Periodic Reporting for period 1 - FOODFORLIFE (Life-long cross-generational priming of the hypothalamus for obesity)
Berichtszeitraum: 2022-01-01 bis 2023-06-30
Evolutionary success drives continuous human adaptation. A particular aspect of human evolution is the on-going change of dietary preference, mainly due to nutrient availability and societal pressures. A common observation, by now also supported by epidemiological surveys and data from paediatric psychiatry (noting that ~30% of pregnancy females are overweight or obese world-wide), is that a correlation exists between the mother's body weight, food preference and intake, and infant size (birth weight), behavioural traits, and cognitive performance of their offspring. However, the molecular and cellular bases of impaired neuroendocrine development and ensuing deficits in metabolic control in children born to obese mothers remain unknown.
This project puts forward the hypothesis that maternal nutrient supply and hormonal influences could effectively "program" foetal organ development. We posit that the hypothalamus, which acts as the neuroendocrine interface linking the brain and periphery, could particularly be affected. Maternal obesity could evoke permanent molecular changes in hypothalamic neurons and glia of the offspring to compromise their plasticity and adaptive repertoire.This notion is on the backdrop of our recent success in defining, by singe-cell RNA-seq and brain-wide imaging, the developmental trajectory of neurons that build the mammalian hypothalamus, and in discovering the function of novel neuronal subtypes. Using our preliminary data, we will build a comprehensive atlas of hypothalamic cell types that undergo prenatal "programming" when mothers are exposed, in preclinical models, to specific nutrients to find "access points" to intervene with impaired brain development. Moreover, we will mechanistically interrogate the developmental trajectories, functional competences, and neurodevelopmental vulnerabilities of specific neurocircuits, and if their malformation (and/or malfunction) is causal to metabolic diseases in affected offspring.
This project puts forward the hypothesis that maternal nutrient supply and hormonal influences could effectively "program" foetal organ development. We posit that the hypothalamus, which acts as the neuroendocrine interface linking the brain and periphery, could particularly be affected. Maternal obesity could evoke permanent molecular changes in hypothalamic neurons and glia of the offspring to compromise their plasticity and adaptive repertoire.This notion is on the backdrop of our recent success in defining, by singe-cell RNA-seq and brain-wide imaging, the developmental trajectory of neurons that build the mammalian hypothalamus, and in discovering the function of novel neuronal subtypes. Using our preliminary data, we will build a comprehensive atlas of hypothalamic cell types that undergo prenatal "programming" when mothers are exposed, in preclinical models, to specific nutrients to find "access points" to intervene with impaired brain development. Moreover, we will mechanistically interrogate the developmental trajectories, functional competences, and neurodevelopmental vulnerabilities of specific neurocircuits, and if their malformation (and/or malfunction) is causal to metabolic diseases in affected offspring.
1) We have identified novel neuronal subtypes and defined their sensitivity to psychoactive drugs,
2) We have discovered novel astrocyte-neutron signaling systems, their sensitivity to maternal nutrient availability, and effects on synapse maturation,
3) We have described novel associations of hormones/neuropeptides and fast neurotransmitters with a view on brain-wide input/output connectivity and functional coupling.
2) We have discovered novel astrocyte-neutron signaling systems, their sensitivity to maternal nutrient availability, and effects on synapse maturation,
3) We have described novel associations of hormones/neuropeptides and fast neurotransmitters with a view on brain-wide input/output connectivity and functional coupling.
This project brings together an innovative constellation of molecular, cellular and circuit neuroscience and neuroendocrinology tools to study cellular specification events in the foetal hypothalamus with a view on life-long changes to bodily metabolism, brain functions, and behavioral and cognitive traits in affected offspring. A particular focus is on periphery-brain communication, and its impact on neurons, astrocytes, and microglia in the hypothalamus.