Inside the Developing Brain to Understand Teen Behavior From Rat Models: Metabolic, Structural, and Functional-Connectivity Alterations Among Limbic Structures Across Three Pre-adolescent Stages.

Adolescence is an age of transition when most brain structures undergo drastic modifications, becoming progressively more interconnected and undergoing several changes from a metabolic and structural viewpoint. In the present study, three MR techniques are used in rats to investigate how metabolites, structures and patterns of connectivity do change. We focused in particular on areas belonging to the limbic system, across three post-weaning developmental stages: from "early" (PND 21-25) to "mid" (i.e., a juvenile transition, PND 28-32) and then to "late" (i.e., the adolescent transition, PND 35-39). The rs-fMRI data, with comparison between early and mid (juvenile transition) age-stage rats, highlights patterns of enhanced connectivity from both Striata to both Hippocampi and from there to (left-sided) Nucleus accumbens (NAcc) and Orbitofrontal Cortex (OFC). Also, during this week there is a maturation of pathways from right Striatum to ipsilateral NAcc, from right OFC to ipsilateral NAcc and vice versa, from left Prefrontal Cortex to ipsilateral OFC and eventually from left Striatum, NAcc and Prefrontal Cortex to contralateral OFC. After only 1 week, in late age-stage rats entering into adolescence, the first pathway mentioned above keeps on growing while other patterns appear: both NAcc are reached from contralateral Striatum, right Hippocampus from both Amygdalae, and left NAcc -further- from right Hippocampus. It's interesting to notice the fact that, independently from the age when these connections develop, Striata of both hemispheres send axons to both Hippocampi and both NAcc sides, both Hippocampi reach left NAcc and OFC and finally both NAcc sides reach right OFC. Intriguingly, the Striatum only indirectly reaches the OFC by passing through Hippocampus and NAcc. Data obtained with DTI highlight how adolescents' neurite density may be affected within sub-cortical gray matter, especially for NAcc and OFC at "late" age-stage (adolescence). Finally, levels of metabolites were investigated by 1H-MRS in the anterior part of the hippocampus: we put into evidence an increase in myo-inositol during juvenile transition and a taurine reduction plus a total choline increase during adolescent transition. In this paper, the aforementioned pattern guides the formulation of hypotheses concerning the correlation between the establishment of novel brain connections and the emergence of behavioral traits that are typical of adolescence.