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• W3145118374 abstract "•SNr neurons project to diverse structures throughout the diencephalon and brain stem•Neuronal subsets project differentially and strongly to distinct brain stem targets•Neuronal subsets differ in their subthreshold and spiking electrophysiology•Neuronal subsets additionally form collaterals that universally target PPN and thalamus Basal ganglia play a central role in regulating behavior, but the organization of their outputs to other brain areas is incompletely understood. We investigate the largest output nucleus, the substantia nigra pars reticulata (SNr), and delineate the organization and physiology of its projection populations in mice. Using genetically targeted viral tracing and whole-brain anatomical analysis, we identify over 40 SNr targets that encompass a roughly 50-fold range of axonal densities. Retrograde tracing from the volumetrically largest targets indicates that the SNr contains segregated subpopulations that differentially project to functionally distinct brain stem regions. These subpopulations are electrophysiologically specialized and topographically organized and collateralize to common diencephalon targets, including the motor and intralaminar thalamus as well as the pedunculopontine nucleus and the midbrain reticular formation. These findings establish that SNr signaling is organized as dense, parallel outputs to specific brain stem targets concurrent with extensive collateral branches that encompass the majority of SNr axonal boutons. Basal ganglia play a central role in regulating behavior, but the organization of their outputs to other brain areas is incompletely understood. We investigate the largest output nucleus, the substantia nigra pars reticulata (SNr), and delineate the organization and physiology of its projection populations in mice. Using genetically targeted viral tracing and whole-brain anatomical analysis, we identify over 40 SNr targets that encompass a roughly 50-fold range of axonal densities. Retrograde tracing from the volumetrically largest targets indicates that the SNr contains segregated subpopulations that differentially project to functionally distinct brain stem regions. These subpopulations are electrophysiologically specialized and topographically organized and collateralize to common diencephalon targets, including the motor and intralaminar thalamus as well as the pedunculopontine nucleus and the midbrain reticular formation. These findings establish that SNr signaling is organized as dense, parallel outputs to specific brain stem targets concurrent with extensive collateral branches that encompass the majority of SNr axonal boutons. Motor actions are the consequence of neuronal computations in circuits that are distributed broadly across the nervous system (Grillner, 2006Grillner S. Biological pattern generation: the cellular and computational logic of networks in motion.Neuron. 2006; 52: 751-766Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar; Kuypers, 2011Kuypers H.G.J.M. Anatomy of the Descending Pathways.in: Terjung R. Comprehensive Physiology. 2011https://doi.org/10.1002/cphy.cp010213Crossref Google Scholar; Towe and Luschei, 2013Towe A.L. Luschei E.S. Motor Coordination. Springer, 2013Google Scholar). Individual components of the motor system have been studied extensively, with prominent attention given to the cerebral cortex, basal ganglia, and cerebellum. These studies have yielded deep insights into local signaling within each structure (Klaus et al., 2019Klaus A. Alves da Silva J. Costa R.M. What, If, and When to Move: Basal Ganglia Circuits and Self-Paced Action Initiation.Annu. Rev. Neurosci. 2019; 42: 459-483Crossref PubMed Scopus (43) Google Scholar; Peters et al., 2017Peters A.J. Liu H. Komiyama T. Learning in the Rodent Motor Cortex.Annu. Rev. Neurosci. 2017; 40: 77-97Crossref PubMed Scopus (37) Google Scholar; Raymond and Medina, 2018Raymond J.L. Medina J.F. Computational Principles of Supervised Learning in the Cerebellum.Annu. Rev. Neurosci. 2018; 41: 233-253Crossref PubMed Scopus (46) Google Scholar). However, the organization and circuit mechanisms that connect nodes of the motor system to each other remain largely unknown. Here we investigate the circuit basis by which outputs of the basal ganglia impinge on the broader motor system. Basal ganglia form an essential component of the volitional motor system and mediate fundamental aspects of behavioral regulation and learning (Alexander et al., 1990Alexander G.E. Crutcher M.D. DeLong M.R. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions.Prog. Brain Res. 1990; 85: 119-146Crossref PubMed Google Scholar; Hikosaka et al., 2014Hikosaka O. Kim H.F. Yasuda M. Yamamoto S. Basal ganglia circuits for reward value-guided behavior.Annu. Rev. Neurosci. 2014; 37: 289-306Crossref PubMed Scopus (112) Google Scholar; Jin and Costa, 2015Jin X. Costa R.M. Shaping action sequences in basal ganglia circuits.Curr. Opin. Neurobiol. 2015; 33: 188-196Crossref PubMed Scopus (61) Google Scholar; Turner and Desmurget, 2010Turner R.S. Desmurget M. Basal ganglia contributions to motor control: a vigorous tutor.Curr. Opin. Neurobiol. 2010; 20: 704-716Crossref PubMed Scopus (215) Google Scholar). Disruption of the basal ganglia network underlies common movement disorders, including Parkinson’s disease and Tourette syndrome (Mink, 2001Mink J.W. Basal ganglia dysfunction in Tourette’s syndrome: a new hypothesis.Pediatr. Neurol. 2001; 25: 190-198Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar; Nelson and Kreitzer, 2014Nelson A.B. Kreitzer A.C. Reassessing models of basal ganglia function and dysfunction.Annu. Rev. Neurosci. 2014; 37: 117-135Crossref PubMed Scopus (146) Google Scholar), and impairs control of the limbs, trunk, and facial, oral, and vocal musculature (DeLong and Georgopoulos, 2011DeLong M.R. Georgopoulos A.P. Motor Functions of the Basal Ganglia.in: Terjung R. Comprehensive Physiology. 2011https://doi.org/10.1002/cphy.cp010221Crossref Google Scholar; Robbins et al., 1986Robbins J.A. Logemann J.A. Kirshner H.S. Swallowing and speech production in Parkinson’s disease.Ann. Neurol. 1986; 19: 283-287Crossref PubMed Google Scholar; Visser and Bloem, 2005Visser J.E. Bloem B.R. Role of the basal ganglia in balance control.Neural Plast. 2005; 12 (discussion 263–272): 161-174Crossref PubMed Scopus (81) Google Scholar). Moreover, basal ganglia dysfunction has also been implicated in cognitive and affective control. Neurons in the volumetrically largest output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr), emit well-established projections to the superior colliculus, motor and intralaminar thalamic nuclei, and the pedunculopontine nucleus (PPN) (Alexander et al., 1990Alexander G.E. Crutcher M.D. DeLong M.R. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions.Prog. Brain Res. 1990; 85: 119-146Crossref PubMed Google Scholar; Hikosaka, 2007bHikosaka O. GABAergic output of the basal ganglia.Prog. Brain Res. 2007; 160: 209-226Crossref PubMed Scopus (101) Google Scholar; Mena-Segovia et al., 2004Mena-Segovia J. Bolam J.P. Magill P.J. Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family?.Trends Neurosci. 2004; 27: 585-588Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). However, the extent to which projections to well-established targets arise from the same or segregated neurons is debated (Anderson and Yoshida, 1977Anderson M. Yoshida M. Electrophysiological evidence for branching nigral projections to the thalamus and the superior colliculus.Brain Res. 1977; 137: 361-364Crossref PubMed Scopus (0) Google Scholar; Beckstead and Frankfurter, 1982Beckstead R.M. Frankfurter A. The distribution and some morphological features of substantia nigra neurons that project to the thalamus, superior colliculus and pedunculopontine nucleus in the monkey.Neuroscience. 1982; 7: 2377-2388Crossref PubMed Scopus (107) Google Scholar; Deniau et al., 1977Deniau J.M. Hammond-Le Guyader C. Feger J. McKenzie J.S. Bilateral projection of nigro-collicular neurons: An electrophysiological analysis in the rat.Neurosci. Lett. 1977; 5: 45-50Crossref PubMed Google Scholar; Parent et al., 1983Parent A. Mackey A. Smith Y. Boucher R. The output organization of the substantia nigra in primate as revealed by a retrograde double labeling method.Brain Res. Bull. 1983; 10: 529-537Crossref PubMed Scopus (83) Google Scholar). SNr neurons exhibit heterogeneous firing responses during behavior (DeLong et al., 1983DeLong M.R. Crutcher M.D. Georgopoulos A.P. Relations between movement and single cell discharge in the substantia nigra of the behaving monkey.J. Neurosci. 1983; 3: 1599-1606Crossref PubMed Google Scholar; Gulley et al., 2002Gulley J.M. Kosobud A.E. Rebec G.V. Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task.Neuroscience. 2002; 111: 337-349Crossref PubMed Scopus (36) Google Scholar; Hikosaka and Wurtz, 1983Hikosaka O. Wurtz R.H. Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades.J. Neurophysiol. 1983; 49: 1230-1253Crossref PubMed Scopus (0) Google Scholar; Jin and Costa, 2010Jin X. Costa R.M. Start/stop signals emerge in nigrostriatal circuits during sequence learning.Nature. 2010; 466: 457-462Crossref PubMed Scopus (319) Google Scholar), suggesting that the nucleus might contain functionally distinct projection types. Moreover, evidence from past studies indicates that the SNr projects to additional domains of the brain stem and diencephalon (Cebrián et al., 2005Cebrián C. Parent A. Prensa L. Patterns of axonal branching of neurons of the substantia nigra pars reticulata and pars lateralis in the rat.J. Comp. Neurol. 2005; 492: 349-369Crossref PubMed Scopus (60) Google Scholar; Chronister et al., 1988Chronister R.B. Walding J.S. Aldes L.D. Marco L.A. Interconnections between substantia nigra reticulata and medullary reticular formation.Brain Res. Bull. 1988; 21: 313-317Crossref PubMed Google Scholar; Gervasoni et al., 2000Gervasoni D. Peyron C. Rampon C. Barbagli B. Chouvet G. Urbain N. Fort P. Luppi P.H. Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons.J. Neurosci. 2000; 20: 4217-4225Crossref PubMed Google Scholar; Pollak Dorocic et al., 2014Pollak Dorocic I. Fürth D. Xuan Y. Johansson Y. Pozzi L. Silberberg G. Carlén M. Meletis K. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei.Neuron. 2014; 83: 663-678Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar; Schneider et al., 1985Schneider J.S. Manetto C. Lidsky T.I. Substantia nigra projection to medullary reticular formation: relevance to oculomotor and related motor functions in the cat.Neurosci. Lett. 1985; 62: 1-6Crossref PubMed Google Scholar; Takakusaki et al., 2003Takakusaki K. Habaguchi T. Ohtinata-Sugimoto J. Saitoh K. Sakamoto T. Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction.Neuroscience. 2003; 119: 293-308Crossref PubMed Scopus (264) Google Scholar; Von Krosigk and Smith, 1991Von Krosigk M. Smith A.D. Descending Projections from the Substantia Nigra and Retrorubral Field to the Medullary and Pontomedullary Reticular Formation.Eur. J. Neurosci. 1991; 3: 260-273Crossref PubMed Google Scholar; Yasui et al., 1992Yasui Y. Nakano K. Nakagawa Y. Kayahara T. Shiroyama T. Mizuno N. Non-dopaminergic neurons in the substantia nigra project to the reticular formation around the trigeminal motor nucleus in the rat.Brain Res. 1992; 585: 361-366Crossref PubMed Scopus (37) Google Scholar). The lack of systematic circuit mapping has hindered comprehensive identification of SNr target regions, and it remains unknown whether the SNr contains distinct classes of projection neurons. To delineate the circuit logic of basal ganglia output signaling and projection cell types in the SNr, we first address the mesoscopic organization of SNr projections and determine the electrophysiological properties of SNr neurons. (1) Which brain regions are the major targets of SNr axonal projections? (2) Do different electrophysiological properties of SNr cells correspond to distinct output populations? (3) Do neurons in the SNr project equally to all major targets, as expected for a global hub-like architecture (Figure 1A), or does the SNr contain segregated projection populations that project preferentially to different targets (Figure 1B)? To address these questions, we combine state-of-the-art viral circuit mapping; high-resolution, whole-brain optical scanning; and electrophysiological recordings of identified projection neurons. To identify the brain regions targeted by basal ganglia outputs, we mapped SNr axonal projections and synaptic terminals across the brain using genetically restricted viral tracing. The predominant population of neurons in the SNr is parvalbumin-positive GABAergic neurons (González-Hernández and Rodríguez, 2000González-Hernández T. Rodríguez M. Compartmental organization and chemical profile of dopaminergic and GABAergic neurons in the substantia nigra of the rat.J. Comp. Neurol. 2000; 421: 107-135Crossref PubMed Google Scholar). We verified that 86.9% ± 1.0% of GABAergic SNr neurons express parvalbumin (14,901 neurons, 39 sections, 4 mice) (Figures 1C and S1A–S1C) throughout the rostral-caudal extent of the nucleus (Figure S1B). To label the axons and presynaptic boutons arising from this population, membrane-bound green fluorescent protein (mGFP) and synaptophysin-mRuby were expressed virally (AAV-DJ-hSyn-FLEX-mGFP-2A-synaptophysin-mRuby) in SNr neurons in parvalbumin-Cre (PV-Cre) mice (Figure 1D). High-resolution, whole-brain slide scanning of SNr projections reveals axon terminations that extend over 7 mm, from the anterior thalamus to the caudal brain stem (Figures 1E–1L). In the diencephalon, SNr targets include major motor (ventromedial [VM] and ventroanterior [VA]) and intralaminar/midline (mediodorsal [MD], centro-lateral/medial [CL/CM], and parafascicular [Pf]) thalamic nuclei (Figures 1E–1G), as in other species (Cebrián et al., 2005Cebrián C. Parent A. Prensa L. Patterns of axonal branching of neurons of the substantia nigra pars reticulata and pars lateralis in the rat.J. Comp. Neurol. 2005; 492: 349-369Crossref PubMed Scopus (60) 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; Utter and Basso, 2008Utter A.A. Basso M.A. The basal ganglia: an overview of circuits and function.Neurosci. Biobehav. Rev. 2008; 32: 333-342Crossref PubMed Scopus (119) Google Scholar), as well as the thalamic reticular nucleus, zona incerta (ZI), fields of Forel, and prerubral field (Figures S2A–S2G). A greater number of targets are observed in the brain stem. Beyond well-established projections to the superior colliculus and PPN (Hikosaka, 2007bHikosaka O. GABAergic output of the basal ganglia.Prog. Brain Res. 2007; 160: 209-226Crossref PubMed Scopus (101) Google Scholar; Figures 1H and 1I), extensive SNr projections target volumetrically large domains of the midbrain reticular formation (MidRF), pontine reticular formation (PNo), and medullary reticular formation (Med; subdivisions parvicellular [PcRT] and intermediate [IRT]) as well as 17 small premotor nuclei (Figures 1H–1K, S2H–S2K, and S3). Downstream brain stem targets span regions that have been implicated in oculomotor and head orientation (superior colliculus, INC/MA3/Su3; Fukushima, 1987Fukushima K. The interstitial nucleus of Cajal and its role in the control of movements of head and eyes.Prog. Neurobiol. 1987; 29: 107-192Crossref PubMed Google Scholar; May et al., 2019May P.J. Billig I. Gamlin P.D. Quinet J. Central mesencephalic reticular formation control of the near response: lens accommodation circuits.J. Neurophysiol. 2019; 121: 1692-1703Crossref PubMed Scopus (6) Google Scholar), orofacial sensorimotor systems (Med, Su5, P5, and L5; Kolta et al., 2010Kolta A. Morquette P. Lavoie R. Arsenault I. Verdier D. Modulation of rhythmogenic properties of trigeminal neurons contributing to the masticatory CPG.Prog. Brain Res. 2010; 187: 137-148Crossref PubMed Scopus (0) Google Scholar; McElvain et al., 2018McElvain L.E. Friedman B. Karten H.J. Svoboda K. Wang F. Deschênes M. Kleinfeld D. Circuits in the rodent brainstem that control whisking in concert with other orofacial motor actions.Neuroscience. 2018; 368: 152-170Crossref PubMed Scopus (22) Google Scholar), hindlimb control (PNo; Brownstone and Chopek, 2018Brownstone R.M. Chopek J.W. Reticulospinal Systems for Tuning Motor Commands.Front. Neural Circuits. 2018; 12: 30Crossref PubMed Scopus (30) Google Scholar), and neuromodulation (PPN and dorsal raphe [DR]) and nuclei implicated in heterogeneous or unknown functions; i.e., the precuneiform nucleus, red nucleus, subdivisions of the periaqueductal gray (PAG), and parabrachial nuclei (Figures S2 and S3). We identified significant SNr projections to 42 distinct regions (Figure 2A). GABAergic neurons throughout the extent of SNr express parvalbumin, encoded by the gene Pvalb (Figures 1C and S1), and GAD2 mRNA (Figure S1C), with large neurons in the dorsolateral SNr highly expressing parvalbumin and smaller neurons in the VM SNr expressing lower levels (Figure S1A; González-Hernández et al., 2001González-Hernández T. Barroso-Chinea P. Acevedo A. Salido E. Rodríguez M. Colocalization of tyrosine hydroxylase and GAD65 mRNA in mesostriatal neurons.Eur. J. Neurosci. 2001; 13: 57-67Crossref PubMed Scopus (49) Google Scholar; González-Hernández and Rodríguez, 2000González-Hernández T. Rodríguez M. Compartmental organization and chemical profile of dopaminergic and GABAergic neurons in the substantia nigra of the rat.J. Comp. Neurol. 2000; 421: 107-135Crossref PubMed Google Scholar). To test whether the smaller percentage of parvalbumin-negative SNr GABAergic neurons project to distinct downstream targets, we performed additional axonal tracing from the SNr in VGAT-Cre mice (Figures S2 and S3). Whole-brain analysis revealed a comparable projection pattern from the SNr in VGAT-Cre and PV-Cre mice (Figures S2L and S2M). Across the 42 downstream targets of the SNr in the diencephalon and brain stem, the density of SNr bouton innervation spans a continuous range over more than one and a half orders of magnitude (Figure 2A, left). When we account for the volume of downstream structures (Figure 2A, center), the total SNr bouton output is enriched in a limited set of structures, including the VM thalamus, PPN, and dorsal zona incerta—6.1%, 5.8%, and 4.6% of the total SNr output, respectively. Nearly two-thirds of the output from the SNr targets the brain stem reticular formations and the colliculi (33.9% across the MidRF, PNo, and PcRT/IRT and 30.9% across the central superior colliculus [CSC], lateral superior colliculus [LSC], medial superior colliculus [MSC], and inferior colliculus [IC]), whereas the remaining 32 structures each receive less than 2% of the total bouton output (Figures 2A, right, and 2D). A quantitative analysis shows that the probability density function for the axonal density is roughly exponentially distributed across the major fraction of SNr targets until a plateau is reached (black scale, Figure 2B). The plateau corresponds to innervation of the densest targets. These targets comprise the well-established SNr targets (i.e., the VA and VM motor thalamus, PPN, and superior colliculus; Figures 2B and 2C); however, the vast majority of total SNr output spans areas outside of these targets (Figure 2D). The SNr targets an expansive and diverse set of anatomical substrates (Figures 2A, S2, and S3) through a continuum of dense-to-sparse projections (Figures 2A–2C). The major fraction of total output is concentrated in several large brain stem regions and, to a lesser extent, the zona incerta and motor thalamus (Figure 2D). Do SNr neurons have diverse intrinsic electrophysiological properties? The spiking responses of SNr neurons during behavior include increases and decreases in rate across broad ranges and variable durations (Gulley et al., 1999Gulley J.M. Kuwajima M. Mayhill E. Rebec G.V. Behavior-related changes in the activity of substantia nigra pars reticulata neurons in freely moving rats.Brain Res. 1999; 845: 68-76Crossref PubMed Scopus (44) Google Scholar; Hikosaka and Wurtz, 1983Hikosaka O. Wurtz R.H. Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades.J. Neurophysiol. 1983; 49: 1230-1253Crossref PubMed Scopus (0) Google Scholar; Jin and Costa, 2010Jin X. Costa R.M. Start/stop signals emerge in nigrostriatal circuits during sequence learning.Nature. 2010; 466: 457-462Crossref PubMed Scopus (319) Google Scholar). It is unknown whether this heterogeneity arises from different synaptic inputs through afferents or network interactions or a spectrum of electrophysiological properties intrinsic to SNr neurons. To assess the firing properties across SNr neurons, we first performed whole-cell patch-clamp recordings from SNr neurons in young adult mouse midbrain slices. Across the population, neurons (120 cells from 14 mice) exhibited a capacity for highly regular and tonic firing (Atherton and Bevan, 2005Atherton J.F. Bevan M.D. Ionic mechanisms underlying autonomous action potential generation in the somata and dendrites of GABAergic substantia nigra pars reticulata neurons in vitro.J. Neurosci. 2005; 25: 8272-8281Crossref PubMed Scopus (109) Google Scholar) (Figure 3A), rapid action potential kinetics (Figure 3B), and sustained, high-rate activity (Figure 3C). Most critical, SNr firing responses to depolarizing inputs are highly linear (R2 = 0.99 ± 0.01) (Figure 3C). The limited adaptation and linearity of the neuronal input-output relation is consistent with open-loop drive for a motor system (Åström and Murray, 2008Åström K.J. Murray R.M. Feedback systems: an introduction for scientists and engineers. Princeton University Press, 2008Crossref Google Scholar), akin to linear neuronal and synaptic properties common in brain stem sensorimotor networks (Kolkman et al., 2011Kolkman K.E. McElvain L.E. du Lac S. Diverse precerebellar neurons share similar intrinsic excitability.J. Neurosci. 2011; 31: 16665-16674Crossref PubMed Scopus (16) Google Scholar; McElvain et al., 2010McElvain L.E. Bagnall M.W. Sakatos A. du Lac S. Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses.Neuron. 2010; 68: 763-775Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) and unlike forebrain projection neurons. In contrast, responses to hyperpolarizing inputs are non-linear, and the capacity for post-inhibitory rebound firing varied significantly across the population (Figure 3D). The broad continuum found for each electrophysiological property (e.g., gain, firing rate ranges, and rebound kinetics) can differentially tune the firing capabilities of individual neurons in the SNr. We next ascertained how the remarkable diversity of SNr cellular properties maps onto specific anatomical projection targets. The large brain stem targets of the SNr have been implicated in disparate behavioral functions, involving distinct body parts and muscle groups. Do distinct SNr neuron pools that project to different downstream effector regions have specialized electrophysiological properties? To test this possibility, we first injected each of the large brainstem regions (Figure 2A, center) with a fluorescent retrograde tracer and targeted whole-cell recordings to labeled projection neurons (Figure 4A). In the hindbrain, the large SNr targets are the Med (i.e., subdivisions PcRT/IRT), PNo, and DR (Figures 1I–1K). Large midbrain targets of the SNr are the IC and superior colliculus (SC) (Figure 1H). Three medial-lateral domains of the SC were treated separately in light of the spatial specificity of their visual and somatosensory inputs (Comoli et al., 2012Comoli E. Das Neves Favaro P. Vautrelle N. Leriche M. Overton P.G. Redgrave P. Segregated anatomical input to sub-regions of the rodent superior colliculus associated with approach and defense.Front. Neuroanat. 2012; 6: 9Crossref PubMed Scopus (77) Google Scholar; Dräger and Hubel, 1976Dräger U.C. Hubel D.H. Topography of visual and somatosensory projections to mouse superior colliculus.J. Neurophysiol. 1976; 39: 91-101Crossref PubMed Google Scholar) and topographical organization of collicular output projections from the LSC, CSC, and MSC (Dean et al., 1988Dean P. Redgrave P. Mitchell I.J. Organisation of efferent projections from superior colliculus to brainstem in rat: evidence for functional output channels.Prog. Brain Res. 1988; 75: 27-36Crossref PubMed Scopus (36) Google Scholar; Redgrave et al., 1987aRedgrave P. Mitchell I.J. Dean P. Descending projections from the superior colliculus in rat: a study using orthograde transport of wheatgerm-agglutinin conjugated horseradish peroxidase.Exp. Brain Res. 1987; 68: 147-167Crossref PubMed Google Scholar, Redgrave et al., 1987bRedgrave P. Mitchell I.J. Dean P. Further evidence for segregated output channels from superior colliculus in rat: ipsilateral tecto-pontine and tecto-cuneiform projections have different cells of origin.Brain Res. 1987; 413: 170-174Crossref PubMed Google Scholar; Wang and Redgrave, 1997Wang S. Redgrave P. Microinjections of muscimol into lateral superior colliculus disrupt orienting and oral movements in the formalin model of pain.Neuroscience. 1997; 81: 967-988Crossref PubMed Scopus (0) Google Scholar; Yasui et al., 1994Yasui Y. Tsumori T. Ando A. Domoto T. Kayahara T. Nakano K. Descending projections from the superior colliculus to the reticular formation around the motor trigeminal nucleus and the parvicellular reticular formation of the medulla oblongata in the rat.Brain Res. 1994; 656: 420-426Crossref PubMed Scopus (39) Google Scholar; Figure S4). We find that SNr neurons projecting to different large brain stem regions exhibit notable electrophysiological specializations (4–7 mice per target; see Figure S5 for injection parameters). Projections to the colliculi arise from neuronal pools with different signaling capabilities. Neurons that project to the LSC and CSC have a relatively rapid rise and fall of their action potential, as seen by plotting its derivative, dV/dt, versus the amplitude of the transmembrane potential, V (Figure 4B, left blue and green curves), and high spontaneous and maximum firing ranges (Figures 4C and 4D). In contrast, projections to the MSC and IC arise from relatively slower neuronal pools (Figures 4B–4D). SNr projections to hindbrain targets exhibit electrophysiological differences such that projections to the PNo and Med exhibit a rapid rise and fall to their action potential and high spike rates (Figures 4B–4D). In contrast, neurons projecting to the DR exhibit slow action potentials, low firing rates, and long time constants and comprise the slowest projection population in the SNr (Figures 4B–4D). Rather than spanning the full diversity in the SNr, the intrinsic parameters of each of these projection populations span a restricted range (Figures 4D, S5C, and S6). This shows that different projection populations have specific functional properties. Neurons in the SNr that project to brain stem areas span a range of post-inhibitory rebound firing capabilities. Robust non-linear rebound firing responses to hyperpolarization are greatest in neurons projecting to the Med and IC, which exhibited bursting up to hundreds of spikes per second and averaged 69 ± 15 Hz and 58 ± 11 Hz, respectively (Figure 4E). In contrast, transient and sustained rebound firing of other projection populations is modest, and neurons projecting to the DR exhibit the lowest capacity for rebound (Figures 4E). Thus, rather than each projection population spanning the full continuum of electrophysiological properties, projections to large brain stem areas arise from subpopulations of SNr neurons whose properties are tuned differentially. SNr-brain stem projection neurons cluster spatially in the SNr (Figure 4F) and form a spatial continuum of electrophysiological properties (Figure S6C). Projection neurons that exhibit slower active and passive properties are concentrated in the medial portion of the nucleus (Figure S6C), which overlaps with terminal fields from associative striatal regions. Slow neurons are additionally located in a small cluster at the dorsal-most extreme portion of the SNr, which extends in the substantia nigra lateralis (SNl) and overlaps with terminal fields from the auditory striatum (Deniau et al., 1996Deniau J.M. Menetrey A. Charpier S. The lamellar organization of the rat substantia nigra pars reticulata: segregated patterns of striatal afferents and relationship to the topography of corticostriatal projections.Neuroscience. 1996; 73: 761-781Crossref PubMed Scopus (128) Google Scholar; Figure 4F). In contrast, rapidly responding projection neurons occupy the lateral half of the SNr (Figures 4F and S6), where sensorimotor striatal afferents terminate (Deniau et al., 1996Deniau J.M. Menetrey A. Charpier S. The lamellar organization of the rat substantia nigra pars reticulata: segregated patterns of striatal afferents and relationship to the topography of corticostriatal projections.Neuroscience. 1996; 73: 761-781Crossref PubMed Scopus (128) Google Scholar), positioning differen" @default.
• W3145118374 created "2021-04-13" @default.
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• W3145118374 date "2021-05-01" @default.
• W3145118374 modified "2023-10-18" @default.
• W3145118374 title "Specific populations of basal ganglia output neurons target distinct brain stem areas while collateralizing throughout the diencephalon" @default.
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