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Relationship: 748

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Hippocampal Physiology, Altered leads to Cognitive Function, Decreased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Hippocampal Physiology, Altered

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Cognitive Function, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	High	Moderate	Kevin Crofton (send email)	Open for citation & comment	WPHA/WNT Endorsed
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Mary Gilbert (send email)	Under Development: Contributions and Comments Welcome
Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	High	Moderate	Kevin Crofton (send email)	Under development: Not open for comment. Do not cite	Under Development
AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Low	Low	Prakash Patel (send email)	Under development: Not open for comment. Do not cite
AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Moderate	Prakash Patel (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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI
humans	Homo sapiens	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

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

Term	Evidence
During brain development	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

It is a well-accepted assertion that hippocampal synaptic integrity and plasticity are essential for spatial information processing in animals and spatial and episodic memory in humans (Burgess, 2002; Martin et al., 2000; Sweatt, 2016). A large number of studies with a variety of techniques and approaches have linked hippocampal functional deficits to decreased spatial ability, context learning, and fear learning. Study of human disease states and conditions where hippocampal function is impaired (i.e., brain trauma, Alzheimer’s disease, temporal lobe epilepsy, Down’s Syndrome), and imaging studies of hippocampal activation during memory challenge, makes itirrefutable that the hippocampus is essential for specific types of cognition abilities. Decades of animal research has reinforced this assertion.

There are many forms of synaptic plasticity and numerous ways in which physiological function of neural circuits can be assessed. Similarly, there are many forms of learning and memory and multiple tasks and specifics associated with these tasks that vary from laboratory to laboratory. An emerging field of computational cognitive neuroscience lies at the intersection of computational neuroscience, machine learning and neural network theory. These computational and theoretical frameworks support the participation of the hippocampal synaptic transmission and plasticity in learning and memory in animals and humans (for review see: Ashby and Helie, 2012).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The weight of evidence for proper hippocampal function and episodic memory in humans and the animal analogue, spatial and fear-based context learning, is strong. Seminal studies over the past 60 years firmly established the cellular basis of behavior with synaptic plasticity (LTP and LTD). And recent work has provided details on the local hippocampal circuitry needed for memory formation and behavioral change (Sweatt, 2016). In humans, virtual reality experiments in large-scale spatial contexts demonstrate the convergence of spatial memory performance in normal patients with fMRI of the hippocampus clearly demonstrating the essentiality of hippocampal function to spatial learning (Burgess, 2002). This assertion is consistent with a wealth of animal data on hippocampal learning and memory. In rodent models, functional impairment of the hippocampus assessed using electrophysiological techniques is correlated with deficits in spatial memory typically assessed using mazes, and memory for context often assessed in fear-based learning paradigms (O’Keefe and Nadel, 1978; Clark et al., 2000; Squire, 2004; Eichenbaum, 2000; Panjo and Bramham, 2014).

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of the KER is rated as strong. It is well accepted that the normal hippocampal function is critical for the acquisition and memory of context and spatially mediated tasks in rodents and humans (Sweatt, 2016).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical support for this KER is strong. The requisite of hippocampal integrity to optimal visuo-spatial context learning (i.e., episodic memory) in humans and spatial learning in rodents is well documented. In vivo recording in conscious behaving animals has demonstrated activity-dependent neural changes taking place in the hippocampus during spatial learning (Gruart and Delgado-Garcia, 2007). Impairments in hippocampal function induced by drugs, chemicals, lesions, mutant or knock out models that cause changes in synaptic transmission, plasticity, and hippocampal network activity, are coincident with deficits in spatial and context-based fear learning (O’Keefe and Nadel, 1978; Bannerman et al., 2014; Lynch, 2004; Verret et al., 2012). Similarly, treatments found to enhance or facilitate hippocampal synaptic transmission and plasticity are associated with improved learning and memory (Deng et al., 2010; Novkovic et al., 2015; Andrade et al., 2015; Trivino-Paredes et al., 2016). For example, n-methyl-d-aspartate (NMDA)-mediated glutamatergic synaptic transmission is essential for the induction of hippocampal synaptic plasticity in the form of LTP. Blockade of this form of plasticity by selective NMDA-receptors blockers impairs LTP and hippocampal tests of learning and memory (reviewed in Sweatt, 2016). Perturbation of hippocampal plasticity and impaired spatial learning have been reported in adult offspring following prenatal ethanol exposure (An and Zhang, 2015). The fyn mutant mouse (fyn is a tyrosine kinase pathway) displays impairments in hippocampal synaptic transmission and plasticity, as well asspatial learning deficits (Grant et al., 1992). Brain-derived neurotrophic factor (BDNF) knock out animals exhibit synaptic plasticity deficits and learning impairments (Aarse et al., 2016; Panja and Bramham, 2014). In the Jacob/Nfsm model which also exhibits pronounced alterations in BDNF-mediated signaling, hippocampal synaptic transmission and plasticity impairments were accompanied by deficits in contextual fear conditioning and novel location recognition tasks (Spilker et al., 2016). Finally, in rodent models of developmental TH insufficiency, impairments in hippocampal synaptic transmission and plasticity are coincident with deficits in learning tasks that require the hippocampus (Opazo et al., 2008; Gilbert and Sui, 2006, Gilbert, 2011, Gilbert et al., 2016).

In humans, hippocampal physiology assessed using neuroimaging reveals activation of hippocampus upon engagement in spatial learning and episodic memory providing a direct linkage of these two specific KEs (Burgess, 2002). In fMRI studies of congenitally hypothyroid children, or children born to women with altered thyroid function during pregnancy, changes in hippocampal activity patterns during memory encoding and retention were observed and associated with memory impairments (Wheeler et al., 2012; 2015; Willoughby et al., 2013; 2014).

Temporal Evidence: The temporal nature of this KER is developmental (Seed et al., 2005). This has been demonstrated in multiple studies. It is well-recognized that there are critical developmental windows for disruption of the functional development of the hippocampus and the integrity of this structure is essential for later development of spatial ability, context learning, and fear learning. A wealth of studies have shown correlation between hippocampal LTP and spatial learning performance, as well as the role of glutamatergic synaptic transmission and BDNF-mediated signaling pathways in these processes (Bramham, 2007; Andero et al., 2014; Morris et al., 1986; Sweatt, 2016; Migaud et al., 1998). Although studies on reversibility are rare, deficits in hippocampal synaptic transmission and plasticity in slices from BDNF knockout animals can be rescued with recombinant BDNF (Patterson et al., 1996).

Dose-Response Evidence: Limited dose-response information is available. Studies have investigated dose-dependency of both electrophysiological and behavioral impairments in animals suffering from developmental TH insufficiency (e.g., Gilbert and Sui, 2006; Gilbert, 2011; Gilbert et al., 2016).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are no inconsistencies in this KER, but there are some uncertainties. It is a widely-held assertion that synaptic transmission and plasticity in the hippocampus underlie spatial learning (Martin et al., 2000; Gruart and Delgado-Garcia, 2007; Bramham, 2007). However, the causative relationship of which specific alterations in synaptic function are associated with specific cognitive deficits is difficult to ascertain given the many forms of learning and memory, and the complexity of synaptic interactions in even the simplest brain circuit.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Information does not exist to develop quantitative relationships between the KEs in this KER.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The majority of data in support of this KER is from rodent models. The evolutionary conservation of the role of the hippocampus in spatial cognitive functions suggests, with some uncertainty, that this KER is also applicable to other mammalian species.

References

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

Aarse J, Herlitze S, Manahan-Vaughan D. The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent. Hippocampus. 2016 Jun;26(6):739-51.

An L, Zhang T. Prenatal ethanol exposure impairs spatial cognition and synaptic plasticity in female rats. Alcohol. 2015 Sep;49(6):581-8.

Andero R, Choi DC, Ressler KJ. BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders. Prog Mol Biol Transl Sci. 2014. 122:169-92.

Andrade-Talavera Y, Benito I, Casañas JJ, Rodríguez-Moreno A, Montesinos ML. Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome. Neurobiol Dis. 2015. 82:516-25

Ashby FG, Helie S. The Neurodynamics of Cognition: A Tutorial on Computational Cognitive Neuroscience. J Math Psychol. 2011 Aug 1;55(4):273-289.

Bannerman DM, Sprengel R, Sanderson DJ, McHugh SB, Rawlins JNP, Monyer H, Seeburg PH (2014) Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15:181-192.

Bramham CR. Control of synaptic consolidation in the dentate gyrus: mechanisms, functions, and therapeutic implications. Prog Brain Res. 2007. 163:453-71.

Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080. Clark RE, Zola SM, Squire LR. Impaired recognition memory in rats after damage to the hippocampus. J Neurosci. 2000 Dec 1;20(23):8853-60.

Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory Nat Rev Neurosci 11:339-350.

Gilbert ME (2011) Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci 124:432-445.

Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.

Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992 Dec 18;258(5090):1903-10.

Gruart A, Delgado-García JM. Activity-dependent changes of the hippocampal CA3-CA1 synapse during the acquisition of associative learning in conscious mice. Genes Brain Behav. 2007 Jun;6 Suppl 1:24-31.

Lynch, M.A. (2004). Long-Term Potentiation and Memory. Physiological Reviews. 84:87-136.

Martin SJ, Grimwood PD, Morris RG. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 2000. 23:649-711.

Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O'Dell TJ, Grant SG. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature. 1998 Dec 3;396(6710):433-9.

Morris RG, Frey U. Hippocampal synaptic plasticity: role in spatial learning or the automaticrecording of attended experience? Philos Trans R Soc Lond B Biol Sci. 1997 Oct 29;352(1360):1489-503. Review

Novkovic T, Mittmann T, Manahan-Vaughan D. BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment. Hippocampus. 2015 Jan;25(1):1-15.

O’Keefe, J. and Nadel, L. (1978). The Hippocampus as a Cognitive Map. Oxford: Oxford University Press.

Opazo MC, Gianini A, Pancetti F, Azkcona G, Alarcón L, Lizana R, Noches V, Gonzalez PA, Marassi MP, Mora S, Rosenthal D, Eugenin E, Naranjo D, Bueno SM, Kalergis AM, Riedel CA (2008), Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 149:5097-5106

Panja, D. and C. R. Bramham (2014). "BDNF mechanisms in late LTP formation: A synthesis and breakdown." Neuropharmacology 76 Pt C: 664-676.

Schultz C, Engelhardt M, Anatomy of the hippocampal formation. Front Neurol Neurosci. 2014. 34:6-17

Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996 Jun;16(6):1137-45.

Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35:664-72.

Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A, Lopez-Rojas J, Montag D, Angenstein F, Bär J, D'Hanis W, Roskoden T, Mikhaylova M, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR. A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. PLoS Genet. 2016 Mar 15;12(3):e1005907Squire LR 2004. Memory systems of the brain: A brief history and current perspective. Neurobiology of Learning and Memory, 82: 171-177

Sweatt JD. Neural plasticity and behavior - sixty years of conceptual advances. J Neurochem. 2016 Oct;139 Suppl 2:179-199. doi: 10.1111/jnc.13580. Review. PubMed PMID: 26875778.

Triviño-Paredes J, Patten AR, Gil-Mohapel J, Christie BR. The effects of hormones and physical exercise on hippocampal structural plasticity. Front Neuroendocrinol. 2016. 41:23-43.

Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012Apr 27;149(3):708-21.

Wheeler SM, McAndrews MP, Sheard ED, Rovet J (2012) Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism. J Int Neuropsychol Soc 18:49-56.

Wheeler SM, McLelland VC, Sheard E, McAndrews MP, Rovet JF (2015) Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism. Front Endocrinol (Lausanne) 6:163.

Willoughby KA, McAndrews MP, Rovet JF (2014) Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid 24:576-584.

Willoughby KA, McAndrews MP, Rovet J (2013) Effects of early thyroid hormone deficiency on children's autobiographical memory performance. J Int Neuropsychol Soc 19:419-429.