Christopher A. Guevara, Kumayl Alloo, Swati Gupta, Romario Thomas, Pamela del Valle, Alexandra R. Magee, Deanna L. Benson, George W. Huntley
{"title":"帕金森氏症 LRRK2-G2019S 风险基因突变促使不同性别的行为和细胞适应慢性可变压力","authors":"Christopher A. Guevara, Kumayl Alloo, Swati Gupta, Romario Thomas, Pamela del Valle, Alexandra R. Magee, Deanna L. Benson, George W. Huntley","doi":"10.3389/fnbeh.2024.1445184","DOIUrl":null,"url":null,"abstract":"Anxiety is a psychiatric non-motor symptom of Parkinson’s that can appear in the prodromal period, prior to significant loss of midbrain dopamine neurons and motor symptoms. Parkinson’s-related anxiety affects females more than males, despite the greater prevalence of Parkinson’s in males. How stress, anxiety and Parkinson’s are related and the basis for a sex-specific impact of stress in Parkinson’s are not clear. We addressed this using young adult male and female mice carrying a G2019S knockin mutation of leucine-rich repeat kinase 2 (<jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup>) and <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice. In humans, <jats:italic>LRRK2</jats:italic><jats:sup>G2019S</jats:sup> significantly elevates the risk of late-onset Parkinson’s. To assess within-sex differences between <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> and control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design whereby <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> and <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice underwent tests of anxiety-like behaviors before (baseline) and following a 28 day (d) variable stress paradigm. There were no differences in behavioral measures between genotypes in males or females at baseline, indicating that the mutation alone does not produce anxiety-like responses. Following chronic stress, male <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact on <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice while significantly increasing latency to feed in <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice. Female <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice were impacted by chronic stress similarly to wildtype females across all behavioral measures. Subsequent post-stress analyses compared cFos immunolabeling-based cellular activity patterns across several stress-relevant brain regions. The density of cFos-activated neurons across brain regions in both male and female <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice was generally lower compared to stressed <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> mice, except for the nucleus accumbens of male <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in some, but not all stress-related brain regions.","PeriodicalId":12368,"journal":{"name":"Frontiers in Behavioral Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress\",\"authors\":\"Christopher A. Guevara, Kumayl Alloo, Swati Gupta, Romario Thomas, Pamela del Valle, Alexandra R. Magee, Deanna L. Benson, George W. Huntley\",\"doi\":\"10.3389/fnbeh.2024.1445184\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Anxiety is a psychiatric non-motor symptom of Parkinson’s that can appear in the prodromal period, prior to significant loss of midbrain dopamine neurons and motor symptoms. Parkinson’s-related anxiety affects females more than males, despite the greater prevalence of Parkinson’s in males. How stress, anxiety and Parkinson’s are related and the basis for a sex-specific impact of stress in Parkinson’s are not clear. We addressed this using young adult male and female mice carrying a G2019S knockin mutation of leucine-rich repeat kinase 2 (<jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup>) and <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice. In humans, <jats:italic>LRRK2</jats:italic><jats:sup>G2019S</jats:sup> significantly elevates the risk of late-onset Parkinson’s. To assess within-sex differences between <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> and control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design whereby <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> and <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice underwent tests of anxiety-like behaviors before (baseline) and following a 28 day (d) variable stress paradigm. There were no differences in behavioral measures between genotypes in males or females at baseline, indicating that the mutation alone does not produce anxiety-like responses. Following chronic stress, male <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact on <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice while significantly increasing latency to feed in <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> control mice. Female <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice were impacted by chronic stress similarly to wildtype females across all behavioral measures. Subsequent post-stress analyses compared cFos immunolabeling-based cellular activity patterns across several stress-relevant brain regions. The density of cFos-activated neurons across brain regions in both male and female <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice was generally lower compared to stressed <jats:italic>Lrrk2</jats:italic><jats:sup>WT</jats:sup> mice, except for the nucleus accumbens of male <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the <jats:italic>Lrrk2</jats:italic><jats:sup>G2019S</jats:sup> mutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in some, but not all stress-related brain regions.\",\"PeriodicalId\":12368,\"journal\":{\"name\":\"Frontiers in Behavioral Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2024-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Behavioral Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3389/fnbeh.2024.1445184\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BEHAVIORAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Behavioral Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fnbeh.2024.1445184","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress
Anxiety is a psychiatric non-motor symptom of Parkinson’s that can appear in the prodromal period, prior to significant loss of midbrain dopamine neurons and motor symptoms. Parkinson’s-related anxiety affects females more than males, despite the greater prevalence of Parkinson’s in males. How stress, anxiety and Parkinson’s are related and the basis for a sex-specific impact of stress in Parkinson’s are not clear. We addressed this using young adult male and female mice carrying a G2019S knockin mutation of leucine-rich repeat kinase 2 (Lrrk2G2019S) and Lrrk2WT control mice. In humans, LRRK2G2019S significantly elevates the risk of late-onset Parkinson’s. To assess within-sex differences between Lrrk2G2019S and control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design whereby Lrrk2G2019S and Lrrk2WT control mice underwent tests of anxiety-like behaviors before (baseline) and following a 28 day (d) variable stress paradigm. There were no differences in behavioral measures between genotypes in males or females at baseline, indicating that the mutation alone does not produce anxiety-like responses. Following chronic stress, male Lrrk2G2019S mice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact on Lrrk2G2019S mice while significantly increasing latency to feed in Lrrk2WT control mice. Female Lrrk2G2019S mice were impacted by chronic stress similarly to wildtype females across all behavioral measures. Subsequent post-stress analyses compared cFos immunolabeling-based cellular activity patterns across several stress-relevant brain regions. The density of cFos-activated neurons across brain regions in both male and female Lrrk2G2019S mice was generally lower compared to stressed Lrrk2WT mice, except for the nucleus accumbens of male Lrrk2G2019S mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the Lrrk2G2019S mutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in some, but not all stress-related brain regions.
期刊介绍:
Frontiers in Behavioral Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the neural mechanisms underlying behavior. Field Chief Editor Nuno Sousa at the Instituto de Pesquisa em Ciências da Vida e da Saúde (ICVS) is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
This journal publishes major insights into the neural mechanisms of animal and human behavior, and welcomes articles studying the interplay between behavior and its neurobiological basis at all levels: from molecular biology and genetics, to morphological, biochemical, neurochemical, electrophysiological, neuroendocrine, pharmacological, and neuroimaging studies.