Abstract
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.
Highlights
The expression of psychiatric symptoms such as anxiety across lifespan still needs important research efforts to dissect and understand their modulation’s biological and environmental basis [1]
We recently showed that the double mutation of the PDK1 PH-domain (PDK1−/−) resulted in an enhancement of negative valence system (NVS) shown as an increase of responses of fear and anxiety-like behaviors in anxiogenic situations [36]
We describe for the first time the in vivo effects of the PDK1 mutation in the PH domain depending on age and genetic load
Summary
The expression of psychiatric symptoms such as anxiety across lifespan still needs important research efforts to dissect and understand their modulation’s biological and environmental basis [1]. The new understanding of psychopathology in terms of dysregulation and dysfunction in essential behavioral features through neurobiology and behavioral neuroscience can provide a promising research scenario [2,3]. In this new conceptualization, fear, aggression, and distress are three draft constructs within the negative valence system (NVS), one of the five domains in the NIMH’s Research Domain. The molecular genetic basis of NVS phenotypes is considered to be in its infancy, yet with few candidate genes nominated for anxiety disorders [5] In this context, basic research on signal transduction provides an advanced close examination
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