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Multiple Local Synaptic Modifications at Specific Sensorimotor Connections After Learning Are Associated with Behavioral Adaptat Research Report: Regular Manuscript Multiple local synaptic modifications at specific sensorimotor connections after learning are associated with behavioral adaptations that are components of a global response change https://doi.org/10.1523/JNEUROSCI.2647-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2647-19.2020 Received: 7 November 2019 Revised: 24 February 2020 Accepted: 25 February 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Title: 2 Multiple local synaptic modifications at specific sensorimotor connections after 3 learning are associated with behavioral adaptations that are components of a global 4 response change 5 Abbreviated title 6 Local synapse changes and global response changes 7 Authors names and affiliations: 8 Shlomit Tam1,3, Itay Hurwitz1,3, Hillel J. Chiel2 and Abraham J. Susswein1* 9 1The Mina and Everard Goodman Faculty of Life Sciences and The Leslie and Susan 10 Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, 11 Ramat Gan, 52900, Israel 12 2Departments of Biology, Neurosciences and Biomedical Engineering, Case Western 13 Reserve University, Cleveland, OH 44106-7080 14 3Contributed equally 15 * Corresponding Author 16 Corresponding Author: 17 A.J. Susswein 18 Bar Ilan University 19 Ramat Gan 52900 Israel 20 Phone: 972 3 531 8388 21 Email: [email protected] 22 Number of pages: 33 23 Number of figures: 7 24 Number of tables: 0 25 Number of Multimedia: 0 26 Number of 3D models: 0 27 Number of words for abstract: 206 28 Number of words for Introduction: 639 29 Number of words for Discussion: 1523 30 Conflict of interest statement: The authors declare no competing financial interests. 1 31 ACKNOWLEDGMENTS 32 The research was supported by Israel Science Foundation Grants 1379/12 and 2396/18, U.S. - 33 Israel Binational Science Foundation Grant No. 2017624, and NSF-IOS-BSF Grant 1754869. We 34 thank Arina Soklakova for performing the behavioral experiment on rejection of a cannula. 35 2 36 Abstract 37 Learning causes local changes in synaptic connectivity and coordinated, global changes affecting 38 many aspects of behavior. How do local synaptic changes produce global behavioral changes? In 39 the hermaphroditic mollusc Aplysia, after learning that food is inedible, memory is expressed as 40 bias to reject a food, and to reduce responses to that food. We now show that memory is also 41 expressed as an increased bias to reject even a non-food object. The increased bias to rejection is 42 partially explained by changes in synaptic connections from primary mechano-afferents to five 43 follower neurons with well-defined roles in producing different feeding behaviors. Previously, 44 these mechanoafferents had been shown to play a role in memory consolidation. Connectivity 45 changes differed for each follower neuron the probability that cells were connected changed; 46 excitation changed to inhibition and vice versa; and connection amplitude changed. Thus, multiple 47 neural changes at different sites underlie specific aspects of a coordinated behavioral change. 48 Changes in the connectivity between mechanoafferents and their followers cannot account for all 49 of the behavioral changes expressed after learning, indicating that additional synaptic sites are 50 also changed. Access to the circuit controlling feeding can help determine the logic and cellular 51 mechanisms by which multiple local synaptic changes produce an integrated, global change in 52 behavior. 53 Significance Statement 54 How do local changes in synapses affect global behavior? Studies on invertebrate preparations 55 usually examines synaptic changes at a specific neural sites, producing a specific behavioral 56 change. However, memory may be expressed by multiple behavioral changes. We report that a 57 change in behavior after learning in Aplysia is accomplished, in part, by regulating connections 58 between mechanoafferents and their synaptic followers. For some followers, the connection 3 59 probabilities change; for others, the connection signs are reversed; in others, the connection 60 strength is modified. Thus, learning produces changes in connectivity at multiple sites, via multiple 61 synaptic mechanisms that are consistent with the observed behavioral change. 62 4 63 Introduction 64 Memory is expressed by changes at specific, local synapses, and also by widespread, global 65 changes in behavior. How are changes at local synapses related to global changes in behavior? In 66 invertebrate model systems, neurons and synapses are readily accessible, but studies have usually 67 focused on single neural sites producing a specific behavioral change (Hawkins and Byrne, 2015; 68 Kandel, 2001). However, the sites examined are unlikely to be the only ones affected. Learning 69 may produce changes at many sites (Benjamin et al., 2000), reflecting the finding that even simple 70 stimuli recruit many neurons (Zecević et al., 1989), with presumably many functions. Changes in 71 multiple aspects of behavior after an experience are particularly striking in humans and in higher 72 animals, in which, with the appropriate experimental techniques, the different aspects are 73 separable (Cohen and Squire, 1980). 74 Multiple changes in behavior arise from multiple changes in the functional connectome, the 75 set of neurons active while performing a behavior (Alivisatos et al., 2012). To examine how a 76 connectome is functionally rewired (Bennet et al., 2018) and how local synaptic changes can 77 globally affect behavior when long-term memory is expressed, we used an associative learning 78 paradigm in which Aplysia try but fail to consume food (Susswein et al., 1986). Training is 79 characterized by progressively fewer attempts to swallow food, until animals completely stop 80 responding. Long-term memory is expressed by a number of changes in behavior. First, animals 81 make fewer attempts to bite and swallow the food, because of an increased likelihood to produce 82 active rejection responses in place of biting and swallowing. Second, there is a decrease in the 83 time required to stop responding to the food. Third, the decrease is taste-specific (Susswein et al., 84 1986). A recent study (McManus et al., 2019) indicated that the decreased response time is 85 explained by a postsynaptic decrease in response of neurons in the cerebral ganglion to the 86 transmitter released by chemoafferents responding to food on the lips. However, this study did 5 87 not account for the increased bias to reject food. Two findings suggested that the changes in 88 behavior which precede cessation of responses might be localized to a group of mechanoafferents 89 in the buccal ganglia that innervate the interior of the mouth. First, the mechanoafferents release 90 peptides biasing motor activity to rejection (Vilim et al., 2010). Second, molecular correlates of 91 long-term memory formation after training with inedible food are localized to these 92 mechanoafferents (Levitan et al., 2012). We therefore focused on the possible role of these 93 mechanoafferents in an increased bias to reject. 94 How could an increase in the likelihood to reject food, rather than to ingest it, be expressed 95 in the nervous system? In general, a number of possible mechanisms for choosing a behavior have 96 been found in the nervous system, ranging from command-neuron like systems in which one 97 behavior suppresses all others, to reorganizing circuitry in which changes in input “carve out” 98 different patterns of neural activity, to population encoding, in which a continuous range of 99 different behaviors can be generated (Kristan 2008; Morton and Chiel 1994). We found that in 100 animals expressing long-term memory that biases feeding to rejection-like activity, the synaptic 101 output of a sub-population of the mechanoafferents is modified, so as to bias the response to 102 rejection. The bias is accomplished in different ways to different followers, indicating that even a 103 specific aspect of the overall change in behavior does not occur at a single neural site, by a specific 104 neural mechanism, but rather arises by regulating multiple synapses simultaneously. For some 105 synapses between mechanoafferents and their followers, the connection probability changes; in 106 others, connection sign (excitation or inhibition) is reversed; in still others, connection amplitude is 107 increased or decreased. Thus, even a single aspect of memory is expressed by changes at a variety 108 of neural sites, via both functional rewiring (adding or eliminating connections) and by changes in 109 relative amplitude. 6 110 Methods 111 Animals 112 Aplysia californica weighing 50-250 g were purchased from Marinus Scientific (Long Beach, CA), 113 and were stored in 600-L tanks filled with natural Mediterranean seawater maintained at 17° C. 114 The animals were fed 2-3 times weekly with Ulva lactuca gathered from the Mediterranean coasts 115 of Israel, or purchased from Seakura (https://www.seakura.co.il/en/), and stored frozen until 116 used. 117 Experimental Design and Statistical Analysis 118 Training and testing memory. As in numerous previous studies examining learning that food is 119 inedible in Aplysia (Katzoff et al., 2002; Katzoff et al., 2006; Levitan et al., 2012; Susswein et al., 120 1986), 24 h before being trained, animals were transferred to 10-L experimental aquaria that were 121 maintained at room temperature (23°C). They were kept two to an aquarium, with the two 122 animals separated by a partition allowing the flow of water. As in previous studies (Susswein et al., 123 1986), the animals were trained with inedible food, the seaweed Ulva wrapped in plastic net. The 124 food induced biting, leading to food entering the buccal cavity, where it induced attempts to 125 swallow.
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