Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity

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Abstract

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

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A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

Linda Madisen, Theresa Zwingman, Susan M. Sunkin … (2009)

The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universal responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in a number of Cre-driver lines, including novel Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.

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A neurotrophic model for stress-related mood disorders.

Ronald S Duman, Lisa M Monteggia (2006)

There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.

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Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States

Aaron L Sarvet, Jacquelyn Meyers, Tulshi D Saha … (2018)

Question What is the national prevalence of DSM-5 major depressive disorder, the DSM-5 anxious/distressed and mixed-features specifiers, and their clinical correlates? Findings In this national survey of 36 309 US adults, the 12-month and lifetime prevalences of major depressive disorder were 10.4% and 20.6%, respectively, with most being moderate (6-7 symptoms) or severe (8-9 symptoms) and associated with comorbidity and impairment. The anxious/distressed specifier characterized 74.6% of major depressive disorder cases, and the mixed-features specifier characterized 15.5%; almost 70% with lifetime major depressive disorder received some type of treatment. Meaning Major depressive disorder remains a serious US health problem, with much to be learned about its specifiers. Importance No US national data are available on the prevalence and correlates of DSM-5 –defined major depressive disorder (MDD) or on MDD specifiers as defined in DSM-5 . Objective To present current nationally representative findings on the prevalence, correlates, psychiatric comorbidity, functioning, and treatment of DSM-5 MDD and initial information on the prevalence, severity, and treatment of DSM-5 MDD severity, anxious/distressed specifier, and mixed-features specifier, as well as cases that would have been characterized as bereavement in DSM-IV . Design, Setting, and Participants In-person interviews with a representative sample of US noninstitutionalized civilian adults (≥18 years) (n = 36 309) who participated in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III). Data were collected from April 2012 to June 2013 and were analyzed in 2016-2017. Main Outcomes and Measures Prevalence of DSM-5 MDD and the DSM-5 specifiers. Odds ratios (ORs), adjusted ORs (aORs), and 95% CIs indicated associations with demographic characteristics and other psychiatric disorders. Results Of the 36 309 adult participants in NESARC-III, 12-month and lifetime prevalences of MDD were 10.4% and 20.6%, respectively. Odds of 12-month MDD were significantly lower in men (OR, 0.5; 95% CI, 0.46-0.55) and in African American (OR, 0.6; 95% CI, 0.54-0.68), Asian/Pacific Islander (OR, 0.6; 95% CI, 0.45-0.67), and Hispanic (OR, 0.7; 95% CI, 0.62-0.78) adults than in white adults and were higher in younger adults (age range, 18-29 years; OR, 3.0; 95% CI, 2.48-3.55) and those with low incomes ($19 999 or less; OR, 1.7; 95% CI, 1.49-2.04). Associations of MDD with psychiatric disorders ranged from an aOR of 2.1 (95% CI, 1.84-2.35) for specific phobia to an aOR of 5.7 (95% CI, 4.98-6.50) for generalized anxiety disorder. Associations of MDD with substance use disorders ranged from an aOR of 1.8 (95% CI, 1.63-2.01) for alcohol to an aOR of 3.0 (95% CI, 2.57-3.55) for any drug. Most lifetime MDD cases were moderate (39.7%) or severe (49.5%). Almost 70% with lifetime MDD had some type of treatment. Functioning among those with severe MDD was approximately 1 SD below the national mean. Among 12.9% of those with lifetime MDD, all episodes occurred just after the death of someone close and lasted less than 2 months. The anxious/distressed specifier characterized 74.6% of MDD cases, and the mixed-features specifier characterized 15.5%. Controlling for severity, both specifiers were associated with early onset, poor course and functioning, and suicidality. Conclusions and Relevance Among US adults, DSM-5 MDD is highly prevalent, comorbid, and disabling. While most cases received some treatment, a substantial minority did not. Much remains to be learned about the DSM-5 MDD specifiers in the general population. This national survey of US adults presents findings on the prevalence, correlates, psychiatric comorbidity, functioning, and treatment of DSM-5 major depressive disorder.

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Author and article information

Contributors

Xin-Yun Lu:

ORCID: http://orcid.org/0000-0002-9103-4542

xylu@augusta.edu

Journal

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol Psychiatry

Title: Molecular Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date (Electronic): 11 January 2021

Publication date PMC-release: 11 January 2021

Publication date (Print): 2021

Volume: 26

Issue: 6

Pages: 2299-2315

Affiliations

[1 ]GRID grid.410427.4, ISNI 0000 0001 2284 9329, Department of Neuroscience & Regenerative Medicine, , Medical College of Georgia at Augusta University, ; Augusta, GA USA

[2 ]GRID grid.440653.0, ISNI 0000 0000 9588 091X, Department of Physiology, , Binzhou Medical University, ; Shandong, China

[3 ]GRID grid.410427.4, ISNI 0000 0001 2284 9329, Department of Medicine, Vascular Biology Center, , Medical College of Georgia at Augusta University, ; Augusta, GA USA

Author information

Yun Lei http://orcid.org/0000-0003-4572-6078

Xin-Yun Lu http://orcid.org/0000-0002-9103-4542

Article

Publisher ID: 1004

DOI: 10.1038/s41380-020-01004-x

PMC ID: 8272726

PubMed ID: 33432188

SO-VID: 8a58f593-afc2-4d5d-ad65-8e9a4ff5440f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 May 2020

Date revision received : 13 December 2020

Date accepted : 15 December 2020

Funding

Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);

Award ID: MH100583

Award ID: MH119456

Award Recipient : Xin-Yun Lu

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)

Funded by: FundRef https://doi.org/10.13039/100000049, U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging);

Award ID: AG062166

Award Recipient : Xin-Yun Lu

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ScienceOpen disciplines: Molecular medicine

Keywords: depression,neuroscience

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ScienceOpen disciplines: Molecular medicine

Keywords: depression, neuroscience

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Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity

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Most cited references 95

A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

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Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States

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