Bridging Naturalistic Behavior and Nucleus Accumbens in Fragile X Syndrome: Behavioral Flexibility and Social Dynamics as Readouts of Sex and Gene Dosage

by Olivier Manzoni, PhD

Fragile X syndrome (FXS) symptoms often differ between the sexes. In females, the presence of both active and silenced copies of the FMR1 gene creates a mosaic pattern of gene expression. This mosaicism often leads to milder cognitive impairments than those seen in males, yet many females with FXS experience significant anxiety.

Despite these important differences, most research to date has focused primarily on males, leaving the biological mechanisms underlying sex-specific symptoms in FXS poorly understood.

Our project addresses this gap by investigating how gene dosage (the number of functional FMR1 gene copies) and sex interact to shape both behavior and brain function in FXS. We focus on the nucleus accumbens (NAc), a key brain region that integrates signals involved in reward, motivation, social behavior, and decision-making, while also contributing to motor control. Disruption of these processes has been implicated in FXS, where altered reward sensitivity, impaired motor coordination, and reduced behavioral flexibility may converge to produce core symptoms.

To uncover the underlying mechanisms, we will use a Fragile X mouse model to study the cellular properties of neurons in the nucleus accumbens and examine how gene dosage influences their structure and electrical activity. In parallel, we will use advanced deep-learning–based behavioral analyses to capture both group social dynamics and individual behavioral flexibility in naturalistic settings.

By integrating detailed analyses of brain circuits with high-resolution behavioral measurements, our goal is to reveal how sex and gene dosage interact to produce distinct symptom profiles in FXS. This combined approach will deepen our understanding of sex differences in FXS and help identify behavioral measures that are relevant for translational and therapeutic research.

Project Objectives

Our primary goal is to understand how variations in gene dosage and sex contribute to the severity of FXS symptoms. To achieve this, we have defined three specific objectives:

• Analyze naturalistic behavior using innovative paradigms that bridge mechanistic precision and real-world relevance, including the Towers Foraging Park to assess adaptive decision-making and the Live Mouse Tracker to study long-term social dynamics across sexes and gene dosages.
• Examine neuronal structure in the nucleus accumbens by reconstructing and measuring dendritic branching patterns and spine morphology, which are critical for communication between brain cells.
• Assess neuronal function by measuring the electrical properties of specific nucleus accumbens neurons to determine how gene dosage and sex shape their activity.

Through this comprehensive investigation of how sex and gene dosage shape brain cells and behavior, our research aims not only to advance understanding of Fragile X syndrome but also to provide insights relevant to other neurodevelopmental disorders with shared biological mechanisms.