Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive Responses to Acute Emotional Stress
Open accessAbstract
The medial prefrontal cortex (mPFC) is an important neural substrate for integrating cognitive-affective information and regulating the hypothalamo–pituitary–adrenal (HPA) axis response to emotional stress. mPFC modulation of stress responses is effected in part via the paraventricular hypothalamic nucleus (PVH), which houses both autonomic (sympathoadrenal) and neuroendocrine (HPA) effector mechanisms. Although the weight of evidence suggests that mPFC influences on stress-related PVH outputs are inhibitory, discordant findings have been reported, and such work has tended to treat this cortical region as a unitary structure. Here we compared the effects of lesions of the dorsal versus ventral aspects of mPFC, centered in the prelimbic and infralimbic fields, respectively, on acute restraint stress-induced activation of PVH cell groups mediating autonomic and neuroendocrine responses. Lesions to the dorsal mPFC enhanced restraint-induced Fos and corticotropin-releasing factor (CRF) mRNA expression in the neurosecretory region of PVH. Ablation of the ventral mPFC decreased stress-induced Fos protein and CRF mRNA expression in this compartment but increased Fos induction in PVH regions involved in central autonomic control. Repetition of the experiments in rats bearing retrograde tracer deposits to label PVH-autonomic projections confirmed that ventral mPFC lesions selectively increased stress-induced Fos expression in identified preautonomic neurons. Finally, hormonal indices of HPA activation in response to acute stress were augmented after dorsal mPFC lesions and attenuated after ventral mPFC lesions. These results suggest that dorsal and ventral aspects of the mPFC differentially regulate neuroendocrine and autonomic PVH outputs in response to emotional stress.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cingulate cortex projects to stress inhibitory areas (dorsomedial hypothalamus and the paraventricular hypothalamic nucleus), whilst the infralimbic cortex projects to stress excitatory areas (stria medullaris and amygdala).
“The cingulate cortex projects to stress inhibitory (dorsomedial hypothalamus and the paraventricular hypothalamic nucleus), whilst the infralimbic cortex projects to stress excitatory areas (stria medullaris and amygdala) (125–128).”
From Childhood Trauma, the HPA Axis and Psychiatric Illnesses: A Targeted Literature Synthesis (2022) · cites this paper as [126]
The Discussion (page not available in our copy) supports the broad distinction: dorsal medial prefrontal connections are associated with stress inhibition, while ventral connections are associated with facilitation, and it mentions ventral connections with the amygdala. It does not establish projections from cingulate cortex to the dorsomedial hypothalamus or from infralimbic cortex to the stria medullaris. It also says medial prefrontal projections are sparse within the paraventricular hypothalamic nucleus itself, rather than supporting the stated direct projection to it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStress results in atrophy of the hippocampus and medial PFC (mPFC).
“By contrast, stress results in atrophy of the hippocampus and medial PFC (mPFC) (Magariños et al., 1997, Vyas et al., 2002, Radley et al., 2006).”
From The impact of developmental timing for stress and recovery (2015) · cites this paper as Radley et al., 2006
IL/25 projects directly to autonomic regions that enhance sympathetic activity, including perifornical area, dorsomedial hypothalamus, dorsolateral periaqueductal gray, lateral parabrachial nucleus, cuneiform nucleus, and lateral septum.
“IL/25 projects directly to a number of autonomic regions which have been found to enhance sympathetic activity, including the perifornical area, dorsomedial hypothalamus, dorsolateral periaqueductal gray, lateral parabrachial nucleus, cuneiform nucleus, and lateral septum, among other regions (4, 33, 35–37, 39, 47, 82, 97, 98).”
From Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders (2012) · cites this paper as [82]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
MacDonald, A. W., Cohen, J. D., Stenger, V. A., & Carter, C. S. (2000) · Science · doi:10.1126/science.288.5472.1835 · Cited by 3,666 · see citing works
Swanson, L. W., & Kuypers, H. G. J. M. (1980) · Journal of Comparative Neurology · doi:10.1002/cne.901940306 · Cited by 1,413 · see citing works
Prefrontal cortex in the rat: Projections to subcortical autonomic, motor, and limbic centers
Gabbott, P. L. A., Warner, T. A., Jays, P. R. L., Salway, P., & Busby, S. J. (2005) · Journal of Comparative Neurology · doi:10.1002/cne.20738 · Cited by 1,227 · see citing works
Pattern and time course of immediate early gene expression in rat brain following acute stress
Cullinan, W. E., Herman, J. P., Battaglia, D. F., Akil, H., & Watson, S. J. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00355-9 · Cited by 1,056 · see citing works
Shin, L. M., Wright, C. I., Cannistraro, P. A., Wedig, M. M., McMullin, K., Martis, B., Macklin, M. L., Lasko, N. B., Cavanagh, S. R., Krangel, T. S., et al. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.3.273 · Cited by 960 · see citing works
Efferent projections of the infralimbic cortex of the rat
Hurley, K. M., Herbert, H., Moga, M. M., & Saper, C. B. (1991) · Journal of Comparative Neurology · doi:10.1002/cne.903080210 · Cited by 777 · see citing works
Radley, J. J., Sisti, H. M., Hao, J., Rocher, A. B., McCall, T., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.006 · Cited by 769 · see citing works
Self-citationBhatnagar, S., Huber, R., Nowak, N., & Trotter, P. (2002) · Journal of Neuroendocrinology · doi:10.1046/j.0007-1331.2002.00792.x · Cited by 227 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Swanson LW (1992) Brain maps: structure of the rat brain. Amsterdam: Elsevier.
Cited by
Sorted by citations
Neural regulation of endocrine and autonomic stress responses
Ulrich-Lai, Y. M., & Herman, J. P. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2647 · Cited by 3,318 · see citing works
Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response
Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B. (2016) · Comprehensive Physiology · doi:10.1002/cphy.c150015 · Cited by 1,819 · see citing works
McEwen, B. S., & Gianaros, P. J. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05331.x · Cited by 1,715 · see citing works
The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course
McEwen, B. S., & Morrison, J. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.028 · Cited by 1,079 · see citing works
Limbic Regulation of Hypothalamo‐Pituitary‐Adrenocortical Function during Acute and Chronic Stress
Jankord, R., & Herman, J. P. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1410.012 · Cited by 578 · see citing works
Tynan, R. J., Naicker, S., Hinwood, M., Nalivaiko, E., Buller, K. M., Pow, D. V., Day, T. A., & Walker, F. R. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.02.001 · Cited by 531 · see citing works
The neurobiology of depression and antidepressant action
Willner, P., Scheel-Krüger, J., & Belzung, C. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.12.007 · Cited by 519 · see citing works
Neural Mechanisms of Stress Resilience and Vulnerability
Franklin, T. B., Saab, B. J., & Mansuy, I. M. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.016 · Cited by 500 · see citing works
Stress-induced prefrontal reorganization and executive dysfunction in rodents
Holmes, A., & Wellman, C. L. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.11.005 · Cited by 469 · see citing works
The Role of BDNF on Neural Plasticity in Depression
Yang, T., Nie, Z., Shu, H., Kuang, Y., Chen, X., Cheng, J., Yu, S., & Liu, H. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00082 · Cited by 435 · see citing works
Brain mediators of cardiovascular responses to social threat
Wager, T. D., Waugh, C. E., Lindquist, M., Noll, D. C., Fredrickson, B. L., & Taylor, S. F. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.05.043 · Cited by 402 · see citing works
Hinwood, M., Morandini, J., Day, T. A., & Walker, F. R. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhr229 · Cited by 420 · see citing works
Choi, D. C., Furay, A. R., Evanson, N. K., Ostrander, M. M., Ulrich-Lai, Y. M., & Herman, J. P. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4301-06.2007 · Cited by 392 · see citing works
Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders
Myers-Schulz, B., & Koenigs, M. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.88 · Cited by 333 · see citing works
Goldwater, D. S., Pavlides, C., Hunter, R. G., Bloss, E. B., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.08.053 · Cited by 333 · see citing works
The mesoaccumbens dopamine in coping with stress
Cabib, S., & Puglisi-Allegra, S. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.04.012 · Cited by 329 · see citing works
McKlveen, J. M., Myers, B., & Herman, J. P. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12272 · Cited by 273 · see citing works
The impact of developmental timing for stress and recovery
Gee, D. G., & Casey, B. J. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2015.02.001 · Cited by 245 · see citing works
“6) consistent with prior work showing similar effects following chronic stress (Cook and Wellman, 2004; Radley et al., 2004, 2006), with some evidence that effects on mPFC were reversible (Radley et al., 2005).”
BackgroundResultA common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response
Radley, J. J., & Sawchenko, P. E. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6040-10.2011 · Cited by 251 · see citing works
Self-citationStress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific
Shansky, R. M., Hamo, C., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp003 · Cited by 248 · see citing works
Lehmann, M. L., & Herkenham, M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0577-11.2011 · Cited by 234 · see citing works
Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion
McKlveen, J. M., Myers, B., Flak, J. N., Bundzikova, J., Solomon, M. B., Seroogy, K. B., & Herman, J. P. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.03.024 · Cited by 237 · see citing works
McKlveen, J. M., Morano, R. L., Fitzgerald, M., Zoubovsky, S., Cassella, S. N., Scheimann, J. R., Ghosal, S., Mahbod, P., Packard, B. A., Myers, B., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.03.2101 · Cited by 224 · see citing works
Cellular and molecular basis for stress-induced depression
Seo, J.-S., Wei, J., Qin, L., Kim, Y., Yan, Z., & Greengard, P. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.118 · Cited by 235 · see citing works
Neural bases of moderation of cortisol stress responses by psychosocial resources.
Taylor, S. E., Burklund, L. J., Eisenberger, N. I., Lehman, B. J., Hilmert, C. J., & Lieberman, M. D. (2008) · Journal of Personality and Social Psychology · doi:10.1037/0022-3514.95.1.197 · Cited by 219 · see citing works
What happens to your brain on the way to Mars
Parihar, V. K., Allen, B., Tran, K. K., Macaraeg, T. G., Chu, E. M., Kwok, S. F., Chmielewski, N. N., Craver, B. M., Baulch, J. E., Acharya, M. M., et al. (2015) · Science Advances · doi:10.1126/sciadv.1400256 · Cited by 217 · see citing works
Uchida, S., Nishida, A., Hara, K., Kamemoto, T., Suetsugi, M., Fujimoto, M., Watanuki, T., Wakabayashi, Y., Otsuki, K., McEwen, B. S., et al. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06218.x · Cited by 203 · see citing works
Tynan, R. J., Beynon, S. B., Hinwood, M., Johnson, S. J., Nilsson, M., Woods, J. J., & Walker, F. R. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1102-0 · Cited by 199 · see citing works
Lanfranchi, P. A., Pennestri, M.-H., Fradette, L., Dumont, M., Morin, C. M., & Montplaisir, J. (2009) · Sleep · doi:10.1093/sleep/32.6.760 · Cited by 198 · see citing works
Childhood Trauma, the HPA Axis and Psychiatric Illnesses: A Targeted Literature Synthesis
Murphy, F., Nasa, A., Cullinane, D., Raajakesary, K., Gazzaz, A., Sooknarine, V., Haines, M., Roman, E., Kelly, L., O'Neill, A., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.748372 · Cited by 181 · see citing works
Neural Regulation of the Stress Response: The Many Faces of Feedback
Myers, B., McKlveen, J. M., & Herman, J. P. (2012) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-012-9801-y · Cited by 175 · see citing works
“Lesion studies indicate that the more ventral components of the mPFC (infralimbic (il) PFC) may be involved in stress excitation (Sullivan and Gratton 1998, 1999; Radley et al. 2006).”
The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder
Woelfer, M., Kasties, V., Kahlfuss, S., & Walter, M. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2018.03.034 · Cited by 171 · see citing works
Sartim, A. G., Guimarães, F. S., & Joca, S. R. L. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.01.033 · Cited by 156 · see citing works
Veer, I. M., Oei, N. Y. L., Spinhoven, P., van Buchem, M. A., Elzinga, B. M., & Rombouts, S. A. R. B. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.12.001 · Cited by 140 · see citing works
Hypothalamic-pituitary – adrenal axis-feedback control
Keller‐Wood, M. (2015) · Comprehensive Physiology · doi:10.1002/cphy.c140065 · Cited by 131 · see citing works
The more physical inactivity, the more agitation in dementia
Scherder, E. J. A., Bogen, T., Eggermont, L. H. P., Hamers, J. P. H., & Swaab, D. F. (2010) · International Psychogeriatrics · doi:10.1017/s1041610210001493 · Cited by 121 · see citing works
Lim, L. W., Prickaerts, J., Huguet, G., Kadar, E., Hartung, H., Sharp, T., & Temel, Y. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.24 · Cited by 116 · see citing works
Sabihi, S., Durosko, N. E., Dong, S. M., & Leuner, B. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.009 · Cited by 106 · see citing works
Michelsen, K. A., van den Hove, D. L., Schmitz, C., Segers, O., Prickaerts, J., & Steinbusch, H. W. (2007) · BMC Neuroscience · doi:10.1186/1471-2202-8-107 · Cited by 100 · see citing works
Ganon-Elazar, E., & Akirav, I. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.01.014 · Cited by 98 · see citing works
Cumulative adversity sensitizes neural response to acute stress: association with health symptoms
Seo, D., Tsou, K. A., Ansell, E. B., Potenza, M. N., & Sinha, R. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.250 · Cited by 88 · see citing works
Musazzi, L., Treccani, G., & Popoli, M. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00060 · Cited by 83 · see citing works
Flak, J. N., Solomon, M. B., Jankord, R., Krause, E. G., & Herman, J. P. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08161.x · Cited by 87 · see citing works
The neurobiology of offensive aggression: Revealing a modular view
de Boer, S. F., Olivier, B., Veening, J., & Koolhaas, J. M. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.04.040 · Cited by 70 · see citing works
Marinho, A. L. Z., Vila-Verde, C., Fogaça, M. V., & Guimarães, F. S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.02.023 · Cited by 68 · see citing works
Vollmer, L. L., Schmeltzer, S., Schurdak, J., Ahlbrand, R., Rush, J., Dolgas, C. M., Baccei, M. L., & Sah, R. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.4955-13.2016 · Cited by 45 · see citing works
Bronson, S. L., Chan, J. C., & Bale, T. L. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.025 · Cited by 49 · see citing works
Sensorimotor Modulation of Mood and Depression: In Search of an Optimal Mode of Stimulation
Canbeyli, R. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00428 · Cited by 42 · see citing works
Kuniishi, H., Ichisaka, S., Matsuda, S., Futora, E., Harada, R., & Hata, Y. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00250 · Cited by 34 · see citing works
Egan, A. E., Thompson, A. M. K., Buesing, D., Fourman, S. M., Packard, A. E. B., Terefe, T., Li, D., Wang, X., Song, S., Solomon, M. B., et al. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.05.030 · Cited by 19 · see citing works
Layer-specific input to medial prefrontal cortex is linked to stress susceptibility
Solakoğlu, S. T., Erdener, Ş. E., Gliko, O., Can, A., Sümbül, U., & Eren-Koçak, E. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03258-x · Cited by 5 · see citing works
- Authors
- Radley, J. J., Arias, C. M., & Sawchenko, P. E.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-12-13
- Volume
- 26
- Issue
- 50
- Pages
- 12967-12976
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674963
- OpenAlex
- W1963910089
- Cited by
- 456
- References
- 8
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 10 · 2023: 16 · 2022: 25 · 2021: 25 · 2020: 64 · 2019: 16 · 2018: 24 · 2017: 18 · 2016: 29 · 2015: 30 · 2014: 24 · 2013: 30 · 2012: 24
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- Fondation pour la Recherche Médicale
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS049196, NS-49196)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- medial prefrontal cortex, regional differentiation, acute emotional stress, restraint stress, paraventricular nucleus, hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor, Fos expression, autonomic stress response, neuroendocrine stress response, prelimbic cortex, infralimbic cortex, retrograde tracing
- MeSH terms
- Acute Disease, Adaptation, Psychological, Adrenocorticotropic Hormone, Animals, Corticotropin-Releasing Hormone, Emotions, Male, Nerve Net, RNA, Messenger, Stress, Psychological, Rats, Sprague-Dawley, Prefrontal Cortex, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
