>Results</h3><p>The MS group showed greater freezing responses than the control group in all retention tests. Whole-brain voxel-based morphometry analyses revealed reduced gray matter volume in the anterior amygdalohippocampal area in MS group rats compared with control rats. These volume changes were negatively associated with freezing time in the third retention test in the MS group.</p></div><div><h3>Conclusions</h3><p>These results suggest that individual variability in the amygdalohippocampal area may be related to long-lasting fear responses after severe stress.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 5","pages":"Article 100334"},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000478/pdfft?md5=cf1987b205b4635030317c492bb218d0&pid=1-s2.0-S2667174324000478-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141052204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13DOI: 10.1016/j.bpsgos.2024.100333
Julia M. Sheffield , Aaron P. Brinen , Brandee Feola , Stephan Heckers , Philip R. Corlett
Psychological treatments for persecutory delusions, particularly cognitive behavioral therapy for psychosis, are efficacious; however, mechanistic theories explaining why they work rarely bridge to the level of cognitive neuroscience. Predictive coding, a general brain processing theory rooted in cognitive and computational neuroscience, has increasing experimental support for explaining symptoms of psychosis, including the formation and maintenance of delusions. Here, we describe recent advances in cognitive behavioral therapy for psychosis–based psychotherapy for persecutory delusions, which targets specific psychological processes at the computational level of information processing. We outline how Bayesian learning models employed in predictive coding are superior to simple associative learning models for understanding the impact of cognitive behavioral interventions at the algorithmic level. We review hierarchical predictive coding as an account of belief updating rooted in prediction error signaling. We examine how this process is abnormal in psychotic disorders, garnering noisy sensory data that is made sense of through the development of overly strong delusional priors. We argue that effective cognitive behavioral therapy for psychosis systematically targets the way sensory data are selected, experienced, and interpreted, thus allowing for the strengthening of alternative beliefs. Finally, future directions based on these arguments are discussed.
{"title":"Understanding Cognitive Behavioral Therapy for Psychosis Through the Predictive Coding Framework","authors":"Julia M. Sheffield , Aaron P. Brinen , Brandee Feola , Stephan Heckers , Philip R. Corlett","doi":"10.1016/j.bpsgos.2024.100333","DOIUrl":"10.1016/j.bpsgos.2024.100333","url":null,"abstract":"<div><p>Psychological treatments for persecutory delusions, particularly cognitive behavioral therapy for psychosis, are efficacious; however, mechanistic theories explaining why they work rarely bridge to the level of cognitive neuroscience. Predictive coding, a general brain processing theory rooted in cognitive and computational neuroscience, has increasing experimental support for explaining symptoms of psychosis, including the formation and maintenance of delusions. Here, we describe recent advances in cognitive behavioral therapy for psychosis–based psychotherapy for persecutory delusions, which targets specific psychological processes at the computational level of information processing. We outline how Bayesian learning models employed in predictive coding are superior to simple associative learning models for understanding the impact of cognitive behavioral interventions at the algorithmic level. We review hierarchical predictive coding as an account of belief updating rooted in prediction error signaling. We examine how this process is abnormal in psychotic disorders, garnering noisy sensory data that is made sense of through the development of overly strong delusional priors. We argue that effective cognitive behavioral therapy for psychosis systematically targets the way sensory data are selected, experienced, and interpreted, thus allowing for the strengthening of alternative beliefs. Finally, future directions based on these arguments are discussed.</p></div>","PeriodicalId":72373,"journal":{"name":"Biological psychiatry global open science","volume":"4 4","pages":"Article 100333"},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667174324000466/pdfft?md5=8d05befc55ed219b58624ffd486006d1&pid=1-s2.0-S2667174324000466-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141026969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}