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Event: 2098

Key Event Title

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

Increase, Abnormal Neural Remodeling

Short name

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Abnormal Neural Remodeling

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Biological Context

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Level of Biological Organization
Tissue

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

Key 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
neurogenesis		decreased
demyelination		increased
neuron death		increased

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
Deposition of Energy Leading to Learning and Memory Impairment	KeyEvent	Vinita Chauhan (send email)	Open for citation & comment

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
dog	Canis lupus familiaris	Low	NCBI
rat	Rattus norvegicus	Moderate	NCBI
mouse	Mus musculus	Moderate	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Juvenile	Low
Adult	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Male	Moderate
Female	Low
Unspecific	Low

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

(Adapted from KE: 618)

Abnormal neural remodeling is a normal process that allows for the encoding of new information and experiences, and it is essential in the functional and structural adaptation of the central nervous system (CNS) (Wang et al., 2010). Remodeling of neural cells can be adaptive but stressors and stimuli that lead to persistent inflammation can degenerate brain cell types like neurons, dendrites, glial cells, astrocytes and oligodendrocytes (Hladik & Tapio, 2016; Makale et al., 2017). Abnormal neural remodeling can encompass a broad range of processes (Marc et al., 2003). Key processes include changes in neurogenesis, synaptic plasticity, and myelination, which are all measurable. Neurogenesis involves the generation of new neurons from neural stem cells, primarily occurring in neurogenic niches such as the hippocampus (Hladik & Tapio, 2016). Synaptic plasticity refers to the ability of synapses to undergo structural and functional modifications in response to activity, facilitating learning and memory formation. This includes processes like long-term potentiation (LTP) and long-term depression (LTD), which enhances or weakens synaptic strength, respectively. Myelination, primarily mediated by oligodendrocytes in the CNS, involves the formation of myelin sheaths around axons, facilitating efficient signal transmission (Stadelmann et al., 2019).

Exposure to environmental toxins or substances during critical developmental periods can negatively influence the many processes involved in abnormal neural remodeling. Prenatal exposure to neurotoxic substances, for instance, may disrupt fetal neurogenesis. Prolonged stress, hormonal imbalances, and the natural aging process can also contribute to abnormal neural remodeling. Studies show that the dendrites of neurons are an important structure for maintaining synaptic plasticity. Changes in dendritic spine density and structure, including decreases in dendritic branch points, length, and area, are correlated with changes in excitatory synaptic transmission strength which can impair brain function (Jandial et al., 2018; Auffret et al., 2009). Dendritic protein synthesis is also required for many types of long-term synaptic plasticity (Sutton & Schuman 2006). Changes to the levels of protein synthesis can greatly affect neuronal communication. When dendritic complexity decreases, there can be a decline in neurogenesis and an increase in neurodegeneration. Neurogenesis is the creation of mature cells from neural stem cells (NSCs) which are involved in learning and memory, and decreased neurogenesis can impair the brain’s function (Hladik & Tapio, 2016). Together these events provoke changes in synaptic plasticity and propagations of action potentials, ultimately leading to the disruption of neuronal signaling (Cekanaviciute et al., 2018). Other types of changes related to abnormal neural remodeling include demyelination of neurons and white matter necrosis which have been associated with altered brain function such as decreased long-term memory formation (Makale et al., 2017; Tomé et al., 2015).

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

Method of Measurement	References	Description	OECD-Approved Assay
MRI Scan	Jiang et al., 2014	Magnetic resonance imaging (MRI) is an imaging technique used to visualize organs and tissues in the body. MRI can be used to view demyelination.	No
Fluoro-Jade stain	Schmued and Hopkins, 2000	Detects and labels degenerating neurons.	No
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) Assay – colorimetric assay used to assess cell metabolic activity based on the reduction of (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.	Riss et al., 2004	Cell viability and proliferation assays can be used to measure increased levels of neurodegeneration or decreased levels of neurogenesis.	Yes
Bromodeoxyuridine (BrdU) labeling	Vallieres et al., 2002	Staining method used to identify proliferating cells and measures neurogenesis.	No
SYNPLA	Dore et al., 2020	Synaptic proximity ligation assay (SYNPLA) is a technique that detects learning-induced synaptic plasticity.	No
ELISA	Falsig et al., 2003; Lund et al., 2006; Monnet-Tschudi et al., 2011	The enzyme-linked immunosorbent assay (ELISA) is a technique that detects and quantifies levels of macromolecules such as peptides, proteins, antibodies, and hormones. It can be used to detect specific molecules in neurons that represent loss in integrity such as PSD-95, synapsin 1 or drebrin.	No
Immunoassay/microscopy	Falsig et al., 2003; Lund et al., 2006; Monnet-Tschudi et al., 2011	Various methods that use the specificity of antigen-antibody binding for detection and quantification of target molecules such as PSD-95, synpasin 1, Ki-67 and drebrin.	No
Western Blot	Yang and Mahmood, 2012	Protein identification from a complex mixture after size separation, transfer to solid support and marking target protein. Specific markers include PSD-95, synpasin 1, Ki-67 and drebrin.	No
Golgi-Cox Method	Zaqout and Kaindl, 2016	Visualizes neuronal morphology in vivo.	No
Whole-cell electrophysiology	Hill and Stephens, 2021	Measures intracellular electrical properties by visualizing ionic currents.	No
Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay	Kressel and Groscurth, 1994	Apoptosis is detected with the TUNEL method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks.	Yes

Domain of Applicability

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

Taxonomic applicability: The ability to process complex spatiotemporal information through neuronal networking is a fundamental process underlying the behavior of all higher organisms. The most studied are the neuronal networks of vertebrates such as rodents (Cekanaviciute et al., 2018) and primates (Wang and Arnsten, 2015). https://pubmed.ncbi.nlm.nih.gov/26876924/Invertebrates hold neural circuitries in various degrees of complexity and there are studies describing how neurons are organized into functional networks to generate behaviour (Wong and Wong, 2004; Marder, 1994).

Life stage applicability: This key event is applicable to all life stages; most evidence is derived from studies in adults (Cekanaviciute et al., 2018; Hladik & Tapio, 2016).

Sex applicability: This key event is not sex specific (Hladik & Tapio, 2016).

Evidence for perturbation by a prototypic stressor: Current literature provides ample evidence of neural remodeling being induced by stressors including ionizing radiation (Allen et al., 2015; Cekanaviciute et al., 2018; J. R. Fike et al., 1984; John R. Fike et al., 1988; Hladik & Tapio, 2016; Kiffer et al., 2020; Mizumatsu et al., 2003; Okamoto et al., 2009; Vipan K. Parihar et al., 2016; Vipan K. Parihar; Rola et al., 2005; Tiller-Borcich et al., 1987).

References

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

Allen, A. R. et al. (2015), “56Fe Irradiation Alters Spine Density and Dendritic Complexity in the Mouse Hippocampus”, Radiation Research, Vol. 184/6, BioOne, Washington, https://doi.org/10.1667/RR14103.1.

Alvarez, M. L. and S. C. Doné. (2014), “SYBR® Green and TaqMan® Quantitative PCR Arrays: Expression Profile of Genes Relevant to a Pathway or a Disease State” (pp. 321–359), Springer Nature, Berlin, https://doi.org/10.1007/978-1-4939-1062-5_27.

Auffret, A. et al. (2009), “Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer’s Disease”, Journal of Neuroscience, Vol. 29/32, Society for Neuroscience, Washington, https://doi.org/10.1523/JNEUROSCI.1856-09.2009.

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), “Central nervous system responses to simulated galactic cosmic rays”, International Journal of Molecular Sciences, Vol. 19/11, Multi-Disciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms19113669.

Chakraborti, A. et al. (2012), “Cranial Irradiation Alters Dendritic Spine Density and Morphology in the Hippocampus”, (P.J. Tofilon,

Ed.) PloS ONE, Vol. 7/7, Public Library of Science, San Francisco, https://doi.org/10.1371/journal.pone.0040844.

Dore, K. et al. (2020), “SYNPLA, a method to identify synapses displaying plasticity after learning”, Proceedings of the National Academy of Sciences, Vol. 117/6, Proceedings of the National Academy of Sciences, https://doi.org/10.1073/pnas.1919911117.

Falsig, J., M. Latta and M. Leist. (2003), “Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95-driven apoptosis”, Journal of Neurochemistry, Vol. 88/1, John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1111/j.1471- 4159.2004.02144.x.

Fike, J. R. et al. (1984), “Computed Tomography Analysis of the Canine Brain: Effects of Hemibrain X Irradiation”, Radiation Research, Vol. 99/2, Allen Press, Lawrence, https://doi.org/10.2307/3576373.

Fike, J. R. et al. (1988), “Radiation dose response of normal brain”, International Journal of Radiation Oncology, Biology, Physics, Vol. 14/1, Elsevier, Amsterdam, https://doi.org/10.1016/0360-3016(88)90052-1.

Harris, K. and J. Stevens. (1989), “Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics”, The Journal of Neuroscience, Vol. 9/8, Society for Neuroscience, Washington, https://doi.org/10.1523/JNEUROSCI.09-08-02982.1989.

Hill, C. L. and G. J. Stephens. (2021), “An Introduction to Patch Clamp Recording” (pp. 1–19), https://doi.org/10.1007/978-1-0716- 0818-0_1.

Hladik, D. and S. Tapio. (2016), “Effects of ionizing radiation on the mammalian brain”, Mutation Research/Reviews in Mutation Research, Vol. 770, Elsevier B. b., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.003.

Kiffer, F. et al. (2020), “Late Effects of 1H + 16O on Short-Term and Object Memory, Hippocampal Dendritic Morphology and Mutagenesis”, Frontiers in Behavioral Neuroscience, Vol. 14, Frontiers Media S.A., https://doi.org/10.3389/fnbeh.2020.00096.

Kressel, M. and P. Groscurth (1994), “Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA”, Cell and tissue research, Vol. 278/3, Nature, https://doi.org/10.1007/BF00331373.

Kukurba, K. R. and S. B. Montgomery. (2015), “RNA Sequencing and Analysis”, Cold Spring Harbor Protocols, Vol. 2015/11, https://doi.org/10.1101/pdb.top084970.

Jandial, R. et al. (2018), “Space–brain: The negative effects of space exposure on the central nervous system”, Surgical Neurology International, Vol. 9/1, https://doi.org/10.4103/sni.sni_250_17.

Jiang, X. et al. (2014), “A GSK-3β Inhibitor Protects Against Radiation Necrosis in Mouse Brain”, International Journal of Radiation Oncology*Biology*Physics, Vol. 89/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijrobp.2014.04.018.

Lodish, H., et al. (2000). Overview of Neuron Structure and Function. https ://www.ncbi.nlm.nih.gov/books/NBK21535/

Lund, S. et al. (2006), “The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions”, Journal of Neuroimmunology, Vol. 180/1–2, Elsevier, Amsterdam, https://doi.org/10.1016/j.jneuroim.2006.07.007.

Makale, M. T. et al. (2017), “Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours”, Nature reviews. Neurology, Vol. 13/1, 52–64. https://doi.org/10.1038/nrneurol.2016.185

Marc, R. E., Jones, B. W., Watt, C. B., & Strettoi, E. (2003). Neural remodeling in retinal degeneration. *Progress in Retinal and Eye Research, 22*(5), 607-655. https://doi.org/10.1016/S1350-9462(03)00039-9.

Marder, E. (1994), “Invertebrate Neurobiology: Polymorphic neural networks”, Current Biology, Vol. 4/8, Elsevier, Amsterdam, https://doi.org/10.1016/S0960-9822(00)00169-X.

Mizumatsu, S. et al. (2003), “Extreme sensitivity of adult neurogenesis to low doses of X-irradiation”, Cancer Research, Vol. 63/14.

Monnet‐Tschudi, F. et al. (2011), “Methods to Assess Neuroinflammation”, Current Protocols in Toxicology, Vol. 50/1, John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1002/0471140856.tx1219s50.

Okamoto, M. et al. (2009), “Effect of radiation on the development of immature hippocampal neurons in vitro”, Radiation Research, Vol. 172/6, BioOne, Washington, https://doi.org/10.1667/RR1741.1.

Parihar, V. K. et al. (2016), “Cosmic radiation exposure and persistent cognitive dysfunction”, Scientific Reports, Vol. 6/June, Nature Publishing Group, Berlin, https://doi.org/10.1038/srep34774.

Parihar, V. K. et al. (2015), “What happens to your brain on the way to Mars”, Science Advances, Vol. ¼, American Association for the Advancement of Science, Washington, https://doi.org/10.1126/SCIADV.1400256.

Riss, T. L. et al. (2004), Cell Viability Assays, Assay Guidance Manual, http://www.ncbi.nlm.nih.gov/pubmed/23805433.

Rola, R. et al. (2005), “High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis”, Radiation Research (Volume 164, pp. 556–560), BioOne, Washington, https://doi.org/10.1667/RR3412.1.

Schmued, L. C. and K. J. Hopkins. (2000), “Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration”, Brain Research, Vol. 874/2, Elsevier, Amsterdam, https://doi.org/10.1016/S0006-8993(00)02513-0.

Stadelmann, C., Timmler, S., Barrantes-Freer, A., & Simons, M. (2019). Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiological Reviews, 99(3), 1381-1431. https://doi.org/10.1152/physrev.00031.2018

Sutton, M. A. and E. M. Schuman. (2006), "Dendritic Protein Synthesis, Synaptic Plasticity, and Memory", Cell, Vol. 127/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.cell.2006.09.014.

Tiller-Borcich, J. K. et al. (1987), "Pathology of Delayed Radiation Brain Damage: An Experimental Canine Model", Radiation