Dopamine neurons modulate neural encoding and expression of depression-related behaviour
Open accessAbstract
Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
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The nucleus accumbens integrates prefrontal, amygdala, and hippocampal signals to control dopamine release from the ventral tegmental area to the telencephalon.
“The nucleus accumbens (NAc) is a critical link in corticomesolimbic reward circuits, integrating information from the prefrontal cortices (PFC), amygdala, and hippocampus to control the release of dopamine from the ventral tegmental area (VTA) back to the telencephalon [19][20][21][22][23].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [20]
Phasic firing changes in ventral tegmental area dopamine neurons are inconsistent across stress models.
“First, phasic firing changes in VTA DA neurons are inconsistent across stress models (66, 69).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [69]
A recent optogenetic study found that dopamine receptors are required for the action of VTA projections into the nucleus accumbens in depression-related escape behavior.
“A recent optogenetic study examining dopaminergic ventral tegmental area (VTA) projections into nucleus accumbens found that dopamine receptors are required for the action of these neurons in depression-related escape behavior.23”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [23]
Chronic mild stress-induced social behavioral deficits are associated with decreased DA release in limbic target regions.
“chronic mild stressinduced social behavioral deficits are associated with decreased DA release in limbic target regions [150].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [150]
Alterations in VTA DA activity affect activity in multiple downstream targets, including the NAc and mPFC, which appear to be particularly important for mediating social avoidance.
“Alterations in VTA DA activity will affect activity in multiple downstream targets, including the NAc and mPFC, which appear to be particularly important for mediating social avoidance [149, 150, 156-159].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [150]
Ventral tegmental area firing is reduced in mice exposed to chronic unpredictable stress, and optogenetic stimulation in this context reverses stress-induced behavioral deficits.
“VTA firing is also reduced in mice exposed to CUS and optogenetic stimulation in this context reverses, instead of promotes, stress-induced behavioral deficits [54].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [54]
Selective inhibition of VTA dopamine neurons induces anhedonia and behavioral despair.
“Selective inhibition of VTA dopamine neurons induces anhedonia and behavioral despair; conversely, phasic activation of VTA dopamine neurons reverses chronic mild/unpredictable stress-induced depression-like phenotypes, a phenomenon dependent on dopamine transmission in the NAc [41].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [41]
Phasic activation of VTA dopamine neurons reverses chronic mild/unpredictable stress-induced depression-like phenotypes, a phenomenon dependent on dopamine transmission in the NAc.
“Selective inhibition of VTA dopamine neurons induces anhedonia and behavioral despair; conversely, phasic activation of VTA dopamine neurons reverses chronic mild/unpredictable stress-induced depression-like phenotypes, a phenomenon dependent on dopamine transmission in the NAc [41].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [41]
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- Authors
- Tye, K. M., Mirzabekov, J. J., Warden, M. R., Ferenczi, E. A., Tsai, H.-C., Finkelstein, J., Kim, S.-Y., Adhikari, A., Thompson, K. R., Andalman, A. S., Gunaydin, L. A., Witten, I. B., & Deisseroth, K.
- Affiliations
- Massachusetts Institute of Technology (US)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tye, Kay M.
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2012-12-12
- Volume
- 493
- Issue
- 7433
- Pages
- 537-541
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4160519
- OpenAlex
- W2117782909
- Cited by
- 1,073
- References
- 34
- Citations by year
- 2026: 47 · 2025: 79 · 2024: 75 · 2023: 78 · 2022: 87 · 2021: 112 · 2020: 67 · 2019: 98 · 2018: 84 · 2017: 68 · 2016: 72 · 2015: 83 · 2014: 70 · 2013: 50 · 2012: 2
- FWCI
- 27.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- W. M. Keck Foundation
- McKnight Foundation
- National Alliance for Research on Schizophrenia and Depression
- Defense Advanced Research Projects Agency
- National Institute of Mental Health (F32 MH880102)
- National Institute on Drug Abuse (DP2DA035149)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP2DK102256)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- midbrain dopaminergic neurons, ventral tegmental area, depression, chronic mild stress, social defeat, nucleus accumbens, neural coding, phasic neuronal activity, optogenetic manipulation, stress resilience, anhedonia, depression-like behavior, freely moving rodents
- MeSH terms
- Animals, Depression, Dopamine, Female, Male, Models, Neurological, Nucleus Accumbens, Phenotype, Stress, Psychological, Time Factors, Ventral Tegmental Area, Rats, Long-Evans, Mice, Rats, Dopaminergic Neurons, Optogenetics
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