MOLECULAR CORRELATE OF MOUSE EXECUTIVE FUNCTION. TOP-DOWN AND BOTTOM-UP COMPLEMENTATIONS BY PRESYNAPTIC VERTEBRATE BRAIN-SPECIFIC Ntng GENE PARALOGS

Abstract

Executive function (EF) is a regulatory construct of learning and general cognitive abilities.Genetic variations underlying the architecture of cognitive phenotypes are likely to affect EF and associated behaviors. Mice lacking one of Ntng gene paralogs, encoding the vertebrate brain-specific presynaptic Netrin-G proteins, exhibit prominent deficits in the EF control.Brain areas responsible for gating the bottom-up and top-down information flows differentially express Ntng1 and Ntng2, distinguishing neuronal circuits involved in perception and cognition. As a result, high and low cognitive demand tasks (HCD and LCD, respectively) modulate Ntng1 and Ntng2 associations either with attention and impulsivity (AI) or working memory (WM), in a complementary manner. During the LCD Ntng2-supported neuronal gating of AI and WM dominates over the Ntng1-associated circuits. This is reversed during the HCD, when the EF requires a larger contribution of cognitive control, supported by Ntng1, over the Ntng2 pathways. Since human NTNG orthologs have been reported to affect human IQ (1), and an array of neurological disorders (2), we believe that mouse Ntng gene paralogs serve an analogous role but influencing brain executive functioning.

Behavior Variability of a Conditional Gene Knockout Mouse as a Measure of Subtle Phenotypic Trait Expression. The Case of Mouse Executive Function Distortion

“…For the calculus details see Fig.2, ST2-1, ST2-2, ST4-1, ST4-2, ST5-1, and ST5-2. The top panel (in italics) indicates the brain areas complementary expressing Ntng gene paralogs (1). !…”

“…As it can be seen from Fig.4A, PreP during LCD, and OE during both, LCD and HCD, are two parameters, the most affected by Ntng1 ablation within Emx1 and 5-HTT-expressing neurons. Similar approach has been used to re-analyze the already reported datasets (1;ST4-1 and ST4-2), incorporating data for the globally ablated Ntng1/2 paralogs (Fig.4B,C), and complementing the current conditional knockout and already published findings(1). Further integrating all generated parameters (ST2-1, and ST2-2) into the global ranks (Fig.5A), we conclude that serotonin plays a substantial role in the AI deficit during HCD and operant conditioning learning throughout the whole process.Adding to that, working memory deficit associated with the Ntng1/2 ablation (1), supports the observed operant conditioning learning difficulties by the Ntng1/2 global knockout mice(Fig.5B, ST4-1, and ST4-2), and complements the AI deficit(Fig.5C, ST5-1, and ST5-2).DISCUSSIONTo assess the degree of Ntng1 gene local ablation on the EF of mouse brain, wehave prepared two mouse lines with the expression of Ntng1 spatially turned off in excitatory cortical and subcortical Emx1 and serotonin transporter-expressing thalamic relay neurons.…”

“…A. Causal genotype-phenotype relationship deduction. C-means fuzzy clustering (Euclidean C-means) was done in a genotype-blind manner using the obtained behavioral ranks(Fig.2)to predict subjects' genotype, as described in(1). See ST3 for the exact values of clustering probabilities.…”