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SRF and its role in acute stress response

The brain is the central organ that ensures immediate and long-term adaptions to stress. Acute stress (AS) and chronic stress (CS) induce several – and distinct – responses including body weight adaption, metabolic and cardiovascular changes, altered memory, learning, locomotor and exploratory behavior. One major neuroendocrine response mechanism to stress is regulated by the hypothalamic–pituitary–adrenal (HPA) axis. HPA axis activation results in secretion of corticosteroids (in rodents corticosterone, CORT) reaching many tissues, including a negative feedback on the brain thereby dampening the stress response.

One molecular hallmark of an AS response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We demonstrate a role of SRF in immediate and long-lasting acute restraint stress responses.

The scientists around Annemarie Zimprich and Gabi Mroz analyzed the serum response factor (SRF), a neuronal activity-induced transcription factor. As previously shown by analysis of Srf mouse mutants, SRF triggers a neuronal IEG response elicited by various stimuli including epileptic seizures, growth factors, or exposure to a novel environment. Impaired IEG induction in Srf mutant mice was associated with failed habituation to a novel object, hyperactivity, impaired conditioned reinforcement, and resilience to CS.

In this study, adult mice with an SRF deletion in glutamatergic neurons (Srf; CaMKIIa-CreERT2) were analysed at the German Mouse Clinic including behavioral, metabolic, cardiologic testing and gene expression profiling. The mice showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity consisting of locomotor activation and corticosterone induction was impaired in Srf mutant mice.

Hyperactivity was even preserved over 6 months suggesting long-term molecular and cellular changes inflicted by SRF ablation on neuronal networks. These findings support previous reports on SRF ablation confined to hippocampal or dopaminoceptive neurons all describing hyperactivity and impaired memory formation. In summary, the findings suggest a role of SRF in immediate AS reactions and long-term stress coping mechanisms.

Annemarie Zimprich & Gabi Mroz & Christopher Meyer zu Reckendorf & Sofia Anastasiadou & Philip Förstner & Lillian Garrett & Sabine M. Hölter & Lore Becker & Jan Rozman & Cornelia Prehn & Birgit Rathkolb & Kristin Moreth & Wolfgang Wurst & Thomas Klopstock & Martin Klingenspor & Jerzy Adamski & Eckhard Wolf & Raffi Bekeredjian & Helmut Fuchs & Valerie Gailus-Durner & Martin Hrabe de Angelis & Bernd Knöll. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms. Mol Neurobiol. 2016 Dec 2. [Epub ahead of print]. Doi: 10.1007/s12035-016-0300-x