PROJECT SUMMARY
Mental health disorders are the leading cause of disability in the U.S., affecting approximately 1 in 5 people.
While the causes are likely multifactorial, hippocampal glutamatergic synapse formation and number are strongly
correlated with mental health outcomes. In utero environmental cues critically alter development of hippocampal
synapses. Over 30% of people in the US are obese and maternal obesity now affects more than 1 million
developing babies in the US annually. Children of obese mothers have a higher risk of anxiety, autism spectrum
disorder (ASD) and reduced cognition. In contrast, maternal exercise (ME) is associated with increased
cognition, emotional resilience, and reduced risk of ASD. The mechanisms underlying both the positive and
negative effects of maternal metabolic state on development are largely unknown. Insulin is a key metabolic
hormone that is upregulated with maternal obesity (MO); however, MO is associated with insulin resistance.
Interestingly, insulin sensitivity is restored by exercise in both MO mothers and offspring. However, critically we
do not know how MO, ME, and insulin affect hippocampal synapse formation. Our preliminary data show that
insulin increases glutamatergic synapse formation through induction of a novel factor called apelin. Moreover,
both insulin and apelin require FNDC5/irisin to promote the effects of BDNF on glutamate synapse formation.
BDNF is a classic neurotrophic factor whose levels rise during development at a critical time for glutamatergic
synaptogenesis. Disruptions in BDNF or its receptor, TrkB, in humans lead to impairments in both cognition and
emotionality. Here, our preliminary data shows that maternal obesity leads to a decrease in hippocampal
synapse formation in vivo. However, a critical gap in our knowledge is how maternal obesity causes this effect.
In contrast, we have found that maternal exercise increases hippocampal synapse formation. Our collaborators
showed that apelin is required for the beneficial effects of maternal exercise on metabolic function in their
offspring. However, while we have found apelin increases synapse formation in vivo, it is not known if it is
required to mediate the effects of exercise, or how this links to the effects of insulin. Our central hypothesis is
that insulin increases synapse formation in the developing hippocampus through the actions of apelin and irisin
to increase BDNF, and that this pathway is blunted by maternal obesity and increased by maternal exercise. We
will test this with the following Specific Aims: 1. Determine if insulin’s neurotrophic actions are mediated by apelin,
irisin and BDNF. 2. Determine if maternal obesity alters synaptic development by miss-regulating insulin, apelin,
irisin and BDNF signaling. 3. Determine if maternal exercise stimulates synaptic development and plasticity via
insulin and apelin regulating the expression of hippocampal BDNF. The rationale for the proposed research is
that understanding how insulin, MO and ME impact BDNF and glutamatergic synapse development, will allow
us to better predict the long-term consequences of different maternal environments and help direct behavioral
and therapeutic strategies to alleviate cognitive and emotional disorders.
