Prenatal domoic acid exposure disrupts mouse pro-social behavior and functional connectivity MRI

Abstract

Domoic acid (DA) is a toxin produced by marine algae and known primarily for its role in isolated outbreaks of Amnestic Shellfish Poisoning and for the damage it inflicts on marine mammals, particularly California sea lions. Lethal effects of DA are often preceded by seizures and coma. Exposure to DA during development can result in subtle and highly persistent effects on brain development and include behavioral changes that resemble diagnostic features of schizophrenia and anomalies in social behavior we believe are relevant to autism spectrum disorder (ASD). To more fully examine this hypothesis, we chose to examine adolescent mice exposed in utero to DA for endpoints relevant to ASD, specifically changes in social behavior and network structure, the latter measured by resting state functional connectivity (rsfcMRI). We found that male offspring exposed in utero to DA expressed reproducible declines in social interaction and atypical patterns of functional connectivity in the anterior cingulate, a region of the default mode network that is critical for social functioning. We also found disruptions in global topology in regions involved in the processing of reward, social, and sensory experiences. Finally, we found that DA exposed males expressed a pattern of local over-connectivity. These anomalies in brain connectivity bear resemblance to connectivity patterns in ASD and help validate DA-exposed mice as a model of this mental disability.

Chronic Subconvulsive Activity during Early Postnatal Life Produces Autistic Behavior in the Absence of Neurotoxicity in the Juvenile Weanling Period

“…This perinatal KA dosing model is consistent with a previously established rodent model of ASD that used low (subconvulsive) doses of demoic acid (DOM) or KA, but their paradigm was initiated in the second postnatal week, which resulted in long-term changes in behavior and histopathology that manifested in adulthood [31]. In a more recent study, DOM was exposed prenatally to mice which caused sex-related behavioral changes that resembled diagnostic features relevant to ASD in males [32,33]. Alterations in sociability, social recognition, and stereotypic behaviors generally have been assessed in adulthood [34].…”

Functional networks and network perturbations in rodents

“…Recently, a mechanism linking immune dysfunction and behavioral impairment such as those observed in ASD has been found, with immune-deficitent SCID mice exhibiting hyperconnectivity between multiple frontal and insular regions (Filiano et al, 2016). The influence of prenatal exposure to toxins, for example domoic acid, has also been studied in the mouse revealing increased connectivity in the anterior part of the DMN but a decrease in the posterior part, as well as increased local connectivity (Mills et al, 2016). These studies demonstrate the value of connectivity imaging in rodent models in elucidating ASD associated mechanisms.…”

Correlated gene expression and anatomical communication support synchronized brain activity in the mouse functional connectome

“…The selection of anesthesia may influence FC (37). Of various anesthetic regimines, we selected low dose isoflurane for the present study based on the following previous findings: 1) Functional connectivity following 1% isoflurane is preserved and comparable to that of awake mice and rats (34,18,35,36,45). 2) c-Fos activation (an immediate early gene) can be observed in isoflurane-anesthetized mice and rats (46)(47)(48).…”