Abstract
Maternal obesity has significant effects on the neurodevelopmental outcomes of the offspring, increasing their propensity to neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorders (ASDs). ASDs emerge from disturbances in the developing ‘social brain’. This includes the amygdala (BLA) and hippocampus (HP) which contribute to the regulation of emotions, social behaviours, and memories.
Disturbances to myelination of these regions during development are thought to be central to the origins of ASDs. Oligodendrocytes (OLs) are responsible for myelination within the central nervous system, providing means to regulate the timings of signals propagating throughout the brain. This is essential during neurodevelopment, through mechanisms of spike timing dependent plasticity. If these mechanisms were undermined and the ability to regulate the temporal propagation of information lessened, such as by myelinogenic disturbances, circuits would have a greater propensity to develop improperly.
Disturbances in the timing of myelination during development may be one of the mechanisms linking maternal obesity to the offspring’s increased risk to ASDs. It was hypothesised that OL development may be disrupted in the BLA and HP, in the offspring of obese mothers. To investigate this, OLs were analysed in offspring of control and maternal high fat diet (mHFD) fed dams, as a mouse model of maternal obesity. At postnatal day 16 (P16), the BLA and HP were labelled for Olig2, a pan OL marker, and MBP, a mature OL marker. At P30, the HP was labelled for Olig2 and MBP. The number and density of Olig2-immunoreactive (IR) cells were calculated, reflecting the size of the total OL lineage. MBP-IR integrated pixel densities (IntDen) were calculated, as a proxy measure for levels of myelination. The number and density of mature OLs, identified through the colocalization of Olig2 and MBP, were also calculated at P16.
The number of OLs within the BLA was unchanged between the control and mHFD offspring at P16. Likewise, MBP-IR IntDen, a measure of myelination, was unchanged between the maternal diet groups. Thus, the OL lineage in the BLA appears unaffected by maternal nutritional adversity in utero. By contrast, MBP-IR IntDen was significantly reduced within the HP of the mHFD offspring at P16. While the total number of OLs was unchanged, there were fewer mature OLs in the HP of the mHFD offspring. Myelination however appeared to normalize with age, as no differences in the number of OLs or MBP-IR IntDen were observed in the HP between the control and mHFD offspring at P30. Thus, myelination of the HP is delayed in the mHFD offspring, likely due to maturational impediments, but normalizes to reach completion.
These data provide insight into the regional effects of maternal obesity on myelination in the offspring. Disturbances during hippocampal myelination may contribute to neural circuit dysfunctions that are seen at an increased incidence in the offspring of obese mothers. Further work is necessary to gain understanding of the mechanisms underpinning these changes in development, and the predisposition to poor health and NDDs, in the offspring of obese mothers.