Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

Pinares-Garcia, Paulo; Stratikopoulos, Marielle; Zagato, Alice; Loke, Hannah; Lee, Joohyung

doi:10.3390/brainsci8080154

Cited by 144 publications

(101 citation statements)

References 333 publications

(417 reference statements)

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“…Therefore, our findings provide important novel information on sex specificity in the ontogeny of these receptors. This higher D1:D2 ratio seen in the IL of females compared to males could contribute to the etiology of female‐dominant disorders such as anxiety disorders (Remes, Brayne, van der Linde, & Lafortune, ) and depression (Noble, ; Pinares‐Garcia, Stratikopoulos, Zagato, Loke, & Lee, ), which also emerge during adolescence and continue into adulthood. Our data also indicate that the sex difference in IL D1:D2 ratio are further enhanced in adults compared to adolescents.…”

Section: Discussionmentioning

confidence: 99%

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Cullity

Madsen

Perry

et al. 2018

J of Comparative Neurology

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Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1‐ or D2‐expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein‐tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.

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Section: Discussionmentioning

confidence: 99%

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Cullity

Madsen

Perry

et al. 2018

J of Comparative Neurology

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“…Sex differences in susceptibility to anxiety, mood, and other neuropsychiatric disorders has been established in humans (99)(100)(101)(102). Therefore, the influence that mPFC physiology and function has on behavior in both males and females has significant translational value for identifying both susceptibility and treatment options.…”

Section: Pl Pyr Girk1 Knockout and Cus Exposure In Femalesmentioning

confidence: 99%

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

Anderson

Loke

Wrucke

et al. 2020

Preprint

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wordsMain Text: 4252 words Abstract Background: Imbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. Methods:In mice harboring a 'floxed' version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function. Results:In males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral-and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice.Conclusions: GIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

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“…This critical physiological process is dependent on not only the actions of sex hormones and other gonadal secretions following gonadal determination, but also the genetic mechanisms mediated by the genes located on the X and Y chromosomes (Arnold, 2017). Besides normal neural functions, sex or gender differences are also noted in the prevalence and symptomatology of many neurological diseases and mental illnesses, such as Alzheimer's disease, autism, depression, and schizophrenia (Bao and Swaab, 2010; Pinares‐Garcia et al, 2018). As sexual differentiation may confer inherent sex‐specific disease vulnerability (Bao and Swaab, 2011; McCarthy, 2016), elucidation of the mechanisms underlying sexual dimorphism in brain structure and function will provide important insights into the etiologies of gender‐biased neuropsychiatric disorders and promote the development of new therapies.…”

Section: Introductionmentioning

confidence: 99%

Androgenic regulation of sexually dimorphic expression of RNA binding motif protein 48 in the developing mouse cortex and hippocampus

Franklin

Armoskus

Taniguchi

et al. 2019

Intl J of Devlp Neuroscience

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To further reveal the molecular mechanism underlying sexual differentiation of the mouse cerebral cortex and hippocampus, we reanalyzed our previous microarray study with Gene Ontology (GO) term enrichment and found that the GO term “RNA binding” was over‐represented among the 89 sexually dimorphic candidate genes. Thus, we selected 16 autosomal genes annotated to the term RNA binding and profiled their mRNA expression in the developing male and female mouse cortex/hippocampus. During the first three weeks after birth, sex differences in mRNA levels of Khdrbs2, Nanos2, Rbm48, and Tdrd3 were observed in the mouse cortex/hippocampus. Of these genes, only the female‐biased expression of Rbm48 in neonates was abolished by prenatal exposure to testosterone propionate (TP), while postnatal treatment of TP three weeks after birth increased Rbm48 and Tdrd3 mRNA levels in both sexes. Regardless of sex, the postnatal cortex/hippocampus also showed a marked increase in the content of androgen receptor (Ar) and estrogen receptor β (Esr2), but a decrease in estrogen receptor α (Esr1) and aromatase (Cyp19a1), which might confer the different responses of Rbm48 to prenatal and postnatal TP. Our results suggest that androgen‐regulated, sexually dimorphic Rbm48 expression might present a novel molecular mechanism by which perinatal androgens control development of sexual dimorphism in cortical and hippocampal structure and function.

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Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

Cited by 144 publications

References 333 publications

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

Androgenic regulation of sexually dimorphic expression of RNA binding motif protein 48 in the developing mouse cortex and hippocampus

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