The Acute Stress Response in the Brain: From Neuromodulation to Molecules

Abstract

All organisms have evolved elaborate systems to mount a stress response, which increases the chances of survival in dangerous situations. The response to acute stress encompasses a myriad of neurochemicals, the stress-mediators, that act in concert throughout the brain and body. One of the most crucial aspects of the stress response is the mobilization and reallocation of energy resources. The brain is the organ that first perceives potential threats and coordinates the stress response, yet the stress response also impacts the brain itself, changing its function and metabolic activity. One brain area with a key role in the stress response is the locus coeruleus (LC), the largest noradrenergic cell population in the central nervous system, located in the pons of the brainstem. The LC sends diffuse projections to the entire brain, thus providing the main supply of norepinephrine (NE) in the brain, and controlling basic functions such as arousal, cognition and vigilance. Theories have proposed that LC activation mediates a rapid shift in the functional connectivity of the brain, to strengthen connections that promote a higher state of alertness, and enhance threat detection. However, causal evidence that the LC is able to directly exert this effect on large-scale brain function was missing. Here, we chemogenetically activated the mouse LC while performing resting-state functional magnetic resonance imaging (fMRI), an approach we termed chemo-connectomics. Our results showed an increase in brain-wide connectivity, and a rapid reconfiguration of the functional connectome that enhanced brain networks tasked with salience processing and threat detection. Even though this experiment was performed in anesthetized mice, these findings mirror the effects observed in fMRI scans of awake human subjects presented with emotionally aversive stimuli. Moreover, we provided clues that alpha1 and beta1 adrenergic receptors might be involved in these effects, by correlating the changes in functional connectivity to the distribution of adrenergic receptors at the mRNA level. These results highlight the role of LC in the stress response, as well as the potential of neuromodulators in regulating whole-brain states. The release of stress-mediators in response to acute stress also affects the brain on a molecular level, in part through the recruitment of intracellular signaling cascades and the regulation of gene expression. Although a large body of literature has focused on such molecular changes in the context of stress-triggered neuropsychiatric disorders, the molecular events that affect cellular function to mediate the healthy, default response to acute stress have not been characterized in detail. Here, we used a multi-omic approach to investigate the molecular response to acute stress in the mouse brain. We focused on the hippocampus (HC), since this area – owing to its connectivity and molecular composition – is at the heart of the stress response. First, we showed that the dorsal (dHC) and ventral HC (vHC), are inherently different at the transcriptome and proteome level. Hence, we performed our analysis in those two regions separately, after an acute swim stress paradigm. We first used phosphoproteomics to identify the signaling events that initiate the cellular response to stress. In addition, we characterized the transcriptional changes that take place over time, as well as the changes on the translatome of excitatory and inhibitory neurons. We found that stress-induced changes in protein phosphorylation and in gene expression are widespread and rapid, but tightly regulated, as they terminate within a few hours after the initiation of stress. Altogether, these results provide the most detailed characterization of the molecular stress response to date, and will hopefully provide a starting point for understanding where the healthy stress-response might be derailed in cases of stress-induced psychopathology.