Social cognition is a fundamental process essential for species survival. Disturbances in social processing have
been identified by the NIMH Research Domain Criteria Initiative as a major domain disrupted across psychiatric
disorders including neurodevelopmental disorders (NDDs) such as autism spectrum disorders (ASD). ASD
prevalence continues to increase at an alarming rate, affecting 1 in 54 U.S. children, and characterized by an
unexplained sexual dimorphism. While ASD has a strong genetic component, the disorder is in most cases,
multifactorial, resulting from sex-specific genetic susceptibilities interacting with environmental factors during
critical developmental periods. Thus environmental exposures, including exposures to endocrine disrupting
chemicals (EDCs), may contribute to the rising prevalence of ASD. However, experimental evidence has not
established a direct link with specific chemicals and mechanisms remain elusive. PBDEs are commercial flame
retardants found in human breast milk that are associated with developmental deficits in children. Our lab has
shown that the commercial PBDE mixture, DE-71, produces ASD-relevant phenotypes that include deficient
social recognition memory, exaggerated repetitive behavior, and altered neuromolecular profiles for the social
neuropeptides, oxytocin (OXT) and vasopressin, and their receptors. PBDEs structurally resemble thyroid
hormones (TH), which are both critical for neurodevelopment of social brain circuits and regulate OXT and AVP.
Therefore, I will test the novel hypothesis that developmental PBDEs produce a hypothyroid state, which disrupts
signaling in the central OXTergic system and malformation of social neural circuits leading to deficient
socioemotional behavior. In mechanistic studies under Aim 1, I will examine the TH targets of PBDEs and the
contribution of TH disruption to altered behavior and neuropeptide phenotypes of PBDE-exposed male and
female offspring using maternal thyroid supplementation. Chemogenetic activation of OXT release within the
PVN will be employed in an attempt to rescue PBDE-induced abnormal phenotypes. In circuit-level studies using
retrograde tract-tracing under Aim 2, I will examine PBDE reprogramming of the reciprocal preflimbic cortex to
basolateral amygdala circuit, which is critical for social recognition ability. Since this circuit depends on OXT
receptor (OXTR) signaling and is purported to receive OXTergic projections from PVN, I will determine if
developmental intranasal OXT rescues structural changes produced by PBDEs. These studies will investigate
the neurodevelopmental effects of maternal transfer of PBDEs across multiple levels of biological organization
and developmental ages to begin to understand mechanisms and critical windows of risk. My findings will provide
critical mechanistic information necessary to break through gaps in knowledge about the possible environmental
risk to NDDs. They will also inform about the role of oxytocin underlying social and emotion recognition behavior
and the mechanisms altering circuit-level function during neurodevelopment. Finally, the findings may eventually
translate to the development of alternative therapeutic approaches to treat psychosocial NDDs.
