Activation, Nicotinic acetylcholine receptor

FMA:61796

FMA Nicotinic acetylcholine receptor

CHEBI:39124

CHEBI calcium ion

PR:000004978

PR calmodulin

GO:0015464

GO acetylcholine receptor activity

GO:0007612

GO learning

GO:0007613

GO memory

D056631

MESH colony collapse

GO:0060756

GO foraging behavior

GO:0030549

GO acetylcholine receptor activator activity

GO:0030545

GO receptor regulator activity

D012380

MESH role

GO:0005488

GO binding

GO:0023052

GO signaling

GO:0005516

GO calmodulin binding

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

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

2018-06-07T09:33:27

Impairment, Learning and memory

Individual

(Adapted from <a href="https://aopwiki.org/events/341" rel="noreferrer noopener" target="_blank">KE: 341</a> - in blue)  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 behavior. On the other hand, non-associative learning can be defined as an alteration in the behavioral 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 characterized 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 neural 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 behavioral 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.  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).  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).  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).  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).  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:  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).  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).  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).  Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986).  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).    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).  Attentional set-shifting (ATSET) task. Measures the ability to relearn cues over various schedules of reinforcement (Heisler et al., 2015).  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.  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.  Toscano CD, Guilarte TR. (2005) Lead neurotoxicity: From exposure to molecular effects. Brain Res Rev. 49: 529-554.  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.  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.  AOPWiki 2016-11-29T18:41:24

2026-04-27T05:48:07

Death/Failure, Colony

Population

2018-06-07T11:15:11

Abnormal, Foraging activity and behavior

Individual

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: "As eusocial insects, honey bees rely on theworker bee caste to forage for nectar, pollen, andwater. Foraged water can be used for evaporative cooling of the hive during warm weather (as reviewed by Jones and Oldroyd, 2006). Nectar and pollen collected by the foragers are the sole food source for the colony, with nectar providing carbohydrates and pollen providing lipids, protein, vitamins, and essential minerals (Brodschneider and Crailsheim, 2010). Upon returning to the hive, forager bees identify non-foraging, food-storing hive bees and deliver their collection by regurgitating nectar carried back in their honey stomach (i.e., foregut of proventriculus; Free, 1959). The hive bees place the nectar in wax cells for processing into honey. Hive bees also aid foragers in unloading pollen from the pollen baskets (corbicula) on the forager's hind legs and place it in cells where it is mixed with nectar to form bee bread, which is stored for consumption by the colony (Winston, 1987). Foragers consume only small amounts of the food they collect. Hive bees consume the food they receive in order to produce proteinrich royal jelly and brood food, which they use to nourish both the queen and the developing brood (Winston, 1987). During winter, the colony survives on the pollen and nectar that was stored as bee bread and honey over the spring, summer, and fall seasons (Seeley and Visscher, 1985). The act of foraging is a perilous and metabolically challenging task that is typically carried out by worker bees in the later stages of life (Woyciechowski and Moroń, 2009). However, the timing of the role change from hive bee to forager can vary depending on the needs of the colony. There are environmental, hormonal, and social cues that determine when and how often foragers search for food and fluid, includingweather, abundance or scarcity of food resources, magnitude of food stockpiled in the hive, health of the colony, and size of the brood (Dreller and Tarpy, 2000). Such cues initiate physiological changes involved in the transition of a worker bee to foraging, which include changes to flight muscles andmetabolic rate. These changes accommodate the reported 70-fold increase in oxygen consumption needed to sustain physical and cognitive activities of the forager bee (Kammer and Heinrich, 1978). It has been documented that the volume of neuropil in mushroom bodies is increased by approximately 15%, and the somata of the Kenyon cells decreased by approximately 29% in foragers compared to day-old bees (Withers et al., 1995). Change in lipid stores also occurs in forager bees prior to foraging, whereby their abdominal lipid is reduced to approximately half that of nurse bees (Chang et al., 2015; Toth and Robinson, 2005). Further, there is lowprotein content in the forager's fat body cells, and vitellogenin (Vtg; egg yolk) protein production is significantly reduced, while juvenile hormone levels are significantly increased (Toth and Robinson, 2005). Another change which occurs at the stage where worker bees become foragers is that their flight muscle fiber thickness decreases and diameter of the myofibrils, which contain the contractile filaments, increases in preparation for prolonged flight during foraging (Correa-Fernandez and Cruz-Landim, 2010)."

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: "• Radio-frequency identification tagging technology to track the frequency and duration of individual foraging events, flight time, foragers homing ability, duration of time spent at a feeder, and duration between feeding • Video tracking software for measures of total distance traveled and time spent in social interaction • Weigh bee-collected pollen from hive entrance trap • Pollen load can also be assessed by scoring the size of amount of pollen in the forager’s corbiculae (pollen basket) relative to the size of the worker bee • Nectar loads from individual forager bees can be measured with a pocket refractometer after inducing regurgitation • Video foragers returning to hive and measure waggle dance circuits performed • Food storage can be measured by visual inspection or digital imaging of the combs with the objective to estimate the percent of cells filled with nectar (uncapped), honey (capped), or pollen"

2018-06-07T10:51:36

Desensitization, Nicotinic acetylcholine receptor

Molecular

CL:0000540

CL neuron

2018-06-07T09:38:50

Weakened, Colony

Population

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: "• Count number of adult bees, presence of sealed and open brood, assess amount of food stores by visual method or by weighing, assess presence/absence of pests and disease, evaluate egg laying patterns of queen • Brood care behavior can be evaluated by filming the brood nest and then recording nursing frequency, total nursing period per hour, and average duration of nursing episodes for individual cells • Cannibalism of brood can be detected by mapping eggs, larvae and pupae present on brood frames and noting developmental stages for each individual, then inspecting daily for missing larvae • Assess health of bee: dry weight, muscle development, protein content"

2018-06-07T11:04:32

Abnormal, Role change within caste

Population

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: "Like most eusocial insects, honey bees exhibit age-based division of labor and progress from nurse to forager as they age (Seeley, 1982). This type of age-related behavioral change termed age polyethism, is a genomically, nutritionally, and hormonally controlled process (Ament et al., 2010; Cheng et al., 2015). Such behavior changes in adult worker bees occur in a predictable sequence as theymove fromcentrally located in-hive activities including cleaning brood cells (0–5 d old), to feeding brood, capping brood, trimming cappings, and attending the queen (2–11 d old), to peripherally located in-hive activities, such as grooming nest-mates, feeding nest-mates, ventilating the hive, producing wax and shaping comb cells, receiving and storing nectar, packing pollen, and processing nectar into honey and pollen into bee bread (11–20 d old), to outside activities, including guarding the hive and foraging (20+ d old) (Seeley, 1982). However, honey bees exhibit phenotypic plasticity whereby the rate of behavioral change is highly flexible, meaning that under different scenarios, based on colony needs, bees will accelerate or reverse their behavioral development. For example, to compensate for a loss of foragers, disease, or nutritional stress, bees will initiate precocious (early behavioral development) foraging (Cheng et al., 2015; Huang and Robinson, 1996). It is biologically plausible that early initiation of foraging could lead to a shortage of hive bees needed to tend to the brood, which could hinder development of the brood. In addition, precocious foraging is correlated with shorter lifespans. Therefore, bees that forage earlier tend to do so at the expense of their longevity which could impact overall colony resource acquisition and productivity (Woyciechowski and Moroń, 2009). However, the relationship may be complex given that with seasonal variation, food availability, predation pressures, and adverse weather conditions that promote greater in-hive activity, older foragers can reverse their behavior, regenerate hypopharyngeal glands, and assume roles within the hive (Huang and Robinson, 1996). Behavioral plasticity is driven, in part, by juvenile hormone (JH) and its interplay with Vtg, acting together in a feed-back loop to control the onset of labor tasks, such as foraging (Page et al., 2012). For example, high Vtg levels suppress JH, delaying onset of foraging behavior,whereas high JH suppresses Vtg, causing a decrease in nursing behavior (Page et al., 2012). Studies exploring drivers of precocious foraging, using both treatment with a JH analog and social manipulation of a single-cohort colony of 1 d old bees in the absence of older foragers, induced precocious foraging, demonstrating that both hormonal and social interactions play a role (Chang et al., 2015; Perry et al., 2015). Active foragers produce a pheromone, ethyl oleate, which is transferred to the hive bees during trophallaxis or oral food exchange, delaying the rate at which bees transition to foraging. Therefore, if the number of foragers diminishes, recruitment to foraging can be accelerated. Additionally, allatectomy (removal of the corpora allata glands that produce JH) led to the discovery that JH is involved in modulating the speed at which bees develop into foragers, but not in activation of foraging itself (Sullivan et al., 2003). However, studies using ribonucleic acid interference (RNAi) to knockdown Vtg production have found the protein to have a prominent role in the initiation of honey bee foraging, causing an increase in JH titer and extreme precocious foraging (3 d old bees) (Guidugli et al., 2005; Marco Antonio et al., 2008). Vitellogenin is synthesized in fat body cells, released to the hemolymph (circulation), and taken up in developing oocytes (Corona et al., 2007). Mature honey bee queens, which lay ~1000 eggs/day, continuously synthesize Vtg at high levels, including during periods when egg laying ceases (Seehuus et al., 2006; Corona et al., 2007). However, in sterile worker bees, Vtg levels have been shown to change throughout their lives, with the highest levels observed in the long-lived winter bees and lowest in the short-lived summer foragers (Münch et al., 2015). In addition to the role Vtg plays as an egg yolk protein, it has a role in oxidative stress resistance (Corona et al., 2007; Seehuus et al., 2006; Amdam et al., 2004)."

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. Seeley, T.D., 1982. Adaptive significance of the age polyethism schedule in honeybee colonies. Behav. Ecol. Sociobiol. 11 (4), 287–293. Ament, S.A., Wang, Y., Robinson, G.E., 2010. Nutritional regulation of division of labor in honey bees: toward a systems biology perspective. Wiley Interdiscip. Rev. Syst. Biol. Med. 2 (5), 566–576. Cheng, L.H., Barron, A.B., Cheng, K., 2015. Effects of the juvenile hormone analogue methoprene on rate of behavioural development, foraging performance and navigation in honey bees (Apis mellifera). J. Exp. Biol. 218, 1715–1724. Huang, Z.Y., Robinson, G.E., 1996. Regulation of honey bee division of labor by colony age demography. Behav. Ecol. Sociobiol. 39 (3), 147–158. Woyciechowski, M., Moroń, D., 2009. Life expectancy and onset of foraging in the honeybee (Apis mellifera). Insect. Soc. 56 (2), 193–201. Page Jr., R.E., Rueppell, O., Amdam, G.V., 2012. Genetics of reproduction and regulation of honeybee (Apis mellifera L.) social behavior. Annu. Rev. Genet. 46, 97–119. Chang, L.H., Barron, A.B., Cheng, K., 2015. Effects of the juvenile hormone analogue methoprene on rate of behavioural development, foraging performance and navigation in honey bees (Apis mellifera). J. Exp. Biol. 218 (11), 1715–1724. Perry, C., Søvik, E., Myerscough, M.R., Barron, A.B., 2015. Rapid behavioral maturation accelerates failure of stressed honey bee colonies. Proc. Natl. Acad. Sci. U. S. A. 112 (11), 3427–3432. Sullivan, J.P., Fahrbach, S.E., Harrison, J.F., Capaldi, E.A., Fewell, J.H., Robinson, G.E., 2003. Juvenile hormone and division of labor in honey bee colonies: effects of allatectomy on flight behavior and metabolism. J. Exp. Biol. 206 (13), 2287–2296. Guidugli, K.R., Nascimento, A.M., Amdam, G.V., Barchuk, A.R., Omholt, S., Simões, Z.L.P., Hartfelder, K., 2005. Vitellogenin regulates hormonal dynamics in the worker caste of a eusocial insect. FEBS Lett. 579, 4961–4965. Marco Antonio, D.S., Guidugli-Lazzarini, K.R., do Nascimento, A.M., Simões, Z.L., Harfelder, K., 2008. RNAi-mediated silencing of vitellogenin gene function turns honeybee (Apis mellifera) workers into extremely precocious foragers. Naturwissenschaften 95 (10), 953–961. Corona,M., Velarde, R.A., Remolina, S.,Moran-Lauter, A.,Wang, Y., Hughes, K.A., Robinson, G.E., 2007. Vitellogenin, juvenile hormone, insulin signaling, and queen honey bee longevity. Proc. Natl. Acad. Sci. 104 (17), 7128–7133. Seehuus, S.C., Norberg, K., Gimsa, U., Krekling, T., Amdam, G.V., 2006. Reproductive protein protects functionally sterile honey bee workers from oxidative stress. PNAS 103 (4), 962–967. Amdam, G.V., Simões, Z.L., Hagen, A., Norber, K., Schrøder, K., Mikkelsen, Ø., Kirkwood, T.B., Omholtk, S.W., 2004. Hormonal control of the yolk precursor vitellogenin regulates immune function and longevity in honeybees. Exp. Gerontol. 39 (5), 767–773.   AOPWiki 2016-11-29T18:41:29

2018-06-07T11:21:43

Altered, Ca2+-calmodulin activated signal transduction

Cellular

2018-06-07T09:46:42

<upstream-id>3a95f460-9041-4162-9c14-5d0ef1d87851</upstream-id> <downstream-id>f469826b-6731-47a4-a05c-545b28a9ce49</downstream-id>

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."

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. Honey Bee Genome Sequencing Consortium, 2006. Insights into social insects from the genome of the honeybee Apis mellifera. Nature 443 (7114), 931. Jones, A.K., Raymond-Delpech, V., Thany, S.H., Gauthier, M., Sattelle, D.B., 2006. The nicotinic acetylcholine receptor gene family of the honey bee, Apis mellifera. Genome Res. 16 (11), 1422–1430. Tomizawa, M., Casida, J.E., 2001. Structure and diversity of insect nicotinic acetylcholine receptors. Pest Manag. Sci. 57 (10), 914–922. Deglise, P., Grunewald, B., Gauthier, M., 2002. The insecticide imidacloprid is a partial agonist of the nicotinic receptor of honeybee Kenyon cells. Neurosci. Lett. 321 (1–2), 13–16. Dupuis, J.P., Gauthier, M., Raymond-Delpech, V., 2011. Expression patterns of nicotinic subunits alpha2, alpha7, alpha8, and beta1 affect the kinetics and pharmacology of ACh-induced currents in adult bee olfactory neuropiles. J. Neurophysiol. 106 (4), 1604–1613. Briggs, C.A., McKenna, D.G., 1998. Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists. Neuropharmacology 37 (9), 1095–1102. Zwart, R., Oortgiesen, M., Vijverberg, H.P., 1994. Nitromethylene heterocycles: selective agonists of nicotinic receptors in locust neurons compared to mouse N1E-115 and BC3H1 cells. Pestic. Biochem. Physiol. 48, 202–213. Lozano, V.C., Bonnard, E., Gauthier, M., Richard, D., 1996.Mecamylamine-induced impairment of acquisition and retrieval of olfactory conditioning in the honeybee. Behav. Brain Res. 81 (1–2), 215–222. Wüstenberg, D.G., Grünewald, B., 2004. Pharmacology of the neuronal nicotinic acetylcholine receptor of cultured Kenyon cells of the honeybee, Apis mellifera. J. Comp. Physiol. A. 190 (10), 807–821. Fenster, C.P., Beckman, M.L., Parker, J.C., Sheffield, E.B., Whitworkth, T.L., Quick, M.W., Lester, R.A., 1999. Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C. Mol. Pharmacol. 55 (3), 432–443. Lee, A.M., Wu, D.F., Dadgar, J., Wang, D., McMahon, T., Messing, R.O., 2015a. PKCε phosphorylates α4β2 nicotinic ACh receptors and promotes recovery from desensitization. Br. J. Pharmacol. 172 (17), 4430–4441. Hug, H., Sarre, T.F., 1993. Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 291, 329–343. 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. Ihara, M., Shimomura, M., Ishida, C., Nishiwaki, H., Akamatsu, M., Sattelle, D.B., Matsuda, K., 2007. A hypothesis to account for the selective and diverse actions of neonicotinoid insecticides at their molecular targets, nicotinic acetylcholine receptors: catch and release in hydrogen bond networks. Invertebr. Neurosci. 7 (1), 47–51.   AOPWiki 2016-11-29T18:41:34

2018-06-07T13:04:00

<upstream-id>f469826b-6731-47a4-a05c-545b28a9ce49</upstream-id> <downstream-id>2f5d611b-2f14-4ff8-9e76-72723b12d584</downstream-id>

AOPWiki 2016-11-29T18:41:37

2016-12-03T16:38:07

<upstream-id>2f5d611b-2f14-4ff8-9e76-72723b12d584</upstream-id> <downstream-id>3a6135c7-f8a0-4408-8c56-486f151abb94</downstream-id>

AOPWiki 2016-11-29T18:41:37

2016-12-03T16:38:07

<upstream-id>3a6135c7-f8a0-4408-8c56-486f151abb94</upstream-id> <downstream-id>34e2df8c-2646-4d4b-b608-4e3c277f5a81</downstream-id>

AOPWiki 2016-11-29T18:41:34

2016-12-03T16:37:58

<upstream-id>34e2df8c-2646-4d4b-b608-4e3c277f5a81</upstream-id> <downstream-id>c9d1a8eb-959c-497f-9fba-6b058f4ed84a</downstream-id>

AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:04

<upstream-id>c9d1a8eb-959c-497f-9fba-6b058f4ed84a</upstream-id> <downstream-id>4a9f6838-ff2d-463f-a0f4-cd3792494f4a</downstream-id>

AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:04

<upstream-id>4a9f6838-ff2d-463f-a0f4-cd3792494f4a</upstream-id> <downstream-id>42645382-595f-49f7-af75-d2835f918b60</downstream-id>

AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:04

<upstream-id>3a95f460-9041-4162-9c14-5d0ef1d87851</upstream-id> <downstream-id>3a6135c7-f8a0-4408-8c56-486f151abb94</downstream-id>

AOPWiki 2016-11-29T18:41:36

2016-12-03T16:38:04

Nicotinic acetylcholine receptor activation followed by desensitization contributes to abnormal foraging and directly leads to colony loss/failure

nAChR activation - colony loss 7

Carlie LaLone

Carlie A. LaLone, U.S. Environmental Protection Agency (LaLone.Carlie@epa.gov)

BY-SA

1.0

adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified non-adjacent

Not Specified

AOPWiki 2016-11-29T18:41:16

2026-01-11T16:56:06