Thursday, November 21, 2024
11/21/2024
Project Summary Rates of neurodevelopmental disorders (NDDs) with socioemotional deficits are rapidly rising, including general and social anxiety disorders (ADs, more common in women). Although environmental factors, including chemical exposures in early development, are universally thought to increase NDD risk, most work to date has almost exclusively focused on genetic factors. One of the few environmental factors implicated in sex-specifically impacting behaviors relevant to NDDs with socioemotional deficits is developmental exposure to flame retardants (FRs). FRs and its components are widely used in electronics, infant products, and furniture, resulting in ubiquitous human exposure. Our previous work has shown that developmental exposure to the chemical FR mixture Firemaster 550 (FM 550) sex-specifically alters anxiety and social behavior in several species. Since it is challenging to directly link environmental chemical exposure to NDD-relevant behavioral and neural endpoints due to the lack of human-typical social behaviors in many laboratory rodents, we have employed the more human-relevant, spontaneously prosocial animal model, the prairie vole (Microtus ochrogaster). In the prairie vole model, developmental FM 550 exposure sex-specifically impacted anxiety, social interaction, exploratory motivation, and social pair bond formation. The greatest effects were detected in females, who displayed generalized and social anxiety, while males displayed a decreased ability to form social pair bonds. The mechanisms by which FM 550 exposure alters the neural systems that are integral to these behaviors and disorders remain poorly understood, providing the rationale for this proposal. Here we focus on dopamine (DA), oxytocin (OT) and vasopressin (AVP) systems in the social brain neural network (SBNN), which includes sexually differentiated brain regions such as the nucleus accumbens (NAcc) that are key for coordinating NDD-relevant behaviors. We will leverage the prairie vole model and our synergistic expertise in developmental neurotoxicology, autoradiography, genetics, electrophysiology, and neurochemistry to identify how FM550 impacts DA/OT/AVP receptor expression, receptor action on neuron function, and DA signaling as assessed using voltammetry in awake behaving animals. Our central hypothesis is that developmental exposure to FM 550 disrupts DA/OT/AVP receptor density, DA/OT/AVP electrical function, and DA signaling in awake, behaving animals. We address this central hypothesis in voles of both sexes. There are three aims: 1) Test the hypothesis that developmental FM 550 exposure impacts DA/OT/AVP receptor density and related gene expression, 2) Test the hypothesis that developmental FM 550 exposure impacts DA/OT/AVP receptor action on neuron electrical function, and 3) Investigate the effects of developmental FM 550 exposure on DA signaling relevant to social interactions. Overall, the proposed studies are significant and high impact because they leverage a unique model animal with enhanced translational value to identify specific novel mechanisms by which DA/OT/AVP receptors, neuron function and DA signaling are vulnerable to developmental chemical exposures.
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