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j The Cerebellum 2004; 3: pp 212 221 j
Activation of climbing ®bers Alan R Gibson, Kris M Horn and Milton Pong
Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
Cells in the inferior olive are the sole source of climbing ®bers to the cerebellum. In this article, we review some of the discharge properties of olivary cells that are important for understanding its functional role in cerebellar processing. It is generally believed that climbing ®ber input supplies the cerebellum with information related to movement errors in order to improve motor performance. As a whole, olivary properties are not consistent with this function. The properties are consistent with the hypothesis that the olive is important for associating arbitrary sensory stimuli with somatosensory events. Although such associations would not be useful for improving the accuracy of motor commands, they may be useful for organizing appropriate behaviors to cope with the predicted event. Keywords: Climbing fibers - olivary cells - cerebellum
Introduction The purpose of this brief review is to highlight a set of inferior olive (IO) response properties that are important for de®ning their role in cerebellar processing. Although most of the properties that we summarize have been known for some time, they are incorporated into few models of cerebellar or olivary action. Since the IO targets the cerebellum, most theories have postulated that the climbing ®bers (CFs) carry movement-related information, which is used in cerebellar processing to improve motor performance. We argue that CFs provide little or no information about self-produced movement and, therefore, are not useful for correcting or improving motor performance. Climbing ®bers signal externally imposed disturbances to particular regions of the body when the animal is not actively moving, and this feature must be basic to their function. The data that we use to support our arguments come from many sources, and there are several excellent and comprehensive summaries of IO response properties.1-8 The climbing ®ber system and the mossy ®ber system constitute the major cerebellar afferent systems. Mossy ®bers have discharge properties that are similar to those of ®bers and cells in other regions of the brain. Mossy ®bers arise from a variety of sources, branch widely in cerebellar cortex, and terminate in synaptic glomeruli within the granular layer. Granular cell axons form parallel ®bers, and each parallel ®ber contacts a large Received 31 January 2004; Accepted 26 June 2004 Correspondence: Alan R Gibson, Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA. Tel: 1 (602) 406 3732. Fax: 1 (602) 406 4172. E-mail:
[email protected] 2004 Taylor & Francis DOI 10.1080/14734220410018995
Gibson AR, Horn KM, Pong M. Activation of climbing fibers Cerebellum 2004; 3: 212-221
number of Purkinje cells. Therefore, each mossy ®ber has a relatively small effect on a large number of Purkinje cells.9 In contrast, climbing ®bers arise only from the IO2,10 and project to the cerebellar cortex in precisely aligned parasagittal zones.11 Each CF branches to fewer than ten Purkinje cells and entwines around their dendritic trees making multiple synaptic contacts.12-14 Therefore, a CF has a large effect on a small number of Purkinje cells.15 Mossy ®ber response properties re¯ect their speci®c source. For example, mossy ®bers arising from cells in the external cuneate nucleus,16,17 which receives input from forelimb muscle spindles,18 report on the position and movement of forelimb joints.19,20 Mossy ®bers arising from the pontine nuclei carry information from various areas of the cerebral cortex including motor and sensory areas.21-25 Collaterals of cortical ®bers in the pyramidal tract provide the cerebellum with a copy of descending motor commands,26 and ®bers from visual areas of cortex can provide information about movements of objects in visual space.27 Mossy ®bers, thus, provide the cerebellum with detailed information about the external world as well as intended and actual body movement. The response properties of cells in the IO and their climbing ®ber axons differ sharply from those of mossy ®bers. Climbing ®ber activation produces a complex spike in the Purkinje cell, which results from an exceptionally strong and characteristic depolarization.15 The large complex spike is relatively easy to record, and much of our knowledge of IO response properties has been gathered by recording complex spikes rather than direct recordings from IO cells.
Olivary cells discharge at low rates Discharge rates of IO cells are extraordinarily low and rarely exceed 5-10 spikes/second.28-30 The contrast with
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Figure 1 Mossy fiber input to the cerebellum provides precise information about movement. (A) The response of a cat external cuneate neuron during the reach-to-grasp task. Cell discharge is tightly related to movement and reaches several hundred impulses per second. (B) Discharge of an external cuneate neuron in the anesthetized cat during passive movement about the shoulder. The discharge rate of a single neuron provides relatively precise information about shoulder position.
mossy ®ber discharge is striking. Figure 1A illustrates the response of a cell in the cat external cuneate nucleus during a reaching task. The cuneate neuron increased its activity shortly before the onset of the reach and discharge remained high throughout the reaching task. If the appropriate joint angle is monitored, the relationship between joint angle and cell discharge rate can be very precise. Figure 1B illustrates the discharge of a cuneate neuron in an anesthetized cat during imposed movement about the shoulder joint. Cell discharge rate closely matched the angle of the shoulder joint. Thus, mossy ®bers arising from the cuneate nucleus provide the
cerebellum with detailed real-time information about limb movement. Figure 2A illustrates the discharge of a cell in the IO during the same reaching task as illustrated for the cuneate neuron in Figure 1A. The IO cell discharged at a low irregular rate that did not change during the reaching task. Over the past several years, our laboratory has recorded the discharge of hundreds of IO cells during reaching - no cell has shown any clear relationship to the movement. IO cells provide little or no information about undisturbed active movement.29,31-33 IO cells, however, do discharge reliably to appropriate
Figure 2 Climbing fiber input to the cerebellum provides no information about active movement. (A) Average discharge rate of a cat rDAO neuron during the reach-to-grasp task. There is no alteration in discharge rate during any phase of the behavior. (B) The neuron responds reliably when the limb is tapped (time 0) during stance.
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stimulation. Somatosensory stimuli, such as taps to the skin, elicit reliable IO responses if the cat is standing quietly (Figure 2B) or even if the cat is anesthetized (Figure 4A). Figure 2B illustrates the typical discharge of an IO cell in response to taps on the limb, one of the most effective ways of activating IO neurons. The IO neuron discharged with one or two spikes for each tap. IO dis-
Figure 3 Brainstem and spinal inputs to cat IO subdivisions. Relative volumes (%) were calculated by summing subdivision areas across sections evenly spaced through the extent of the IO. Shading indicates approximate volumes of cellular areas responding to somatosensory, vestibular and visual stimuli. Although many regions contain cells responding to visual and vestibular stimuli, the relative strengths of the responses vary greatly between subdivisions. Somatosensory includes cells which respond to light touch, vibration, deep pressure, passive displacement, nociceptive stimuli, visceral stimulation, etc. Vestibular cells respond to rotation in the dark. Visual cells respond to light flashes or slowly moving textured stimuli. Inhibitory inputs from the cerebellar nuclei and lateral vestibular nucleus are not shown. Abbreviations: AOS, accessory optic system; D, nucleus Darkschewitsch; DAO, dorsal accessory olive; dc, dorsal cap of Kooy; dmcc, dorso-medial cell column; INC, interstitial nucleus of Cajal; MAO, medial accessory olive; NOT, nucleus of the optic tract; PH, nucleus praepositus hypoglossi; PO, principal olive; Psol, parasolitary nucleus; PTA, anterior pretectal nucleus; RNp, parvocellular red nucleus; SC, superior colliculus; SP, spinal cord; 5, trigeminal nucleus; V, vestibular nuclei (Data from: 2, 4-8, 31, 43, 49, 50, 68, 104-113).
charge reliably signals that the body has been touched but provides little information about the characteristics of that touch other than it exceeded response threshold. Olivary neurons are refractory for approximately 100 ms following discharge, which limits their ability to ®re at high rates.34-37 Thus, the information carried by a climbing ®ber is de®ned by the stimulus properties required to elicit cell discharge rather than its discharge rate. Several investigators have suggested or implied that various forms of spatial or temporal summation could recover parametric information from CF discharge.38-41 Summation essentially converts a single spike response into a multiple spike response. However, temporal summation requires repetitive presentation of the same stimulus and is unlikely to occur naturally. Spatial summation could only occur in the cerebellar nuclei, since each Purkinje cell receives only a single climbing ®ber. This review approaches the IO from the standpoint of a single-unit analysis. As with many other cells in the nervous system, each IO cell discharges optimally to appropriate stimulation. Different regions of the IO can be characterized by common response properties of the cells within a region, such as somatosensory or vestibular responsiveness. Within a region, however, individual cells code additional information such as what part of the body has been touched and/or the direction of stimulation that activated the cell. While it is possible in principle to extract speci®c parametric information by summing across cells, summation would destroy much of the unique information coded by the individual cell. At least for the Purkinje cell, it is likely that the function of the IO is served by one or a few CF discharges.31,42,43 Response characteristics of individual IO cells must be a major clue as to their function.
Somatosensory properties of IO neurons It is likely that all IO cells respond to stimulation related to the body and not to distant events (teleceptive stimuli). The somatosensory properties of the IO are the most obvious example of this, but cells responding to vestibular and visual stimulation also report on disturbances of the body. Cells responding to somatosensory, vestibular and/or visual stimulation include essentially the entire IO (Figure 3). Large regions of the IO receive afferents from the spinal cord, dorsal column nuclei and trigeminal nucleus, and the great majority of olivary neurons respond to somatosensory stimulation.5,31,44-46 In the anesthetized preparation, the rostral dorsal accessory olive (rDAO) is the most sensitive IO division. Cells in rDAO respond to slight movements of the body hair or touch to the skin and have well-de®ned receptive ®elds on the contralateral body surface.44 Individual receptive ®elds can range from smaller than one toe to larger than an entire limb. The
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receptive ®eld organization of rDAO forms a map of the entire surface of the animal.5,31 The discharge of an individual rDAO cell signals to the cerebellum that a particular part of the body has been touched or, more accurately, disturbed (rDAO cells respond to multiple modalities of stimulation, see section under `Modality convergence'). Other divisions of the olive, such as the principal olive (PO) and medial accessory olive (MAO), are more dif®cult to activate in the anesthetized preparation but are highly sensitive in the awake preparation.31 The refractoriness in the anesthetized preparation probably re¯ects the fact that much of the input to these regions is relayed through nuclei in the mesencephalon,47 as opposed to the relatively direct sensory pathways providing input to rDAO.48,49 In the alert cat, both PO and MAO are highly responsive to touch, slight displacements of the limb, or vibration.31 Cells responding to vibration are particularly sensitive and even slight taps to the table or ¯oor upon which the animal is standing can elicit reliable IO responses. In contrast to rDAO cells, MAO cells can have complex receptive ®elds which may include inhibitory as well as excitatory input regions on multiple parts of the body. Although the functions of these complex receptive ®elds are not obvious, they may be tuned to detect stimuli that occur during speci®c behaviors such as mating or ®ghting.
Vestibular and visual input to the IO Several regions of the IO31 receive input from the vestibular nuclei.50,51 As with somatosensory cells, individual vestibular IO cells are relatively insensitive to the strength (speed and amplitude) of movement and do not distinguish well between slow, fast, small or large movements.43 However, they are sensitive to the direction of movement. Therefore, IO cells responding to vestibular input signal that the body has moved or has been moved in a particular direction. Some of the cells responsive to vestibular input are also sensitive to visual stimulation, and IO regions responding to vestibular stimulation contain visual cells.52-55 The dorsal cap (DC) contains the greatest concentration of IO cells responding to visual stimulation. The DC receives input from the dorsal terminal nucleus (DTN) of the accessory optic system (AOS,).56,57 Visual stimulation of AOS cells requires large textured stimuli moving slowly in particular directions. When viewed by humans, such stimuli produce a sensation of body movement. Soodak and Simpson58 concluded that the AOS is a visual system organized to detect self-motion in a reference frame similar to the semicircular canals. The AOS complements the vestibular system by responding optimally to lower speeds.58 Thus olivary cells receiving input from the AOS supply an input to the cerebellum that signals selfmotion.
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The dorsal cap projects to the ¯occulus, and it is generally assumed that this signal represents eye movement error (retinal slip), which is used to correct eye and head tracking performance.59,60 However, the complex spike response to imposed retinal slip is too slow to account for immediate tracking corrections, and the response is unreliable since a complex spike occurs on only 35% of trials with induced retinal slip.61 Although it has been argued that the complex spike response could produce adaptive changes over long periods of time, it is unlikely that this slow unreliable response would result in an ef®cient learning mechanism. Especially when one considers that mossy ®bers are providing short latency, precise and reliable information about the same perturbations. Visual climbing ®bers in the ¯occulus also respond to non-visual, probably vestibular, stimulation.62 Certainly, the CF input to the ¯occulus cannot be a simple retinal slip error signal. Rather than signaling tracking error, visually responsive IO cells may be signaling direction of body or head movement (either self-produced or imposed), which could be represented by cells that respond to visual and vestibular stimulation. If so, they are analogous to many other cells in the IO that signal direction of passive body movement.31,63
Missing teleceptive input The orderly and detailed mapping of the body surface in the IO (especially in rDAO) is reminiscent of visual and auditory space mapping that exist in many other parts of the nervous system. Therefore, it is surprising that visual and auditory representations of external space are, at best, poorly represented in the IO.5 [If auditory and visual stimuli are of suf®cient intensity to produce startle, then many Purkinje cells respond with a complex spike.64 However, these complex spikes could result from a wide variety of stimuli associated with startle.] The IO may receive some highly processed indirect input that carries information about external space, but, if so, the representation is not apparent in olivary recordings from either anesthetized or behaving animals.
Missing muscle spindle input The most detailed parametric information about movement arises from muscle spindles.65 The cerebellum receives a massive rapidly conducting mossy ®ber input from spindle afferents via the spinocerebellar pathways and the external cuneate nucleus.17,66,67 Surprisingly, there is no clear input from primary spindle afferents to the IO. Activating IO cells by shocking nerves typically requires stimulus strengths well above those required to activate Ia ®bers,6-8,17,66,67 which carry information from primary spindle afferents. Although, as we have seen, the external cuneate nucleus provides a mossy ®ber input to the cerebellum carrying detailed information about limb
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movement, the external cuneate provides little or no input to the IO.68 Armstrong et al.34 reported activation of some IO neurons at Ia strengths when using multiple nerve shocks, suggesting an indirect olivary input from spindles. In collaborative studies with Dr Thomas Hamm, we used vibratory stimulation of exposed muscles to search for Ia spindle input to the olive. Vibratory stimulation strongly and selectively activates muscle spindles. We found no short latency activation in the IO in response to vibration. However, the vibration did produce a strong re¯ex contraction of the muscles, and the contraction resulted in long latency activation of IO cells. Mechanical stimulation of the muscles with a probe indicated that the olivary response was probably due to stretch of the muscle tendon. The response could be due to group Ib (Golgi tendon organs) or group II and III nerve ®ber afferents, which have heavy projections to the IO.6-8,34 Group II and III ®bers are medium and slowly conducting pathways that carry information about touch, noxious stimulation, etc.
Nociceptive input to the IO The large group III ®ber response in the IO, suggests that IO cells might respond to noxious stimulation. Indeed, noxious stimuli are particularly effective in eliciting IO discharge and produce, for the IO, high rates of repetitive discharge (Figure 4B).69-71 Repetitive CF discharge will completely inhibit Purkinje cell simple spike discharge,72 so noxious stimuli may effectively remove speci®c parts of cerebellar cortex from participating in neural processing.
The c-®ber response of the IO has been cited as support for the motor error theory of IO function,73 as it is argued that any movement resulting in pain would be an error (although errors producing pain are as likely to be errors of judgment as of motor control). However, nociceptive activation could not provide speci®c information for movement correction since a painful result could be the result of errors in force, timing, direction or a combination of such factors. Also, nociceptive activation could not distinguish between self-produced and imposed stimuli. Pain produces strong alterations in movement. Maybe the high IO discharge rate removes painful regions of the body from being incorporated into movements, which might help minimize additional damage.
Visceral input to the IO Many studies have demonstrated that the IO can transmit information about visceral stimulation to the cerebellum.74-77 Perrin and Crousillat78 used both splanchnic nerve stimulation and mechanical stimulation of gastrointestinal and peritoneal receptors. Cells in DAO and the caudal medial accessory olive responded well to gastric distension, displacement of the stomach, movement of the peritoneum, etc. Surprisingly, cells responsive to visceral stimulation also responded to stimulation of the limbs and thorax. Visceral and somatic convergence appears to be the rule rather than the exception for climbing ®ber responses, since many Purkinje cells that respond with CF's to renal or vagal nerve stimulation respond also to cutaneous stimulation.75,76 The frequent convergence of visceral and somatic inputs onto IO cells
Figure 4 Olivary neurons respond to more than one sensory modality. A cell responsive to cutaneous stimulation (A) also responds when thermal stimulation reaches nociceptive levels in an anesthetized cat (B).
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suggests that these cells respond to general disturbances of the body. The cat mesentery contains many Pacinian corpuscles,79 and this visceral input might contribute to the high sensitivity to vibration exhibited by many IO cells.
Modality convergence The previous discussion indicates that IO neurons may respond to more than one modality of stimulation visually responsive cells respond to body motion and cells responding to visceral stimulation respond to limb stimulation. Additionally, cells responding to cutaneous stimulation respond to stimulation of the tissue underlying the skin.5 In fact, it may be that all cells in the IO respond to stimulation via multiple modalities. All cells in rDAO appear to respond to both cutaneous and nociceptive stimulation.69,70,80 Figure 4A illustrates recordings from an rDAO neuron that responded well to taps to the thorax. When a heat lamp was directed to the same spot on the skin, the cell responded at a steady low rate of about 3 spikes/sec until the temperature of a thermistor placed just above the skin reached approximately 50 °C, at which point the cell began responding in a tonic fashion and doubled its discharge rate (Figure 4B). Fifty degrees centigrade is near the threshold that nociceptive ®bers respond to thermal stimulation.81 Since rDAO cells respond to cutaneous, deep tissue stimulation and nociceptive input, they are responsive to at least three modalities of input. These inputs, however, respect the receptive ®eld de®ned by cutaneous stimulation. The discharge of a single rDAO neuron reports that a speci®c region of the body has been stimulated, but it does not identify the nature of that stimulation.
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IO cells are inhibited during active movement Since IO cells are highly sensitive to touch and slight displacements of the limbs, one would expect to see an increase in IO discharge during active movement, but they show little or no increase.2,29,31,32,82 Figure 5A illustrates the response of the rDAO to cutaneous shocks delivered while the cat is standing motionless. Each shock elicits a strong rDAO response. Figure 5B illustrates recordings of the same cell to the shock while the cat is reaching. The IO response is inhibited during the movement.2,29,33,83 It is likely that the inhibition is mediated, at least in part, by the large GABAergic projection to the IO from the cerebellar output nuclei.84-88
Lack of response to movement error The most popular hypothesis of olivary action postulates that the IO provides the cerebellum with information about movement error.89 If so, this could explain the lack of discharge during active movement, since, normally, no error is present. Andersson and Armstrong28 demonstrated that CS spikes occurred on some trials when a rung was allowed to unexpectedly drop while a cat walked along a horizontal ladder. They, as well as others,73 interpreted this ®nding as support for the error detection theory. However, stepping on a loose rung is not an error of motor control, since the cat accurately placed his paw on the loose rung. In a more colloquial sense, it is an error since the step produced an undesired result. To test the error hypothesis, we trained cats to reach and grasp a lever in response to a cue tone. After training, the cats would attempt to grasp the lever in response to the tone even when the lever was displaced to a position beyond their reach. IO cells responsive to forelimb
Figure 5 Olivary sensitivity is reduced during movement. A shock applied to the forelimb during stance reliably elicits cell discharge (A). During reaching, the same shock elicits no olivary response (B).
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Figure 6 Reaching errors do not activate olivary neurons. An olivary cell that is highly responsive to taps during stance (A) fails to discharge during normal reaches (B) or during attempted grasps of a handle moved beyond the cat's reach (C).
stimulation were recorded in every major division of the IO during attempts to grasp the missing handle. No cell showed increased discharge during the failed grasping attempts. Figure 6 illustrates discharge of an IO neuron to taps on the limb (6A), during reaching to grasp a handle (6B), and during reaching to grasp the displaced handle (6C). The cell responded reliably to the taps but had no increased discharge during normal reaches or during reaches for the displaced handle. IO cells do not respond to reaching errors - they require appropriate somatosensory stimulation.90
closure and can occur after the onset of lid movement. IO divisions other than rDAO may respond to the puff, but rDAO has the shortest latency responses,5,8 thus it is unlikely that any IO response occurs early enough to be in the causal loop of the unconditioned response (i.e., the eye blink). However, the IO response could provide the cerebellum with a representation of the US for associative learning. The typical experimental US, such as a puff to the eye or an electrical shock to the limb, is restricted to a speci®c part of the body and activates multiple sensory modali-
Conclusions Cells in the IO are highly sensitive to somatosensory and proprioceptive stimulation to speci®c parts of the body, and these responses can be mediated via multiple sensory modalities. Cells in the IO do not respond during active movement or during movement error. These are general properties of the IO, and they are not consistent with theories requiring IO activity to supply a signal related to active movement. If the IO projected to brain regions other than the cerebellum, its afferent anatomy and response properties would be widely interpreted as a relatively straightforward, albeit unusual, sensory nucleus. Yet the somatotopy of IO input does align with the somatotopy of cerebellar output,80,91 and it is likely that the signals supplied by the IO are useful in the control of movement. What could that role be? Only one popular hypothesis of olivary action ®ts well with the response properties of its neurons. That hypothesis postulates that the IO provides the cerebellum with a representation of the unconditioned stimulus (US) during classical conditioning.92-97 Figure 7 illustrates rDAO responses to a puff of air applied to the eye. Notice that IO discharge occurs in close association with lid movement, but the discharge is variable in relation to lid
Figure 7 Olivary responses to an eye puff are too slow to mediate lid closure. Two examples of neural activity in the IO during a puff of air to the eye. The olivary responses occur near the time of lid closure, but the responses are variable in relation to lid movement and, often, the IO cells respond after the onset of lid movement.
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ties, which might produce sensations of touch, deep pressure and pain. The temporal association of an arbitrary conditioned stimulus, such as a tone, with the US forms a learned response (conditioned response, CR). In the typical classical conditioning experiment, the measured CR is relatively simple, such as an eye blink or limb withdrawal. In more natural settings the CR may include a wide variety of complex behaviors, such as approach or avoidance, which have survival value to the animal.98 Most importantly, the conditioned stimulus bears no relation to the animal's motor performance. Rather, it enables the animal to organize motor behaviors in response to a normally neutral stimulus, which, through association, has become predictive of the US. A less commonly held hypotheses that climbing ®bers serve a `resetting' function42,99-101 might also ®t well with IO response properties. The dendritic tree of the Purkinje cell is not invaded by somatic spiking102 so local dendritic potentials established by mossy ®ber activity might persist until the occurrence of a complex spike. Recently, Jorntell and Ekerot103 have demonstrated that activation of parallel ®bers without activation of climbing ®bers produces long lasting increases in the size of Purkinje cell
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simple spike receptive ®elds. The induced ®elds can be returned to their original state by pairing parallel ®ber activation with climbing ®ber activation. Their results could be interpreted as support for a CF resetting function, but we are still left with the question as to why the response properties of inferior olive neurons are suited for resetting. More experiments are needed to test the various hypotheses; for example suppression of IO responses during movement predicts that conditioning paradigms would not be effective when the US is presented during movement. Additionally, there is no evidence that taste and smell are represented in the IO, which would be expected if its activity represents the US. Clearly, we do not know what function is accomplished by IO activity, but hypotheses about function need to incorporate the large amount of knowledge that is available about IO response properties. Acknowledgements
We thank Drs Mitchell Glickstein and Jerry Simpson for many constructive comments.
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