BTBR T+ Itpr3tf/J (BTBR) mice are an Autism Spectrum Disorder (ASD)-like model that exhibit behavioral and physiological deficits similar to those observed in patients with ASD. While behavioral therapy is a first line of treatment in ASD patients, comparable non-pharmacological treatments are less explored in murine models. Here, we administer a bio-behavioral intervention for BTBR mice by way of environmental enrichment (EE) -an experimental housing paradigm previously shown to improve systemic metabolism, learning/memory, anxious behavior, neurogenesis, locomotion, and immunocompetence in C57BL/6 mice. Juvenile BTBR mice were randomized to standard or EE housing and were subjected to metabolic and behavioral assessments up to 17 weeks. Following EE exposure, we report an EE-induced metabolic and behavioral phenotype. Male BTBR mice responded metabolically to EE, displaying reduced adiposity, increased lean mass, improved glycemic control, and decreased circulating leptin. The gene expressions of brain-derived neurotrophic factor (Bdnf) and its receptor (Ntrk2/TrkB) were upregulated in several brain areas in EE-BTBR males. EE-BTBR females showed modest reduction of adiposity and no changes in glycemic control, circulating leptin, or Bdnf/Ntrk2 gene expression. With regard to behavior, EE resulted in decreased anxiety, and increased social affiliation. Together, these results suggest that EE improves metabolic and behavioral health in BTBR mice.

BTBR T+ Itpr3tf/J (BTBR) mice are used as a model of autism spectrum disorder (ASD), displaying similar behavioral and physiological deficits observed in patients with ASD. Our recent study found that implementation of an enriched environment (EE) in BTBR mice improved metabolic and behavioral outcomes. Brain-derived neurotrophic factor (Bdnf) and its receptor tropomyosin kinase receptor B (Ntrk2) were upregulated in the hypothalamus, hippocampus, and amygdala by implementing EE in BTBR mice, suggesting that BDNF-TrkB signaling plays a role in the EE-BTBR phenotype. Here, we used an adeno-associated virus (AAV) vector to overexpress the TrkB full-length (TrkB.FL) BDNF receptor in the BTBR mouse hypothalamus in order to assess whether hypothalamic BDNF-TrkB signaling is responsible for the improved metabolic and behavioral phenotypes associated with EE. Normal chow diet (NCD)-fed and high fat diet (HFD)-fed BTBR mice were randomized to receive either bilateral injections of AAV-TrkB.FL or AAV-YFP as control, and were subjected to metabolic and behavioral assessments up to 24 weeks post-injection. Both NCD and HFD TrkB.FL overexpressing mice displayed improved metabolic outcomes, characterized as reduced percent weight gain and increased energy expenditure. NCD TrkB.FL mice showed improved glycemic control, reduced adiposity, and increased lean mass. In NCD mice, TrkB.FL overexpression altered the ratio of TrkB.FL/TrkB.T1 protein expression and increased phosphorylation of PLCγ in the hypothalamus. TrkB.FL overexpression also upregulated expression of hypothalamic genes involved in energy regulation and altered expression of genes involved in thermogenesis, lipolysis, and energy expenditure in white adipose tissue and brown adipose tissue. In HFD mice, TrkB.FL overexpression increased phosphorylation of PLCγ. TrkB.FL overexpression in the hypothalamus did not improve behavioral deficits in either NCD or HFD mice. Together, these results suggest that enhancing hypothalamic TrkB.FL signaling improves metabolic health in BTBR mice.