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Key Event: 2371

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Reduced, Corticotropin-Releasing Factor

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Reduced CRF
Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
central nervous system

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
peptide biosynthetic process increased
receptor binding occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Binding of Alpha 1-Adrenergics to Antagonists Leading to Depression KeyEvent Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Corticotropin-releasing factor (CRF) is a 41-amino acid peptide that acts as both a neurotransmitter and a hormonal modulator. It is widely distributed in the central nervous system and peripheral tissues. Initially identified in the hypothalamus, CRF plays a critical role in coordinating the neuroendocrine stress response by stimulating the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. (DOMIN et al., 2024; HASHIMOTO, 1979; VALE et al., 1981).

The release of CRF is a central step in the body's response to real or perceived threats. Its activation in various neuronal types triggers functional and structural changes that modulate neuroplasticity, directly impacting circuits involved in emotional regulation, cognitive functions, and the control of endocrine and autonomic systems (Reveg et al., 2014).

Furthermore, CRF contributes to the effects of stress on the hippocampus by promoting learning and memory deficits. It does this by causing dendritic and synaptic alterations, such as spine instability and a reduction in dendritic branching, which directly impair synaptic plasticity (Wang et al., 2011; PAWLAK et al., 2005; CHEN et al., 2012; CHEN et al., 2004; DONG et al., 2012). There is evidence suggesting that chronic stress in rats reduces the expression of Alpha1 receptors in the hypothalamus and brainstem. (MIYAHARA Et Al; 1999)

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

1- Radioimmunoassay (RIA) / Enzyme-linked immunoassay (ELISA)

  • CRF peptide levels in plasma, cerebrospinal fluid (CSF), or tissue extracts.

  • Example:

  • Suda et al. (1985) measured CRF in plasma of pregnant women with RIA, showing rising concentrations during gestation.
  • Inda et al. (1998) used ELISA to quantify CRF in CSF of depressed patients.

2- In situ hybridization (ISH) / Quantitative PCR

  • Measures mRNA expression of CRF in hypothalamus, amygdala, or other brain regions

  • Example: 

  • Makino et al. (1994) used ISH to show stress increases CRF mRNA in paraventricular nucleus of rats.
  • Korosi et al. (2006) measured CRF mRNA in hippocampus of rat pups exposed to early-life stress.

3- Immunohistochemistry (IHC)

  • Detects CRF protein localization and relative abundance in brain tissue.

  • Example:

  • Hauger et al. (2006) reviewed CRF immunohistochemistry findings showing upregulation in stress-related brain regions.

4-Western blotting / Protein assays

  • Used to confirm increased CRF protein expression in homogenized brain or pituitary tissue.

  • Example:

    • Feng et al. (2007) used Western blot to quantify CRF protein increases after chronic stress in rat hypothalamus.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The available evidence indicates that this AOP is best characterized in mammals, including rodents, sheep, and humans, in which the corticotropin-releasing factor (CRF/CRH) system and its associated proteins exhibit structural and functional conservation. Comparative studies suggest that the core elements of this pathway, such as CRF, CRH-R1 receptors, and the CRH-BP binding protein, are evolutionarily preserved across vertebrates, allowing for broader potential applicability, although caution is warranted in non-mammalian species (SEASHOLTZ et al., 2002; JENSEN et al., 2018).

With regard to life stage, this AOP is applicable from the fetal and perinatal periods through adulthood and aging. The development of the hypothalamic–pituitary–adrenal (HPA) axis involves critical windows of vulnerability, such that early disruptions in CRF signaling may produce long-lasting neuroendocrine and behavioral effects, while alterations in adults and the elderly tend to be associated with mood disorders, anxiety, and cognitive decline (ALCÁNTARA-ALONSO, 2019; KOROSI; BARAN; MEANEY, 2012; SCHULKIN, 2017).

Both sexes are susceptible to the consequences of increased CRF; however, differences modulated by gonadal hormones, differential expression of CRH-BP, and receptor polymorphisms may influence the magnitude and nature of the effects (GARCIA et al., 2019; ORAND; AGUILERA, 2015).

In terms of tissues and organs, the domain of applicability primarily involves the hypothalamus (particularly the paraventricular nucleus), the amygdala, and the pituitary, which together integrate the HPA axis. Peripheral sources of CRF, such as the placenta, are particularly relevant for exposures during the perinatal period (KOROSI; BARAN; MEANEY, 2012).

Detection of alterations in CRF can be performed using different experimental methods, including mRNA analysis (ISH, qPCR), protein quantification (IHC, Western blot), measurement of extracellular release (microdialysis), and biofluid assays (ELISA or RIA in plasma and cerebrospinal fluid). It is important to consider pre-analytical factors, which may influence data interpretation (KWON et al., 2017; MERLO PICH et al., 1995).

References

List of the literature that was cited for this KE description. More help

DOZE, Van A.; PAPAY, Robert S.; GOLDENSTEIN, Brianna L.; GUPTA, Manveen K.; COLLETTE, Katie M.; NELSON, Brian W.; LYONS, Mariaha J.; DAVIS, Bethany A.; LUGER, Elizabeth J.; WOOD, Sarah G.. Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity. Molecular Pharmacology, [S.L.], v. 80, n. 4, p. 747-758, out. 2011. Elsevier BV. http://dx.doi.org/10.1124/mol.111.073734.

HASHIMOTO, Kozo; YUNOKI, Sho; TAKAHARA, Jiro; OFUJI, Tadashi. ACTH release in pituitary cell cultures. Effect of neurogenic peptides and neurotransmitter substances on ACTH release induced by hypothalamic corticotropin releasing factor (CRF). Endocrinologia Japonica, [S.L.], v. 26, n. 1, p. 103-109, 1979. Japan Endocrine Society. http://dx.doi.org/10.1507/endocrj1954.26.103.

DOMIN, Helena; ŚMIAłOWSKA, Maria. The diverse role of corticotropin-releasing factor (CRF) and its CRF1 and CRF2 receptors under pathophysiological conditions: insights into stress/anxiety, depression, and brain injury processes. Neuroscience & Biobehavioral Reviews, [S.L.], v. 163, p. 105748, ago. 2024. Elsevier BV. http://dx.doi.org/10.1016/j.neubiorev.2024.105748. 

REGEV, Limor; BARAM, Tallie Z.. Corticotropin releasing factor in neuroplasticity. Frontiers In Neuroendocrinology, [S.L.], v. 35, n. 2, p. 171-179, abr. 2014. Elsevier BV. http://dx.doi.org/10.1016/j.yfrne.2013.10.001. 

VALE, Wylie; SPIESS, Joachim; RIVIER, Catherine; RIVIER, Jean. Characterization of a 41-Residue Ovine Hypothalamic Peptide That Stimulates Secretion of Corticotropin and β-Endorphin. Science, [S.L.], v. 213, n. 4514, p. 1394-1397, 18 set. 1981. American Association for the Advancement of Science (AAAS). http://dx.doi.org/10.1126/science.6267699. 

WANG, Xiao-Dong; RAMMES, Gerhard; KRAEV, Igor; WOLF, Miriam; LIEBL, Claudia; SCHARF, Sebastian H.; RICE, Courtney J.; WURST, Wolfgang; HOLSBOER, Florian; DEUSSING, Jan M.. Forebrain CRF1Modulates Early-Life Stress-Programmed Cognitive Deficits. The Journal Of Neuroscience, [S.L.], v. 31, n. 38, p. 13625-13634, 21 set. 2011. Society for Neuroscience. http://dx.doi.org/10.1523/jneurosci.2259-11.2011. 

PAWLAK, Robert; RAO, B. S. Shankaranarayana; MELCHOR, Jerry P.; CHATTARJI, Sumantra; MCEWEN, Bruce; STRICKLAND, Sidney. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proceedings Of The National Academy Of Sciences, [S.L.], v. 102, n. 50, p. 18201-18206, 5 dez. 2005. Proceedings of the National Academy of Sciences. http://dx.doi.org/10.1073/pnas.0509232102. 

CHEN, Y; A KRAMÁR, E; CHEN, L y; BABAYAN, A H; ANDRES, A L; GALL, C M; LYNCH, G; BARAM, T Z. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Molecular Psychiatry, [S.L.], v. 18, n. 4, p. 485-496, 13 mar. 2012. Springer Science and Business Media LLC. http://dx.doi.org/10.1038/mp.2012.17. 

DONG, Hongxin; MURPHY, Keely M.; MENG, Liping; MONTALVO-ORTIZ, Janitza; ZENG, Ziling; KOLBER, Benedict J.; ZHANG, Shanshan; MUGLIA, Louis J.; CSERNANSKY, John G.. Corticotrophin Releasing Factor Accelerates Neuropathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease. Journal Of Alzheimer'S Disease, [S.L.], v. 28, n. 3, p. 579-592, 7 fev. 2012. SAGE Publications. http://dx.doi.org/10.3233/jad-2011-111328. 

MIYAHARA, Satoru; KOMORI, Teruhisa; FUJIWARA, Ryoichi; SHIZUYA, Koji; YAMAMOTO, Masato; OHMORI, Masaki; OKAZAKI, Yuji. Effects of single and repeated stresses on the expression of mRNA for α1-adrenoceptors in the rat hypothalamus and midbrain. European Journal Of Pharmacology, [S.L.], v. 379, n. 1, p. 111-114, ago. 1999. Elsevier BV. http://dx.doi.org/10.1016/s0014-2999(99)00498-7.

WOLFE, C. D. A.; PATEL, S. P.; CAMPBELL, E. A.; LINTON, E. A.; ANDERSON, J.; LOWRY, P. J.; JONES, M. T.. Plasma corticotrophin‐releasing factor (CRF) in normal pregnancy. Bjog: An International Journal of Obstetrics & Gynaecology, [S.L.], v. 95, n. 10, p. 997-1002, out. 1988. Wiley. http://dx.doi.org/10.1111/j.1471-0528.1988.tb06503.x. 

TOTH, Mate; GRESACK, Jodi e; A BANGASSER, Debra; PLONA, Zach; VALENTINO, Rita J; FLANDREAU, Elizabeth I; MANSUY, Isabelle M; MERLO-PICH, Emilio; A GEYER, Mark; RISBROUGH, Victoria B. Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice. Neuropsychopharmacology, [S.L.], v. 39, n. 6, p. 1409-1419, 11 dez. 2013. Springer Science and Business Media LLC. http://dx.doi.org/10.1038/npp.2013.336. 

Suda, T., Tomori, N., Yajima, F., Sumitomo, T., Nakagami, Y., Ushiyama, T., & Demura, H. (1985). Plasma corticotropin‐releasing factor in normal pregnancy and pregnancy‐induced hypertension. The Journal of Clinical Endocrinology & Metabolism, 61(5), 1042–1046. https://doi.org/10.1210/jcem-61-5-1042

Merlo Pich, E., Lorang, M., Yeganeh, M., Rodriguez de Fonseca, F., Raber, J., Koob, G. F., & Weiss, F. (1995). Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. Proceedings of the National Academy of Sciences, 92(18), 8729–8733. https://doi.org/10.1073/pnas.92.18.8729

Makino, S., Smith, M. A., & Gold, P. W. (1994). Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology, 134(9), 3299–3309. https://doi.org/10.1210/en.134.9.3299

Hauger, R. L., Risbrough, V., Brauns, O., & Dautzenberg, F. M. (2006). Corticotropin releasing factor (CRF) receptor signaling: relevance to stress-related disorders. Brain Research, 1071(1), 68–85. https://doi.org/10.1016/j.brainres.2005.11.074

Korosi, A., Baram, T. Z., & Dube, C. M. (2006). Early-life programming of hypothalamic-pituitary-adrenal function by maternal care: life-long impact of CRF. Endocrinology, 147(4), 1577–1585. https://doi.org/10.1210/en.2005-1136 

SEASHOLTZ, Af; VALVERDE, Ra; DENVER, Rj. Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals. Journal Of Endocrinology, [S.L.], v. 175, n. 1, p. 89-97, 1 out. 2002. Bioscientifica. http://dx.doi.org/10.1677/joe.0.1750089. 

JENSEN, M. A.; BLATZ, D. J.; LALONE, C. A. Defining the biologically plausible taxonomic domain of applicability of an adverse outcome pathway: a case study linking nicotinic acetylcholine receptor activation to colony death. Environmental Toxicology and Chemistry, v. 42, n. 1, p. 71-87, 2023. DOI: 10.1002/etc.5501.

LEE, K. W.; RHEE, J. S.; RAISUDDIN, S.; PARK, H.; LEE, J. S. The remarkable conservation of corticotropin-releasing hormone (CRH)-binding protein in the honeybee (Apis mellifera) dates the CRH system to a common ancestor of insects and vertebrates. General and Comparative Endocrinology, v. 158, n. 1, p. 54-60, ago. 2008. DOI: 10.1016/j.ygcen.2008.05.002.

VALVERDE, R. A.; SEASHOLTZ, A. F.; CORTRIGHT, D. N.; DENVER, R. J. Molecular and biochemical characterization of the mouse brain corticotropin-releasing hormone-binding protein. Molecular and Cellular Endocrinology, v. 173, n. 1-2, p. 29-40, fev. 2001. DOI: https://doi.org/10.1016/S0303-7207(00)00437-8.