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Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish

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Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. Loss of the habenula intrinsic neuromodulator Kisspeptin1 affects learning in larval zebrafish Lupton, Charlotte; Sengupta, Mohini; Cheng, Ruey‑Kuang; Chia, Joanne; Thirumalai, Vatsala; Jesuthasan, Suresh 2017 Lupton, C., Sengupta, M., Cheng, R.‑K., Chia, J., Thirumalai, V., & Jesuthasan, S. (2017). Loss of the habenula intrinsic neuromodulator Kisspeptin1 affects learning in larval zebrafish. eNeuro, 4(3), e0326‑16.2017‑. doi:10.1523/ENEURO.0326‑16.2017 https://hdl.handle.net/10356/107013 https://doi.org/10.1523/ENEURO.0326‑16.2017 © 2017 Lupton et al. This is an open‑access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Downloaded on 29 Sep 2021 15:54:33 SGT New Research Cognition and Behavior Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish Joanne Chia,5 Vatsala ء,Ruey-Kuang Cheng,4 ء,Mohini Sengupta,3 ء,Charlotte Lupton,1,2 and Suresh Jesuthasan2,4,6 ء,Thirumalai,3 DOI:http://dx.doi.org/10.1523/ENEURO.0326-16.2017 1Department of Animal and Plant Sciences, University of Sheffield, Sheffield, S10 2TN, UK, 2Institute for Molecular and Cell Biology, 138673, Singapore, 3National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, 560065, India, 4Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore, 5National University of Singapore Graduate School for Integrative Sciences and Engineering, 117456, Singapore, and 6Duke-NUS Graduate Medical School, 169857 Singapore Abstract Learning how to actively avoid a predictable threat involves two steps: recognizing the cue that predicts upcoming punishment and learning a behavioral response that will lead to avoidance. In zebrafish, ventral habenula (vHb) neurons have been proposed to participate in both steps by encoding the expected aversiveness of a stimulus. vHb neurons increase their firing rate as expectation of punishment grows but reduce their activity as avoidance learning occurs. This leads to changes in the activity of raphe neurons, which are downstream of the vHb, during learning. How vHb activity is regulated is not known. Here, we ask whether the neuromodulator Kisspeptin1, which is expressed in the ventral habenula together with its receptor, could be involved. Kiss1 mutants were generated with CRISPR/Cas9 using guide RNAs targeted to the signal sequence. Mutants, which have a stop codon upstream of the active Kisspeptin1 peptide, have a deficiency in learning to avoid a shock that is predicted by light. Electrophysiology indicates that Kisspeptin1 has a concentration-dependent effect on vHb neurons: depolarizing at low concentrations and hyperpo- larizing at high concentrations. Two-photon calcium imaging shows that mutants have reduced raphe response to shock. These data are consistent with the hypothesis that Kisspeptin1 modulates habenula neurons as the fish learns to cope with a threat. Learning a behavioral strategy to overcome a stressor may thus be accompanied by physiological change in the habenula, mediated by intrinsic neuromodulation. Key words: Calcium imaging; electrophysiology; habenula; intrinsic neuromodulation; mutant; operant learning Significance Statement Learning to deal with adversity can positively affect one’s ability to cope with challenges in the immediate future. Control thus causes short-term change in the brain. Here, we show that the neuromodulator Kisspeptin1 is involved in learning to avoid a punishment. The expression pattern of this gene and electrophysiological recordings suggest that this molecule may function by modulating the ventral habenula, a region of the brain that mediates fear by regulating serotonin release. Kisspeptin1 could thus be a potential player in resilience developed as a result of control, extending previous findings that it can reduce fear. Introduction On first encountering a threat in a novel environment, When faced with an aversive stimulus, animals respond there may be panic and poorly directed attempts at es- in a manner that is dependent on context and experience. cape. If the animal repeatedly encounters the threat and Received October 25, 2016; accepted March 30, 2017; First published May 8, Author contributions: CL, MS, RKC, VT, and SJ designed research; CL, MS, 2017. and RKC performed research; CL, MS, RKC, JC, and VT analyzed data; SJ Authors report no conflict of interest. wrote the paper. May/June 2017, 4(3) e0326-16.2017 1–9 New Research 2 of 9 becomes familiar with a safe escape route, it will be able What is the mechanism of change in vHb activity as to quickly remove itself from danger. Better still, if the learning occurs? Amo et al. (2014) have proposed that animal is able to recognize a cue that reliably predicts excitation is regulated via feedback from serotonergic the impending threat, it will be able to escape before the neurons in the raphe to the entopeduncular nucleus, aversive stimulus is present. This, in essence, is the phe- which is the teleost homolog of the basal ganglia (Turner nomenon of active avoidance. Several theories have been et al., 2016). Whether additional mechanisms are involved proposed to explain the mechanism underlying active is unknown. Here, we examine the possibility that a avoidance. In the two-factor theory, the animal first de- change in habenula neurons accompanies the learning velops a fear of the conditioning stimulus (CS) that is process. In particular, we examine the potential involve- paired with the aversive stimulus, by Pavlovian condition- ment of the neuromodulator Kisspeptin1, which is ex- ing. Cotermination of the CS and the threat [uncondi- pressed in the vHb together with its receptor (Kitahashi tioned stimulus (US)] then drives learning. Expectation has et al., 2009). In zebrafish, two paralogs of kiss1 have been a critical role, and actions that lead to better-than- identified. These have nonoverlapping expression, with predicted outcomes are reinforced (Maia, 2012). The first kiss1 being restricted to the habenula and kiss2 ex- time an aversive stimulus is encountered, the predicted pressed in the hypothalamus and posterior tuberculum outcome would be negative. However, if an escape route (Kitahashi et al., 2009). This allows a specific test of the has been learned, then the predicted outcome becomes role of kiss1 in the habenula using genetics. positive. In mammals, kiss1 is expressed in the hypothalamus How is active avoidance implemented in the brain? One and is well studied in the context of reproduction (Pinilla structure that may be involved is the lateral habenula. As et al., 2012; Clarke et al., 2015). Burst firing of hypotha- first shown in monkeys, unexpected punishment leads to lamic neurons leads to the release of Kisspeptin1 (Kelly increased activity in lateral habenula neurons, whereas an et al., 2013), which causes sustained depolarization of unexpected reward leads to inhibition (Matsumoto and gonadotropin-releasing hormone (GnRH) neurons (Han Hikosaka, 2007, 2009). Direct evidence for an involvement et al., 2005). Kisspeptin1 is also expressed in the hip- of this structure in active avoidance comes from ze- pocampus, where it causes an increase in EPSC ampli- brafish, in which the homolog of the lateral habenula is tude and contributes to increased excitability (Arai, 2009). termed the ventral habenula (vHb; Amo et al., 2010). In the zebrafish habenula, Kisspeptin1 has been proposed Silencing vHb neurons reduces the ability of zebrafish to to depolarize vHb neurons, based on its ability to induce learn active avoidance (Amo et al., 2014). In the naive c-fos expression (Ogawa et al., 2014). However, delivery animal, unexpected punishment leads to phasic activity in of Kisspeptin1 decreases fear, which is inconsistent with vHb neurons (Amo et al., 2014). As the animal learns to evidence that excitation of vHb neurons is aversive (Amo associate a CS with the threat, there is tonic firing in et al., 2014). Moreover, killing Kisspeptin1 receptor–ex- response to the CS in vHb neurons. This causes excita- pressing neurons in ventral habenula neurons mimics the tion of serotonergic neurons in the dorsal raphe. As the effect of Kisspeptin1 delivery (Ogawa et al., 2014), which animal learns to escape, there is decreased tonic firing. would not be expected if Kisspeptin1 causes depolariza- Tonic activity in the vHb has thus been proposed to tion. Rather, these observations suggest that Kisspeptin1 encode aversive reward expectation value, and learning can also cause hyperpolarization. Here, we ask whether active avoidance is associated with a change in vHb Kisspeptin1 could be involved in learning avoidance, by activity in response to the CS (Amo et al., 2014). assessing the ability of a kiss1 mutant to learn and whether Kiss1 has the ability to both depolarize and hy- -Star Graduate Academy, under the ARAP scheme. perpolarize vHb neurons, which would make Kiss1 signalءCL was funded by the A MS was supported by Senior Research Fellowship from Council of Scientific ing a potential mechanism for alteration of vHb neuron and Industrial Research. JC was funded by the National University of Singa- activity during avoidance learning. pore Graduate School. This work was supported by core funding from Institute for Molecular and Cell Biology
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