TY - JOUR
T1 - The Impact of the PI3K/Akt Signaling Pathway in Anxiety and Working Memory in Young and Middle-Aged PDK1 K465E Knock-In Mice
AU - Giménez-Llort, Lydia
AU - Santana-Santana, Mikel
AU - Bayascas, José Ramón
N1 - Funding Information:
LG-L designed and performed the behavioral tests and illustrated the graphical abstract and the proposed wheels of correlation. MS-S constructed and analyzed the matrix of data and illustrated the results. JB provided the animals and financial support. All authors participated in the scientific discussions and contributed to the writing of the manuscript.
Funding Information:
We thank Jessica Pairada and N?ria Moix (Estabulari de Rosegadors of the Universitat de Lleida) for animal care. Funding. This work was funded by the Ministerio de Econom?a y Competitividad (MINECO), Programa Estatal de Investigaci?n, Desarrollo e Innovaci?n Orientada a los Retos de la Sociedad (SAF2014-52813-R) to JB.
Publisher Copyright:
© Copyright © 2020 Giménez-Llort, Santana-Santana and Bayascas.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/8
Y1 - 2020/5/8
N2 - Dysfunction and dysregulation at the genetic, neural, and behavioral levels point at the fine-tuning of broadly spread networks as critical for a wide array of behaviors and mental processes through the life span. This brain-based evidence, from basic to behavioral neuroscience levels, is leading to a new conceptualization of mental health and disease. Thus, the Research Domain Criteria considers phenotypic differences observed among disorders as explained by variations in the nature and degree of neural circuitry disruptions, under the modulation of several developmental, compensatory, environmental, and epigenetic factors. In this context, we aimed to describe for the first time the in vivo behavioral impact of tweaking the PI3K/Akt signaling pathway known to play an essential role in the regulation of cellular processes, leading to diverse physiological responses. We explored the effects in young (YA, 3–4 months of age) and mature (MA, 11–14 months of age) male and female PDK1 K465E knock-in mice in a battery of tests under different anxiogenic conditions. The results evidenced that the double mutation of the PDK1 pleckstrin homology (PH) domain resulted in an enhancement of the negative valence system shown as an increase of responses of fear- and anxiety-like behaviors in anxiogenic situations. Interestingly, this seemed to be specific of YA and found regulated at middle age. In contrast, cognitive deficits, as measured in a spatial working memory task, were found in both YA and MA mutants and independently of the level of their anxious-like profiles. These distinct age- and function-dependent impacts would be in agreement with the distinct cortical and limbic deficits in the Akt signaling in the brain we have recently described in these same animals. The elicitation of age- and neuronal-dependent specific patterns suggests that fine-tuning the intensity of the PKB/Akt signal that enables diverse physiological response has also its in vivo translation into the negative valence system and age is a key regulatory factor.
AB - Dysfunction and dysregulation at the genetic, neural, and behavioral levels point at the fine-tuning of broadly spread networks as critical for a wide array of behaviors and mental processes through the life span. This brain-based evidence, from basic to behavioral neuroscience levels, is leading to a new conceptualization of mental health and disease. Thus, the Research Domain Criteria considers phenotypic differences observed among disorders as explained by variations in the nature and degree of neural circuitry disruptions, under the modulation of several developmental, compensatory, environmental, and epigenetic factors. In this context, we aimed to describe for the first time the in vivo behavioral impact of tweaking the PI3K/Akt signaling pathway known to play an essential role in the regulation of cellular processes, leading to diverse physiological responses. We explored the effects in young (YA, 3–4 months of age) and mature (MA, 11–14 months of age) male and female PDK1 K465E knock-in mice in a battery of tests under different anxiogenic conditions. The results evidenced that the double mutation of the PDK1 pleckstrin homology (PH) domain resulted in an enhancement of the negative valence system shown as an increase of responses of fear- and anxiety-like behaviors in anxiogenic situations. Interestingly, this seemed to be specific of YA and found regulated at middle age. In contrast, cognitive deficits, as measured in a spatial working memory task, were found in both YA and MA mutants and independently of the level of their anxious-like profiles. These distinct age- and function-dependent impacts would be in agreement with the distinct cortical and limbic deficits in the Akt signaling in the brain we have recently described in these same animals. The elicitation of age- and neuronal-dependent specific patterns suggests that fine-tuning the intensity of the PKB/Akt signal that enables diverse physiological response has also its in vivo translation into the negative valence system and age is a key regulatory factor.
KW - PI3K/Akt
KW - RDoC
KW - aging
KW - animal model
KW - anxiety
KW - cognition
KW - fine tuning
KW - signaling pathway
UR - http://www.scopus.com/inward/record.url?scp=85085153247&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fnbeh.2020.00061
DO - https://doi.org/10.3389/fnbeh.2020.00061
M3 - Article
C2 - 32457586
AN - SCOPUS:85085153247
VL - 14
JO - Frontiers in Behavioral Neuroscience
JF - Frontiers in Behavioral Neuroscience
SN - 1662-5153
M1 - 61
ER -