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Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems

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Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Ogawa, Sachie K., Jeremiah Y. Cohen, Dabin Hwang, Naoshige Uchida, and Mitsuko Watabe-Uchida. 2014. “Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems.” Cell Reports 8 (4) (August): 1105–1118. doi:10.1016/j.celrep.2014.06.042. Published Version doi:10.1016/j.celrep.2014.06.042 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:16953008 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Cell Reports Article Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems Sachie K. Ogawa,1 Jeremiah Y. Cohen,1,2,* Dabin Hwang,1 Naoshige Uchida,1 and Mitsuko Watabe-Uchida1,* 1Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA 2Present address: The Solomon H. Snyder Department of Neuroscience, Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA *Correspondence: [email protected] (J.Y.C.), [email protected] (M.W.-U.) http://dx.doi.org/10.1016/j.celrep.2014.06.042 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). SUMMARY learning from negative reinforcement (Daw et al., 2002; Dayan and Huys, 2008; Deakin and Graeff, 1991; den Ouden et al., Serotonin and dopamine are major neuromodula- 2013), processing reward value (Nakamura et al., 2008; Seymour tors. Here, we used a modified rabies virus to identify et al., 2012), and temporal discounting (Doya, 2002; Miyazaki monosynaptic inputs to serotonin neurons in the dor- et al., 2011). Although it is known that DR and MR project to over- sal and median raphe (DR and MR). We found that lapping, yet distinct forebrain structures (Azmitia and Segal, inputs to DR and MR serotonin neurons are spatially 1978; Vertes and Linley, 2008; Vertes et al., 1999), experimental shifted in the forebrain, and MR serotonin neurons manipulations in DR and MR have yielded equivocal results, and how serotonin neurons in these areas function remains elusive. receive inputs from more medial structures. Then, Forebrain-projecting dopamine neurons are mainly found in we compared these data with inputs to dopamine the ventral tegmental area (VTA) and the substantia nigra pars neurons in the ventral tegmental area (VTA) and sub- compacta (SNc). Neurophysiological recordings in behaving an- stantia nigra pars compacta (SNc). We found that imals have demonstrated that many putative dopamine neurons DR serotonin neurons receive inputs from a remark- signal the discrepancy between actual and expected reward, ably similar set of areas as VTA dopamine neurons that is, reward prediction error (Bayer and Glimcher, 2005; Mat- apart from the striatum, which preferentially targets sumoto and Hikosaka, 2009; Schultz et al., 1997). Although VTA dopamine neurons. Our results suggest three major and SNc contain diverse cell types forming complex circuits, input streams: a medial stream regulates MR seroto- recent studies have clarified the regulation and functional roles nin neurons, an intermediate stream regulates DR of dopamine neurons (Cohen et al., 2012; Lammel et al., 2012; serotonin and VTA dopamine neurons, and a lateral Steinberg et al., 2013; Tan et al., 2012; Tsai et al., 2009; van Zes- sen et al., 2012). Furthermore, monosynaptic inputs to dopamine stream regulates SNc dopamine neurons. These re- neurons in VTA and SNc were identified from the whole brain us- sults provide fundamental organizational principles ing a rabies-virus-based transsynaptic tracing method (Watabe- of afferent control for serotonin and dopamine. Uchida et al., 2012). These studies have provided a foundation of our understanding of the anatomy and physiology of dopamine INTRODUCTION neurons as well as their diversity (Lammel et al., 2013; Roeper, 2013). Serotonin and dopamine are major neuromodulators essential Compared to dopamine, our understanding of serotonin has for flexible behavior. Both are released from small populations been limited. One reason is that DR and MR contain a diverse of neurons in the midbrain and brainstem. A unique feature of collection of cell types (Hioki et al., 2010). It has thus been diffi- these neurons is that they receive and integrate inputs from cult to identify serotonin neurons while recording in behaving an- many brain areas, and broadcast their outputs through long imals (Allers and Sharp, 2003; Kocsis et al., 2006; Nakamura axons to many brain areas (Jacobs and Azmitia, 1992). Despite et al., 2008; Ranade and Mainen, 2009). Furthermore, although the importance of these neurotransmitters in normal behav- previous studies identified afferents to the DR and MR (Aghaja- iors and psychiatric disorders, their regulation remains poorly nian and Wang, 1977; Gervasoni et al., 2000; Marcinkiewicz understood. et al., 1989; Peyron et al., 1998; Soiza-Reilly and Commons, Forebrain-projecting serotonin neurons are found in the dorsal 2011; Vertes and Linley, 2008), technical limitations of conven- raphe (DR) and median raphe (MR). They are thought to be tional tracers have made it difficult to distinguish between synap- involved in diverse functions including the regulation of sleep- tic inputs to serotonin versus nonserotonin neurons. wake cycles (Lydic et al., 1983; McGinty and Harper, 1976), mo- To understand the organizing principles of afferents to seroto- tor facilitation (Jacobs and Fornal, 1997), defensive behavior nin neurons, we applied a rabies-virus-based tracing method (Deakin and Graeff, 1991), behavioral inhibition (Soubrie, 1986), (Watabe-Uchida et al., 2012; Wickersham et al., 2007) to identify Cell Reports 8, 1105–1118, August 21, 2014 ª2014 The Authors 1105 DR-targeted MR-targeted Control A coronal B D sagittal DR MR 5-100-5 (mm) coronal C E DR DR1 DR7 DR3 DR4 DR5 DR8DR6 MR1 MR7 MR4 MR5 MR3 MR12 coronal MR13 GFP mCherry Serotonin GFP mCherry Serotonin MR FGHI 10000 DR DR7 DR mRt DR7 DR7 CLi DR1 DR1 DR1 Pn DR6 DR6 8000 DR6 IPL DR3 DR3 DR3 IPA DR5 DR5 DR5 MR DR4 DR4 6000 DR4 DR8 DR8 DR8 MR1 MR1 MR1 Mouse Mouse MR7 MR7 4000 Mouse MR7 MR3 MR3 MR3 MR4 MR4 MR4 Cell count (Input) MR5 MR5 2000 MR5 MR13 MR13 r: 0.57 MR13 MR12 MR12 (P<0.05) MR12 MR 0 0 100 200 300 400 500 600 700 800 0 2000 4000 6000 8000 10000 0 200 400 600 800 020406080100 Cell count (Starter) Cell count (Input) Cell count (Starter) Starter (%) coronal J PAGSC PAG DS LHb DR BNST mRt RRF Pa SLE Ce DR-targeted MR PSTh MR Acb LH IPN VTA IPN VP VP SO RS PAG MHb MHb LHb DR LS mRt Pa ZI MR MS SLE MR MR-targeted MR LH VTA IPN DB LPO SO rostral caudal Figure 1. Identification of Monosynaptic Inputs to Serotonin Neurons with Rabies Virus and Sert-Cre Mice (A–C) Injection site in the raphe nuclei of DR-targeted and MR-targeted Sert-Cre mice brains in low- (A), middle- (B), and high-magnification images (C). Bregma: À4.65 mm. The EGFP expression and immunoreactivity to mCherry and serotonin are shown in green, red, and blue, respectively. The white rectangles indicate the magnified regions. White arrowheads point at neurons that are triple-positive for EGFP, mCherry, and serotonin (starter neurons that are serotonergic), and (legend continued on next page) 1106 Cell Reports 8, 1105–1118, August 21, 2014 ª2014 The Authors monosynaptic inputs to DR and MR serotonin neurons We identified starter neurons based on coexpression of mCherry throughout the brain. We then compared the distributions of in- and EGFP (Figures 1A–1I). Almost all double-positive neurons puts to DR and MR serotonin neurons. (95.8%) were found to be serotonin neurons (Figure 1C), by cos- In addition, dopamine and serotonin are thought to be involved taining of an antibody against serotonin. Near the center of injec- in related functions such as processing reward and punishment tion sites, 30.5% of serotonin neurons were double positive for and are thought to interact (Boureau and Dayan, 2011; Kapur mCherry and EGFP. We found a small number of mCherry- and and Remington, 1996). However, little is known about the EGFP-double-positive neurons in neighboring serotonin-con- anatomical basis of these interactions. We therefore compared taining nuclei: the pontine reticular nucleus (Pn), mesencephalic the data obtained for serotonin with those obtained for dopamine reticular formation (mRt), caudal linear nucleus of the raphe neurons in a previous study (Watabe-Uchida et al., 2012). These (CLi), and parts of the interpeduncular nucleus (IPN). However, results provide foundational information as to the global organi- these neurons made up a small fraction of total starter neurons zation of monosynaptic inputs to subdivisions of the serotonin in most animals (Figure 1I). Starter neurons tiled almost the entire and dopamine systems. DR or MR (see Supplemental Experimental Procedures). Across animals, the number of EGFP-positive neurons was roughly pro- RESULTS portional to the number of starter neurons (Input = a $ Starter + b; a = 8.2, p < 0.05; b = 1075, p = 0.42; Figures 1F–1H). Whole-Brain Mapping of Monosynaptic Inputs to These results, together with previous studies (Miyamichi et al., Serotonin Neurons 2013; Wall et al., 2013; Watabe-Uchida et al., 2012; Wickersham To demonstrate monosynaptic inputs to DR and MR serotonin et al., 2007), indicate that EGFP-positive neurons outside injec- neurons, we used a retrograde transsynaptic tracing system tion sites represent transsynaptically labeled monosynaptic in- based on a modified rabies virus (SADDG-EGFP(EnvA); Wicker- puts to serotonin neurons.
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