Amygdala-Ventral Pallidum Pathway Decreases Dopamine Activity After Chronic Mild Stress in Rats
Open accessAbstract
Background Major depressive disorder affects more than 15% of the population across their lifespan. In this study, we used the well-characterized unpredictable chronic mild stress (CMS) model of depression to examine this condition.Methods Sprague-Dawley rats were presented randomly with mild stressors for 4 weeks, with body weight and sucrose intake monitored weekly. Locomotor activity and elevated plus maze test/forced swim test were conducted on Week 5; ventral tegmental area dopamine (DA) neuron activity was assessed within 1 week after the behavioral test with three indices: DA neuron population activity (defined as the number of spontaneously firing DA neurons); mean firing rate; and percent burst firing (i.e., the proportion of action potentials occurring in bursts).Results Consistent with previous studies, we found that, compared with control subjects, rats that underwent the CMS procedure were slower in gaining body weight and developed anxiety- and despair-like behavior. We now report a significant decrease in DA neuron population activity of CMS rats, and this decrease is restored by pharmacologically attenuating the activity of either the basolateral nucleus of the amygdala (BLA) or the ventral pallidum (VP). Moreover, pharmacological activation of the amygdala in nonstressed rats decreases DA neuron population activity similar to that with CMS, which is reversed by blocking the BLA-VP pathway.Conclusions The CMS rat depression model is associated with a BLA-VP-ventral tegmental area inhibition of DA neuron activity. This information can provide insight into the circuitry underlying major depressive disorder and serve as a template for refining therapeutic approaches to this disorder.
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Chronic mild or chronic cold stress reduce ventral tegmental area population activity.
“chronic mild or chronic cold stress instead reduce VTA population activity [50, 51].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [51]
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Cites
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.593 · Cited by 20,391 · see citing works
Predictive reward signal of dopamine neurons
Schultz, W. (1998) · Journal of Neurophysiology · doi:10.1152/jn.1998.80.1.1 · Cited by 4,564 · see citing works
THE AMYGDALA MODULATES THE CONSOLIDATION OF MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES
McGaugh, J. L. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144157 · Cited by 2,296 · see citing works
The mesolimbic dopamine reward circuit in depression
Nestler, E. J., & Carlezon, W. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.09.018 · Cited by 2,059 · see citing works
Brain Maps: Structure of the Rat Brain
Swanson, L. W. (1992) · Medical Entomology and Zoology · Cited by 1,851 · see citing works
Stress, memory and the amygdala
Roozendaal, B., McEwen, B. S., & Chattarji, S. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2651 · Cited by 1,760 · see citing works
Brain maps: structure of the rat brain
Guillery, R. W. (1993) · Trends in Neurosciences · doi:10.1016/0166-2236(93)90187-q · Cited by 1,677 · see citing works
Differential projections of the infralimbic and prelimbic cortex in the rat
Vertes, R. P. (2004) · Synapse · doi:10.1002/syn.10279 · Cited by 1,550 · see citing works
The mysterious motivational functions of mesolimbic dopamine
Salamone, J. D., & Correa, M. (2012) · Neuron · doi:10.1016/j.neuron.2012.10.021 · Cited by 1,418 · see citing works
Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons
Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H.-C., Pomeranz, L., Christoffel, D. J., et al. (2013) · Nature · doi:10.1038/nature11713 · Cited by 1,156 · see citing works
Floresco, S. B., West, A. R., Ash, B., Moore, H., & Grace, A. A. (2003) · Nature Neuroscience · doi:10.1038/nn1103 · Cited by 1,106 · see citing works
Self-citationDopamine neurons modulate neural encoding and expression of depression-related behaviour
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., et al. (2013) · Nature · doi:10.1038/nature11740 · Cited by 1,073 · see citing works
Regulation of firing of dopaminergic neurons and control of goal-directed behaviors
Grace, A. A., Floresco, S. B., Goto, Y., & Lodge, D. J. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.03.003 · Cited by 1,034 · see citing works
Self-citationCortico-Basal Ganglia Reward Network: Microcircuitry
Sesack, S. R., & Grace, A. A. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.93 · Cited by 985 · see citing works
Self-citationGrace, A. A., & Bunney, B. S. (1983) · Neuroscience · doi:10.1016/0306-4522(83)90135-5 · Cited by 937 · see citing works
Self-citationUsing the rat forced swim test to assess antidepressant-like activity in rodents
Slattery, D. A., & Cryan, J. F. (2012) · Nature Protocols · doi:10.1038/nprot.2012.044 · Cited by 903 · see citing works
Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task
Pizzagalli, D. A., Iosifescu, D., Hallett, L. A., Ratner, K. G., & Fava, M. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.03.001 · Cited by 780 · see citing works
Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings
Leppänen, J. M. (2006) · Current Opinion in Psychiatry · doi:10.1097/01.yco.0000191500.46411.00 · Cited by 632 · see citing works
Stress-Induced Anhedonia in Mice is Associated with Deficits in Forced Swimming and Exploration
Strekalova, T. V., Spanagel, R., Bartsch, D., Henn, F. A., & Gass, P. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300532 · Cited by 564 · see citing works
Floresco, S., Todd, C. L., & Grace, A. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-13-04915.2001 · Cited by 556 · see citing works
Self-citationAmygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies
Hamilton, J. P., Siemer, M., & Gotlib, I. H. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.57 · Cited by 492 · see citing works
Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice
Mineur, Y. S., Belzung, C., & Crusio, W. E. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.07.029 · Cited by 459 · see citing works
Are you or aren’t you? Challenges associated with physiologically identifying dopamine neurons
Ungless, M. A., & Grace, A. A. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.02.003 · Cited by 431 · see citing works
Self-citationNeurobiology of chronic mild stress: parallels to major depression
Hill, M. N., Hellemans, K. G. C., Verma, P., Gorzalka, B. B., & Weinberg, J. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.07.001 · Cited by 420 · see citing works
Guilloux, J., Seney, M. L., Edgar, N. M., & Sibille, E. L. (2011) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2011.01.019 · Cited by 362 · see citing works
Chronic Mild Stress and Sucrose Consumption: Validity as a Model of Depression
Forbes, N., Stewart, C. A., Matthews, K., & REID, I. (1996) · Physiology & Behavior · doi:10.1016/s0031-9384(96)00305-8 · Cited by 281 · see citing works
Lodge, D. J., & Grace, A. A. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300963 · Cited by 280 · see citing works
Self-citationRoozendaal, B., Castello, N. A., Vedana, G., Barsegyan, A., & McGaugh, J. L. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2008.06.010 · Cited by 216 · see citing works
Guidotti, G., Calabrese, F., Anacker, C., Racagni, G., Pariante, C. M., & Riva, M. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.225 · Cited by 200 · see citing works
Surget, A., Wang, Y., Leman, S., Ibargüen-Vargas, Y., Edgar, N. M., Griebel, G., Belzung, C., & Sibille, E. L. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.76 · Cited by 195 · see citing works
Amygdala Volume Marks the Acute State in the Early Course of Depression
van Eijndhoven, P., van Wingen, G. A., van Oijen, K., Rijpkema, M., Goraj, B. M., Verkes, R. J., Voshaar, R. C. O., Fernández, G., Buitelaar, J. K., & Tendolkar, I. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.10.027 · Cited by 178 · see citing works
DETECTION OF FACIAL EXPRESSIONS OF EMOTIONS IN DEPRESSION
Suslow, T., Junghanns, K., & Arolt, V. (2001) · Perceptual and Motor Skills · doi:10.2466/pms.2001.92.3.857 · Cited by 177 · see citing works
Valenti, O., Lodge, D. J., & Grace, A. A. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5310-10.2011 · Cited by 173 · see citing works
Self-citationGrippo, A. J., Beltz, T. G., Weiss, R. M., & Johnson, A. K. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.07.010 · Cited by 167 · see citing works
Dynamics of the dopaminergic system as a key component to the understanding of depression
Yadid, G., & Friedman, A. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)00913-8 · Cited by 160 · see citing works
Novelty-seeking behavior predicts vulnerability in a rodent model of depression
Stedenfeld, K. A., Clinton, S. M., Kerman, I. A., Akil, H., Watson, S. J., & Sved, A. F. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.02.001 · Cited by 153 · see citing works
Valenti, O., Gill, K. M., & Grace, A. A. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08038.x · Cited by 131 · see citing works
Self-citationZimmerman, J. M., & Maren, S. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07223.x · Cited by 127 · see citing works
Is depression associated with dysfunction of the central reward system?
Martin-Söelch, C. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370313 · Cited by 123 · see citing works
Solomon, M. B., Furay, A. R., Jones, K., Packard, A. E. B., Packard, B. A., Wulsin, A. C., & Herman, J. P. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.014 · Cited by 96 · see citing works
Hippocampal and Amygdalar Volumes in Psychotic and Nonpsychotic Unipolar Depression
Keller, J., Shen, L., Gomez, R. G., Garrett, A. S., Solvason, H. B., Reiss, A. L., & Schatzberg, A. F. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07081257 · Cited by 90 · see citing works
SIEGLE, G. J., KONECKY, R. O., THASE, M. E., & CARTER, C. S. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb07105.x · Cited by 87 · see citing works
Savitz, J. B., Hodgkinson, C. A., Martin-Söelch, C., Shen, P., Szczepanik, J. E., Nugent, A. C., Herscovitch, P., Grace, A. A., Goldman, D. A., & Drevets, W. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054108 · Cited by 69 · see citing works
Self-citationElmslie, K. S., & Yoshikami, D. (1985) · Brain Research · doi:10.1016/0006-8993(85)90685-7 · Cited by 67 · see citing works
Maslowski, R. J., & Napier, T. C. (1994) · Neuroscience · doi:10.1016/0306-4522(94)90347-6 · Cited by 66 · see citing works
Johnson, L. R., Hou, M., Prager, E. M., & LeDoux, J. E. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00023 · Cited by 61 · see citing works
First, M. B., FRANCES, A. J., & Pincus, H. A. (2004) · Medical Entomology and Zoology · Cited by 51 · see citing works
Mechanisms of antidepressant action: An integrated dopaminergic perspective
Porcelli, S., Drago, A., Fabbri, C., & Serretti, A. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2011.03.005 · Cited by 49 · see citing works
Chang, C., & Grace, A. A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2420-12.2013 · Cited by 44 · see citing works
Self-citationDoes decreased sucrose intake indicate loss of preference in CMS model?
Weiss, J. M. (1997) · Psychopharmacology · doi:10.1007/s002130050472 · Cited by 42 · see citing works
Yeung, M., Lu, L. D., Hughes, A. M., et al. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.027 · Cited by 25 · see citing works
Huang, A. C. W., & Hsiao, S. (2002) · Behavioral Neuroscience · doi:10.1037//0735-7044.116.4.646 · Cited by 22 · see citing works
Decreased approach motivation in depression
Wang, C. E., Brennen, T., & Holte, A. (2006) · Scandinavian Journal of Psychology · doi:10.1111/j.1467-9450.2006.00525.x · Cited by 20 · see citing works
Huang, A. C. W., & Hsiao, S. (2002) · Behavioral Neuroscience · doi:10.1037/0735-7044.116.4.646 · Cited by 19 · see citing works
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Grace, A. A. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.57 · Cited by 1,166 · see citing works
Self-citationThe chronic mild stress (CMS) model of depression: History, evaluation and usage
Willner, P. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.08.002 · Cited by 959 · see citing works
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Belujon, P., & Grace, A. A. (2017) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx056 · Cited by 754 · see citing works
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Bagot, R. C., Parise, E. M., Peña, C. J., Zhang, H.-X., Maze, I., Chaudhury, D., Persaud, B., Cachope, R., Bolaños-Guzmán, C. A., Cheer, J. F., et al. (2015) · Nature Communications · doi:10.1038/ncomms8062 · Cited by 491 · see citing works
The molecular and cellular mechanisms of depression: a focus on reward circuitry
Fox, M. E., & Lobo, M. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0415-3 · Cited by 232 · see citing works
Belujon, P., & Grace, A. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.014 · Cited by 225 · see citing works
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Friedman, A. K., Juarez, B., Ku, S. M., Zhang, H., Calizo, R. C., Walsh, J. J., Chaudhury, D., Zhang, S., Hawkins, A., Dietz, D. M., et al. (2016) · Nature Communications · doi:10.1038/ncomms11671 · Cited by 172 · see citing works
Weber-Stadlbauer, U., Richetto, J., Labouesse, M. A., Bohacek, J., Mansuy, I. M., & Meyer, U. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.41 · Cited by 170 · see citing works
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Zhong, P., Vickstrom, C. R., Liu, X., Hu, Y., Yu, L., Yu, H.-G., & Liu, Q.-S. (2018) · eLife · doi:10.7554/elife.32420 · Cited by 99 · see citing works
“VTA dopamine neuron AP firing is altered in chronic stress models of depression (Cao et al., 2010; Chang and Grace, 2014; Moreines et al., 2017; Tye et al., 2013), and modulating this firing can reverse or enhance the development and/or expression of depression-like behavior (Chaudhury et al.,…”
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- Authors
- Chang, C.-H., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Chang, Chun-hui
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 76
- Issue
- 3
- Pages
- 223-230
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3969414
- OpenAlex
- W2081697362
- Cited by
- 239
- References
- 54
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 19 · 2023: 30 · 2022: 25 · 2021: 23 · 2020: 13 · 2019: 27 · 2018: 21 · 2017: 17 · 2016: 15 · 2015: 12 · 2014: 3
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01mh057440-26a1, 5r01mh101180-05)
- National Institute of Mental Health (R01-MH101180, MH-57440, R01-MH057440, R37MH057440)
- 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
- ventral tegmental area, chronic mild stress, depression, basolateral amygdala, ventral pallidum, burst firing, anxiety-like behavior, despair-like behavior, major depressive disorder, neural circuits
- MeSH terms
- Animals, Depression, Male, Motor Activity, Neural Pathways, Stress, Psychological, Rats, Sprague-Dawley, Ventral Tegmental Area, Maze Learning, Rats, Dopaminergic Neurons, Basal Forebrain, Basolateral Nuclear Complex
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