Homeostatic regulation of feeding and metabolism is a complex physiological process leading to pathologies such as obesity and diabetes when imbalanced. This critical function is tightly regulated by the brain, and particularly the hypothalamus. Besides the canonical neuronal hypothalamic circuits, non-neuronal cells such as astrocytes play a fundamental role in this essential homeostatic control 1 . Akin to neurons, astrocytes can respond to nutrients and metabolic factors such as leptin and insulin 2,3 , thus revealing an important role of astrocyte-neuron cooperation in the control of systemic metabolism. However, the underpinning cellular and molecular mechanisms controlling the neuron-astrocyte communication, the synaptic transmission in feeding circuits and ultimately the homeostatic metabolism are still unclear. Here, we propose to disentangle the functionality of neuron-astrocyte communication in the regulation of hypothalamic synaptic transmission and plasticity in health and obesity.
In a first aim, we will test whether manipulating astrocytes acutely can induce changes in synaptic neuronal transmission. We will therefore combine DREADD and/or optogenetic-mediated astrocytic calcium signaling manipulation with calcium imaging technique and neuronal whole-cell recordings in acute brain slices 4 and further correlate changes in synaptic transmission and plasticity with calcium waves in specific astrocytes networks. We will further investigate the synaptic plasticity mechanisms triggered by chronic astrocyte manipulations. We will tackle this problematic with chronic manipulations of astrocyte signaling using transgenic mouse line in which either the calcium pathway or vesicular release will be perturbed specifically in astrocytes. We will then perform whole-cell recordings from hypothalamic neurons and assess synaptic transmission parameters and plasticity. Finally, we will assess the functionality of astrocytes signaling and synaptic plasticity on food intake and metabolism. To this aim, we will combine either acute or chronic astrocyte-signaling manipulations (as described above) with in vivo calcium imaging from hypothalamic neurons in combination with behavioral paradigms to investigate the functional role of astrocytes and astrocyte signaling in food intake and energy homeostasis. This project will provide a new framework in studying hypothalamic astrocyte-neuronal network functions and potentially generate novel anti-obesity therapeutic strategies.
1. García-Cáceres, C. et al. Role of astrocytes, microglia, and tanycytes in brain control of
systemic metabolism. Nat. Neurosci. 22, 7–14 (2019).
2. Gao, Y. et al. Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity.
Diabetes 66, 2555–2563 (2017).
3. García-Cáceres, C. et al. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with
Nutrient Availability. Cell 166, 867–880 (2016).
4. Lefort, S., Tomm, C., Floyd Sarria, J.-C. C. & Petersen, C. C. The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex. Neuron 61, 301–16 (2009).