Maternal Immune Activation Alters Adult Behavior, Gut Microbiome and Juvenile Brain Oscillations in Ferrets

Abstract

Maternal immune activation (MIA) has been identified as a causal factor in psychiatric disorders by epidemiological studies in humans and mechanistic studies in rodent models. Addressing this gap in species between mice and human will accelerate the understanding of the role of MIA in the etiology of psychiatric disorders. Here, we provide the first study of MIA in the ferret (Mustela putorius furo), an animal model with a rich history of developmental investigations due to the similarities in developmental programs and cortical organization with primates. We found that after MIA by injection of PolyIC in the pregnant mother animal, the adult offspring exhibited reduced social behavior, less eye contact with humans, decreased recognition memory, a sex-specific increase in amphetamine-induced hyperlocomotion, and altered gut microbiome. We also studied the neurophysiological properties of the MIA ferrets in development by in-vivo recordings of the local field potential (LFP) from visual cortex in five- to six-week-old animals, and found that the spontaneous and sensory-evoked LFP had decreased power, especially in the gamma frequency band. Overall, our results provide the first evidence for the detrimental effect of MIA in ferrets and support the use of the ferret as an intermediate model species for the study of disorders with neurodevelopmental origin.

Putative modulation of the gut microbiome by probiotics enhances preference for novelty in a preliminary double-blind placebo-controlled study in ferrets

“…The adult ferrets used in this study were born to 6 pregnant ferrets in house. As previously described [7], at G30, i.e., day 30 of gestation, the pregnant mother animals were randomly assigned to receive either 10 mg/kg PolyIC (polyinosinic:polycytidylic acid, potassium salt, Sigma-Aldrich, St. Louis, MO, dissolved 10 mg/ml in PBS) or 1 ml/kg PBS via intraperitoneal (i.p.) injection under anesthesia introduced by 4-5% then sustained by 1-2% isoflurane.…”

“…The kits were kept with their mother until weaning at postnatal day 42. At this time, the male ferrets were separated for single housing [7].…”

“…Each sample was collected within 5 min of deposit and immediately frozen in a dry ice bath (−80 o C) before further processing. The 16S rDNA amplicon sequencing was performed at the University of North Carolina Microbiome Core Facility (Chapel Hill, NC) as previously described [7]. Briefly, DNA was extracted from stool samples using MagMAX Total Nucleic Acid Isolation kit (Thermo Fisher Scientific, Waltham, MA).…”

“…Behavioral tests were performed around the time-point of the first sample collection (Time-point A) and after sample collection at Time Point C. No behavioral assessments were performed at Timepoint B since the goal of the study was to investigate behavioral changes after completion of a course of probiotic administration. All behavioral tests were performed in a well-illuminated white 1.5 X 1.5 m 2 arena as previously described [7]. The arena was cleaned with 70% ethanol between tests on different animals, and the tests were conducted by experimenters blind to the group membership of the animals.…”

“…Despite this, it has remained unclear if probiotic interventions have long term effects and whether they modulate the gut ecosystem and behavior in the adult offspring in the MIA model. To address this gap, we performed a double-blind placebo-controlled probiotic intervention study in adult ferrets in our recently developed ferret MIA model [7]. Ferrets share important features of structure and function of the central nervous system with humans [8,9] and have emerged as promising, cost-effect intermediate model system for translational neuroscience studies [10].…”