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• W1997128521 abstract "Recent studies indicate that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) convey distinct signals. To explore this difference, we comprehensively identified each area's monosynaptic inputs using the rabies virus. We show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas. SNc and VTA dopamine neurons receive contrasting excitatory inputs: the former from the somatosensory/motor cortex and subthalamic nucleus, which may explain their short-latency responses to salient events; and the latter from the lateral hypothalamus, which may explain their involvement in value coding. We demonstrate that neurons in the striatum that project directly to dopamine neurons form patches in both the dorsal and ventral striatum, whereas those projecting to GABAergic neurons are distributed in the matrix compartment. Neuron-type-specific connectivity lays a foundation for studying how dopamine neurons compute outputs. Recent studies indicate that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) convey distinct signals. To explore this difference, we comprehensively identified each area's monosynaptic inputs using the rabies virus. We show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas. SNc and VTA dopamine neurons receive contrasting excitatory inputs: the former from the somatosensory/motor cortex and subthalamic nucleus, which may explain their short-latency responses to salient events; and the latter from the lateral hypothalamus, which may explain their involvement in value coding. We demonstrate that neurons in the striatum that project directly to dopamine neurons form patches in both the dorsal and ventral striatum, whereas those projecting to GABAergic neurons are distributed in the matrix compartment. Neuron-type-specific connectivity lays a foundation for studying how dopamine neurons compute outputs. Tracing direct inputs to midbrain dopamine (DA) neurons using rabies virus DA neurons receive direct inputs from autonomic, motor and somatosensory areas Direct cortical and subthalamic inputs may explain short-latency excitation of SNc The largest numbers of direct inputs come from dorsal and ventral striatum patches A central goal of neuroscience is to understand brain function in terms of interactions among a network of diverse types of neurons. A critical step is to understand the inputs and outputs of a given type of neuron in an intact network. Electrophysiological and optical imaging techniques have advanced our understanding of outputs, but our progress in understanding the nature of inputs has been slow. Establishing methods to efficiently identify inputs to a given type of neuron will facilitate our understanding of how neurons communicate. Dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) play pivotal roles in various brain functions including motivation, reinforcement learning, and motor control (Cohen et al., 2012Cohen J.Y. Haesler S. Vong L. Lowell B.B. Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area.Nature. 2012; 482: 85-88Crossref PubMed Scopus (816) Google Scholar; Ikemoto, 2007Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.Brain Res. Brain Res. Rev. 2007; 56: 27-78Crossref PubMed Scopus (1057) Google Scholar; Redgrave and Gurney, 2006Redgrave P. Gurney K. The short-latency dopamine signal: a role in discovering novel actions?.Nat. Rev. Neurosci. 2006; 7: 967-975Crossref PubMed Scopus (517) Google Scholar; Schultz, 2007Schultz W. Multiple dopamine functions at different time courses.Annu. Rev. Neurosci. 2007; 30: 259-288Crossref PubMed Scopus (973) Google Scholar; Wise, 2004Wise R.A. Dopamine, learning and motivation.Nat. Rev. Neurosci. 2004; 5: 483-494Crossref PubMed Scopus (2332) Google Scholar). Electrophysiological studies have shown that dopamine neurons are activated phasically (100–500 ms) by unpredicted reward or sensory cues that predict reward (Bromberg-Martin et al., 2010Bromberg-Martin E.S. Matsumoto M. Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting.Neuron. 2010; 68: 815-834Abstract Full Text Full Text PDF PubMed Scopus (1391) Google Scholar; Schultz et al., 1997Schultz W. Dayan P. Montague P.R. A neural substrate of prediction and reward.Science. 1997; 275: 1593-1599Crossref PubMed Scopus (5893) Google Scholar). In contrast, they do not respond to fully predicted reward, and their activity is transiently suppressed by negative outcomes (e.g., when a predicted reward is omitted or the animal expects or receives negative outcomes). Thus, dopamine neurons appear to calculate the difference between the expected and actual reward (i.e., reward prediction errors). Reward prediction error may not be the only function of dopamine neurons, however. For example, several studies have suggested that dopamine neurons are activated by noxious stimuli (Brischoux et al., 2009Brischoux F. Chakraborty S. Brierley D.I. Ungless M.A. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli.Proc. Natl. Acad. Sci. USA. 2009; 106: 4894-4899Crossref PubMed Scopus (579) Google Scholar; Joshua et al., 2008Joshua M. Adler A. Mitelman R. Vaadia E. Bergman H. Midbrain dopaminergic neurons and striatal cholinergic interneurons encode the difference between reward and aversive events at different epochs of probabilistic classical conditioning trials.J. Neurosci. 2008; 28: 11673-11684Crossref PubMed Scopus (214) Google Scholar; Redgrave and Gurney, 2006Redgrave P. Gurney K. The short-latency dopamine signal: a role in discovering novel actions?.Nat. Rev. Neurosci. 2006; 7: 967-975Crossref PubMed Scopus (517) Google Scholar). Indeed, a recent study in nonhuman primates found at least two types of dopamine neurons, saliency coding and value coding, that are activated and inhibited, respectively, by aversive events (Matsumoto and Hikosaka, 2009Matsumoto M. Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals.Nature. 2009; 459: 837-841Crossref PubMed Scopus (914) Google Scholar). Importantly, saliency-coding dopamine neurons were found preferentially in the dorsolateral part of the midbrain dopamine nuclei (i.e., mainly SNc) while reward-value-coding dopamine neurons were found in the more ventromedial part (i.e., mainly VTA). Furthermore, responses in SNc were generally earlier than those in VTA. These findings raise the possibility that inputs encoding noxious stimuli or saliency specifically innervate SNc dopamine neurons. Although efforts have been made to identify the sources of such inputs, they remain unidentified (Bromberg-Martin et al., 2010Bromberg-Martin E.S. Matsumoto M. Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting.Neuron. 2010; 68: 815-834Abstract Full Text Full Text PDF PubMed Scopus (1391) Google Scholar; Coizet et al., 2010Coizet V. Dommett E.J. Klop E.M. Redgrave P. Overton P.G. The parabrachial nucleus is a critical link in the transmission of short latency nociceptive information to midbrain dopaminergic neurons.Neuroscience. 2010; 168: 263-272Crossref PubMed Scopus (57) Google Scholar; Dommett et al., 2005Dommett E. Coizet V. Blaha C.D. Martindale J. Lefebvre V. Walton N. Mayhew J.E. Overton P.G. Redgrave P. How visual stimuli activate dopaminergic neurons at short latency.Science. 2005; 307: 1476-1479Crossref PubMed Scopus (229) Google Scholar; Jhou et al., 2009Jhou T.C. Fields H.L. Baxter M.G. Saper C.B. Holland P.C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.Neuron. 2009; 61: 786-800Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar; Matsumoto and Hikosaka, 2007Matsumoto M. Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons.Nature. 2007; 447: 1111-1115Crossref PubMed Scopus (884) Google Scholar). More generally, although the aforementioned findings indicate that dopamine neurons integrate diverse kinds of information, the mechanisms by which the firing of dopamine neurons is regulated in a behavioral context remain largely unknown (Bromberg-Martin et al., 2010Bromberg-Martin E.S. Matsumoto M. Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting.Neuron. 2010; 68: 815-834Abstract Full Text Full Text PDF PubMed Scopus (1391) Google Scholar; Lee and Tepper, 2009Lee C.R. Tepper J.M. Basal ganglia control of substantia nigra dopaminergic neurons.J. Neural Transm. Suppl. 2009; 73: 71-90PubMed Google Scholar; Sesack and Grace, 2010Sesack S.R. Grace A.A. Cortico-basal ganglia reward network: microcircuitry.Neuropsychopharmacology. 2010; 35: 27-47Crossref PubMed Scopus (723) Google Scholar). A critical step toward understanding the aforementioned questions is to know what kinds of inputs dopamine neurons in the VTA and SNc receive. Circuit-tracing experiments have been performed to address this question (Geisler et al., 2007Geisler S. Derst C. Veh R.W. Zahm D.S. Glutamatergic afferents of the ventral tegmental area in the rat.J. Neurosci. 2007; 27: 5730-5743Crossref PubMed Scopus (365) Google Scholar; Geisler and Zahm, 2005Geisler S. Zahm D.S. Afferents of the ventral tegmental area in the rat-anatomical substratum for integrative functions.J. Comp. Neurol. 2005; 490: 270-294Crossref PubMed Scopus (297) Google Scholar; Graybiel and Ragsdale, 1979Graybiel A.M. Ragsdale Jr., C.W. Fiber connections of the basal ganglia.Prog. Brain Res. 1979; 51: 237-283PubMed Google Scholar; Phillipson, 1979Phillipson O.T. Afferent projections to the ventral tegmental area of Tsai and interfascicular nucleus: a horseradish peroxidase study in the rat.J. Comp. Neurol. 1979; 187: 117-143Crossref PubMed Scopus (458) Google Scholar; Sesack and Grace, 2010Sesack S.R. Grace A.A. Cortico-basal ganglia reward network: microcircuitry.Neuropsychopharmacology. 2010; 35: 27-47Crossref PubMed Scopus (723) Google Scholar; Swanson, 2000Swanson L.W. Cerebral hemisphere regulation of motivated behavior.Brain Res. 2000; 886: 113-164Crossref PubMed Scopus (659) Google Scholar; Zahm et al., 2011Zahm D.S. Cheng A.Y. Lee T.J. Ghobadi C.W. Schwartz Z.M. Geisler S. Parsely K.P. Gruber C. Veh R.W. Inputs to the midbrain dopaminergic complex in the rat, with emphasis on extended amygdala-recipient sectors.J. Comp. Neurol. 2011; 519: 3159-3188Crossref PubMed Scopus (47) Google Scholar), but limitations of conventional tracing methods have hampered a full understanding of inputs to dopamine neurons. For example, conventional tracing cannot distinguish between dopaminergic and nondopaminergic cells (e.g., GABAergic neurons). Furthermore, SNc dopamine neurons form a thin layer and are heavily interconnected with the neighboring substantia nigra pars reticulata (SNr), and conventional tracing might label inputs to SNr in addition to SNc. Finally, there are many axons of passage through or near these structures, which may take up tracers nonspecifically. Thus, it is unclear whether neurons in a given area project to VTA or SNc and whether they actually make synaptic contacts with dopamine neurons. Electron microscopy can resolve several of these issues (e.g., Bolam and Smith, 1990Bolam J.P. Smith Y. The GABA and substance P input to dopaminergic neurones in the substantia nigra of the rat.Brain Res. 1990; 529: 57-78Crossref PubMed Scopus (229) Google Scholar; Carr and Sesack, 2000Carr D.B. Sesack S.R. Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons.J. Neurosci. 2000; 20: 3864-3873PubMed Google Scholar; Omelchenko et al., 2009Omelchenko N. Bell R. Sesack S.R. Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area.Eur. J. Neurosci. 2009; 30: 1239-1250Crossref PubMed Scopus (153) Google Scholar; Omelchenko and Sesack, 2010Omelchenko N. Sesack S.R. Periaqueductal gray afferents synapse onto dopamine and GABA neurons in the rat ventral tegmental area.J. Neurosci. Res. 2010; 88: 981-991PubMed Google Scholar; Somogyi et al., 1981Somogyi P. Bolam J.P. Totterdell S. Smith A.D. Monosynaptic input from the nucleus accumbens—ventral striatum region to retrogradely labelled nigrostriatal neurones.Brain Res. 1981; 217: 245-263Crossref PubMed Scopus (141) Google Scholar), but this technique is not suitable for a comprehensive identification of inputs. Another approach is to combine anatomical methods with electrophysiological or optogenetic techniques (Chuhma et al., 2011Chuhma N. Tanaka K.F. Hen R. Rayport S. Functional connectome of the striatal medium spiny neuron.J. Neurosci. 2011; 31: 1183-1192Crossref PubMed Scopus (202) Google Scholar; Collingridge and Davies, 1981Collingridge G.L. Davies J. The influence of striatal stimulation and putative neurotransmitters on identified neurones in the rat substantia nigra.Brain Res. 1981; 212: 345-359Crossref PubMed Scopus (91) Google Scholar; Grace and Bunney, 1985Grace A.A. Bunney B.S. Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity.Brain Res. 1985; 333: 271-284Crossref PubMed Scopus (211) Google Scholar; Lee and Tepper, 2009Lee C.R. Tepper J.M. Basal ganglia control of substantia nigra dopaminergic neurons.J. Neural Transm. Suppl. 2009; 73: 71-90PubMed Google Scholar; Xia et al., 2011Xia Y. Driscoll J.R. Wilbrecht L. Margolis E.B. Fields H.L. Hjelmstad G.O. Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area.J. Neurosci. 2011; 31: 7811-7816Crossref PubMed Scopus (160) Google Scholar). However, the validity of this approach has been called into question after these studies (Chuhma et al., 2011Chuhma N. Tanaka K.F. Hen R. Rayport S. Functional connectome of the striatal medium spiny neuron.J. Neurosci. 2011; 31: 1183-1192Crossref PubMed Scopus (202) Google Scholar; Xia et al., 2011Xia Y. Driscoll J.R. Wilbrecht L. Margolis E.B. Fields H.L. Hjelmstad G.O. Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area.J. Neurosci. 2011; 31: 7811-7816Crossref PubMed Scopus (160) Google Scholar) failed to demonstrate well-accepted direct projections from striatum to dopamine neurons in the VTA and SNc (Bolam and Smith, 1990Bolam J.P. Smith Y. The GABA and substance P input to dopaminergic neurones in the substantia nigra of the rat.Brain Res. 1990; 529: 57-78Crossref PubMed Scopus (229) Google Scholar; Collingridge and Davies, 1981Collingridge G.L. Davies J. The influence of striatal stimulation and putative neurotransmitters on identified neurones in the rat substantia nigra.Brain Res. 1981; 212: 345-359Crossref PubMed Scopus (91) Google Scholar; Grace and Bunney, 1985Grace A.A. Bunney B.S. Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity.Brain Res. 1985; 333: 271-284Crossref PubMed Scopus (211) Google Scholar; Lee and Tepper, 2009Lee C.R. Tepper J.M. Basal ganglia control of substantia nigra dopaminergic neurons.J. Neural Transm. Suppl. 2009; 73: 71-90PubMed Google Scholar; Somogyi et al., 1981Somogyi P. Bolam J.P. Totterdell S. Smith A.D. Monosynaptic input from the nucleus accumbens—ventral striatum region to retrogradely labelled nigrostriatal neurones.Brain Res. 1981; 217: 245-263Crossref PubMed Scopus (141) Google Scholar). To resolve these methodological issues, we combined the Cre/loxP gene expression system (Gong et al., 2007Gong S. Doughty M. Harbaugh C.R. Cummins A. Hatten M.E. Heintz N. Gerfen C.R. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs.J. Neurosci. 2007; 27: 9817-9823Crossref PubMed Scopus (612) Google Scholar) with rabies-virus-based transsynaptic retrograde tracing (Wickersham et al., 2007bWickersham I.R. Lyon D.C. Barnard R.J. Mori T. Finke S. Conzelmann K.K. Young J.A. Callaway E.M. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons.Neuron. 2007; 53: 639-647Abstract Full Text Full Text PDF PubMed Scopus (813) Google Scholar) to comprehensively identify monosynaptic inputs to a genetically defined neural population (Haubensak et al., 2010Haubensak W. Kunwar P.S. Cai H. Ciocchi S. Wall N.R. Ponnusamy R. Biag J. Dong H.W. Deisseroth K. Callaway E.M. et al.Genetic dissection of an amygdala microcircuit that gates conditioned fear.Nature. 2010; 468: 270-276Crossref PubMed Scopus (599) Google Scholar; Miyamichi et al., 2011Miyamichi K. Amat F. Moussavi F. Wang C. Wickersham I. Wall N.R. Taniguchi H. Tasic B. Huang Z.J. He Z. et al.Cortical representations of olfactory input by trans-synaptic tracing.Nature. 2011; 472: 191-196Crossref PubMed Scopus (371) Google Scholar; Wall et al., 2010Wall N.R. Wickersham I.R. Cetin A. De La Parra M. Callaway E.M. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus.Proc. Natl. Acad. Sci. USA. 2010; 107: 21848-21853Crossref PubMed Scopus (251) Google Scholar). This technique allowed us to identify the sources of monosynaptic inputs to VTA and SNc dopamine neurons in the entire brain. We then asked whether we can identify different sources of candidate excitatory inputs that may account for rapid activation of SNc dopamine neurons by salient events, in contrast to activation of VTA dopamine neurons by reward values, and whether there are indeed direct projections from the striatum to dopamine neurons. We show that SNc dopamine neurons receive relatively strong excitatory inputs from the somatosensory and motor cortices, as well as subthalamic nucleus (STh), whereas VTA dopamine neurons receive strong inputs from the lateral hypothalamus (LH). Furthermore, we show that neurons in the striatum project directly to VTA and SNc dopamine neurons, forming “patch” compartments in both the ventral striatum (VS) and dorsal striatum (DS). We used the modified rabies virus SADΔG-GFP(EnvA), which has two key modifications that determine the specificity of its initial infection and transsynaptic spread (Wickersham et al., 2007bWickersham I.R. Lyon D.C. Barnard R.J. Mori T. Finke S. Conzelmann K.K. Young J.A. Callaway E.M. Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons.Neuron. 2007; 53: 639-647Abstract Full Text Full Text PDF PubMed Scopus (813) Google Scholar). First, this virus is pseudotyped with an avian virus envelope protein (EnvA) and therefore cannot infect mammalian cells. In mammalian brains, the initial infection thus occurs only when a host neuron is engineered to express a cognate receptor (e.g., TVA). Second, the gene for the rabies virus envelope glycoprotein (RG), which is required for transsynaptic spread, is replaced by the gene for a fluorescent marker (enhanced green fluorescent protein; EGFP). Transsynaptic transfer thus occurs only from neurons that exogenously express RG. Our strategy was to express TVA and RG only in a genetically defined cell population (Haubensak et al., 2010Haubensak W. Kunwar P.S. Cai H. Ciocchi S. Wall N.R. Ponnusamy R. Biag J. Dong H.W. Deisseroth K. Callaway E.M. et al.Genetic dissection of an amygdala microcircuit that gates conditioned fear.Nature. 2010; 468: 270-276Crossref PubMed Scopus (599) Google Scholar; Miyamichi et al., 2011Miyamichi K. Amat F. Moussavi F. Wang C. Wickersham I. Wall N.R. Taniguchi H. Tasic B. Huang Z.J. He Z. et al.Cortical representations of olfactory input by trans-synaptic tracing.Nature. 2011; 472: 191-196Crossref PubMed Scopus (371) Google Scholar; Wall et al., 2010Wall N.R. Wickersham I.R. Cetin A. De La Parra M. Callaway E.M. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus.Proc. Natl. Acad. Sci. USA. 2010; 107: 21848-21853Crossref PubMed Scopus (251) Google Scholar). Thus, we generated adeno-associated viruses (AAVs) that express either TVA or RG (AAV5-FLEX-TVA-mCherry and AAV8-FLEX-RG, respectively). We used the transmembrane type of the TVA receptor protein (TVA950) to generate a fusion protein with a red fluorescent protein (mCherry). TVA and RG proteins were expressed under the control of a high-specificity Cre/loxP recombination system (a modified Flex switch) and different promoters (EF-1α and CAG, respectively) (Figure 1A). To visualize monosynaptic inputs to dopamine neurons, we injected AAV5-FLEX-TVA-mCherry and AAV8-FLEX-RG stereotaxically into VTA or SNc of transgenic mice that express Cre in dopamine neurons (dopamine transporter-Cre or DAT-Cre) (Bäckman et al., 2006Bäckman C.M. Malik N. Zhang Y. Shan L. Grinberg A. Hoffer B.J. Westphal H. Tomac A.C. Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus.Genesis. 2006; 44: 383-390Crossref PubMed Scopus (255) Google Scholar). After 14 days, SADΔG-GFP(EnvA) was injected into the same area and the brain was analyzed after 7 days (Figure 1B). The whole brain was sectioned at 100 μm, and every third section was processed for further analysis. The starter cells were identified based on the coexpression of TVA-mCherry and EGFP (Figures 1C and 1H; Figure S1 available online). Coexpressing neurons were found only in the injected area, while EGFP-positive neurons outside the injected area did not express TVA-mCherry, indicating that they are transsynaptically labeled neurons. We found a large number of these transsynaptically labeled neurons (Figure 1D;6.1 × 103 ± 4.2 × 103 neurons; mean ± SD, n = 12 mice), although the number of labeled neurons varied across animals, in part due to different injection volumes (Figures 1E and 1F). Nevertheless, the numbers of transsynaptically labeled neurons were roughly proportional to the numbers of starter neurons (Figure 1G). To examine the specificity of tracing, we first repeated the aforementioned procedure in mice with no Cre expression (Figure 1D, right). This resulted in much smaller numbers of EGFP-labeled neurons both outside and near the injection site (87 ± 61 neurons outside VTA or SNc and 31 ± 21 neurons in VTA or SNc; mean ± SD) compared to the aforementioned result. This small degree of labeling was likely due to inevitable contamination of the unpseudotyped rabies virus that occurred during the viral preparation. Note that these numbers should be regarded as the upper bounds of nonspecific labeling, as some of the labeled neurons are likely dopamine neurons and their inputs. Next, to examine the specificity of the initial infection and to verify that the transsynaptic spread is under the tight control of RG expression, we repeated the experiment without AAV8-FLEX-RG in DAT-Cre mice. A larger number of labeled neurons were found at the injection site, and 97% of the labeled neurons coexpressed tyrosine hydroxylase, a marker for dopamine neurons. Furthermore, very few neurons were found outside the injection site. This result confirms that the TVA proteins were expressed specifically in Cre-expressing neurons and that transsynaptic spread did not occur without RG protein. Together, these results suggest that labeled neurons outside the injection site represent monosynaptic inputs to dopamine neurons, while the injection site contains a small number of nonspecifically labeled neurons that contributed very little labeling outside the injection site (∼1.3%). In the following analysis, we will focus on labeled neurons outside the injection site. Figure 2 shows the sections obtained from two mice that were administered the selective injections into VTA and SNc (v001 and s003; see Figure 1H). Using custom software, we identified anatomical areas based on a standard mouse atlas (Franklin and Paxinos, 2008Franklin B.J. Paxinos G. The mouse brain in stereotaxic coordinates. Compact third eddition. Academic Press, San Diego, CA2008Google Scholar) using fluorescent Nissl staining; the location of each neuron was registered on the anatomical coordinate. We then counted the number of neurons in each area. To correct for the variability in the total number of neurons, the numbers were normalized by the total number of input neurons (Figure 3, left; Figure S2). We further computed the density of labeled neurons in each area by dividing the number by the area (mm2) on each section (Figure 3, right). For each group, four animals that had preferential injections into VTA or SNc were used to generate Figure 3 (v009, v001, v010, and v004 for VTA; and s001, s004, s003, and s006 for SNc; note that v008 and v007 were not included because these mice had a small number of labeled neurons). Consistent results were obtained even when we restricted our analysis to three animals with higher specificity for each group. Furthermore, we have verified that the patterns of labeling are similar at 5 days (n = 3 mice, VTA) and 9 days (n = 2 mice, VTA) after the injection of SADΔG-GFP(EnvA) compared to the main data set obtained at 7 days after injection (Pearson correlations for the mean numbers of labeled neurons across areas were r = 0.82 and 0.95 between 5 versus 7 days and 7 versus 9 days, respectively; p < 10−7 for both). This suggests that the results we report here are temporally stable and not affected by gross cell death over time.Figure 3Comparison of Input Areas between VTA and SNc Dopamine NeuronsShow full caption(Left) Number of input neurons in each area. Numbers are normalized by the total number of input neurons. Mean ± SEM (n = 4 mice).(Right) Density of input neurons in each area. Mean ± SEM. BNST, bed nucleus of stria terminalis; IPAC, interstitial nucleus of the posterior limb of the anterior commissure; Extended amygdala and substantia innominata are included in sublenticular extended amygdala (SLE).View Large Image Figure ViewerDownload Hi-res image Download (PPT) (Left) Number of input neurons in each area. Numbers are normalized by the total number of input neurons. Mean ± SEM (n = 4 mice). (Right) Density of input neurons in each area. Mean ± SEM. BNST, bed nucleus of stria terminalis; IPAC, interstitial nucleus of the posterior limb of the anterior commissure; Extended amygdala and substantia innominata are included in sublenticular extended amygdala (SLE). Across the whole brain, the most abundant labeling was found in the basal ganglia (striatum and pallidum) (Figure 3). In these areas, labeled neurons are predominantly found ipsilateral to the injection site (e.g., Figure 1D). Both for VTA- and SNc-targeted animals, labeled neurons formed continuous bands that ran from the striatum to specific hypothalamic areas (Figure 2). The densely labeled bands for VTA and SNc dopamine neurons showed rough segregation such that the areas projecting to SNc dopamine neurons were found in the more dorsal and lateral parts in this continuum, relative to those projecting to VTA dopamine neurons (Figure 2, Figure 3, Figure 4). These bands often did not reflect the boundaries of anatomically identified areas (Franklin and Paxinos, 2008Franklin B.J. Paxinos G. The mouse brain in stereotaxic coordinates. Compact third eddition. Academic Press, San Diego, CA2008Google Scholar), but the densely labeled regions included various areas in the striatum and pallidum and, more posteriorly, the basal forebrain and hypothalamus (Figure 2, Figure 3, Figure 4). In terms of numbers, the most prominent labeling was observed in the striatum partly due to its large volume, with greater emphasis on the ventral portion (nucleus accumbens [Acb] and olfactory tubercle [Tu]) in VTA-targeted mice and on the DS in SNc-targeted mice. In the amygdala, the central nucleus of the amygdala (Ce; in particular, the lateral central nucleus of amygdala [CeL]) was found to project to both VTA and SNc dopamine neurons (e.g., Figures 4D and 4E) while other amygdala regions, including the cortical amygdala, did not project much to dopamine neurons in either area. In pallidal areas, more ventral and medial structures such as the ventral pallidum (VP) and sublenticular extended amygdala (EA) project predominantly to VTA dopamine neurons, whereas more dorsal and lateral structures such as the globus pallidus (GP) and entopeduncular nucleus (EP) project predominantly to SNc dopamine neurons (Figures 4A–4C). The bed nucleus of stria terminalis (BNST; in particular, its dorsal lateral division [STLD]) projects to both VTA and SNc (Figure S6A). From the basal forebrain and hypothalamic areas, VTA dopamine neurons receive the greatest input from the LH (including the peduncular part of the lateral hypothalamus [PLH]). VTA dopamine neurons also receive inputs from scattered neurons in the diagonal band of Broca (DB) and medial and lateral preoptic areas (MPA and LPO) (Figures 3, 4A, 4D, and S3C). In these areas, the paraventricular hypothalamic nucleus (Pa) is unique in that it contains densely labeled neurons, for both VTA- and SNc-targeted cases (Figure S6B). In contrast, in SNc-targeted cases, fewer neurons were labeled in hypothalamic areas except Pa, while the STh contained a dense collection of neurons that project preferentially to SNc dopamine neurons (Figures 4D–4F). Para-STh (PSTh) and zona incerta project both to VTA and SNc dopamine neurons with a slight bias to VTA. Together, these results show that VTA and SNc dopamine" @default.
• W1997128521 created "2016-06-24" @default.
• W1997128521 creator A5007312610 @default.
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• W1997128521 date "2012-06-01" @default.
• W1997128521 modified "2023-10-16" @default.
• W1997128521 title "Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons" @default.
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