Activation, Nicotinic acetylcholine receptor

FMA:61796

FMA Nicotinic acetylcholine receptor

GO:0015464

GO acetylcholine receptor activity

GO:0007612

GO learning

GO:0007613

GO memory

GO:0019098

GO reproductive behavior

MP:0001386

MP abnormal maternal nurturing

GO:0002164

GO larval development

D056631

MESH colony collapse

GO:0030549

GO acetylcholine receptor activator activity

GO:0030545

GO receptor regulator activity

GO:0099536

GO synaptic signaling

WIKI increased

WIKI decreased

WIKI abnormal

2-Imidazolidinimine, 1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-, (2E)-

2016-11-29T18:42:27

WCS_9606

common toxicological species human

10116

NCBI rat

WCS_7227

common ecological species fruit fly

WCS_7955

common ecological species zebrafish

WCS_160004

common ecological species gastropods

10090

NCBI mouse

WCS_9606

common toxicological species humans

10095

NCBI mice

9685

NCBI cat

WikiUser_2

ApacheUser Honey bee

Activation, Nicotinic acetylcholine receptor

Molecular

Text fromTable 2 of LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775: "• Radiolabeled nAChR agonists, (e.g., [3H] imidacloprid) or nAChR subunit specific antibodies to detect location and subunit composition of nAChR • Ligand competition studies evaluating [3H] agonist displacement to determine ligand affinities to the nAChR • Whole-cell voltage clamp electrophysiological measurements with agonists to measure nAChR activation"

CL:0000540

CL neuron

LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. STOTEN. 584-585, 751-775. Karlin, A., 2002. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3 (2), 102–114. Jones, A.K., Sattelle, D.B., 2010. Diversity of insect nicotinic acetylcholine receptor subunits. Adv. Exp. Med. Biol. 683, 25–43. Lindstrom, J.M., 2003. Nicotinic acetylcholine receptors of muscles and nerves. Ann. N. Y. Acad. Sci. 998 (1), 41–52. Tomizawa,M., Casida, J.E., 2003. Selective toxicity of neonictinoids attributable to specificity of insect and mammalian nicotinic receptors. Annu. Rev. Entomol. 48, 339–364. Dani, J.A., Bertrand, D.D., 2007. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.Annu. Rev. Pharmacol. Toxicol. 47, 699–729. Matsuda, K., Kanaoka, S., Akamatsu,M., Sattelle, D.B., 2009. Diverse actions and target-site selectivity of neonicotinoids: structural insights. Mol. Pharmacol. 76 (1), 1–10. LaLone, C.A., Villeneuve, D.L., Lyons, D., Helgen, H.W., Robinson, S.L., Swintek, J.A., Saari, T.W., Ankley, G.T., 2016. Sequence alignment to predict across species susceptibility (SeqAPASS): a web-based tool for addressing the challenges of cross-species extrapolation of chemical toxicity. Toxicol. Sci. 153 (2), 228–245. AOPWiki 2016-11-29T18:41:25

2018-06-07T09:33:27

Impairment, Learning and memory

Individual

Learning can be defined as the process by which new information is acquired to establish knowledge by systematic study or by trial and error (Ono, 2009). Two types of learning are considered in neurobehavioral studies: a) associative learning and b) non-associative learning. Associative learning is based on making associations between different events. In associative learning, a subject learns the relationship among two different stimuli or between the stimulus and the subject’s behaviour. On the other hand, non-associative learning can be defined as an alteration in the behavioural response that occurs over time in response to a single type of stimulus. Habituation and sensitization are some examples of non-associative learning. The memory formation requires acquisition, retention and retrieval of information in the brain, which is characterised by the non-conscious recall of information (Ono, 2009). There are three main categories of memory, including sensory memory, short-term or working memory (up to a few hours) and long-term memory (up to several days or even much longer). Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition of, or retrieval of, a learned event, the hippocampal-based memory systems have received the most study. For example, the hippocampus has been shown to be critical for spatial-temporal memory, visio-spatial memory, verbal and narrative memory, and episodic and autobiographical memory (Burgess et al., 2000; Vorhees and Williams, 2014). However, there is substantial evidence that fundamental learning and memory functions are not mediated by the hippocampus alone but require a network that includes, in addition to the hippocampus, anterior thalamic nuclei, mammillary bodies cortex, cerebellum and basal ganglia (Aggleton and Brown, 1999; Doya, 2000; Mitchell et al., 2002, Toscano and Guilarte, 2005; Gilbert et al., 2006, 2016). Thus, damage to variety of brain structures can potentially lead to impairment of learning and memory. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990).While the prefrontal cortex and frontostriatal neuronal circuits have been identified as the primary sites of higher-order cognition in vertebrates, invertebrates utilize paired mushroom bodies, shown to contain ~300,000 neurons in honey bees (Menzel, 2012; Puig et al., 2014). For the purposes of this KE (AO), impaired learning and memory is defined as an organism’s inability to establish new associative or non-associative relationships, or sensory, short-term or long-term memories which can be measured using different behavioural tests described below.

In laboratory animals: in rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, Hebb-Williams maze, passive avoidance and Spontaneous alternation and most commonly, the Morris water maze (MWM). Test of novelty such as novel object recognition, and fear based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. A brief description of these tasks follows. 1) RAM, Barnes, MWM, Hebb-Williams maze are examples of spatial tasks, animals are required to learn the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze), or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014). The Hebb-Williams maze measures an animal’s problem solving abilities by providing no spatial cues to find the target (Pritchett & Mulder, 2004). 2) Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention – I have seen one of these objects before, but not this one (Cohen and Stackman, 2015). 3) Contextual Fear conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009). 4) Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2001). 5) Operant Responding. Performance on operant responding reflects the cortex’ ability to organize processes (Rabin et al., 2002).  In humans:  A variety of standardized learning and memory tests have been developed for human neuropsychological testing, including children (Rohlman et al., 2008). These include episodic autobiographical memory, perceptual motor tests, short and  long term memory tests, working memory tasks, word pair recognition memory; object location recognition memory. Some have been incorporated in general tests of intelligence (IQ) such as the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler. Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include: 1) Rey Osterieth Complex Figure test (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006). 2) Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1994; Talley, 1986). 3) Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994). 4) Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986). 5) Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2011). 6) Staged Autobiographical Memory Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buy lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014). 7) Attentional set-shifting (ATSET) task. Measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015). 8. Comprehensive developmental inventory for infants and toddlers (CDIIT).  The CDIIT was designed and standardized in 1996, and it measures the global, cognitive, language, motor, gross motor, fine motor, social, self-help and behavioral developmental status of children from 3 to 71 months old (Wang et al., 1998). In Honey Bees: For over 50 years an assay for evaluating olfactory conditioning of the proboscis extension reflex (PER) has been used as a reliable method for evaluating appetitive learning and memory in honey bees (Guirfa and Sandoz, 2012; LaLone et al., 2017). These experiments pair a conditioned stimulus (e.g., an odor) with an unconditioned stimulus (e.g., sucrose) provided immediately afterward, which elicits the proboscis extension (Menzel, 2012). After conditioning, the odor alone will lead to the conditioned PER. This methodology has aided in the elucidation of five types of olfactory memory phases in honey bee, which include early short-term memory, late short-term memory, mid-term memory, early long-term memory, and late long-term memory (Guirfa and Sandoz, 2012). These phases are dependent on the type of conditioned stimulus, the intensity of the unconditioned stimulus, the number of conditioning trials, and the time between trials. Where formation of short-term memory occurs minutes after conditioning and decays within minutes, memory consolidation or stabilization of a memory trace after initial acquisition leads to mid-term memory, which lasts 1 d and is characterized by activity of the cAMP-dependent PKA (Guirfa and Sandoz, 2012). Multiple conditioning trials increase the duration of the memory after learning and coincide with increased Ca2+-calmodulin-dependent PKC activity (Guirfa and Sandoz, 2012). Early long-term memory, where a conditioned response can be evoked days to weeks after conditioning requires translation of existing mRNA, whereas late long-term memory requires de novo gene transcription and can last for weeks (Guirfa andSandoz, 2012)."

Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans. Recently, larval zebrafish has also been suggested as a model for the study of learning and memory (Roberts et al., 2013). Life stage applicability: This key event is applicable to various life stages such as during brain development and maturity (Hladik & Tapio, 2016).  Sex applicability: This key event is not sex specific (Cekanaviciute et al., 2018), although sex-dependent cognitive outcomes have been recently ; Parihar et al., 2020).  Evidence for perturbation by a prototypic stressor: Current literature provides ample evidence of impaired learning and memory being induced by ionizing radiation (Cekanaviciute et al., 2018; Hladik & Tapio, 2016).

High Mixed

High

During brain development

High

Adult, reproductively mature

High High High High High High

Aggleton JP, Brown MW. (1999) Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci. 22: 425-489. Alexander RD (1990) Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development. Ethology and Sociobiology 11:241-303. Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 120:501-507. Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080. Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176. Cekanaviciute, E., S. Rosi and S. Costes. (2018), "Central Nervous System Responses to Simulated Galactic Cosmic Rays", International Journal of Molecular Sciences, Vol. 19/11, Multidisciplinary Digital Publishing Institute (MDPI) AG, Basel,  https://doi.org/10.3390/ijms19113669.  Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176. Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents. In: Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009. D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60-90. Doya K. (2000) Complementary roles of basal ganglia and cerebellum in learning and motor control. Curr Opin Neurobiol. 10: 732-739. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41-50. Fivush R. The development of autobiographical memory. Annu Rev Psychol. 2011;62:559-82. 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, Rovet J, Chen Z, Koibuchi N. (2012) Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 33: 842-52. 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. Guirfa, M., Sandoz, J.C., 2012. Invertebrate learning and memory: fifty years of olfactory conditioning of the proboscis extension response in honeybees. Learn. Mem. 19 (2), 54–66. Herold, C, Lässer, MM, Schmid, LA, Seidl, U, Kong, L, Fellhauer, I, Thomann,PA, Essig, M and Schröder, J. (2015). Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia. Front. Psychiatry, 6: 53. 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.  Heisler, J. M. et al. (2015), "The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice", Journal of Visualized Experiments, 96, JoVe, Cambridge, https://doi.org/10.3791/51944. Heisler, J. M. et al. (2015), "The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice", Journal of Visualized Experiments, 96, JoVe, Cambridge, https://doi.org/10.3791/51944.  LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. STOTEN. 584-585, 751-775. Lezak MD (1984) Neuropsychological assessment in behavioral toxicology--developing techniques and interpretative issues. Scand J Work Environ Health 10 Suppl 1:25-29. Lezak MD (1994) Domains of behavior from a neuropsychological perspective: the whole story. Nebr Symp Motiv 41:23-55. Makris SL, Raffaele K, Allen S, Bowers WJ, Hass U, Alleva E, Calamandrei G, Sheets L, Amcoff P, Delrue N, Crofton KM.(2009) A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect.  Jan;117(1):17-25. Menzel, R., 2012. The honeybee as a model for understanding the basis of cognition. Nat. Rev. Neurosci. 13 (11), 758–768. Mitchell AS, Dalrymple-Alford JC, Christie MA. (2002) Spatial working memory and the brainstem cholinergic innervation to the anterior thalamus. J Neurosci. 22: 1922-1928. OECD. 2007. OECD guidelines for the testing of chemicals/ section 4: Health effects. Test no. 426: Developmental neurotoxicity study. www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed may 21, 2012]. OECD (2008) Nr 43 GUIDANCE DOCUMENT ON MAMMALIAN REPRODUCTIVE TOXICITY TESTING AND ASSESSMENT. ENV/JM/MONO(2008)16 Ono T. (2009) Learning and Memory. Encyclopedia of neuroscience. M D. Binder, N. Hirokawa and U. Windhorst (Eds). Springer-Verlag GmbH Berlin Heidelberg. pp 2129-2137. Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in Behavioral Neuroscience, Vol. 14, https://doi.org/10.3389/fnbeh.2020.535885.  Pritchett, K. and G. Mulder. (2004), "Hebb-Williams mazes.", Contemporary topics in laboratory animal science, Vol. 43/5, http://www.ncbi.nlm.nih.gov/pubmed/15461441.  Puig, M.V., Antzoulatos, E.G., Miller, E.K., 2014. Prefrontal dopamine in associative learning and memory. Neuroscience 282, 217–229. Rabin, B. M. et al. (2002), "Effects of Exposure to 56Fe Particles or Protons on Fixed-ratio Operant Responding in Rats", Journal of Radiation Research, Vol. 43/S, https://doi.org/10.1269/jrr.43.S225.  Roberts AC, Bill BR, Glanzman DL. (2013) Learning and memory in zebrafish larvae. Front Neural Circuits 7: 126. Rohlman DS, Lucchini R, Anger WK, Bellinger DC, van Thriel C. (2008) Neurobehavioral testing in human risk assessment. Neurotoxicology. 29: 556-567. Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical applications of the Rey-Osterieth complex figure test. Nature Protocols, 1: 892-899. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376. Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267. Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver. <div> <div>T.M. Wang, C.W. Su, H.F. Liao, L.Y. Lin, K.S. Chou, S.H. Lin The standardization of the comprehensive developmental inventory for infants and toddlers Psychol. Test., 45 (1998), pp. 19-46</div> <div> </div> <div>Toscano CD, Guilarte TR. (2005) Lead neurotoxicity: From exposure to molecular effects. Brain Res Rev. 49: 529-554.</div> </div> U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances. Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332. <div> <div>Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014 Jul;9:1-11.</div> </div>   AOPWiki 2016-11-29T18:41:24

2023-06-26T12:44:45

Abnormal, Roll change within caste

Population

AOPWiki 2016-11-29T18:41:25

2016-12-03T16:37:50

Reduced, Brood care

Population

AOPWiki 2016-11-29T18:41:25

2016-12-03T16:37:50

impaired, Larval development

Population

AOPWiki 2016-11-29T18:41:25

2016-12-03T16:37:50

Death/Failure, Colony

Population

2018-06-07T11:15:11

Desensitization, Nicotinic acetylcholine receptor

Molecular

Text from Table 2 in LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775: "• Electrophysiological characterization for investigation of desensitization. Patch-clamp, number of channel openings per unit time  • Immunoblotting to determine phosphotyrosine content of purified nAChR"

CL:0000540

CL neuron

LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. STOTEN. 584-585, 751-775. Quick, M.W., Lester, R.A., 2002. Desensitization of neuronal nicotinic receptors. J. Neurobiol. 53 (4), 457–478. Srinivasan, R., Richards, C.I., Xiao, C., Rhee, D., Pantoja, R., Dougherty, D.A., Miwa, J.M., Lester, H.A., 2012. Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the endoplasmic reticulumstress response.Mol. Pharmacol. 81 (6), 759–769. Flores, C.M., Rogers, S.W., Pabreza, L.A.,Wolfe, B.B., Kellar, K.J., 1992. A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is upregulated by chronic nicotine treatment. Mol. Pharmacol. 41 (1), 31–37. Marszalec, W., Yeh, J.Z., Narahashi, T., 2005. Desensitization of nicotine acetylcholine receptors: modulation by kinase activation and phosphatase inhibition. Eur. J. Pharmacol. 514 (2–3), 83–90. Christen, V., Mittnter, F., Fent, K., 2016. Molecular effects of neonicotinoids in honey bees (Apis mellifera). Environ. Sci. Technol. 50 (7), 4071–4081. Ochoa, E.L., Chattopadhyay, A., McNamee, M.G., 1989. Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. Cell. Mol. Neurobiol. 9 (2), 141–178. Simasko, S.M., Soares, J.R., Weiland, G.A., 1986. Two components of carbamylcholine-induced loss of nicotinic acetylcholine receptor function in the neuronal cell line PC12. Mol. Pharmacol. 30 (1), 6–12. Hopfield, J.F., Tank, D.W., Greengard, P., Huganir, R.L., 1988. Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336 (6200), 677–680. Thany, S.H., Lenaers, G., Raymond-Delpech, V., Sattelle, D.B., Lapied, B., 2007. Exploring the pharmacological properties of insect nicotinic acetylcholine receptors. Trends Pharmacol. Sci. 28 (1), 14–22.   AOPWiki 2016-11-29T18:41:26

2018-06-07T09:38:50

Decrease of neuronal network function

Neuronal network function, Decreased

Organ

Biological state: There are striking differences in neuronal network formation and function among the developing and mature brain. The developing brain shows a slow maturation and a transient passage from spontaneous, long-duration action potentials to synaptically-triggered, short-duration action potentials. Furthermore, at this precise developmental stage the neuronal network is characterised by "hyperexcitability”, which is related to the increased number of local circuit recurrent excitatory synapses and the lack of γ-amino-butyric acid A (GABAA)-mediated inhibitory function that appears much later. This “hyperexcitability” disappears with maturation when pairing of the pre- and postsynaptic partners occurs and synapses are formed generating population of postsynaptic potentials and population of spikes followed by developmental GABA switch. Glutamatergic neurotransmission is dominant at early stages of development and NMDA receptor-mediated synaptic currents are far more times longer than those in maturation, allowing more calcium to enter the neurons. The processes that are involved in increased calcium influx and the subsequent intracellular events seem to play a critical role in establishment of wiring of neural circuits and strengthening of synaptic connections during development (reviewed in Erecinska et al., 2004). Neurons that do not receive glutaminergic stimulation are undergoing developmental apoptosis. During the neonatal period, the brain is subject to profound alterations in neuronal circuitry due to high levels of synaptogenesis and gliogenesis. For example, in neuroendocrine regions such as the preoptic area-anterior hypothalamus (POA-AH), the site of gonadotropin-releasing hormone (GnRH) system is developmentally regulated by glutamatergic neurons. The changes in the expression of the N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B system begin early in postnatal development, before the onset of puberty, thereby playing a role in establishing the appropriate environment for the subsequent maturation of GnRH neurons (Adams et al., 1999). Biological compartments: Neural network formation and function happen in all brain regions but it appears to onset at different time points of development (reviewed in Erecinska et al., 2004). Glutamatergic neurotransmission in hippocampus is poorly developed at birth. Initially, NMDA receptors play important role but the vast majority of these premature glutamatergic synapses are “silent” possibly due to delayed development of hippocampal AMPA receptors. In contrast, in the cerebral cortex the maturation of excitatory glutamatergic neurotransmission happens much earlier. The “silent” synapses disappear by PND 7-8 in both brain regions mentioned above. There is strong evidence suggesting that NMDA receptor subunit composition controls synaptogenesis and synapse stabilization (Gambrill and Barria, 2011). It is established fact that during early postnatal development in the rat hippocampus, synaptogenesis occurs in parallel with a developmental switch in the subunit composition of NMDA receptors from NR2B to NR2A. It is suggested that early expression of NR2A in organotypic hippocampal slices reduces the number of synapses and the volume and dynamics of spines. In contrast, overexpression of NR2B does not affect the normal number and growth of synapses. However, it does increase spine motility, adding and retracting spines at a higher rate. The C terminus of NR2B, and specifically its ability to bind CaMKII, is sufficient to allow proper synapse formation and maturation. Conversely, the C terminus of NR2A was sufficient to stop the development of synapse number and spine growth. These results indicate that the ratio of synaptic NR2B over NR2A controls spine motility and synaptogenesis, and suggest a structural role for the intracellular C terminus of NR2 in recruiting the signalling and scaffolding molecules necessary for proper synaptogenesis. Interestingly, it was found that genetic deletion of NR3A accelerates glutamatergic synaptic transmission, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1. Consistent, the deletion of NR3A accelerates the expression of the glutamate receptor subunits NR1, NR2A, and GluR1 sugesting that glutamatergic synapse maturation is critically dependent upon activation of NMDA-type glutamate receptors (Henson et al., 2012). General role in biology: The development of neuronal networks can be distinguished into two phases: an early ‘establishment’ phase of neuronal connections, where activity-dependent and independent mechanisms could operate, and a later ‘maintenance’ phase, which appears to be controlled by neuronal activity (Yuste and Sur, 1999). These neuronal networks facilitate information flow that is necessary to produce complex behaviors, including learning and memory (Mayford et al., 2012).

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? In vivo: The recording of brain activity by using electroencephalography (EEG), electrocorticography (ECoG) and local field potentials (LFP) assists towards the collection of signals generated by multiple neuronal cell networks. Advances in computer technology have allowed quantification of the EEG and expansion of quantitative EEG (qEEG) analysis providing a sensitive tool for time-course studies of different compounds acting on neuronal networks' function (Binienda et al., 2011). The number of excitatory or inhibitory synapses can be functionally studied at an electrophysiological level by examining the contribution of glutamatergic and GABAergic synaptic inputs. The number of them can be determined by variably clamping the membrane potential and recording excitatory and inhibitory postsynaptic currents (EPSCs or IPSCs) (Liu, 2004). In vitro: Microelectrode array (MEA) recordings are also used to measure electrical activity in cultured neurons (Keefer et al., 2001, Gramowski et al., 2000; Gopal, 2003; Johnstone et al., 2010). MEAs can be applied in high throughput platforms to facilitate screening of numerous chemical compounds (McConnell et al., 2012). Using selective agonists and antagonists of different classes of receptors their response can be evaluated in a quantitative manner (Novellino et al., 2011; Hogberg et al., 2011). Patch clamping technique can also be used to measure neuronal network activity.In some cases, if required, planar patch clamping technique can also be used to measure neuronal networks activity (e.g., Bosca et al., 2014).

In vitro studies in brain slices applying electrophysiological techniques showed significant variability among species (immature rats, rabbits and kittens) related to synaptic latency, duration, amplitude and efficacy in spike initiation (reviewed in Erecinska et al., 2004).

UBERON:0000955

UBERON brain

High Mixed

High

During brain development

High High High High

Adams MM, Flagg RA, Gore AC., Perinatal changes in hypothalamic N-methyl-D-aspartate receptors and their relationship to gonadotropin-releasing hormone neurons. Endocrinology. 1999 May;140(5):2288-96. Binienda ZK, Beaudoin MA, Thorn BT, Ali SF. (2011) Analysis of electrical brain waves in neurotoxicology: γ-hydroxybutyrate. Curr Neuropharmacol. 9: 236-239. Bosca, A., M. Martina, and C. Py (2014) Planar patch clamp for neuronal networks--considerations and future perspectives. Methods Mol Biol, 2014. 1183: p. 93-113. Erecinska M, Cherian S, Silver IA. (2004) Energy metabolism in mammalian brain during development. Prog Neurobiol. 73: 397-445. Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A. 2011:108(14):5855-60. Gopal K. (2003) Neurotoxic effects of mercury on auditory cortex networks growing on microelectrode arrays: a preliminary analysis. Neurotoxicol Teratol. 25: 69-76. Gramowski A, Schiffmann D, Gross GW. (2000) Quantification of acute neurotoxic effects of trimethyltin using neuronal networks cultures on microelectrode arrays. Neurotoxicology 21: 331-342. Henson MA, Larsen RS, Lawson SN, Pérez-Otaño I, Nakanishi N, Lipton SA, Philpot BD. (2012) Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One. 7(8). Hogberg HT, Sobanski T, Novellino A, Whelan M, Weiss DG, Bal-Price AK. (2011) Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32: 158-168. Johnstone AFM, Gross GW, Weiss D, Schroeder O, Shafer TJ. (2010) Use of microelectrode arrays for neurotoxicity testing in the 21st century Neurotoxicology 31: 331-350. Keefer E, Norton S, Boyle N, Talesa V, Gross G. (2001) Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays. Neurotoxicology 22: 3-12. Liu G. (2004) Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites. Nat Neurosci. 7: 373-379. Mayford M, Siegelbaum SA, Kandel ER. (2012) Synapses and memory storage. Cold Spring Harb Perspect Biol. 4. pii: a005751. McConnell ER, McClain MA, Ross J, LeFew WR, Shafer TJ. (2012) Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology 33: 1048-1057. Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, Schroeder O, Jügelt K, Chiappalone M, Benfenati F, Martinoia S, Tedesco MT, Defranchi E, D'Angelo P, Whelan M. (2011) Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng. 4: 4. Yuste R, Peinado A, Katz LC. (1992) Neuronal domains in developing neocortex. Science 257: 665-669. AOPWiki 2016-11-29T18:41:24

2018-05-28T11:36:00

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Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775: "It has been demonstrated in various models that nAChR agonism does indeed lead to desensitization. For example, upon exposure of human α7 nAChR expressed in African clawed frog (Xenopus laevis) oocytes to classical nAChR agonists, including nicotine, Briggs and McKenna (1998) showed that even weak or low concentrations of an agonist could act asmore potent inhibitors than activators of the receptor through desensitization. Further, in another examplemeasuring current across the neuron and activity of the natural nAChR ligand and ACh neurotransmitter, Zwart et al. (1994) demonstrated that six nAChR agonists induced nAChR-mediated inward ionic current, and that their continued presence significantly blocked ACh-induced inward current in whole-cell voltage-clamped African locust (Locusta migratoria) thoracic ganglion neurons. In that study, it was shown that concentrations of 0.1 μM and 10 μM imidacloprid induced ACh-inward current with peak amplitudes of 4% and 30%, respectively (Zwart et al., 1994). Continued exposure to 0.1 μMimidacloprid led to desensitization that reduced the amplitude of 1 mM ACh-induced inward current by 73%; whereas, continued exposure to 10 μM imidacloprid completely blocked inward current indicting that the potency to block the ACh-induced ion current was greater than the potency to induce inward current (Zwart et al., 1994). Specific evidence of desensitization exists in honey bees as well. Exposure of cultured Kenyon cells from honey bee brains to imidacloprid yielded partial nAChR agonist activity, eliciting 36% of the ACh-induced current and causing desensitization of the receptor after prolonged (16 s) exposure (Deglise et al., 2002). Further, when 10−5 M imidacloprid was co-applied with ACh, the mean amplitude of ACh-induced currents was significantly lowered (64%) compared to ACh coapplication with saline, thereby providing evidence that imidacloprid antagonized the ACh-induced receptor activation by out-competing ACh for the same binding site (Deglise et al., 2002). Interestingly, an antagonist of the nAChR (mecamylamine) demonstrated similar properties, likely affecting neurotransmission, in that direct injection into the brain hemolymph of honey bee was shown to not only impair olfactory learning but, in patch-clamp experiments with cultured Kenyon cells, completely block the ACh-induced current (Lozano et al., 1996; Wüstenberg and Grünewald, 2004). Recovery from desensitization depends on the availability of phosphorylation sites on the nAChR subunits and the number of phosphotyrosine residues. Mutation of key PKC phosphorylation sites on the rat α4 nAChR subunit expressed in Xenopus oocytes resulted in impaired recovery from deep desensitization (Fenster et al., 1999). Further inhibition of PKC or knockout of PKC in a mouse model (Prkce−/−) also led to impaired recovery from desensitization (Lee et al., 2015a). Phosphorylation sites on nAChR subunits as well as PKC isozymes continue to be identified. Cross species differences in those sites may contribute to the differences in sensitivity to various chemicals that act on the nAChR (Hug and Sarre, 1993). Demonstration that perturbation to PKC can impact recovery fromdesensitization is an important piece of evidence, describing a potential feedback loop linking the downstreamKE of altered Ca2+-calmodulin activated signal transduction back to desensitization (see Fig. 2; step 6). Kinases phosphorylate nAChR subunits, indicating that disruption of downstream signaling could further impact nAChR desensitization status."

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4310c7a2d0> AOPWiki 2016-11-29T18:41:34

2018-06-07T13:04:00

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ab17cb8> AOPWiki 2016-11-29T18:41:34

2016-12-03T16:37:59

<upstream-id>77fd4324-7291-4753-b333-ebbbe37c2f7a</upstream-id> <downstream-id>5c2ba149-6931-4134-a933-44cfdf7a259c</downstream-id> Learning and memory is one of the outcomes of the functional expression of neurons and neural networks from mammalian to invertebrates. Damage or destruction of neurons by chemical compounds during development when they are in the process of synapses formation, integration and formation of neural networks, will derange the organization and function of these networks, thereby setting the stage for subsequent impairment of learning and memory. Exposure to the potential developmental toxicants during neuronal differentiation and synaptogenesis will increase risk of functional neuronal network damage leading to learning and memory impairment. Impairments in learning and memory are measured using behavioral techniques. It is well accepted that these alterations in behavior are the result of structural or functional changes in neurocircuitry. Functional impairments are often measured using field potentials of critical synaptic circuits in hippocampus and cortex. A number of studies have been performed in rodent models that reveal deficits in both excitatory and inhibitory synaptic transmission in the hippocampus as a result of developmental thyroid insufficiency (Wang et al., 2012; Oerbeck et al., 2003; Wheeler et al., 2011; Wheeler et al., 2015; Willoughby et al., 2014; Davenport and Dorcey, 1972; Tamasy et al., 1986; Akaike, 1991; Axelstad et al., 2008; Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016). A well-established functional readout of memory at the synaptic level is known as long-term potentiation (LTP) (i.e., a persistent strengthening of synapses based on recent patterns of activity). Deficiencies in LTP are generally regarded as potential substrates of learning and memory impairments. In rodent models where synaptic function is impaired by TH deficiencies, deficits in hippocampus-mediated memory are also prevalent (Gilbert and Sui, 2006; Gilbert et al., 2016; Gilbert, 2011; Gilbert et al., 2016).

A number of studies have consistently reported alterations in synaptic transmission resulting from developmental TH disruption, and leading to decreased cognition.

Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy and its discovery suggested that changes in synaptic strength could provide the substrate for learning and memory (reviewed in Lynch, 2004). Moreover, LTP is intimately related to the theta rhythm, an oscillation long associated with learning. Learning-induced enhancement in neuronal excitability, a measurement of neural network function, has also been shown in hippocampal neurons following classical conditioning in several experimental approaches (reviewed in Saar and Barkai, 2003). On the other hand, memory requires the increase in magnitude of excitatory postsynaptic currents (EPSCs) to be developed quickly and to be persistent for few weeks at least without disturbing already potentiated contacts. Once again, a substantial body of evidence has demonstrated that tight connection between LTP and diverse instances of memory exist (reviewed in Lynch, 2004). A review on Morris water maze (MWM) as a tool to investigate spatial learning and memory in laboratory rats also pointed out that the disconnection between neuronal networks rather than the brain damage of certain regions is responsible for the impairment of MWM performance. Functional integrated neural networks that involve the coordination action of different brain regions are consequently important for spatial learning and MWM performance (D'Hooge and De Deyn, 2001). Moreover, it is well accepted that alterations in synaptic transmission and plasticity contribute to deficits in cognitive function. There are a number of studies that have linked exposure to TPO inhibitors (e.g., PTU, MMI), as well as iodine deficient diets, to changes in serum TH levels, which result in alterations in both synaptic function and cognitive behaviors (Akaike et al., 1991; Vara et al., 2002; Gilbert and Sui, 2006; Axelstad et al., 2008; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016), described in the indirect KER "Decrease of TH synthesis leads to learning and memory deficits".

Developmental hypothyroidism reduces the functional integrity in brain regions critical for learning and memory. Neurophysiological indices of synaptic transmission of excitatory and inhibitory circuitry are impaired in the hippocampus of hypothyroid animals. Both hippocampal regions (area CA1 and dentate gyrus) exhibit alterations in excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Vara et al., 2002; Sui and Gilbert, 2003; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). These alterations persist into adulthood despite a recovery to euthyroid conditions in blood. The latter observation indicates that these alterations represent permanent changes in brain function caused by transient hormones insufficiencies induced during critical window of development.   Because the adult hippocampus is involved in learning and memory, it is a brain region of remarkable plasticity. Use-dependent synaptic plasticity is critical during brain development for synaptogenesis and fine tuning of synaptic connectivity. In the adult brain, similar plasticity mechanisms underlie use-dependency that underlies learning and memory, as exhibited in LTP model of synaptic memory. Hypothyroidism during development reduces the capacity for synaptic plasticity in juvenile and adult offspring (Vara et al., 2002; Sui and Gilbert, 2003; Dong et al., 2005; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). Decrease of neuronal network function and plasticity are observed coincident with deficits in learning tasks that require the hippocampus. - Wang et al., 2012: This study showed that maternal subclinical hypothyroidism impairs spatial learning in the offspring, as well as the efficacy and optimal time of T4 treatment in pregnancy. Female adult Wistar rats were randomly divided into six groups: control, hypothyroid (H), subclinical hypothyroid (SCH) and SCH treated with T4, starting from GD10, GD13 and GD17, respectively, to restore normal TH levels. Results indicate that progenies of SCH and H groups demonstrated significantly longer mean latency in the water maze test (on the 2nd training day, latency was ~83% higher in H group, and ~50% higher in SCH), and a lower amplification percentage of the amplitude (~15% lower in H group, and 12% lower in SCH), and slope of the field excitatory postsynaptic potential (fEPSP) recording (~20% lower in H group, and 17% lower in SCH), compared to control group. T4 treatment at GD10 and GD13 significantly shortened mean latency and increased the amplification percentage of the amplitude and slope of the fEPSPs of the progeny of rats with subclinical hypothyroidism. However, T4 treatment at GD17 showed only minimal effects on spatial learning in the offspring. Altogether these data indicate direct correlation between decrease of neural network function and learning and memory deficits. - Liu et al., 2010 This study assessed the effects of hypothyroidism in 60 female rats who were divided into three groups: (i) maternal subclinical hypothyroidism (total thyroidectomy with T4 infusion), (ii) maternal hypothyroidism (total thyroidectomy without T4 infusion), and (iii) control (sham operated). The Morris water maze tests revealed that pups from the subclinical hypothyroidism group showed long-term memory deficits, and a trend toward short-term memory deficits. - Gilbert and Sui, 2006 Administration of 3 or 10 ppm PTU to pregnant and lactating dams via the drinking water from GD6 until PND30 caused a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. Baseline synaptic transmission was impaired in PTU-exposed animals: mean EPSP slope (by ~60% with 10 ppm PTU) and population spike amplitudes (by ~70% with 10 ppm PTU) in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams. High-dose animals (10 ppm) demonstrated very little evidence of learning despite 16 consecutive days of training (~5-fold higher mean latency to find the hidden platform, used as an index of learning). - Gilbert et al., 2016 Exposure to PTU during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. Developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes in neonate hippocampus and was accompanied by deficits in hippocampal-based learning (e.g., mean latency to find a hidden platform, at 2nd trial resulted ~60% higher in rats treated with 10 ppm PTU). - Gilbert, 2011 Trace fear conditioning deficits to context and to cue reported in animals treated with PTU and who also displayed synaptic transmission and LTP deficits in hippocampus. Baseline synaptic transmission was impaired in PTU-exposed animals (by ~50% in animal treated with 3 ppm PTU). EPSP slope amplitudes in the dentate gyrus were reduced in a dose-dependent manner in adult offspring of PTU-treated dams.   BPA, an environmental toxicant known to inhibit NIS-mediated iodide uptake (Wu Y et al., 2016) has been found to cause learning and memory deficits in rodents as described below: - Jang et al., 2012 In this study, pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were analysed. Exposure of F0 mice to BPA (10 mg/kg) decreased hippocampal neurogenesis (~ 30% decrease of hippocampal BrdU+ cells vs control) in F2 female mice. High-dose BPA (10 mg/kg) caused neurocognitive deficit (i.e., reduced memory retention) as shown by passive avoidance testing (~ 33% decrease vs control) in F2 mice. Furthermore, 10 mg/kg BPA decreased the hippocampal levels of BDNF (~ 35% lower vs control) in F2 mice. These results suggest that BPA exposure (NIS inhibitor) in pregnant mothers could decrease hippocampal neurogenesis (decreased number of neurons) and cognitive function in future generations.   In humans, the data linking these two specific KE are much more limited, but certainly clear reductions in IQ, with specific impairments in hippocampus-mediated functions have been observed. - Wheeler et al., 2015 This study assessed hippocampal functioning in adolescents with congenital hypothyroidism (CH), using functional magnetic resonance imaging (fMRI). 14 adolescents with CH and 14 typically developing controls (TDC) were studied. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When the groups were directly compared, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing, in order to compensate for the effects induced by TH deficit in the brain. - Wheeler et al., 2012 In this study hippocampal neuronal network function was measured based on synaptic performance using fMRI and was altered while subjects engaged in a memory task. Data showed paired word recognition deficits in adolescents with congenital hypothyroidism (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years), with no impairment on simple word lists. Analysis of functional magnetic resonance imaging showed that adolescents with congenital hypothyroidism had both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life. - Willoughby et al., 2013 Analogously, in this study, fMRI revealed increased hippocampus activation with word pair recognition task in CH and children born to women with hypothyroxinemia during midgestation. These differences in functional activation were not seen with single word recognition, but were revealed when retention of word pair associations was probed. The latter is a task requiring engagement of the hippocampus. A series of important findings suggest that the biochemical changes that happen after induction of LTP also occur during memory acquisition, showing temporality between the two KEs (reviewed in Lynch, 2004). - Morris et al., 1986 This study found that blocking the NMDA receptor of the neuronal network with AP5 inhibits spatial learning in rats. Most importantly, in the same study they measured brain electrical activity and recorded that this agent also inhibits LTP, however, they have not proven that spatial learning and LTP inhibition are causally related. Since then a number of NMDA receptor antagonists have been studied towards their ability to induce impairment of learning and memory. It is worth mentioning that similar findings have been found in human subjects: - Grunwald et al., 1999 By combining behavioural and electrophysiological data from patients with temporal lobe epilepsy exposed to ketamine, involvement of NMDA receptors in human memory processes was demonstrated.   The last KE preceding the AO (learning and memory deficits), i.e. "Decreased Neural Network Function", is also common to the AOP 13, entitled "Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities" (<a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/13</a>). In this AOP 13, data on lead (Pb) exposure as reference chemical are reported. While these studies do not refer to TH disruption, they provide empirical support for the same KER described in the present AOP. Pb2+: Exposure to low levels of Pb2+, during early development, has been implicated in long-lasting behavioural abnormalities and cognitive deficits in children (Needleman et al., 1975; Needleman and Gatsonis, 1990; Bellinger et al., 1991; 1992; Baghurst et al., 1992; Leviton et al., 1993; Needleman et al., 1996; Finkelstein et al., 1998; Lanphear et al., 2000; 2005; Canfield et al., 2003; Bellinger 2004; Lanphear et al., 2005; Surkan et al., 2007; Jusko et al., 2008; Neal and Guilarte, 2010) and experimental animals (Brockel and Cory-Slechta, 1998; Murphy and Regan, 1999; Moreira et al., 2001). Multiple lines of evidence suggest that Pb2+ can impair hippocampus-mediated learning in animal models (reviewed in Toscano and Guilarte, 2005). - Jett et al., 1997 Female rats exposed to Pb2+ through gestation and lactation have shown more severe impairment of memory than male rats with similar Pb2+ exposures. - De Souza Lisboa et al., 2005 This study reported that exposure to Pb2+ during both pregnancy and lactation caused depressive-like behaviour (detected in the forced swimming test) in female but not male rats. - Anderson et al., 2012 This study investigated the neurobehavioral outcomes in Pb2+-exposed rats (250, 750 and 1500 ppm Pb2+ acetate in food) during gestation and through weaning and demonstrated that these outcomes are very much influenced by sex and rearing environment. In females, Pb2+ exposure lessened some of the benefits of enriched environment on learning, whereas, in males, enrichment does help to overcome detrimental effects of Pb2+ on learning. Regarding reference memory, environmental enrichment has not been beneficial in females when exposure to Pb2+ occurs, in contrast to males. - Jaako-Movits et al., 2005 Wistar rat pups were exposed to 0.2% Pb2+ via their dams' drinking water from PND 1 to PND 21 and directly via drinking water from weaning until PND 30. At PND 60 and 80, the neurobehavioural assessment has revealed that developmental Pb2+ exposure induces persistent increase in the level of anxiety and inhibition of contextual fear conditioning. The same behavioural syndrome in rats has been described in Salinas and Huff, 2002. - Finkelstein et al., 1998 These observations are in agreement with observations on humans, as children exposed to low levels of Pb2+ displayed attention deficit, increased emotional reactivity and impaired memory and learning. - Kumar and Desiraju, 1992 In Wistar rats fed with lead acetate (400 µg/g body weight/day) from PND 2 until PND 60, EEG findings showed statistically significant reduction in the delta, theta, alpha and beta band EEG spectral power in motor cortex and hippocampus, but not in delta and beta bands power of motor cortex in wakeful state. After 40 days of recovery, animals were assessed for their neurobehaviour, and revealed that Pb2+ treated animals showed more time and sessions in attaining criterion of learning than controls. Further data obtained using animal behavioral techniques demonstrate that NMDA mediated synaptic transmission is decreased by Pb2+ exposure (Cory-Slechta, 1995; Cohn and Cory-Slechta, 1993 and 1994). - Xiao et al., 2014 Rat pups from parents exposed to 2 mM PbCl2 three weeks before mating until their weaning (pre-weaning Pb2+) and weaned pups exposed to 2 mM PbCl2 for nine weeks (post-weaning Pb2+) were assessed for their spatial learning and memory by MWM on PND 85-90. The study revealed that both rat pups in pre-weaning Pb2+ and post-weaning Pb2+ groups performed significantly worse than those in the control group. The number of synapses in pre-weaning Pb2+ group increased significantly, but it was still less than that of control group. The number of synapses in post-weaning Pb2+ group was also less than that of control group, although the number of synapses had no differences between post-weaning Pb2+ and control groups before MWM. In both pre-weaning Pb2+ and post-weaning Pb2+ groups, synaptic structural parameters such as thickness of postsynaptic density (PSD), length of synaptic active zone and synaptic curvature increased, whereas width of synaptic cleft decreased compared to controls. The last KE preceding the AO (learning and memory deficits), i.e. "Decreased Neural Network Function", is also common to the AOP 17, entitled " Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins during brain development leads to impairment of learning and memory" (<a href="https://aopwiki.org/aops/13">https://aopwiki.org/aops/17</a>). In this AOP 17, data on mercury exposure as reference chemical are reported. While these studies do not refer to TH disruption, they provide empirical support for the same KER described in the present AOP. Sokolowski et al. 2013. Rats at postnatal day 7 received a single injection of methylmercury (0.6 microgr/g, that caused caspase activation in the hilus of granule cell layer in hippocampus. At PD 21, a decrease in cell number or 22% in hilus and of 27% in granule cell layer, as well as a decreased proliferation of neural precursor cells of 25% were observed. This was associated with a decrease of spatial memory as assessed by Morris water maze. Eddins et al., 2008. Mice exposed during postnatal week 1-3 to 2-5 mg/kg mercury chloride in 0.01 ml/g of NaCl injectd s.c. The behavioral tests at 3 months of age revealed learning deficits (radial maze), which was associated with increased levels of monoamines in frontal cortex. Zanoli et al., 1994. Single injection of methylmercury (8 mg/kg by gavage) at gestational day 15. Offsprings analyzed at 14, 21, and 60 days of age exhibited a decrease in the number of muscarinic receptors at 14 and 21 days and a decrease in avoidance latency at 60 days, indicating learning and memory deficits. Zanoli et al., 2001. Single injection of methylmercury (8 mg/kg) at gestational day 8. Brain was removed at PD 21 and 60. An  increase in tryptophan level in hippocampus was detected at both days. At PD 21, a decrease in anthranilic acid and an increase in quinolinic acid was found. No change in glutamic acid nor in aspartic acid were detected. Montgomery et al., 2008. C57/B6 mice exposed during pregnancy (GD 8-18) with food containing methylmercury (0.01 mg/kg body wheight). Tested when adult, they showed deficits in motor function, coordination, overall activity and impairment in reference memory. Glover et al., 2009. Balb mice exposed to methylmercury in diet (low dose: 1.5 mg/kg; high dose: 4.5 mg/kg) during 11 weeks (6 weeks prior mating, 3 weeks during gestation and 2 weeks post-partum). Offsprings tested at PD 15 showed an accumulation of Hg in brain (0.08 mg/kg for low dose and 0.25 mg/kg for the high dose). At hte cellular level, there was alterations in gene expression for cytoskeleton, cell processes, cell adhesion, cell differentiation, development), which could be all involved in cellular network formation. This was associated with behavioral impairment, i.e. a decrease in exploratory activity measured in open field. Onishchenko et al., 2007. Pregnant mice received 0.5 mg methylmercury/kg/day in drinking water from gestational dy 7 until day 7 after delivery. Offspring behavior was monitored at 5-15 and 26-36 weeks of age. Mercury-induced alterations in reference memory were detected. Cagiano et al., 1990. Pregnant rat received at GD 15 8mg/kg of methylmercury by gavage. Offsprings were tested at day 16, 21 and 60. A reduced functional activity of glutamatergic system associated with disturbances in learning and memory were observed. Rice, 1992. Female monkeys exposed to 10, 25 and 50 microg/kg/day to methylmercury. Male unexposed. Infants separated from mother at birth and exposed to similar doses did not show gross intellectual impairment, but interferences with temporal discrimination. Sahin et al., 2016. Exposure of rat pups for 5 weeks or 5 months with mercury chloride (4.6 microg/kg as first injection, followed each day by 0.07 microg/kg/day). Learning and memory impairment measured by passive avoidance and Morris-water-maze was found in 5-weeks group, but not in the 5-month group. This was accompanied by hearing loss. In humans: Orenstein et al., 2014. Maternal peripartum hair mercury level was measured to assess prenatal mercury exposure. The concentrations of mercury was found in the range of 0.3-5.1 microg/g, similar to fish eating population in US. However, statistical analyses revealed that each microg/g increase in hair Hg was associated with a decrement in visula memory, learning and verbal memory. Yorifuji et al., 2011. A survey of the Minamata exposed population made in 1971 to assess pre- and post-natal exposure revealed a methylmercury-induced impairment of intelligence as well as behavioral dysfunction.

One of the most difficult issues for neuroscientists is to link neuronal network function to cognition, including learning and memory. It is still unclear what modifications of neuronal circuits need to happen in order to alter motor behaviour as it is recorded in a learning and memory test (Mayford et al., 2012), meaning that there is no clear understanding about how these two KEs are connected. The direct relationship of alterations in neural network function and specific cognitive deficits is difficult to ascertain given the many forms that learning and memory can take and the complexity of synaptic interactions in even the simplest brain circuit. Linking of neurophysiological assessments to learning and memory processes have, by necessity, been made across simple monosynaptic connections and largely focused on the hippocampus. Alterations in synaptic function have been found in the absence of behavioral impairments. This may result from measuring only one component in the complex brain circuitry that underlies 'cognition', behavioral tests that are not sufficiently sensitive for the detection of subtle cognitive impairments, and behavioral plasticity whereby tasks are solved by the animal via different strategies developed as a consequence of developmental insult. Finally, in order to provide empirical support for this KER, data on the effects of lead (Pb) exposure are reported. Several epidemiological studies where Pb2+ exposure levels have been studied in relation to neurobehavioural alterations in children have been reviewed in Koller et al. 2004. This review has concluded that in some occasions there is negative correlation between Pb2+ dose and cognitive deficits of the subjects due to high influence of social and parenting factors in cognitive ability like learning and memory (Koller et al. 2004), meaning that not always Pb2+ exposure is positively associated with learning and memory impairment in children. Mercury Olczak et al., 2001. Postnatal exposure of rats to Thimerosal (4 injections with 12, 240, 1440 and 3000 microgHg/kg per injection). Effects were measured in adult, which exhibited alterations in dopaminergic system with decline in the density of striatal D2 receptors, with a higher sensitivity for males. No alterations in spatial learning and memory was observed, but impairments of motor activity, increased anxiety (open fiel measurment), which are other symptoms of autism spectrum disorder. Franco et al., 2006. Lactational exposure of mice to methylmercury in drinking water (10 mg/L). Analysis at weaning revealed only impairment in motor performances. Franco et al., 2007. Lactational exposure of mice with mercury chloride (0.5 and 1.5 mg/kg,  i.p. injection once a day).. At weaning , animals exhibited an increased level of mercury in cerebellum associated with motor deficit. Cardenas et al., 2017 showed that maternal red blood cell mercury of 3.8 ng/g was associated to increased DNA methylation of PON1 in umbilical cord blood only in male and observed deficit in cognitive performances, such as visual motor ability, vocabiary and verbal intellgence.

There is not enough quantitative information how much change decrease of neuronal network functions leads to learning and memory deficits. However, qualitatively is well documented that decrease of LTP is directly linked to learning and memory deficits. There is very limited information on the degree of quantitative change in neural network function required to alter cognitive behaviors. This is a result of the diversity of methods for measuring both neuronal network function and learning and memory deficits, which hamper cross-study analyses. This highlights the need to develop empirical data based models of this KER. It is well known that the altered balance between excitatory and inhibitory synapses affects learning and memory, although no quantitative data are available.

High Mixed

High

During brain development

High High High

Synaptic transmission and plasticity are achieved via mechanisms common across taxonomies. LTP has been recorded in aplysia, lizards, turtles, birds, mice, guinea pigs, rabbits and rats. Deficiencies in hippocampally based learning and memory following developmental hypothyroidism have been documented mainly in rodents and humans.

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Nicotinic acetylcholine receptor activation contributes to abnormal roll change within the worker bee caste leading to colony loss/failure 2

nAChR activation - colony loss 8

Agnes Aggy

Carlie A. LaLone, U.S. Environmental Protection Agency

BY-SA

1.29

1.0

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AOPWiki 2016-11-29T18:41:16

2023-09-25T16:26:49