Whisking control by motor cortex
|Cornelius Schwarz and Shubhodeep Chakrabarti (2015), Scholarpedia, 10(3):7466.||doi:10.4249/scholarpedia.7466||revision #150634 [link to/cite this article]|
The rodent whiskers (the so-called vibrissae) are an active scanning sensorimotor system with major perceptual functions. Apart from tactile perception, the whisker motor system also has important contributions to the animals’ navigation and orientation capabilities. The whisker motor system is highly modular with circuits processing basic motor commands, rhythmic whisking, and modulating the motor actions using information from incoming tactile signals. The vibrissal primary motor cortex (vM1) reflects these functional divisions by displaying a distinct set of sub-areas with different functions. Like the primate fingertip system, vM1 displays direct cortico-motoneurons (CM) cells, in principle compatible with the notion that vM1 is involved in directly computing patterns of muscle activity. There is strong evidence, however, that vM1 action on the muscles is rather indirect with important brainstem premotor networks bearing the responsibility of computing muscle activity patterns. The connectivity of the different vM1 modules to central pattern generators (CPGs), generating the basic rhythmic movement patterns and the trigeminal brainstem loop (TBL), the brainstem sensorimotor reflex arc, representing the lowest hierarchy of sensorimotor interactions, are being unearthed by current investigations.
Key Words: Motor cortex, whisking, central pattern generator, topography, motor planning, rhythmic whisking region.
Various authors have used various nomenclature systems to refer to the different modules within vM1. Some of them were based on cytoarchitectonically defined subregions observed in histological examination of tissue whereas others were derived from functional assessment of cortical function. We use the following nomenclature in this article.
AGm: AGm is the medial agranular cortex, defined cytoarchitectonically. Functionally it corresponds to the vM1 representation. Part of AGm overlaps with the functionally defined area, rhythmic whisking region or RW.
TZ: The transitional zone between AGm and AGl, previously classified as part of the retraction face (RF) region, was first called TZ by Alloway and colleagues, again using cytoarchitectonic criteria. TZ has previously been shown to be interconnected with both AGm and AGl (Weiss and Keller, 1994), and to be the main recipient of vS1 projections to vM1 (Smith and Alloway, 2013).
AGl: AGl is the lateral agranular cortex, defined using cytoarchitectonic boundaries and mainly corresponds, functionally, to the forelimb region of M1.
PMPF: The prefrontal and premotor subregion of M1, defined using functional criteria lies towards the frontal pole of M1 bordering pre-frontal cortex. Part of it was also previously classified as belonging to the so-called RF. For a graphical representation of the above areas, see Fig. 1.
The rodent whisker-related sensorimotor system is outstanding as a model system because these animals use their mobile whiskers to “actively scan” their environment (Carvell and Simons, 1990). Active scanning means that rodents deploy energy to objects (via whisker movements) and gain information by sensing the object’s reﬂections, in the form of ﬁne object-dependent whisker vibrations (Hentschke et al., 2006; Ferezou et al., 2007; Wolfe et al., 2008). This is akin to active scanning using echo-location or electro-sensation of bats, cetaceans, and ﬁsh, and is performed by humans in very similar ways using their ﬁnger tips (Gamzu and Ahissar, 2001). It is comprehensible that the active scanning property will emphasize sensorimotor interplay even more as known from other motor systems, as any change in movement strategy fundamentally changes the character of incoming sensory sensation and vice versa. One critical constraint of the tactile system is that it is a ‘near’ sense, i.e. whiskers need to be held in touch of the object of interest, and while in touch, movements need to be optimized to serve the purpose of fine discrimination of location, texture, and shape. Despite the critical dependence on tactile inputs, scanning movements are voluntarily initiated and maintained – even without tactile input - and have a stereotyped, relative simple rhythmic basis, onto which the modulation by tactile signals is superimposed (Gao et al., 2001; Landers and Zeigler, 2006).
The study of active scanning whisker movements and their modulation by tactile inputs is in its early stages. However, considering the above-mentioned sensorimotor interplay, and other functions of the whisker system like animal navigation, one should not be surprised to find a functionally parceled system serving different functions with sensorimotor interconnections on each level of the neuronal hierarchy. In fact, active ongoing research has revealed a highly modulatory system serving either more basic motor functions (rhythmic scanning) or sensorimotor feedback of different types and complexities.
The Organization of the Rat Vibrissal Motor Cortex (vM1)
Spatial extent and motor map
The first functional mapping of rat vM1 was performed using electrical stimulation from the cortical surface (Settlage et al., 1949) and later refined using intracortical microstimulation (ICMS)(Hall and Lindholm, 1974; Hicks and D’Amato, 1977; Sapienza et al., 1981; Neafsey and Sievert, 1982; Gioanni and Lamarche, 1985; Neafsey et al., 1986). These studies together delineated a motor cortical area that occupied the frontal and dorsomedial aspects of the rat neocortex and contained a movement map of body parts arranged topographically. Cytoarchitectonically, M1 can be subdivided into three fields which occupy the area between the midline and the primary somatosensory cortex (Fig. 1). The two more medial fields together constitute vibrissal M1, and are related mainly to whisker and face movements (medial agranular and transitional zone; AGm and TZ) while the lateral one, adjoining the somatosensory cortex, is related to trunk and limb movements (lateral agranular zone AGl) (Donoghue and Parham, 1983; Brecht et al., 2004a; Smith and Alloway, 2013). As schematized in Fig 1, AGm lies along the midline extending into the medial bank down to the cingulate cortex and is characterized by a broad layer V and a thin layer III whereas AGl has a thick layer III and a reduced layer V. TZ is characterized by intermediate layer III and V thickness (Zilles et al., 1980; Donoghue and Wise, 1982; Brecht et al., 2004a; Smith and Alloway, 2013). Whereas AGm and AGl neurons primarily have dense interconnections within their respective cytoarchitectonic boundaries, TZ neurons are interconnected with both AGm and AGl (Weiss and Keller, 1994). Corresponding to their body representations, one target of subcortical projections from AGm and TZ is the superior colliculus, while AGl connects to the spinal cord instead (Neafsey et al., 1986). The exact reaches of M1 toward the frontal pole and its borders with the premotor and prefrontal cortices is poorly understood (Neafsey et al., 1986; Conde et al., 1990, 1995; Uylings et al., 2003) and therefore we call this anterior aspect the premotor and prefrontal cortices (PMPF). On its extreme medial aspect, M1 contains a special representation of movements of the eye (saccades) and eyelids (Hall and Lindholm, 1974; Neafsey et al., 1986; Brecht et al., 2004a).
The vM1 occupies a large portion of the motor cortex and there is considerable debate about the exact nature of the topographic map of the vibrissal pad. Some authors have described single whisker responses using ICMS although others have shown that the number of whiskers showing evoked movement varies with the level of anesthesia used (Brecht et al., 2004a; Haiss and Schwarz, 2005). Single cell microstimulation in vivo has consistently yielded multi-whisker movements (Brecht et al., 2004b) supporting the hypothesis that muscle synergies or movements might be represented in vM1 rather than individual muscles.
Vibrissal M1 is densely and reciprocally connected with almost all other vibrissal cortical areas including the primary and secondary somatosensory cortices (S1 and S2) and vM1 in the contralateral hemisphere (Fig. 2). The most important cortical projection to vM1 is the one originating from ipsilateral S1 barrel cortex (vS1). These projections arise predominantly from neurons in the supra- and infragranular layers of vS1 that are aligned with the layer IV inter-barrel septa, although layer IV itself does not project to M1 (Alloway et al., 2004; Chakrabarti and Alloway, 2006). This projection from the vS1 is most likely the main source for tactile input to vM1 as tactile responses in vM1 are dependent on a viable vS1 (Farkas et al., 1999; Chakrabarti et al., 2008; Aronoff et al., 2010). Furthermore, the projection from vS1 to vM1 is anisotropic with septal regions located along rows showing significantly greater convergence in vM1 than the ones along the whisker arcs (Hoffer et al., 2003). The projection from vS1 to vM1 is limited to a millimeter wide area straddling TZ in the medio lateral direction, an area from which tactile responses can be readily recorded in vM1 (Smith and Alloway, 2013). More medial areas in vM1 are devoid of tactile responses (Gerdjikov et al., 2013; Smith and Alloway, 2013). The connection between vS1 and vM1 is reciprocal with the vM1-vS1 projection arising mainly from layers II/III and Va and targeting preferentially the deeper layers but also layer I as well as the septal regions in Layer IV in vS1 (Sato and Svoboda, 2010; Mao et al., 2011; Petreanu et al., 2012; Zagha et al., 2013; Kinnischtzke et al., 2014). The vM1 projections to vS1 primarily target VIP expressing interneurons in vS1 resulting in whisking related modulation of vS1 activity (Lee et al., 2013).
The S2 vibrissal region (vS2) also projects to vM1 with the terminals intermingled with those arising from S1 (Reep et al., 1990; Colechio and Alloway, 2009; Smith and Alloway, 2013). Projections from the posterior parietal cortex (PPC) terminate in AGm adjoining the TZ (Fabri and Burton, 1991; Reep et al., 1994; Colechio and Alloway, 2009; Smith and Alloway, 2013). Projections to vibrissal M1 connections from other somatosensory cortical regions lateral to S2 such as the parietal ventral cortex (PV) and perirhinal cortex (PR) have also been reported but the exact region of termination within vM1 remains unclear (Krubitzer et al., 1986; Reep et al., 1990; McIntyre et al., 1996; Kyuhou and Gemba, 2002; Colechio and Alloway, 2009).
The intrinsic connections of the different vM1 sub-divisions are strikingly different. Using anterograde tracer deposits in AGm (vM1) and the TZ, Weiss and Keller showed that whereas the majority of the axons labeled following a AGm tracer deposit were restricted in the same compartment, TZ injections produced axonal labeling in both AGm, TZ as well as AGl hinting at different functional connectivities of these modules (Weiss and Keller, 1994). Further, the intrinsic connectivity has a distinct laminar organization with Layer V cells projecting horizontally to Layers V and III whereas the Layer III collaterals tend to be restricted to the superficial layers (Aroniadou and Keller, 1993).
Finally both vM1's in the two hemispheres are strongly interconnected with each other (Porter and White, 1983; Miyashita et al., 1994) this interconnection being significantly stronger than the one connecting the two M1 forelimb representations (Colechio and Alloway, 2009), a finding that might have implications for the bilateral co-ordination of whisking as reported in many behavioral studies (Gao et al., 2003; Towal and Hartmann, 2006; Mitchinson et al., 2007).
Vibrissal M1 also has both afferent and efferent connectivity with various ipsilateral thalamic nuclei, viz., the mediodorsal group of nuclei (MD), the centrolateral group (CL) and the medial aspect of the posterior nucleus (POm) (Cicirata et al., 1986; Rouiller et al., 1991; Miyashita et al., 1994; Alloway et al., 2008a, 2009). Fig. 3 provides a complete schematic of thalamic and subcortical connectivities of vM1, both ipsi- and contralaterally. Further, the interanteromedial group (IAM), the anteromedial group (AM) and the ventrolateral (VL) and ventromedial (VM) groups of thalamic nuclei receive projections from vM1 of both hemispheres and may reflect the thalamic counterpart of interhemispheric whisking coordination pathways (Cicirata et al., 1986; Rouiller et al., 1991; Miyashita et al., 1994; Alloway et al., 2008b, 2009; Hooks et al., 2013). It has been suggested that the reciprocal connections between vM1 and POm play a vital role in the motor gating of ascending sensory information via the paralemniscal pathway. One possible hypothesis holds that bi-synaptic disinhibition triggered by vM1 connections to the zona incerta switches POm neurons from burst to regular firing during whisking activity (Lavallee et al., 2005; Trageser et al., 2006; Urbain and Deschenes, 2007) although zona incerta has a highly complex projection pattern which could modulate POm activity in a variety of ways.
Other sub-cortical connections
In addition, vM1 also projects to a number of other subcortical structures such as the pontocerebellum (Schwarz and Möck, 2001), dorsolateral neostriatum (Alloway et al., 2006, 2009), intermediate and deep layers of the superior colliculus (Miyashita et al., 1994; Alloway et al., 2010) as well as bilaterally to the claustrum (Smith and Alloway, 2010; Smith et al., 2012). The main subcortical recipients of vM1 cortical motor output are summarized schematically in Fig. 3. However, arguably the most critical for vibrissal movement are the putative pathways from vM1 that convey motor commands to vibrissal musculature. Direct projections from vM1 to vibrissal motoneurons in the facial nucleus have been difficult to demonstrate with anterograde tracing methods (Miyashita et al., 1994; Hattox et al., 2002; Grinevich et al., 2005; Alloway et al., 2010). However, monosynaptic tracing, a method that uses injection of a deficient rabies virus in the muscles with targeted expression of the deficient protein in motoneurons gave rise to an important breakthrough - clearly revealing the presence of direct CM projections (Sreenivasan et al., 2014). This feature is remarkable because it likens the vibrissal system to that of the primate hand, which also is characterized by direct projections of M1 to motoneurons (Rathelot and Strick, 2006). Despite the presence of direct connections, both motor systems are strongly dependent on subcortical circuitry to generate normal movements, and the function of CM connections remains a mystery. Especially, the role of M1 in computing motor commands needed to realize detailed patterns of muscle activity remains unknown. Hand spasticity developing in primates after M1 lesions clearly points to an important functional role of remaining subcortical inputs for patterning hand muscle activity. The analogous situation in the whisker motor system allows an even clearer interpretation: whisking movements after a vM1 lesion recover to almost normal kinematic profiles (Gao et al., 2003), suggesting that vM1 is not needed at all to compute normal spatiotemporal muscle activities. The enigmatic CM connection appears to have more modulatory functions - likely on a slower timescale than that used to convey patterned drive to sets of muscles.
Which subcortical centers are responsible for detailed pattern generation? Several brainstem regions receive motor cortex projections and in turn project to the facial motoneurons and are therefore candidates for an oligosynaptic motor pathway controlling whisking. Amongst these are the reticular formation, superior colliculus, nucleus ambiguus, the deep mesencephalic nucleus, the periaqueductal gray, the interstitial nucleus of the medial longitudinal fasciculus and the red nucleus (Reep et al., 1987; Miyashita et al., 1994; Hattox et al., 2002; Smith and Alloway, 2010). Particularly promising candidates are the intermediate reticular formation (IRt) containing a central pattern generator (CPG)(Moore et al., 2013) which generates rhythmic whisking movements and receives projections from the contralateral vM1 (Alloway et al., 2010; Sreenivasan et al., 2014) as well as the lateral paragigantocellularis (LPGi) which also receives projections from both ipsi- and contralateral vM1 and projects in turn to the facial motoneurons (Takatoh et al., 2013).
In summary, the subcortical motor projections can be organized into four basic groups as shown in Fig. 3. First, there are the vM1 projections to thalamus and zona incerta. Second there are vM1 projections to the neostriatum, pontine nuclei and claustrum which form cortico-subcortical loops for higher order functions which are not yet clearly understood. Third, there are vM1 projections to various groups of brainstem nuclei, the second order motoneurons which in turn project to the intrinsic/extrinsic premotor neurons in the facial nucleus. Finally there are the direct CM projections to the facial nucleus.
Functional modules of vM1
There is mounting evidence that the motor control of whisking is achieved through the concerted action of different motor cortical modules with different functional specializations. As discussed above they are connected either directly to the vibrissal motoneurons in the facial nucleus or indirectly via brainstem centers such as CPGs, shown in red arrows in Fig. 3 or the TBL, depicted in blue (Chakrabarti and Schwarz, 2014a, 2014b). Presently, three modules have been described in more detail, and can be delineated using functional assessment (ICMS and tactile responses/connectivity). A region located medio-caudally evokes rhythmic whisking upon prolonged ICMS, and was thus named the rhythmic whisking region or RW (Haiss and Schwarz, 2005). In contrast a fronto-lateral area evokes whisker retraction accompanied by face and body movements and was called the retraction face region (RF) (Haiss and Schwarz, 2005). The presence of RW and RF modules have been also confirmed in the mouse vM1 (Ferezou et al., 2007; Matyas et al., 2010). Electrophysiological monitoring and tract tracing has led to the redefinition of RF into two distinct regions - a so-called transitional zone or TZ located in the cytoarchitectonically defined transitional region between AGm and AGl and receiving tactile input from vS1 (Smith and Alloway, 2013) and a rostral area devoid of such tactile input which we name PMPF because of its putative premotor and prefrontal functions (Neafsey and Sievert, 1982; Uylings et al., 2003). It is quite possible that with future explorations in this area, of which very little is known, further modules will be discovered. Further, vS1 has been shown to access premotor neurons in the spinal trigeminal nuclei (Sreenivasan et al., 2014) that are part of the TBL, the brainstem sensorimotor reflex arc (Nguyen and Kleinfeld, 2005). Via these connections it evokes whisker retraction movements upon ICMS (Matyas et al., 2010). As will be apparent from the following sections, even the functional roles of RW and TZ, the best investigated parts of vM1, are presently far from clear. What is missing (and therefore should be an immediate target of research) is the elucidation of the differential projection patterns of each of these modules to the brainstem premotor circuits, which hopefully will help to clarify their functions.
Rhythmic Whisking region (RW)
As shown in Fig. 4A, prolonged ICMS in RW in awake rats elicits rhythmic whisking which is virtually indistinguishable from natural whisking in rats (Haiss and Schwarz, 2005). Under different types of anesthesia, these rhythmic whisking movements have been found to be either strongly suppressed (Cramer and Keller, 2006) or reduced to monophasic protraction movements (Sanderson et al., 1984; Haiss and Schwarz, 2005). Electrophysiological recordings in RW in awake rats (Fig. 4B), trained to generate explorative whisking, showed no coherence of spiking with whisking on the frequency scale of a whisker stroke, ~10 Hz (Friedman et al., 2006, 2012; Gerdjikov et al., 2013). RW, therefore, does not seem to be involved in the programming of whisker trajectories in a stroke by stroke fashion. Interestingly, RW cell firing rates firstly encode either decrements or increments of these movement parameters, and secondly, follow rather than anticipate abrupt whisking onset (Gerdjikov et al., 2013). RW, thus, shows a loose relation to movement with part of the activity signaling whisker quiescence rather than movement and little involvement in movement initiation. Further, RW does not receive any tactile signals about whisker contact with an object (Gerdjikov et al., 2013).
The rather abstract RW motor signals may constitute input signals to the CPG, depicted in Fig. 4C, which has been recently found in the ventral part of the intermediate band of the reticular formation (vIRt) near the Bötzinger complex (Moore et al., 2013). This CPG receives projections from vM1, as shown in Fig. 4D (Sreenivasan et al., 2014). In contrast to RW (Gao et al., 2003), the blockade of vIRt entirely prevents whisking and its activation generates continuous rhythmic whisking (Moore et al., 2013; Fig. 4C). As activity anticipating whisker movement has not been found in RW, speaking against a classical motor function, an alternative speculation is that RW may be an internal monitor of CPG function (Gerdjikov et al., 2013).
Premotor and Prefrontal region (PMPF)
The earlier described Retraction Face region (RF) was defined as the area of vM1 where ICMS in the awake rat evokes monophasic whisker retraction in concert with face and body movements. In the anesthetized rat, face and body movements are typically absent (Haiss and Schwarz, 2005). In the light of new evidence, we classify the region previously described as RF into two distinct functional zones, - the transitional zone (TZ) and the frontal Prefrontal and Premotor region (PMPF), the latter devoid of any sensory input (Smith and Alloway, 2013). Not much is known about the functionality of PMPF in comparison to its extensively studied neighbor TZ, except that ICMS here evokes whisker and face retraction as in TZ. A possible hypothesis that whisker retraction seen in both PMPF and TZ could be involved in orientation responses is discussed below in next section but a delineation of the functional properties of this region needs systematic future exploration.
Transitional Zone (TZ)
The best studied part of the erstwhile RF is the more caudal part sandwiched between RW and the body and limb representations which has been shown to receive direct projections from vS1 (Krubitzer et al., 1986; Koralek et al., 1990; Reep et al., 1990; Miyashita et al., 1994; Alloway et al., 2004; Chakrabarti and Alloway, 2009; Colechio and Alloway, 2009; Aronoff et al., 2010; Tennant et al., 2011; Mao et al., 2011; Smith and Alloway, 2013). Judging from published coordinates of electrode placement, and reports of tactile inputs many previous studies on rat vM1 neuronal activity have focused on TZ (Fig. 5A). Sensory responses to whisker deflections in the TZ are dependent on the intactness of vS1 (Farkas et al., 1999; Chakrabarti et al., 2008), as shown in Fig. 5B and have been observed by several studies (Farkas et al., 1999; Kleinfeld et al., 2002; Chakrabarti et al., 2008; Aronoff et al., 2010; Petreanu et al., 2012) . Experiments in anesthetized animals have shown that when moving the electrode from TZ toward the medial bank (likely corresponding to RW), the strength of ICMS evoked movements becomes stronger while tactile responses vanish as illustrated in Fig 5C (Smith and Alloway, 2013). It is important to mention here that part of what has been cytoarchitectonically defined as AGm has been functionally classified as RW (Haiss and Schwarz, 2005). In line with the above evidence from the Alloway lab, our recordings from RW also failed to show any sensory responses in the awake animal upon contact with a real object (Gerdjikov et al., 2013). Sensory projections from vS1 to TZ have also been shown to activate inhibitory TZ neurons with shorter latencies and larger magnitudes than their excitatory neighbors, thus selectively activating a feedforward inhibitory network in vM1 and possibly allowing sensory input to dynamically recruit different motor cortical modules (Murray and Keller, 2011). Further, clipping of whiskers during early development has been shown to cause a reduction in the size of TZ as measured using ICMS raising the possibility of a critical phase for a dependency of TZ on tactile inputs during development (Keller et al., 1996).
Reports on movement coding of TZ neurons are diverse. LFP recordings, most likely collected in the TZ, were reported to reflect rhythmic whisking (Ahrens and Kleinfeld, 2004) although unit recordings failed to confirm the same. There are some rare cells in a wide region overlapping PMPF and TZ that are modulated by whisking rhythm (Hill et al., 2011), but whether a specific readout is formed from them to generate rhythmic whisking is an open question. Calcium transients in axonal terminals of TZ neurons projecting to layer 1 in vS1, recorded in mice performing an object localization task, were reported to carry a host of behavioral signals on a slow time scale, which encompass whisking activity and touch (Petreanu et al., 2012).
Another possible functional interpretation of the ICMS-evoked whisker retraction is that it takes part in guiding navigation. Neurons presumably located in TZ were found to encode direction of orientation responses, including whole body orientation movements accompanied by concomitant whisker retraction (Erlich et al., 2011). Inactivation of vM1 impaired such orientation movements which argues in favor of TZ being involved in the co-ordination of head, body and whisker movements and therefore having possible connections to a far wider variety of brainstem (face) and spinal cord (body) motor centers than RW.
Still another possible functional explanation comes from the observation that ICMS-evoked retraction movements give way to rhythmic whisker movements after lesions of vS1 (Matyas et al., 2010). According to this view TZ is the putative vM1 module that is perhaps involved in adapting rhythmic whisking patterns according to tactile inputs.
Barrel Cortex (vS1)
From the findings of Matyas et al. (2010) which showed that vM1 mediated whisker retraction is critically dependent on the intactness of vS1 and vS1 by itself evokes retraction movements upon ICMS (Matyas et al., 2010), it could well be concluded that vS1 itself is a motor structure. These investigators further showed that vM1 and vS1 project to partially overlapping subgroups of premotor neurons in the brainstem. The biggest difference was found for regions in the intermediate and parvocellular portions of the reticular formation and the facial nucleus which receive predominant vM1 input whereas vS1 predominantly targeted the trigeminal nuclei pars oralis, interpolaris and to a lesser extent caudalis (Sreenivasan et al., 2014).
Whisking control - the extent of cortical involvement
In summary the understanding of control of whisking movements by sensorimotor cortex is complicated by the existence of different functional motor modules in vM1 and contributions of vS1, and by their differential connection to a variety of brainstem centers including only partially known CPGs and reflex arcs – not to speak of interconnections on all hierarchical levels of sensorimotor integration that we ignored in this review. Despite the complexity, the functional organization of whisker motor control is beginning to emerge. One basic property of the system is that cortex sensorimotor cortex is not likely to contain rhythm generating functions itself, despite the existence of CM cells in vM1 and activity modulated by whisker phase in vM1 and vS1. This will allow the future characterization of CM connections, the function of which is ignored in the primate fingertip system as well. The second basic property is that brainstem premotor circuits are differentially controlled by vM1 and vS1 and fall apart in at least two functional domains, one motor (the CPG(s)), and one sensorimotor (the TBL(s)). Sorting out the premotor neuronal elements contributing to these brainstem networks and their cortical control presents the main challenge for immediate future research.
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