Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress

Q: What are the key findings of this study?

Mas receptor knockout mice exposed to chronic unpredictable stress exhibited 30% higher plasma corticosterone (364 vs 280 ng/ml, p<0.0001) and enhanced depression-like and anxiety-like behaviors compared to wild-type controls.

Q: What is the clinical evidence from this study?

Population: Adult male Mas receptor knockout mice and wild-type controls aged 8-12 weeks exposed to chronic unpredictable stress or control conditions (n=32). Intervention: Genetic deletion of Mas receptor (Mas knockout) with chronic unpredictable stress (CUS) exposure vs. Wild-type mice with and without chronic unpredictable stress exposure. Primary outcome: Plasma corticosterone levels, fasting blood glucose, depression-like behavior (immobility in forced swimming test and tail suspension test), anxiety-like behavior (time spent in open arms of elevated plus maze), and BDNF levels in brain regions after CUS (p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS, p=<0.0001).

Q: What does this research mean for the field?

Genetic deletion of the Mas receptor exacerbates HPA axis hyperactivity, increasing plasma corticosterone by 30%, and enhances depression- and anxiety-like behaviors in mice exposed to chronic unpredictable stress. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate how genetic deletion of the Mas receptor influences neuroendocrine, behavioral, and neurochemical coping mechanisms during exposure to chronic unpredictable stress.

Sthéfanie C. A. Gonçalves; Andressa da Silveira Silva; Bruna Karen Oliveira Nogueira; Flávio A. G. Mourão; Marco Antônio Peliky Fontes; M BADER; Robson A. S. Santos; Maria Jose Campagnole-Santos; Lucas M. Kangussu

doi:10.1007/s12035-026-05747-6

January 1, 2026Molecular NeurobiologyOpen Access

Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress

View Full Paper

Ask AI

Bookmark

Share

Key result

Mas receptor knockout drives ~30% higher stress-induced corticosterone and worsens depression and anxiety in mice.

p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS
P<0.0001
n=32

Figures

Why the study?

The renin-angiotensin system and Mas receptor modulate stress responses, but the impact of genetic deletion of Mas on chronic unpredictable stress consequences was unclear.

Does genetic deletion of the Mas receptor exacerbate neuroendocrine and behavioral responses to chronic unpredictable stress in mice?

Key Points

To evaluate how genetic deletion of the Mas receptor influences neuroendocrine, behavioral, and neurochemical coping mechanisms during exposure to chronic unpredictable stress.
Wild-type and Mas knockout mice were exposed to random stressors over 21 consecutive days in a chronic unpredictable stress protocol (n=8 per group; n=7 for select assays).
Assessed plasma corticosterone, fasting capillary blood glucose, and behavioral responses using the tail suspension test, forced swim test, and elevated plus maze.
Quantified brain-derived neurotrophic factor protein concentrations across brain areas including the prefrontal cortex and hippocampus.
Under chronic stress, Mas knockout mice displayed significantly elevated plasma corticosterone levels (364 ± 5.4) compared to wild-type mice (280 ± 8.1; p < 0.0001; Cohen's d = 1.35).
Mas knockout mice exhibited heightened anxiety-like behavior at baseline, spending less time in open arms (13 ± 1.3%) than wild-type controls (24 ± 1.3%, p < 0.0001; Cohen's d = 1.06).
Prefrontal cortex brain-derived neurotrophic factor levels were significantly lower in stressed Mas knockout mice (66 ± 5) than in stressed wild-type mice (93 ± 4.3; p = 0.0217; Cohen's d = 1.02).

Structured PICO

Does genetic deletion of the Mas receptor exacerbate neuroendocrine and behavioral responses to chronic unpredictable stress in mice?

P

Population

Adult male Mas knockout (Mas KO) mice and wild-type C57BL/6J (WT) controls, aged 8-12 weeks.

I

Intervention

Genetic deletion of the Mas receptor combined with exposure to Chronic Unpredictable Stress (CUS) for 21 consecutive days.

C

Comparator

Wild-type (WT) mice exposed to CUS, and non-stressed control mice (WT and Mas KO).

O

Outcome

Plasma corticosterone levels, capillary blood glucose levels, depression-like behavior (assessed by Tail Suspension Test and Forced Swimming Test), anxiety-like behavior (assessed by Elevated Plus Maze), and brain-derived neurotrophic factor (BDNF) levels.surrogate

Main Result

Effect estimate: p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS

Absolute Event Rate: 364% vs 280%

p-value: p=<0.0001

Genetic deletion of the Mas receptor exacerbates HPA axis hyperactivation, anxiety- and depression-like behaviors, and BDNF reduction in response to chronic stress, highlighting the neuroprotective role of the Ang-(1-7)/Mas axis.

Limitations

Exclusive use of male mice limits generalizability to females.
Absence of pharmacological intervention groups limits assessment of Mas receptor’s direct therapeutic effects.
No gene expression profiling or inflammatory marker assessments were performed to elucidate molecular mechanisms.
Absence of experimental groups treated with selective Mas agonists or antagonists limits a direct pharmacological assessment.
Complementary molecular analyses, such as gene expression profiling and the assessment of inflammatory marker evaluation, were not performed.

Implication

May offer new target for stress-related neuropsychiatric symptoms in CV disease; extends evidence for neuroprotective role of Ang-(1-7)/Mas axis.

Abstract

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic–pituitary–adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1–7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Gonçalves et al. (2026) studied Adult male Mas receptor knockout mice and wild-type controls aged 8-12 weeks exposed to chronic unpredictable stress or control conditions (n=32). Genetic deletion of Mas receptor (Mas knockout) with chronic unpredictable stress (CUS) exposure vs. Wild-type mice with and without chronic unpredictable stress exposure was evaluated on Plasma corticosterone levels, fasting blood glucose, depression-like behavior (immobility in forced swimming test and tail suspension test), anxiety-like behavior (time spent in open arms of elevated plus maze), and BDNF levels in brain regions after CUS (p<0.0001, Cohen’s d=1.35 for corticosterone levels higher in Mas KO vs WT under CUS, p=<0.0001). Mas receptor knockout mice exposed to chronic unpredictable stress exhibited 30% higher plasma corticosterone (364 vs 280 ng/ml, p<0.0001) and enhanced depression-like and anxiety-like behaviors compared to wild-type controls.

synapsesocial.com/papers/69a3d8caec16d51705d2fe55 https://doi.org/10.1007/s12035-026-05747-6

View Full Paper

Ask AI

Bookmark

Share

Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading