Dr. Hector Horacio Sagarnaga Muñoz

Feedforward inhibition of stress by
brainstem neuropeptide Y neurons
Yan Zhang 1,2,3,13, Jiayi Shen4,13, Famin Xie 1
, Zhiwei Liu4
, Fangfang Yin5
,
Mingxiu Cheng6,7, Liang Wang 4
, Meiting Cai3
, Herbert Herzog8,9, Ping Wu5
,
Zhi Zhang 1 , Cheng Zhan 3,4 & Tiemin Liu 1,2,10,11,12
Resistance to stress is a key determinant for mammalian functioning. While
many studies have revealed neural circuits and substrates responsible for initi-
ating and mediating stress responses, little is known about how the brain resists
to stress and prevents overreactions. Here, we identified a previously unchar-
acterized neuropeptide Y (NPY) neuronal population in the dorsal raphe nucleus
and ventrolateral periaqueductal gray region (DRN/vlPAG) with anxiolytic effects
in male mice. NPYDRN/vlPAG neurons are rapidly activated by various stressful sti-
muli. Inhibiting these neurons exacerbated hypophagic and anxiety responses
during stress, while activation significantly ameliorates acute stress-induced
hypophagia and anxiety levels and transmits positive valence. Furthermore,
NPYDRN/vlPAG neurons exert differential but synergic anxiolytic effects via inhibi-
tory projections to the paraventricular thalamic nucleus (PVT) and the lateral
hypothalamic area (LH). Together, our findings reveal a feedforward inhibition
neural mechanism underlying stress resistance and suggest NPYDRN/vlPAG neurons
as a potential therapeutic target for stress-related disorders.
Stress affects the physiological functions and behaviors of individuals,
yielding both positive and negative outcomes. On the positive side,
stressors trigger the fight and flight response that is crucial to the
performance and survival under threats1
. On the negative side,
impaired adaptation and resistance to stressful events can precipitate
the onset or relapse of symptoms in a range of psychiatric and beha-
vioral disorders, including anxiety2
, depression3
, hyperphagia4 or
hypophagia5
, and even posttraumatic stress disorder (PTSD)6
. A bal-
ance between two opposing stress and anti-stress mechanisms deter-
mines the overall impact of stress. The former renders organisms more
sensitive and vulnerable to stress-related disorders, while the later
imparts resilience and resistance. Thus, identifying mechanisms that
make individuals resistant or less vulnerable to stressful stimuli is an
important approach for the prevention of stress-related disorders.
Recent studies showed that many brain areas (such as the amygdala4
,
hypothalamus7 and hippocampus8
) are implicated in initiating or
mediating stress-induced changes in emotion and behavior. However,
relatively little is known about the neuronal mechanisms of anti-stress,
especially at the neural circuit level.
Neuropeptide Y (NPY) is a 36-amino-acid peptide that plays
important roles in the control of many basic physiological functions
and behaviors, including vasoconstriction9
, energy metabolism10, and
Received: 17 January 2024
Accepted: 20 August 2024
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1
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. 2
Human Phenome Institute, Fudan University,
Shanghai, China. 3
Hefei National Research center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China. 4
Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of
China, Hefei, China. 5
Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China. 6
National Institute of Biological Sciences,
Beijing, China. 7
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. 8
St Vincent’s Centre for Applied Medical
Research, Faculty of Medicine, UNSW, Sydney, NSW, Australia. 9
Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. 10Shanghai Key
Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, China. 11Department of Endo-
crinology and Metabolism, Zhongshan Hospital, Shanghai, China. 12School of Life Sciences, Inner Mongolia University, Hohhot, China. 13These authors
contributed equally: Yan Zhang, Jiayi Shen. e-mail: z_zhang@fudan.edu.cn; zhancheng@ustc.edu.cn; tiemin_liu@fudan.edu.cn
Nature Communications | (2024) 15:7603 1
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