Hyperthermia elevates brain temperature and improves behavioural signs in animal models of Autism spectrum disorder

Abstract

Autism Spectrum Disorders (ASD) are predominantly developmental in nature and largely genetically determined. There are some human data supporting the idea that fever can improve symptoms in some individuals but the human data for this are limited and there are almost no data to support this from animal models. In the current study, we used a whole body hyperthermia (WBH) protocol and systemic inflammation induced by bacterial endotoxin (LPS) to dissociate temperature and inflammatory elements of fever in order to examine the impact of these environmental stressors on behavioural signs in two animal models relevant to ASD: C58BL/6 and Shank3B- mice. While only LPS induced inflammatory signatures in the brain, WBH and LPS induced both overlapping and distinct neuronal cFos activation in several brain regions and modest effects on heat shock gene expression. In behavioural experiments LPS significantly suppressed most activities over 24-48 hours while WBH reduced repetitive behaviours and improved social interaction in C58BL/6 mice. In Shank3B- mice WBH significantly reduced compulsive grooming. The data are the first, to our knowledge, to demonstrate that elevated body temperature, in the absence of underpinning inflammation, can improve some behavioural signs in two distinct animal models of ASD. Given the developmental and genetic nature of ASD, evidence that symptoms may be ameliorated by environmental perturbations indicates that there are possibilities for improving function in these individuals.

Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability

“…While our research group and others have reported that repeated oxytocin treatment can lead to increased sociability in mouse models [16,38,39,129], not all investigators have observed prosocial effects with chronic oxytocin regimens [130]. Results from clinical studies examining chronic oxytocin effects in ASD have been similarly mixed [131][132][133].…”

“…Mouse models play an important role in understanding the causes of ASD [35]. C58/J is an inbred mouse strain that exhibits low sociability primarily in males and deficits in social transmission of food preference [36][37][38]. In the 3-chamber social choice test used to assess sociability, our research group has found that C58/J mice exhibit divergent phenotypes with approximately 50% of mice exhibiting positive sociability and 50% exhibiting social avoidance [37].…”

“…In the 3-chamber social choice test used to assess sociability, our research group has found that C58/J mice exhibit divergent phenotypes with approximately 50% of mice exhibiting positive sociability and 50% exhibiting social avoidance [37]. C58/J mice also develop motor stereotypic behaviors including backflipping, "jackhammer" jumping, and upright scrabbling which could reflect abnormal repetitive and social behavior in ASD [37,38]. Studies have demonstrated that oxytocin has prosocial effects in adolescent and adult C58/J mice following a subchronic oxytocin treatment regimen and that enhanced sociability was still present two weeks following treatment [39,40].…”