Exposure to maternal over-nutrition during early life predisposes offspring to obesity, hyperphagia and alterations in macronutrient preferences and motivation for high-fat foods1-4. Whilst molecular and structural alterations in hypothalamic feeding circuits have been implicated in the programming of hyperphagia, the alterations in reward-related behaviours indicate the mesolimbic dopamine pathway is also vulnerable to programming. One factor proposed to link maternal obesity to altered development of the offspring brain is leptin. Adipocyte-derived leptin acts as a neurotrophic factor in the hypothalamus: projections from the arcuate nucleus to its target regions are impaired in genetically leptin-deficient ob/ob mice5. Here, we investigated whether leptin also plays a role in the development of the mesolimbic dopamine pathway. We paid particular attention to the dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens based on their well-documented role in motivated behaviours.
Explants from the ventral midbrain, from which the VTA originates, were dissected from mice at embryonic day 13. Explants were cultured ex vivo for 48 hours in the absence (n=5) or presence (n=6) of leptin at a physiological concentration. Immunohistochemistry was performed to label dopaminergic neurites (using a tyrosine hydroxylase antibody) as well as overall neurites (using a GAP-43 antibody).
The density of dopaminergic axonal projections within 150µM from the explant edge was significantly reduced in leptin-treated ventral midbrain explants compared to the untreated explants (p<0.05). However, the density of GAP-43-immunoreactive projections was unaffected, suggesting that the leptin-mediated inhibition of neurite outgrowth was specific to dopaminergic neurons. We are currently examining the effects of leptin deficiency and hyperleptinaemia on the development of this pathway to confirm the in vivo relevance of these findings.
In conclusion, these preliminary data suggest that leptin modulates neural development in the mesolimbic dopamine pathway and is a candidate programming factor in models of maternal over-nutrition.