The acute stress response mobilizes energy to meet situational demands and re-establish homeostasis. However, the underlying molecular cascades are unclear. Here, we use a brief swim exposure to trigger an acute stress response in mice, which transiently increases anxiety, without leading to lasting maladaptive changes. Using multiomic profiling, such as proteomics, phospho-proteomics, bulk mRNA-, single-nuclei mRNA-, small RNA-, and TRAP-sequencing, we characterize the acute stress-induced molecular events in the mouse hippocampus over time. Our results show the complexity and specificity of the response to acute stress, highlighting both the widespread changes in protein phosphorylation and gene transcription, and tightly regulated protein translation. The observed molecular events resolve efficiently within four hours after initiation of stress. We include an interactive app to explore the data, providing a molecular resource that can help us understand how acute stress impacts brain function in response to stress.

Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer’s disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcAβ mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcAβ mice, and non-transgenic littermates of 14 months-of-age were either treated with the bradykinin receptors 1 and 2 blocker noscapine or received normal drinking water as control over 3 months (n = 8–11/group) and all mice were assessed using fMRI at the end of the treatment period. Perfusion MRI using an arterial spin labeling technique showed regional hypoperfusion in arcAβ compared to non-transgenic controls, which was alleviated by noscapine treatment. Similarly, measuring cerebral blood volume changes upon pharmacological stimulation using vessel dilator acetazolamide revealed recovery of regional impairment of cerebral vascular reactivity in arcAβ mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (Aβ) and inflammation levels in brain sections. Immunohistological stainings for Aβ deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcAβ mice. In addition, levels of soluble and insoluble Aβ38, Aβ40, Aβ42 were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcAβ mice using electro-chemiluminescent based immunoassay. In summary, bradykinin receptors blockade recovered cerebral vascular dysfunction in a mouse model of cerebral amyloidosis. fMRI methods revealed the functional deficit in disease condition and were useful tools to monitor the treatment response.

Studying the stress response is a major pillar of neuroscience research not only because stress is a daily reality but also because the exquisitely fine-tuned bodily changes triggered by stress are a neuroendocrinological marvel. While the genome-wide changes induced by chronic stress have been extensively studied, we know surprisingly little about the complex molecular cascades triggered by acute stressors, the building blocks of chronic stress. The acute stress (or fight-or-flight) response mobilizes organismal energy resources to meet situational demands. However, successful stress coping also requires the efficient termination of the stress response. Maladaptive coping-particularly in response to severe or repeated stressors-can lead to allostatic (over)load, causing wear and tear on tissues, exhaustion, and disease. We propose that deep molecular profiling of the changes triggered by acute stressors could provide molecular correlates for allostatic load and predict healthy or maladaptive stress responses. We present a theoretical framework to interpret multiomic data in light of energy homeostasis and activity-dependent gene regulation, and we review the signaling cascades and molecular changes rapidly induced by acute stress in different cell types in the brain. In addition, we review and reanalyze recent data from multiomic screens conducted mainly in the rodent hippocampus and amygdala after acute psychophysical stressors. We identify challenges surrounding experimental design and data analysis, and we highlight promising new research directions to better understand the stress response on a multiomic level.

The acute stress response mobilizes energy to meet situational demands and re-establish homeostasis. However, little is known about the nature and dynamics of the underlying molecular cascades. We used a brief forced swim exposure to trigger a strong stress response in mice, which transiently increases anxiety, but does not lead to lasting maladaptive behavioral changes. Using multiomic profiling we characterize the stress-induced molecular events in the hippocampus over time, across molecular scales, and down to the level of cell types and single cells. Our results unveil the complexity and specificity of the healthy stress response, with widespread changes in protein phosphorylation and gene transcription, but tightly regulated protein translation. All observed molecular events resolve efficiently within 4 hours after initiation of stress. The data are accessible through an interactive web portal, creating an extensive molecular resource that will help understand how stress impacts brain function in health and disease.

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here we combine RNA-sequencing with selective pharmacological, chemogenetic and optogenetic manipulations to isolate the contribution of the locus coeruleus - noradrenaline (LN-NA) system to the acute stress response. We reveal that NA-release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC mediated hippocampal function, and offer new molecular targets for understanding LC function in health and disease.

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1−/− mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1−/− mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature, and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1-/- mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1-/- mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1, and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

Chronic stress exposure in adolescence can lead to a lasting change in stress responsiveness later in life and is associated with increased mental health issues in adulthood. Here we investigate whether the Chronic Social Instability (CSI) paradigm influences the behavioral and molecular responses to novel acute stressors in mice, and whether it alters physiological responses influenced by the noradrenergic system. Using large cohorts of mice, we show that CSI mice display a persistent increase in exploratory behaviors in the open field test alongside small but widespread transcriptional changes in the ventral hippocampus. However, both the transcriptomic and behavioral responses to novel acute stressors are indistinguishable between groups. In addition, the pupillometric response to a tail shock, known to be mediated by the noradrenergic system, remains unaltered in CSI mice. Ultra-high performance liquid chromatography analysis of monoaminergic neurotransmitter levels in the ventral hippocampus also shows no differences between control or CSI mice at baseline or in response to acute stress. We conclude that CSI exposure during adolescence leads to persistent changes in exploratory behavior and gene expression in the hippocampus, but it does not alter the response to acute stress in adulthood and is unlikely to alter the function of the noradrenergic system.