4a930182f4c21f74128d9e5d0d0c7f01 biomedicines_a2021v9n7p747.pdf 2a22db44dfaed488601584f006fb1adc46aed91a biomedicines_a2021v9n7p747.pdf d9223c539655fba2b7c2b6463dd1cb8edb37fa43ad93faebb8e2ee12c51185d0 biomedicines_a2021v9n7p747.pdf Title: Fine-Tuning the PI3K/Akt Signaling Pathway Intensity by Sex and Genotype-Load: Sex-Dependent Homozygotic Threshold for Somatic Growth but Feminization of Anxious Phenotype in Middle-Aged PDK1 K465E Knock-In and Heterozygous Mice Subject: According to the Research Domain Criteria (RDoC), phenotypic differences among disorders may be explained by variations in the nature and degree of neural circuitry disruptions and/or dysfunctions modulated by several biological and environmental factors. We recently demonstrated the in vivo behavioral translation of tweaking the PI3K/Akt signaling, an essential pathway for regulating cellular processes and physiology, and its modulation through aging. Here we describe, for the first time, the in vivo behavioral impact of the sex and genetic-load tweaking this pathway. The anxiety-like phenotypes of 61 mature (11–14-month-old) male and female PDK1 K465E knock-in, heterozygous, and WT mice were studied. Forced (open-field) anxiogenic environmental conditions were sensitive to detect sex and genetic-load differences at middle age. Despite similar neophobia and horizontal activity among the six groups, females exhibited faster ethograms than males, with increased thigmotaxis, increased wall and bizarre rearing. Genotype-load unveiled increased anxiety in males, resembling female performances. The performance of mutants in naturalistic conditions (marble test) was normal. Homozygotic-load was needed for reduced somatic growth only in males. Factor interactions indicated the complex interplay in the elicitation of different negative valence system’s items and the fine-tuning of PI3K/Akt signaling pathway intensity by genotype-load and sex. Keywords: RDoC; PI3K/Akt; signaling pathway; sex; genetic load; fine tuning; anxiety; aging Author: Mikel Santana-Santana, José-Ramón Bayascas and Lydia Giménez-Llort Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Jul 7 09:35:55 2021 CEST ModDate: Wed Jul 7 09:42:59 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2103472 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SLVAZP+VnURWPalladioL Type 1 Custom yes yes no 10 0 FYPCTW+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 SKFODU+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 IMGWYE+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 HJOMHV+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 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LFCOGI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 156 0 LFCOGJ+PalatinoLinotype CID TrueType Identity-H yes yes yes 159 0 LFCOGK+PalatinoLinotype TrueType WinAnsi yes yes no 165 0 LFCOGM+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 168 0 LFCOGI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 178 0 LFCOGJ+PalatinoLinotype CID TrueType Identity-H yes yes yes 181 0 LFCOGK+PalatinoLinotype TrueType WinAnsi yes yes no 187 0 LFCOGM+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 190 0 QDCWHF+EURM10 Type 1 Builtin yes yes no 203 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:30:24 CEST RepresentationInformation: biomedicines_a2021v9n7p747.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:58:05 CEST Size: 2103472 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 432 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Generation of PDK1K465E/K465E Mice and Genotyping Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Behavioral Assessments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Statistics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Somatic Growth/Bodyweight Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Open Field Test Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Marble Burying Test Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Homozygous-Load of the Mutant Gene Is Needed for the Reduced Somatic Growth Effects Only in Mutant Males Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Similar Neophobia and Locomotion, but Increased Anxiety-Like Phenotype in Mutant Females and Feminized Anxious-Like Phenotype of Mutant Males Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Performance of Mutants Can Resemble Normal under Naturalistic Anxiogenic Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Fine-Tuning the PI3K/Akt Signaling Pathway Intensity by Sex and Genotype-Load: Sex-Dependent Homozygotic Threshold for Somatic Growth but Feminization of Anxious Phenotype in Middle-Aged PDK1 K465E Knock-In and Heterozygous Mice Author: Mikel Santana-Santana, José-Ramón Bayascas and Lydia Giménez-Llort Subject: According to the Research Domain Criteria (RDoC), phenotypic differences among disorders may be explained by variations in the nature and degree of neural circuitry disruptions and/or dysfunctions modulated by several biological and environmental factors. We recently demonstrated the in vivo behavioral translation of tweaking the PI3K/Akt signaling, an essential pathway for regulating cellular processes and physiology, and its modulation through aging. Here we describe, for the first time, the in vivo behavioral impact of the sex and genetic-load tweaking this pathway. The anxiety-like phenotypes of 61 mature (11 14-month-old) male and female PDK1 K465E knock-in, heterozygous, and WT mice were studied. Forced (open-field) anxiogenic environmental conditions were sensitive to detect sex and genetic-load differences at middle age. Despite similar neophobia and horizontal activity among the six groups, females exhibited faster ethograms than males, with increased thigmotaxis, increased wall and bizarre rearing. Genotype-load unveiled increased anxiety in males, resembling female performances. The performance of mutants in naturalistic conditions (marble test) was normal. Homozygotic-load was needed for reduced somatic growth only in males. Factor interactions indicated the complex interplay in the elicitation of different negative valence system’s items and the fine-tuning of PI3K/Akt signaling pathway intensity by genotype-load and sex. 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