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Memory-Relevant Mushroom Body Output Synapses Are Cholinergic University of Massachusetts Medical School eScholarship@UMMS GSBS Student Publications Graduate School of Biomedical Sciences 2016-03-16 Memory-Relevant Mushroom Body Output Synapses Are Cholinergic Oliver Barnstedt University of Oxford Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_sp Part of the Neuroscience and Neurobiology Commons Repository Citation Barnstedt O, Owald D, Felsenberg J, Brain R, Moszynski J, Talbot CB, Perrat PN, Waddell S. (2016). Memory-Relevant Mushroom Body Output Synapses Are Cholinergic. GSBS Student Publications. https://doi.org/10.1016/j.neuron.2016.02.015. Retrieved from https://escholarship.umassmed.edu/ gsbs_sp/1994 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Student Publications by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Article Memory-Relevant Mushroom Body Output Synapses Are Cholinergic Highlights Authors d Mushroom body Kenyon cell function requires ChAT and Oliver Barnstedt, David Owald, VAChT expression Johannes Felsenberg, ..., Clifford B. Talbot, Paola N. Perrat, d Kenyon cell-released acetylcholine drives mushroom body Scott Waddell output neurons Correspondence d Blocking nicotinic receptors impairs mushroom body output neuron activation [email protected] (D.O.), [email protected] (S.W.) d Acetylcholine interacts with coreleased neuropeptide In Brief Fruit fly memory involves plasticity of mushroom body synapses. Barnstedt et al. identified acetylcholine as the mushroom body neurotransmitter. Mushroom body output neuron activation requires nicotinic acetylcholine receptors. Impaired receptor function reduces physiological responses and alters odor-driven behavior. Barnstedt et al., 2016, Neuron 89, 1237–1247 March 16, 2016 ª2016 The Authors http://dx.doi.org/10.1016/j.neuron.2016.02.015 Neuron Article Memory-Relevant Mushroom Body Output Synapses Are Cholinergic Oliver Barnstedt,1 David Owald,1,3,* Johannes Felsenberg,1 Ruth Brain,1 John-Paul Moszynski,1 Clifford B. Talbot,1 Paola N. Perrat,2 and Scott Waddell1,* 1Centre for Neural Circuits and Behaviour, The University of Oxford, Tinsley Building, Mansfield Road, Oxford OX1 3SR, UK 2Department of Neurobiology, UMass Medical School, Worcester, MA 01605, USA 3Present address: Institute of Neurophysiology, Charite´ – Universita¨ tsmedizin Berlin, 10117 Berlin, Germany *Correspondence: [email protected] (D.O.), [email protected] (S.W.) http://dx.doi.org/10.1016/j.neuron.2016.02.015 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). SUMMARY vertical lobes (Shomrat et al., 2011). Analogies have also been drawn to the vertebrate amygdala, basal ganglia, and pallium Memories are stored in the fan-out fan-in neural ar- (Hige et al., 2015; Waddell 2013; Tomer et al., 2010). It is therefore chitectures of the mammalian cerebellum and hippo- of interest to understand the logic of how the MB operates and to campus and the insect mushroom bodies. However, what level functional principles relate to those of similar neural whereas key plasticity occurs at glutamatergic structures across phyla. Importantly, recent studies suggest that synapses in mammals, the neurochemistry of the in the Drosophila MB cellular mechanisms of neural plasticity can memory-storing mushroom body Kenyon cell output be directly linked to behavioral change (Owald et al., 2015). In all insects the axons from different subpopulations of KCs are synapses is unknown. Here we demonstrate a role Drosophila arranged into separate parallel bundles, or lobes (Strausfeld et al., for acetylcholine (ACh) in . Kenyon cells 2009). Some of the anatomical subdivision serves individual sen- express the ACh-processing proteins ChAT and sory modalities such as olfaction, gustation, and vision (Strausfeld VAChT, and reducing their expression impairs et al., 1998; Murthy et al., 2008; Honegger et al., 2011; Campbell learned olfactory-driven behavior. Local ACh appli- et al., 2013; Caron et al., 2013; Vogt et al., 2014; Aso et al., cation, or direct Kenyon cell activation, evokes activ- 2014a), while certain KCs may be multimodal (Strausfeld et al., ity in mushroom body output neurons (MBONs). 2009; Kirkhart and Scott, 2015). The primary sensory input to MBON activation depends on VAChT expression Drosophila KCs occurs in the MB calyx where their dendrites in Kenyon cells and is blocked by ACh receptor receive divergent fan-out input from around 50 classes of cholin- antagonism. Furthermore, reducing nicotinic ACh re- ergic olfactory projection neurons (Yasuyama et al., 2002; Caron ceptor subunit expression in MBONs compromises et al., 2013). Odor-specific activity in the projection neuron popu- lation is transformed into activation of fairly sparse subpopulations odor-evoked activation and redirects odor-driven 0 0 of KCs across the ab, a b and g divisions in the overall MB behavior. Lastly, peptidergic corelease enhances ensemble (Honegger et al., 2011; Campbell et al., 2013; Lin ACh-evoked responses in MBONs, suggesting an et al., 2014a). Reinforcing dopaminergic neurons that innervate interaction between the fast- and slow-acting trans- nonoverlapping zones of the MB lobes are believed to assign pos- mitters. Therefore, olfactory memories in Drosophila itive or negative values to odor-activated KCs during learning (Mao are likely stored as plasticity of cholinergic synapses. and Davis, 2009; Claridge-Chang et al., 2009; Aso et al., 2012; Liu et al., 2012; Burke et al., 2012; Waddell, 2013). Comprehensive anatomical studies have characterized all of the dopaminergic INTRODUCTION input and the output pathways of the MB (Tanaka et al., 2008; Aso et al., 2014a). Remarkably, information from the 2,000 KCs Understanding how memories are formed, stored, and retrieved converges, or fans-in, onto the dendrites of 21 different types of from neural networks is an important pursuit of neuroscience. mushroom body output neurons (MBONs). The MBONs tile the The insect mushroom bodies (MBs) are prominent bilateral brain MB lobes into 15 discrete compartments, and each one has a cor- structures that have been extensively studied for their universal responding set of afferent dopaminergic neurons (DANs). This role in learned behavior (Strausfeld et al., 1998; Heisenberg, anatomy alone suggests that learning-related plasticity alters 2003; Farris, 2013; Perisse et al., 2013a; Menzel, 2014). In the odor drive to downstream MBONs whose dendrites occupy the larger eusocial insects, such as honeybees, the MBs are same zones as the reinforcing dopaminergic neurons (Aso et al., comprised of a few 100,000 intrinsic neurons or Kenyon cells 2014b; Owald and Waddell, 2015). Indeed, several studies have (KCs), whereas the smaller fruit fly MBs have only around 2,000 shown that reinforcer quality is represented in discrete dopami- neurons per hemisphere. The anatomy of the MB has been nergic zones on the MB lobes (Aso et al., 2012; Das et al., 2014; compared to the fan-out, fan-in neural architecture of the mamma- Galili et al., 2014; Lin et al., 2014b; Huetteroth et al., 2015; Yama- lian cerebellum and hippocampus (Farris, 2011; Stevens, 2015; gata et al., 2015) and have documented altered odor drive to spe- Menzel, 2014; Owald and Waddell, 2015) and to the cephalopod cific MBONs after learning (Se´ journe´ et al., 2011; Plac¸ ais et al., Neuron 89, 1237–1247, March 16, 2016 ª2016 The Authors 1237 A Figure 1. Kenyon Cells Express ChAT and VAChT, and Compromised ChAT or VAChT Expression Impairs MB Function (A) MBs label with an antibody to ChAT (upper row) and an antibody to VAChT (bottom row). Pseudocolored images of single confocal sec- tions at the level of the MB g lobe. OK107- GAL4-driven UAS-ChATRNAi in KCs reduces anti-ChAT label in the MB. UAS-VAChTRNAi re- duces anti-ChAT and anti-VAChT immunoreac- tivity in MB. See Figure S1 for additional data. Scale bar, 20 mm. BC(B) Quantification of (A). Anti-ChAT label is significantly lower in MBs in UAS-ChATRNAi; OK107-GAL4 and UAS-VAChTRNAi;OK107-GAL4 flies as compared to all genetic controls. Anti- VAChT signal is significantly lower in MBs in UAS-VAChTRNAi;OK107-GAL4 flies (n = 3–9, as- terisks denote p < 0.05; one-way ANOVA, Tu- key’s HSD post hoc test). Similar results are evident in the a, a0, b, and b0 lobes (data not shown). (C) Aversive olfactory memory expression re- quires ACh function in KCs. Performance of UAS- ChATRNAi;OK107-GAL4 and UAS-VAChTRNAi; OK107-GAL4 flies is significantly different from that of heterozygous controls (n = 6, asterisks denote p < 0.01; one-way ANOVA, Tukey’s HSD post hoc test). See Figures S2A–S2C for additional experiments. Error bars in (B) and (C) represent the standard error of the mean (SEM). 2013; Pai et al., 2013; Owald et al., 2015; Bouzaiane et al., 2015). Drosophila KCs. A significant part of KC-MBON communication Interestingly, reward learning appears to reduce drive to output is carried by cholinergic transmission from KCs that activates pathways that direct avoidance behavior, whereas aversive nicotinic ACh receptors on MBONs. Our data therefore suggest learning increases drive to avoidance pathways while reducing that fly memories are formed by dopamine-directed plasticity at drive to approach pathways (Owald et al., 2015). Learning requires cholinergic KC-MBON synapses. dopamine receptors and cAMP signaling in the KCs (Kim et al., 2007; Qin et al., 2012; Zars et al., 2000; McGuire et al., 2003; RESULTS Blum et al., 2009; Trannoy et al., 2011), which implies a presynap- tic mechanism of plasticity at KC-MBON junctions. In fact, a Drosophila Kenyon Cell Function Requires ChAT recent study (Hige et al., 2015) demonstrated that pairing odor Expression presentation with activation of aversive dopaminergic neurons Cholinergic neurons express ChAT to synthesize ACh and the ve- drives odor-specific synaptic depression at KC-MBON junctions.
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