Sunday, May 18, 2025
5/18/2025
Disruption of restorative processes in chronic stress: An integrated cellular approach - Abstract Chronic stress is pervasive in our society and linked to a reduced quality of life and increased risk for developing chronic diseases. Treatment options, including changes in lifestyle, exercise, and anxiolytics, are only partially effective and would benefit from a deeper understanding of the cellular mechanisms underlying the negative effects of chronic stress on the brain. Here we start by focusing on key restorative processes that occur during the inactive phase - the light period in rodents and the dark period in humans - when animals are asleep and for many hours brain activity is characterized by the presence of spindles and slow waves. These restorative processes involve integrated changes in astrocytes and neurons and include glymphatic clearance and renormalization (weakening) of synaptic strength. The former, by removing metabolic waste, reduces the risk of toxic waste build-up and the latter, by reducing the strength of synapses and the size of the perisynaptic astrocytic coverage, keeps the cost of synaptic activity under control and promotes future learning. It has been known for decades that the activity of the noradrenergic neurons of the locus coeruleus (LC) decreases during the inactive phase, leading to a progressive decline in noradrenaline (NE) levels in the brain. However, we and others have recently found that this decline is not monotonic: there are large, infraslow NE oscillations (INO) that occur in association with spindles and slow waves. We postulate that INO, combined with progressively lower NE levels and slow waves, are key to promote the cellular restorative processes occurring during the inactive phase. Based on this observation, we will use a mouse model of chronic stress to test the novel hypothesis that chronic stress disrupts the slow wave rich inactive phase and its complex NE dynamics, thereby impairing both astrocytic and neuronal restorative processes, including glymphatic clearance and renormalization of synaptic strength and of perisynaptic astrocytic coverage. To test our hypothesis we will combine recordings of brain activity (EEG/EMG), neuromodulators’ dynamics (voltammetry and NE sensors), serial block-face scanning electron microscopy, and brain fluid dynamics, along with optogenetic manipulation of NE/LC. We will use memory performance and sensitivity to painful stimulation as behavioral measures of the cellular restorative processes. Finally, we will test whether a non-pharmacological intervention, mild acoustic stimulation, can counteract the negative effects of chronic stress on astrocytes and neurons by restoring normal INO and slow waves. The proposal is organized in 2 aims. Aim 1 will define the cellular targets for the NE dynamics, including glymphatic clearance, synaptic weakening and renormalization of astrocytic synaptic coverage and glycogen storage. Aim 2 will test whether mild auditory stimulation in chronic stress can boost slow waves and normalize INO, thus improving the cellular restorative processes, memory performance and pain threshold. The proposed experiments are challenging but will benefit from the complementary expertise of the Nedergaard and Cirelli labs. If successful, the experiments will provide fundamental new insights into the biology of both astrocytes and neurons and their dysfunction in chronic stress.
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