Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression.

Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. However, the inherent impact of maternal genetics on in-utero inflammation and fetal neurodevelopment in the absence of strong external inflammatory exposures is not known. We used the PtenWT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. PtenWT/m3m4 (Momm3m4) or PtenWT/WT (MomWT) females, their offspring, and placental interface were analyzed for inflammatory markers, gene expression, and cellular phenotypes at E17.5. Postnatal behavior was tested by comparing pups from Momm3m4 vs. MomWT. Mothers of the PtenWT/m3m4 genotype (Momm3m4) showed inadequate induction of IL-10 mediated immunosuppression during pregnancy. Low IL-10 in the mother was directly correlated with decreased complement expression in the fetal liver. Fetuses from Momm3m4 had increased breakdown of the blood-brain-barrier, neuronal loss, and lack of glial cell maturation during in-utero stages. This impact of maternal genotype translated to a postnatal increase in the risk of newborn mortality, visible macrocephaly and ASD-like repetitive and social behaviors. Depending on maternal genotype, non-predisposed (wildtype) offspring showed ASD-like phenotypes, and phenotypic penetrance was decreased in predisposed pups from MomWT. Our study introduces the concept that maternal genetics alone, without any added external inflammatory insults, can modulate fetal neurodevelopment and ASD-related phenotypes in the offspring via alteration of IL-10 mediated materno-fetal immunosuppression.

Delay discounting in the pigeon: In search of a magnitude effect.

The magnitude effect, where larger outcomes are discounted proportionally less than smaller outcomes, is a well-established phenomenon in delay discounting by human participants. To this point in the literature magnitude effects have not been reliably evidenced in nonhuman animals. , however, used a concurrent-chains arrangement with pigeon and found evidence for a magnitude effect. Grace et al. suggested that in many delay discounting experimental arrangements with nonhuman animals (e.g., adjusting amount, adjusting delay) the organism is not given the opportunity to directly compare outcomes of different sizes. They suggest that because of the lack of direct comparison it is difficult for the organism to determine the relative size of each outcome, which in turn mutes the effect of the amount differences between outcomes. As a test of this "comparison hypothesis," the present experiment was conducted to assess whether the magnitude effect would be evidenced in pigeon when using an adjusting amount procedure where outcomes of different amounts were presented proximally. In the present arrangement, pigeons were presented two choice panels in an operant chamber where each panel was associated with an independent adjusting amount delay discounting task, but with differing outcome amounts (i.e., a 32-food pellet panel and an 8-food pellet panel). In this arrangement the choice panels alternated in their availability within a session from trial block to trial block. The present findings indicate no reliable effect of amount, even when the outcomes were proximal and thus readily comparable. This result suggests that the lack of magnitude effect is not driven by the organism's ability to compare the difference in amount between choice alternatives.

Towards validation of delay discounting in the pigeon.

A series of procedures were conducted in an attempt to assess various forms of validity related to the use of pigeons in research on delay discounting. In separate experimental arrangements, pigeons pressed a treadle, pecked a lit key, pecked a darkened key, or pecked a lit key with a hold as the required response. First, the obtained results were consistent with what would be necessary if the construct of delay discounting were being measured, which provides evidence of face validity. Second, criterion validity was assessed by comparing individual differences in rates of discounting across procedures. Third, to assess internal validity, each pigeon repeated the Treadle, Key Peck, and Dark Key procedures. Again, at both the aggregate and individual levels, the obtained indifference points did not differ systematically between replications. Finally, to assess external validity, discounting was observed regardless of the procedure, where the patterns of data at the aggregate level, and generally at the individual level, were orderly and well described by a hyperbolic function. In addition, rates of discounting were similar when pigeons pecked a lit key, a dark key, or a key with a hold; and each of those rates of discounting tended to be steeper than when treadle pressing. Generally speaking, pigeons that discounted relatively steeply on one procedure also tended to discount relatively steeply on the other procedures. The procedures evidence some of the necessary elements involved with the use of pigeons in research on delay discounting.