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• W2034192215 abstract "•Midbrain nMLF neurons make direct excitatory connections to spinal motoneurons (Mns)•Mns exhibit systematic differences in membrane time constants (tau)•Tonic nMLF input exploits tau to selectively recruit Mns by temporal summation•nMLF, Mn, and behavioral responses to light stimuli support the phenomenon’s utility Motor responses of varying intensities rely on descending commands to heterogeneous pools of motoneurons. In vertebrates, numerous sources of descending excitatory input provide systematically more drive to progressively less excitable spinal motoneurons. While this presumably facilitates simultaneous activation of motor pools, it is unclear how selective patterns of recruitment could emerge from inputs weighted this way. Here, using in vivo electrophysiological and imaging approaches in larval zebrafish, we find that, despite weighted excitation, more excitable motoneurons are preferentially activated by a midbrain reticulospinal nucleus by virtue of longer membrane time constants that facilitate temporal summation of tonic drive. We confirm the utility of this phenomenon by assessing the activity of the midbrain and motoneuron populations during a light-driven behavior. Our findings demonstrate that weighted descending commands can generate selective motor responses by exploiting systematic differences in the biophysical properties of target motoneurons and their relative sensitivity to tonic input. Motor responses of varying intensities rely on descending commands to heterogeneous pools of motoneurons. In vertebrates, numerous sources of descending excitatory input provide systematically more drive to progressively less excitable spinal motoneurons. While this presumably facilitates simultaneous activation of motor pools, it is unclear how selective patterns of recruitment could emerge from inputs weighted this way. Here, using in vivo electrophysiological and imaging approaches in larval zebrafish, we find that, despite weighted excitation, more excitable motoneurons are preferentially activated by a midbrain reticulospinal nucleus by virtue of longer membrane time constants that facilitate temporal summation of tonic drive. We confirm the utility of this phenomenon by assessing the activity of the midbrain and motoneuron populations during a light-driven behavior. Our findings demonstrate that weighted descending commands can generate selective motor responses by exploiting systematic differences in the biophysical properties of target motoneurons and their relative sensitivity to tonic input. All movements must be executed with varying degrees of precision and strength. Our best understanding of how graded movements are produced arises from studies of mammalian hindlimb motoneurons, where increases in movement intensity are accomplished by the addition of larger, less excitable motor units capable of generating more powerful muscle contractions (Burke, 1979Burke R.E. The role of synaptic organization in the control of motor unit activity during movement.Prog. Brain Res. 1979; 50: 61-67Crossref PubMed Scopus (20) Google Scholar, Cope and Pinter, 1995Cope T.C. Pinter M.J. The size principle: Still working after all these years.News Physiol. Sci. 1995; 10: 280-286Google Scholar, Enoka and Stuart, 1984Enoka R.M. Stuart D.G. Henneman Size Principle - Current Issues.Trends Neurosci. 1984; 7: 226-228Abstract Full Text PDF Scopus (48) Google Scholar, Heckman and Enoka, 2012Heckman C.J. Enoka R.M. Motor unit.Compr. Physiol. 2012; 2: 2629-2682PubMed Google Scholar, Mendell, 2005Mendell L.M. The size principle: a rule describing the recruitment of motoneurons.J. Neurophysiol. 2005; 93: 3024-3026Crossref PubMed Scopus (24) Google Scholar). The appropriate recruitment of these motor units relies on descending inputs, whose activity generates motor responses matched to behavioral demands (Alstermark and Isa, 2012Alstermark B. Isa T. Circuits for skilled reaching and grasping.Annu. Rev. Neurosci. 2012; 35: 559-578Crossref PubMed Scopus (150) Google Scholar, Drew et al., 2004Drew T. Prentice S. Schepens B. Cortical and brainstem control of locomotion.Prog. Brain Res. 2004; 143: 251-261Crossref PubMed Scopus (264) Google Scholar, Dubuc et al., 2008Dubuc R. Brocard F. Antri M. Fénelon K. Gariépy J.F. Smetana R. Ménard A. Le Ray D. Viana Di Prisco G. Pearlstein E. et al.Initiation of locomotion in lampreys.Brain Res. Brain Res. Rev. 2008; 57: 172-182Crossref PubMed Scopus (121) Google Scholar, Le Ray et al., 2011Le Ray D. Juvin L. Ryczko D. Dubuc R. Chapter 4—supraspinal control of locomotion: the mesencephalic locomotor region.Prog. Brain Res. 2011; 188: 51-70Crossref PubMed Scopus (56) Google Scholar, Lemon, 2008Lemon R.N. Descending pathways in motor control.Annu. Rev. Neurosci. 2008; 31: 195-218Crossref PubMed Scopus (922) Google Scholar). Studies of a variety of descending inputs have revealed that less excitable hindlimb motoneurons receive greater effective excitatory synaptic input than more excitable ones (Binder et al., 1998Binder M.D. Robinson F.R. Powers R.K. Distribution of effective synaptic currents in cat triceps surae motoneurons. VI. Contralateral pyramidal tract.J. Neurophysiol. 1998; 80: 241-248PubMed Google Scholar, Burke and Rymer, 1976Burke R.E. Rymer W.Z. Relative strength of synaptic input from short-latency pathways to motor units of defined type in cat medial gastrocnemius.J. Neurophysiol. 1976; 39: 447-458PubMed Google Scholar, Grillner et al., 1970Grillner S. Hongo T. Lund S. The vestibulospinal tract. Effects on alpha-motoneurones in the lumbosacral spinal cord in the cat.Exp. Brain Res. 1970; 10: 94-120Crossref PubMed Scopus (236) Google Scholar, Grillner et al., 1971Grillner S. Hongo T. Lund S. Convergent effects on alpha motoneurones from the vestibulospinal tract and a pathway descending in the medial longitudinal fasciculus.Exp. Brain Res. 1971; 12: 457-479Crossref PubMed Scopus (86) Google Scholar, Powers et al., 1993Powers R.K. Robinson F.R. Konodi M.A. Binder M.D. Distribution of rubrospinal synaptic input to cat triceps surae motoneurons.J. Neurophysiol. 1993; 70: 1460-1468PubMed Google Scholar, Westcott et al., 1995Westcott S.L. Powers R.K. Robinson F.R. Binder M.D. Distribution of vestibulospinal synaptic input to cat triceps surae motoneurons.Exp. Brain Res. 1995; 107: 1-8Crossref PubMed Scopus (20) Google Scholar). One unresolved issue that has been technically difficult to address in vivo is how weighted descending inputs optimized for synchronous activation of motor pools could generate differential activation of spinal motoneurons, as required for gradations in movement intensity. Here, we address this issue by examining the descending control of axial motor pools in larval zebrafish. As in all vertebrates, in zebrafish larvae, descending commands exert differential control of movement intensity, from powerful escape responses to precise capture maneuvers (Borla et al., 2002Borla M.A. Palecek B. Budick S. O’Malley D.M. Prey capture by larval zebrafish: evidence for fine axial motor control.Brain Behav. Evol. 2002; 60: 207-229Crossref PubMed Scopus (107) Google Scholar, Eaton et al., 1984Eaton R.C. Nissanov J. Wieland C.M. Differential activation of Mauthner and non-Mauthner startle circuits in the zebrafish - implications for functional substitution.J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 1984; 155: 813-820Crossref Scopus (75) Google Scholar, Gahtan et al., 2005Gahtan E. Tanger P. Baier H. Visual prey capture in larval zebrafish is controlled by identified reticulospinal neurons downstream of the tectum.J. Neurosci. 2005; 25: 9294-9303Crossref PubMed Scopus (231) Google Scholar, Liu and Fetcho, 1999Liu K.S. Fetcho J.R. Laser ablations reveal functional relationships of segmental hindbrain neurons in zebrafish.Neuron. 1999; 23: 325-335Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar). To do so, they utilize identified spinal motoneurons organized from ventral to dorsal according to their size, excitability, target musculature, and sequence of recruitment (McLean et al., 2007McLean D.L. Fan J. Higashijima S. Hale M.E. Fetcho J.R. A topographic map of recruitment in spinal cord.Nature. 2007; 446: 71-75Crossref PubMed Scopus (274) Google Scholar, Menelaou and McLean, 2012Menelaou E. McLean D.L. A gradient in endogenous rhythmicity and oscillatory drive matches recruitment order in an axial motor pool.J. Neurosci. 2012; 32: 10925-10939Crossref PubMed Scopus (65) Google Scholar). Specifically, the ventral-most cells in the pool are the most excitable and are recruited first. This topographic pattern of recruitment provides a unique opportunity to examine how descending inputs interact with a heterogeneously excitable motor pool to generate appropriately graded actions. To this end, we focused on descending inputs arising from the nucleus of the medial longitudinal fasciculus (nMLF), a spatially compact, readily identifiable source of reticulospinal drive implicated in visuomotor behaviors (Gahtan and O’Malley, 2003Gahtan E. O’Malley D.M. Visually guided injection of identified reticulospinal neurons in zebrafish: a survey of spinal arborization patterns.J. Comp. Neurol. 2003; 459: 186-200Crossref PubMed Scopus (60) Google Scholar, Gahtan et al., 2005Gahtan E. Tanger P. Baier H. Visual prey capture in larval zebrafish is controlled by identified reticulospinal neurons downstream of the tectum.J. Neurosci. 2005; 25: 9294-9303Crossref PubMed Scopus (231) Google Scholar, Kimmel et al., 1982Kimmel C.B. Powell S.L. Metcalfe W.K. Brain neurons which project to the spinal cord in young larvae of the zebrafish.J. Comp. Neurol. 1982; 205: 112-127Crossref PubMed Scopus (194) Google Scholar, Orger et al., 2008Orger M.B. Kampff A.R. Severi K.E. Bollmann J.H. Engert F. Control of visually guided behavior by distinct populations of spinal projection neurons.Nat. Neurosci. 2008; 11: 327-333Crossref PubMed Scopus (186) Google Scholar). We demonstrate that the preferential recruitment of more excitable motoneurons can be achieved by weighted drive from an identified nMLF neuron to the axial motor pool, because commensurate differences in membrane time constants facilitate the temporal summation of tonic inputs. We then explore the activity patterns within the nMLF and spinal motoneurons in response to changes in ambient light levels to assess the behavioral relevance of this phenomenon. Increases and decreases in whole-field illumination are sufficient to make identified neurons within the nMLF fire tonically at frequencies that lead to temporal summation, and also to generate preferential activation of more excitable, ventral motoneurons. Thus, our findings now provide a generalizable mechanism for graded recruitment patterns via weighted descending inputs that relies on the biophysical properties of target motoneurons and their sensitivity to tonic drive. We first examined the axon collateral distribution in the spinal cord of nMLF neurons, including the identified Medial-Medial (MeM); Medial-Lateral, caudal (MeLc); and Medial-Lateral, rostral (MeLr) neurons (Figures 1A1–1A3 ). Neurons within the nMLF were first retrogradely labeled by dye injection into the spinal cord, and then one of the three identified nMLF somata was filled with a different colored dye by single-cell electroporation (Figures 1B and 1C). Given the known dorso-ventral patterning of spinal motoneuron recruitment (McLean et al., 2007McLean D.L. Fan J. Higashijima S. Hale M.E. Fetcho J.R. A topographic map of recruitment in spinal cord.Nature. 2007; 446: 71-75Crossref PubMed Scopus (274) Google Scholar, Menelaou and McLean, 2012Menelaou E. McLean D.L. A gradient in endogenous rhythmicity and oscillatory drive matches recruitment order in an axial motor pool.J. Neurosci. 2012; 32: 10925-10939Crossref PubMed Scopus (65) Google Scholar), we examined axon collateral distributions parasagitally (Figures 1D1–1D4), and their dorso-ventral distribution was analyzed between body segments 5–14, where the height (distance between the dorsal and ventral boundaries) of the spinal cord is relatively constant. In five fish, two of the nMLF neurons (MeLr/MeLc, MeLr/MeM, or MeLc/MeM) were electroporated using different colored dyes for direct comparison of projection patterns within fish (Figures 1B, 1C, 1E, and 1F). While all identified nMLF neurons had main axons that descended ventro-medially in the spinal cord, there were differences in the dorso-ventral distribution of collaterals arising from the main axon. Compared to the MeLr, the MeM and MeLc axon collaterals extended more dorsally in the spinal cord (Figures 1E–1H). Like the MeLr, smaller, nonidentified neurons within the nMLF had axon collaterals that remained ventral (Figure S1 available online). Due to the finer processes of the smaller cells, we could not be totally confident that their axons were completely filled. However, for the spinal projection patterns of the larger MeM, MeLc, and MeLr neurons, where we could be confident of complete filling, the differences in dorso-ventral projection held true for pooled data from multiple fish (Figure 1I, n = 5 for each cell type). Thus, the most dorsal axon collaterals (above spinal dorso-ventral division 0.5) were exclusively from the MeM and MeLc neurons. To relate these projection patterns to potential connections with axial motoneurons, we performed single-cell electroporations of the MeM, MeLc, and MeLr neurons in the pargmn2Et enhancer trap line, in which motoneurons are labeled with GFP (Figures 2A1 and 2A2). The MeM and MeLc both had extensive axon collaterals that reached the dorsal-most aspect of the axial motor column (Figures 2B1 and 2C1). There were also extensive ventral collaterals (Figures 2B1 and 2C1), where motoneurons are more numerous (Menelaou et al., 2014Menelaou E. VanDunk C. McLean D.L. Differences in the morphology of spinal V2a neurons reflect their recruitment order during swimming in larval zebrafish.J. Comp. Neurol. 2014; 522: 1232-1248Crossref PubMed Scopus (40) Google Scholar). Collaterals throughout the dorso-ventral axis penetrated the soma layer, which is most obvious from a coronal view (Figures 2B2 and 2C2). Digital reconstructions followed by registration to anatomical landmarks confirmed this pattern and also demonstrated that both the MeM and MeLc had bilateral projections (Figure 2E). Thus, one of the potential targets included large, dorsally located, early-born “primary” motoneurons (PMns) (Myers, 1985Myers P.Z. Spinal motoneurons of the larval zebrafish.J. Comp. Neurol. 1985; 236: 555-561Crossref PubMed Scopus (155) Google Scholar). To confirm this potential connection, we performed in vivo paired patch-clamp recordings from the large identified nMLF neurons and large identified PMns (Figure 2F). Consistent with the anatomical observations, we found evidence for direct synaptic connections to PMns from the MeM and MeLc neurons (Figures 2G and 2H). Current-evoked firing in the MeM or MeLc neurons elicited excitatory postsynaptic potentials (EPSPs) in PMns with two components (Figures 2G and 2H). The early component had a short, relatively fixed latency in both the MeM (mean ±SEM, 0.92 ± 0.10 ms, coefficient of variation or CV = 0.04) and MeLc (1.05 ± 0.07 ms, CV = 0.04) and a relatively fixed amplitude in both classes (MeM, 1.89 ± 0.29 mV, CV = 0.08; MeLc, 2.39 ± 0.61 mV, CV = 0.07; n = 4 MeM-PMn and 9 MeLc-PMn pairs). In addition, the early component followed MeM and MeLc action potentials reliably without failure, even at extremely high firing rates (up to 500 Hz). These features suggest a monosynaptic, electrical connection between the MeM and MeLc neurons and PMns. The later component occurred less reliably and had larger variability in both latency (MeM, 1.62 ± 0.07 ms, CV = 0.13; MeLc, 1.88 ± 0.36 ms, CV = 0.24) and peak amplitude (MeM, 1.23 ± 0.11 mV, CV = 0.20; MeLc, 1.84 ± 0.17 mV, CV = 0.16), which is more consistent with a chemical connection (Kimura et al., 2006Kimura Y. Okamura Y. Higashijima S. alx, a zebrafish homolog of Chx10, marks ipsilateral descending excitatory interneurons that participate in the regulation of spinal locomotor circuits.J. Neurosci. 2006; 26: 5684-5697Crossref PubMed Scopus (221) Google Scholar, McLean et al., 2008McLean D.L. Masino M.A. Koh I.Y. Lindquist W.B. Fetcho J.R. Continuous shifts in the active set of spinal interneurons during changes in locomotor speed.Nat. Neurosci. 2008; 11: 1419-1429Crossref PubMed Scopus (193) Google Scholar). In contrast to the MeM and MeLc, the more ventrally located MeLr axon collaterals ramified laterally in the neuropil layer (Figures 2D1, 2D2, and 2E), as did the collaterals of the smaller nMLF cells (Figure S1). However, since the dendrites and axons of all axial motoneurons intermingle in the neuropil (Kishore and Fetcho, 2013Kishore S. Fetcho J.R. Homeostatic regulation of dendritic dynamics in a motor map in vivo.Nat. Commun. 2013; 4: 2086Crossref PubMed Scopus (14) Google Scholar), this did not rule out the possibility that the MeLr and smaller nMLF cells could still make contact with more dorsal motoneurons. Consistent with this idea, we found connections between MeLr neurons and PMns (Figure 2I) that also contained an early component with a relatively fixed latency (1.28 ± 0.22 ms, CV = 0.05) and amplitude (1.07 ± 0.14 mV, CV = 0.08) and a later component with more variable latency (2.05 ± 0.32 ms, CV = 0.13) and amplitude (0.92 ± 0.06 mV, CV = 0.32; n = 3 MeLr-PMn pairs). Despite the greater likelihood that MeLr-PMn connections were axonal and/or dendritic and thus more distant from the somatic recording site, we found no significant differences in the amplitude of the early component EPSP among the three identified neurons (Figure 2J). Only the late component demonstrated any statistically significant difference, and this was restricted to the MeLc-PMn connection, when compared to the MeM and MeLr pairs (Figure 2J). Thus, the anatomical and physiological data suggest that nMLF neurons have the capacity to make connections to neurons distributed throughout the axial motor pool, which include the smaller, more ventrally distributed, later-born “secondary” motoneurons (SMns; Myers, 1985Myers P.Z. Spinal motoneurons of the larval zebrafish.J. Comp. Neurol. 1985; 236: 555-561Crossref PubMed Scopus (155) Google Scholar). We next investigated the nature of connectivity between PMns and SMns and focused on connections arising from the MeLc neuron, due to its more superficial, accessible location in the nMLF and the greater likelihood of finding somatic connections throughout the axial motor pool based on its anatomy. To reveal the nature of connectivity between the MeLc neuron and the axial motor pool, we targeted PMns and SMns located between body segments 10–13. Similar to the MeLc-PMn connection, the MeLc-elicited EPSPs in SMns also contained an early, reliable component with relatively constant latency (1.20 ± 0.05 ms, CV = 0.06) and amplitude (2.57 ± 0.38 mV, CV = 0.07; n = 13 MeLc-SMn pairs). There was also a later, less reliable component with more variable latency (2.25 ± 0.09 ms, CV = 0.26) and amplitude (2.76 ± 0.41 mV, CV = 0.25; n = 10 MeLc-SMn pairs). In both PMns and SMns, dual component EPSPs were resistant to a reduction in the likelihood of neurotransmission after perfusion of high-divalent cation extracellular solution (Figures 3A and 3B), consistent with a monosynaptic connection (Frankenhaeuser and Hodgkin, 1957Frankenhaeuser B. Hodgkin A.L. The action of calcium on the electrical properties of squid axons.J. Physiol. 1957; 137: 218-244PubMed Google Scholar). Furthermore, the later component in both classes was sensitive to a mixture of the glutamate receptor antagonists NBQX/AP5, consistent with a glutamatergic, chemical synaptic connection (Figures 3A and 3B). Critically, however, in control solutions the amplitude of both the electrical and glutamatergic components was indistinguishable between PMns and SMns, despite dramatic differences in input resistance (Rin) between the two populations (Figures 3E1 and 3G1). This is consistent with experiments that failed to demonstrate any difference in EPSP amplitudes related to Rin in limb motoneurons (Burke and Rymer, 1976Burke R.E. Rymer W.Z. Relative strength of synaptic input from short-latency pathways to motor units of defined type in cat medial gastrocnemius.J. Neurophysiol. 1976; 39: 447-458PubMed Google Scholar, Grillner et al., 1970Grillner S. Hongo T. Lund S. The vestibulospinal tract. Effects on alpha-motoneurones in the lumbosacral spinal cord in the cat.Exp. Brain Res. 1970; 10: 94-120Crossref PubMed Scopus (236) Google Scholar, Grillner et al., 1971Grillner S. Hongo T. Lund S. Convergent effects on alpha motoneurones from the vestibulospinal tract and a pathway descending in the medial longitudinal fasciculus.Exp. Brain Res. 1971; 12: 457-479Crossref PubMed Scopus (86) Google Scholar). In addition, although the chemical component was highly variable, we found that it was more reliable in PMns than in SMns (Figure 3F). Both observations are consistent with the idea that descending drive is weighted such that less excitable motoneurons receive more excitation, and we now extend this observation to individual reticulospinal inputs. Despite similarities in the amplitudes of MeLc-evoked EPSPs in PMns and SMns, we did observe differences in their waveforms (Figures 3C and 3D). Both the electrical and chemical components of EPSPs in SMns were broader and had a slower decay than EPSPs in PMns. To quantify this observation, we took advantage of the variable reliability of the later chemical component to separately analyze PSPs with purely electrical components and those with clear chemical components. Specifically, we focused on how the following features of EPSPs related to the Rin of spinal motoneurons: (1) 10%–90% rise time, (2) half width, and (3) decay time constant (Figure 3E2–3E4). For purely electrical components, the rise time, half width, and decay time constant increased with motoneuron Rin (Figures 3E2–3E4). We confirmed that this observation was not contaminated by a residual chemical contribution by measuring the same properties in the presence of NBQX/AP5 (Figure S2). Although the early electrical component precluded measurement of the rise time of the chemical component, this same pattern was evident when we analyzed PSPs containing a clear chemical component (Figures 3G2 and 3G3). The systematic broadening of the chemical as well as the electrical component is most simply explained by longer membrane time constants, although it is possible that SMns also express a higher ratio of NMDA to AMPA receptors or generally have slower postsynaptic kinetics. Furthermore, in the MeM- and MeLr-PMn pairs, MeM- and MeLr-elicited EPSPs also show narrower waveform and a fast decay similar to the MeLc-elicited EPSPs in PMns, suggesting that this feature is not restricted to the MeLc-motoneuron connection and instead reflects an intrinsic attribute of PMns (Figure S2). The slower decay of EPSPs in higher Rin SMns could provide a larger time window for EPSP summation. To test whether differences in temporal summation could indeed generate differences in motoneuron recruitment, we evoked action potentials up to 600 Hz in the MeLc neuron (“Pre”) using current steps and examined whether the motoneuron (“Post”) could be driven to fire (Figures 4A and 4B). In the nine MeLc-PMn pairs, we never observed firing in the PMn (Figure 4A). On the other hand, for three MeLc-SMn pairs, firing the MeLc neuron could make the SMn fire (Figure 4B). When we examined the response of the PMn and SMn at the onset of the current step (Figures 4C and 4D), we found that at low MeLc firing rates PMns and SMns showed a relatively equivalent amount of summation, as quantified by generating a slope from the peak of the first two PSPs in the train (Figure 4E). However, while the PMn exhibited little increase in slope at progressively increasing MeLc firing rates (low gain), in the SMn the increased temporal summation produced an ever-increasing slope with increasing MeLc firing rates (high gain). We then compared the relative gain of responses to current steps in eight motoneurons where the MeLc was driven to fire over a comparable frequency range (100–600 Hz). The excitatory gain systematically increases with increases in the EPSP decay time constant (Figure 4F), as expected if Rin was contributing to the efficacy of temporal summation. The contribution of Rin to temporal summation of EPSPs assumes that there are systematic differences in membrane time constant related to Rin. To examine the relationship between membrane time constant and motoneuron Rin, we performed whole-cell recordings from individual spinal motoneurons (n = 41), which covered the full range of motoneuron Rin (∼30–1000 MΩ) (Menelaou and McLean, 2012Menelaou E. McLean D.L. A gradient in endogenous rhythmicity and oscillatory drive matches recruitment order in an axial motor pool.J. Neurosci. 2012; 32: 10925-10939Crossref PubMed Scopus (65) Google Scholar). A brief (1 ms) hyperpolarizing current was delivered, and membrane potential decay was fitted with a single exponential equation to calculate the time constant. Similar to the EPSP decay time constant, the membrane decay time constant measured somatically also increased with motoneuron Rin (Figure 4G). Thus, the entire motor pool exhibits a gradient in both Rin and membrane time constant that would provide systematically greater temporal summation of excitatory inputs. The findings thus far suggest that nMLF neurons have the potential to make contacts with spinal motoneurons throughout the dorso-ventral axis either via somatic or axonal/dendritic connections. In addition, our assessment of MeLc output to axial motoneurons suggests that it is biased to less excitable cells but can result in selective activation of more excitable ones via temporal summation. To do so, however, the MeLc must fire tonically at frequencies exceeding 200 Hz (Figures 4B and 4D). Given that these are extremely rapid rates of firing, it is not clear if this would occur naturally. To begin to address this question, we investigated in more detail the activity patterns of neurons within the nMLF during motor behavior. Our first goal was to identify a sensory stimulus that would drive reliable activation of the nMLF. Given its acknowledged sensitivity to visual stimuli (Orger et al., 2008Orger M.B. Kampff A.R. Severi K.E. Bollmann J.H. Engert F. Control of visually guided behavior by distinct populations of spinal projection neurons.Nat. Neurosci. 2008; 11: 327-333Crossref PubMed Scopus (186) Google Scholar, Sankrithi and O’Malley, 2010Sankrithi N.S. O’Malley D.M. Activation of a multisensory, multifunctional nucleus in the zebrafish midbrain during diverse locomotor behaviors.Neuroscience. 2010; 166: 970-993Crossref PubMed Scopus (32) Google Scholar), we chose a simple, controllable source of photic stimulation, namely a light emitting diode (LED), to generate sudden increases and decreases in whole-field illumination. We then utilized calcium imaging to assess activity in the nMLF combined with peripheral motor nerve recordings to monitor motor responses (Figure 5A). In these experiments, the fish is immobilized with α-bungarotoxin, and the bursts of motor activity that would normally drive movements (“fictive”) can be monitored (Figure 5A). In response to an LED, motor activity was reliably observed in response to both light onset and offset (Figure 5B). In some instances, spontaneous motor activity unrelated to light stimuli was also observed (gray arrowheads, Figure 5B). There was no significant difference in the delay related to whether the light was turned on or turned off (light onset, 219.32 ± 17.91 ms; light offset, 215.11 ± 11.60 ms; Mann-Whitney U test, p > 0.05, n = 10 fish). Next, to examine the recruitment pattern of neurons within the nMLF, the location of cells was normalized using the midline of the brain and the center of the MeLr neuron as medio-lateral (M-L) references (Figure 5C). While the responses to light onset within the nMLF were highly variable (Figure 5E), the vast majority exceeded the 9% ΔF/F value, which can be used as a conservative estimate of suprathreshold activity (Figure S3) (Bhatt et al., 2007Bhatt D.H. McLean D.L. Hale M.E. Fetcho J.R. Grading movement strength by changes in firing intensity versus recruitment of spinal interneurons.Neuron. 2007; 53: 91-102Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, Fetcho and O’Malley, 1995Fetcho J.R. O’Malley D.M. Visualization of active neural circuitry in the spinal cord of intact zebrafish.J. Neurophysiol. 1995; 73: 399-406PubMed Google Scholar). Averages of responses binned according to M-L location revealed significantly less activity in neurons found in the most medial bin and those found in the four most lateral bins (Figure 5G). The MeM, which is located in the most medial bin, also responded less robustly than either the MeLr or MeLc in response to light onset (Figure 5G). In contrast, responses to light offset were more homogeneous (Figure 5E), with no significant difference related to binned M-L location or neuron identity (Figure 5G). These data suggest that whole-field changes in illumination are a reliable means to generate motor responses and to activate neurons distributed throughout the nMLF. How might this compare to responses in the axial motor pool? When we examined the recruitment patterns of axial motoneurons distributed throughout the dorso-ventral plane (Figure 5D), both light onset and offset consistently activated predominantly ventral motoneurons (Figures 5F and 5H). The contrasting responses of the nMLF and axial motor pools are readily apparent by representing activity as a simple re" @default.
• W2034192215 created "2016-06-24" @default.
• W2034192215 creator A5026658676 @default.
• W2034192215 creator A5066280688 @default.
• W2034192215 date "2014-08-01" @default.
• W2034192215 modified "2023-10-15" @default.
• W2034192215 title "Selective Responses to Tonic Descending Commands by Temporal Summation in a Spinal Motor Pool" @default.
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