Whisking pattern generation
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Author: Prof. Phil Zeigler, Psychology Department, Hunter College of the City University of New York
Author: Prof. Asaf Keller, Department of Anatomy and Neurobiology, University of Maryland School of Medicine
Dr. Phil Ziegler accepted the invitation on 7 June 2008 (self-imposed deadline: 7 September 2008).
Whisking Pattern Generation H. Philip Zeigler and Asaf Keller
The delineation of central mechanisms underlying the generation and modulation of rhythmic movement patterns in vertebrates [Central Pattern Generators: CPGs], including respiration and locomotion, swallowing, chewing and licking, has been an important goal of systems neuroscience. Common to many of these functions is the operation of small ensembles of premotor neurons that generate patterned drive to motoneurons, producing relatively simple repetitive patterns of movement even after the removal of any identifiable phasic sensory inputs. However, while the generation of these patterns in the absence of phasic peripheral influences is one defining criterion for CPGs, another is their susceptibility to modulation by both sensory inputs and descending control mechanisms. An additional commonality is the ubiquity of chemical modulation, often by serotonergic mechanisms. These three sets of factors, endogenous rhythm generation, descending (e.g. cortical and neuromodulatory) influences and peripheral sensory inputs, interact to provide adaptive control of the rhythmic behavior pattern.
Rodent whisking behavior has many features that make it an excellent model for the study of such interactions. It has a relatively simple motor plant, its peripheral innervation is well-described, as are its central sensory and motor pathways, and the system is not complicated by a proprioceptive loop, but it receives sensory feedback (see Nguyen and Kleinfeld, 2005). In recent years, behavioral studies of whisking in both head-fixed and freely moving rodents have been facilitated by the development of optoelectronic and videographic methods (Bermejo et al., 1998; Knutsen et al., 2005). Together, the relatively simple mechanics and advanced monitoring techniques available for this system have facilitated investigations of the underlying control circuitry. Here we review recent progress in the analysis of central pattern generation mechanisms in rodents and suggest that its mediating mechanisms, though similar in many respects to those of the more classic models, have a number of novel features of interest, including the active participation of vibrissae motoneurons in the generation of the whisking rhythm.
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Whisking musculature
The mystacial vibrissae are sinus hairs, each emerging from a follicle that is embedded in the mystacial pad. Protraction of the vibrissae is an active process, affected by contraction of the intrinsic muscles. These are small sling-like muscles that wrap around the base of each follicle and attach to the pad surrounding the next caudal vibrissa. Retraction of the vibrissae can occur passively, through the elastic properties of the tissue. Retraction is also aided by active contraction of a set of extrinsic muscles that are involved with movement of not only the vibrissae, but also of several parts of the face, such as the lips and nares. Kleinfeld, Zeigler and colleagues (Hill et al., 2008) have developed a model to describe the interactions between these intrinsic and extrinsic musculature. This model proposes that the periodic motion of the vibrissae and mystacial pad during whisking results from three phases of muscle activity. First, the vibrissae are thrust forward as the rostral extrinsic muscle, musculus (m.) nasalis, contracts to pull the pad and initiate protraction. Second, late in protraction, the intrinsic muscles pivot the vibrissae farther forward. Third, retraction involves the cessation of m. nasalis and intrinsic muscle activity and the contraction of the caudal extrinsic muscles m. nasolabialis and m. maxillolabialis to pull the pad and the vibrissae backward. The model suggests that the combination of extrinsic and intrinsic muscle activity leads to a more extended range of vibrissa motion than would be available from the intrinsic muscles alone.
The follicular muscles are structurally homogeneous: In addition, essentially all follicular muscles are of the fast-twitch type and lack proprioceptors. Analyses by Brecht and collaborators (Jin et al., 2004) demonstrate that >90% of the muscle fibers are of type 2B, which have high levels of anaerobic glycolytic enzymes providing a rapid source of ATP and high maximum velocity of contraction but are less fatigue resistant than other muscle fiber types. The high percentage of type 2B fibers distinguishes the intrinsic vibrissa musculature from skeletal muscles and may have evolved for fast scanning of the sensory environment. A comparable analysis of the extrinsic muscles has not been reported, but they are presumed to contain a mix of slow and fast-twitch fibers, as well as proprioceptors.
Whisking motoneurons
Both the extrinsic and follicular muscles are innervated by motoneurons whose parent somata reside in the facial nucleus ipsilateral to the innervated vibrissa pad. Relatively little is known about the motoneurons innervating the extrinsic muscles, but the follicular muscles are innervated by motoneurons (“whisking motoneurons”) in the lateral and intermediate subdivision of the facial nucleus. These motoneurons are arranged, roughly, in a somatotopic manner corresponding to the arrangement of the vibrissae. Available evidence suggests that, with rare exception, each motoneuron innervates only one vibrissa follicle, and that the motoneurons have no axon collaterals within the facial nucleus or in any other structure. Further, there are no known interneurons in the lateral facial nucleus, which appears to be composed exclusively of motoneurons and glial cells.
Although the facial nucleus contains a large number of gap junctions, these appear to primarily involve glial cells. Attempts to identify gap junctions, or electrical coupling among facial motoneurons have so far been unsuccessful.
Some rhythmic motor functions, including locomotion, breathing and chewing, are generated by motoneurons that have intrinsic membrane properties that allow them to function as intrinsic or conditional bursters. For example, they may express plateau potentials, which generate prolonged firing in response to brief current injections, and a hyperpolarization-activated cationic current (Ih) active at or near resting membrane potential. None of these properties characterize whisking motoneurons, suggesting that they are not intrinsically bursting and that they require rhythmic synaptic inputs, or a neuromodulatory drive, to generate rhythmic firing. Below we consider potential sources of these synaptic inputs, and hypothetical mechanisms through which they might generate rhythmic whisking.
Afferents to whisking motoneurons
In an attempt to identify potential contributors to rhythm generation in this system Hattox et al (Hattox et al., 2002) systematically labeled and identified the origin of afferents to whisking motoneurons. A very large number of brainstem, metencephalic and midbrain nuclei were found to provide unilateral, and sometimes bilateral, innervation to the lateral facial nucleus. In addition Brecht and collaborators (Grinevich et al., 2005), identified a pathway providing a direct, though sparse, connection between the motor cortex and whisking motoneurons.
The plethora of regions innervating the whisking motoneurons suggests that rhythm generation is this system is subject to control by a large number of centers that might be active during different behavioral states. Of particular interest were the findings that some of these regions also received direct inputs from the vibrissa representation in the motor cortex, suggesting that these hypothetical rhythm generators could be controlled voluntarily. Subsequent studies have attempted to narrow down this list by seeking to identify causal relationships between activity in these afferents and whisking behaviors.
Brainstem reticular formation
The brainstem reticular formation originates a particularly dense projection to the facial nucleus. Several lines of anatomical and physiological evidence implicate it in a whisking CPG. Motoneurons in this region are involved in a number of rhythmic motor acts in mammals, such as licking, mastication, and locomotion (for review see Buttner-Ennever and Holstege, 1986). Similarly, the reticular formation in birds contains the CPG for rhythmic acts such as pecking and jaw movements (Berkhoudt et al., 1982; Wild et al., 1985). In rodents, microstimulation of neurons in this region evokes rhythmic whisking, suggesting that these neurons may control whisking behaviors by driving the motoneurons. In support of this idea, electrical stimulation of neurons in the reticular formation evokes monosynaptic EPSPs in facial motoneurons in the cat. Below we discuss the potential role of an important subset of these reticular formation neurons: the serotonergic neurons of the the raphe and the lateral paragigantocellularis nucleus.
Trigeminal nuclei
The trigeminal nerve carries sensory inputs from the vibrissae and innervates the principal trigeminal nucleus as well as the three spinal trigeminal nuclei (oralis, inter- polaris, and caudalis). Injection of retrograde markers in facial nucleus produced labeling in the spinal trigeminal nuclei which was sparse, exclusively ipsilateral, and observed predominantly in the nucleus caudalis. Nevertheless, as demonstrated by Nguyen and Kleinfeld (Nguyen and Kleinfeld, 2005) trigeminal inputs to facial motoneurons can evoke a rapidly depressing reflex that might provide a positive sensory feedback to the vibrissa musculature during whisking behaviors.
Red nucleus
The dorsal regions of the red nucleus project to the contralateral facial nucleus, suggesting that this structure is involved in relaying inputs from the olivocerebellar system to whisking motoneuorns. This is of interest because the characteristic frequency of rhythmic activity in the olivocerebellar system is similar to the frequency of rhythmic whisking (see, e.g., Lang et al., 1997). However, inactivation of the inferior olive does not affect exploratory vibrissa movements (Semba and Komisaruk, 1984), so this rhythmic activity may not be causally related to these movements. Furthermore, stimulation of the red nucleus does not reliably evoke vibrissa movements (Isokawa-Akesson and Komisaruk, 1987). Thus, the role of the red nucleus in modulating vibrissa movements is at present unclear.
Cholinergic activating system
The pedunculopontine tegmental nucleus (PPTg) is part of the brainstem cholinergic activating system, critical for controlling arousal and states of vigilance. It sends dense, presumably cholinergic inputs to the lateral facial nucleus. Ongoing work by M. Deschenes and colleagues suggests that these cholinergic inputs might “prime” the whisking motoneurons for movement onset.
Superior colliculus
A particularly dense projection to lateral facial motoneurons arises from both (contralateral and ipsilateral) superior colliculi (SC) and electrical stimulation of SC elicits contralateral vibrissa movements. SC also receives dense projections from the vibrissa representation of the motor cortex suggesting its role in rhythmic whisking can be voluntarily regulated. Because SC also forms reciprocal connections with trigeminal nuclei relaying vibrissal information it is likely to be involved in integrating inputs from motor behaviors with inputs from somatosensory, visual, and auditory sensory modalities. For these reasons the superior colliculus was the object of a series of studies to be discussed in a later section.
Whisking behavior
We demonstrated above that whisking behavior cannot emerge from the intrinsic properties of the pertinent motoneurons, or from interactions among them. Rather, rhythmic whisking must be governed by inputs these motoneurons receive from some or all the myriad of nuclei that project to these motoneurons. Formulating testable hypotheses regarding the nature of these rhythm generators requires a comprehensive description of the whisking behaviors, which we summarize below. (For a more complete description see other chapters in this entry.)
Whisking: Development, kinematics and bilateral coordination
In rat pups, small, uncoordinated movements of the vibrissae are evident as early as days P10-14, a few days before eye opening and before the initial appearance of reliable motor maps to stimulation of the cortical vibrissal motor area (vMcx; AK, unpublished observations). During the next two weeks the movements gradually increase in both amplitude and frequency, maturing at the characteristic modal frequency for whisking in air (5-9 Hz) by the end of the first month (Welker, 1964; Landers and Zeigler, 2006). Over the same period, there is a parallel increase in the bilateral coordination of whisking on the two sides.
In adult rats, the rhythmic vibrissa movements used in “active sensing” (whisking and palpation) exhibit a range of frequencies from 5-20 Hz <<UNLESS THERE IS A REFERENCE FOR 1-HZ RHYTHM>>, with dominant frequencies of 5-9 Hz in both head-fixed and freely moving animals (Carvell and Simons, 1990; Gao et al., 2001; Hill et al., 2008). [Note that the whisking parameters reported here were computed from observations on the behavior of the laboratory rat. No comparable data are available for rats observed under more natural conditions and mice are reported to whisk at significantly higher frequencies (Jin et al., 2004)]. However, as with other rhythmic movements, whisking patterns are strongly influenced by signals from peripheral receptors. Higher frequencies (15-25 Hz) have been reported during palpation of objects (“foveation”) (Berg and Kleinfeld, 2003a) and, during texture discriminations, modulation of movement parameters (amplitude, frequency and bandwidth) is correlated with discriminanda properties (Carvell and Simons, 1990; Harvey et al., 2001). Whisking rates may also be brought under voluntary control using behavioral contingencies such as operant reinforcement schedules (Gao et al., 2003b). The brain mechanisms thought to mediate such voluntary control are discussed below.
Observations of whisking in air (without vibrissal contacts) convey a strong impression of bilateral synchrony, but even under head fixed conditions the activity of bilaterally homologous vibrissae is not always in phase or identical in amplitude (see Fig.2 in Gao et al., 2001). Indeed, under natural conditions rats may exhibit considerable bilateral asynchrony, with persistent whisking on one side and no movements on the other (Wineski, 1985; Towal and Hartmann, 2006). In contrast, during whisking in air, vibrissae movements on the same side of the face are synchronous, with similar protraction amplitudes and topographies (Bermejo et al., 2005) (but see Sachdev et al., 2002). The mechanisms responsible for either bilateral or unilateral synchrony is presently unknown (see below).
Whisking behavior patterns: effects of deafferentation
The observation that rhythmic movements persist after sensory denervation (Welker, 1964), decerebration (Lovick, 1972) and cortical ablations (Semba and Komisaruk, 1984) suggested the operation of a central pattern generating mechanism. Subsequently, a detailed analysis of whisking in air in head-fixed animals, using high-resolution optoelectronic monitoring methods for kinematic analysis (Gao et al., 2001) demonstrated that deafferentation (infraorbital nerve section:IOx) when carried out in a single-stage procedure, did not affect the generation, spectral properties, kinematics, or bilateral coordination of the normal rhythmic whisking pattern. After unilateral section, there was an immediate and significant increase in whisking frequency on both sides of the face that was abolished by subsequent section of the contralateral sensory nerve. Taken in conjunction with the observations of bilateral whisking asynchrony in normal rats, these data suggest, first, the existence of distinct right and left CPGs with separate outputs to homolateral motoneurons and, second, some degree of coupling of the right and left CPGs.
Additional support for these conclusions comes from a deafferentation study carried out in developing rat pups (Landers and Zeigler, 2006). Unilateral IO section at P7 (before the emergence of vibrissae movements) has no effect on whisking behavior, while transection at P12 significantly delays the emergence of the normal whisking rhythm, but only on the treated side. Whisking rhythms on the untreated side emerged at the normal time, but with a slightly, but significantly increased frequency. Bilateral IOx delayed the emergence of normal whisking until almost the end of the first postnatal month. Once normal whisking had emerged, re-sectioning of the sensory nerve had no effect on the re-emergence of vibrissae movements. In pups in which unilateral sensory denervation is combined with contralateral motor denervation thus reducing the afference generated by active whisking) not only is the initial emergence of whisking significantly delayed but whisking frequency remains significantly reduced two months postnatally.
Taken together, the deafferentation data from adults and pups help to delineate some of the functional properties of central pattern generation mechanisms for whisking, including independent, but closely coupled CPGs on the two sides, and a sensitive period during, but not after which, trigeminal afference is critical for the normal development of rhythmic movement patterns. Given that the circuitry for such complex motor patterns as locomotion and suckling is constructed during embryonic development (Nishimaru and Kudo, 2000; Kozlov et al., 2003), trigeminal afference during development seems to contribute primarily to the shaping of pre-existing pattern-generating circuitry.
Hypotheses concerning the neural substrate for the whisking CPG
To date, the elusive CPG has yet to be identified, and neither has it been established whether there exist one or several such CPGs. Indeed, it is entirely feasible that whisking is not governed by a conventional CPG, but, rather, that whisking is controlled by one or more rhythm generators that do not have an intrinsic propensity to generate output at a fixed rhythm. As of this writing, only three potential rhythm generators for whisking have been studied in detail: the serotonergic brainstem nuclei, the motor cortex, and the superior colliculus.
Serotonin and rhythmic whisking
Cranial and spinal motor nuclei, including whisking motoneurons in the lateral facial nucleus, receive some of the densest serotonergic inputs in the brain (Li et al., 1993; Hattox et al., 2003). These inputs arise from several brainstem nuclei known to contain serotonergic neurons, including the raphe magnus and the lateral paragigantocellularis nucleus (Bellintani-Guardia et al., 1996). These serotonergic nuclei also receive dense inputs from the vibrissa representation of the motor cortex (Hattox et al., 2003).
Serotonin is an important modulator of many rhythmic motor acts, including locomotion, respiration, chewing, suckling and licking (Das and Fowler, 1995). Like other spinal and cranial motoneurons, facial motoneurons respond to serotonin both in vivo (VanderMaelen and Aghajanian, 1980) and in vitro (Larkman et al., 1989) with an increase in excitability mediated by a membrane depolarization, an increase in input resistance, and a decrease in their firing threshold. These observations provide an anatomical, behavioral and physiological rationale for implicating serotonin in the regulation of rhythmic whisking.
A series of studies from the Keller laboratory has provided direct evidence for a prominent role of serotonin in initiating and regulating whisking (Hattox et al., 2002; Hattox et al., 2003; Cramer and Keller, 2006; Friedman et al., 2006; Cramer et al., 2007). Indeed, these authors have argued that serotonin may be both necessary and sufficient for rhythmic whisking. In brief, their findings are:
- Infusion of serotonin receptor antagonists into the facial nucleus (in vivo) suppresses voluntary whisking.
- Stimulation (electrical or chemical) of LPGi evokes vibrissa movements.
- Rhythmic whisking evoked by intracortical microstimulation (ICMS) of the rhythmic protraction region of motor cortex is suppressed by serotonin receptor antagonists.
- The tonic activity of putative serotonergic pre-motoneurons recorded in vivo is positively correlated with the frequency of whisking evoked by cortical stimulation.
- In vitro, serotonin, or its receptor agonists, drives facial motoneurons to fire at, or below, whisking frequencies. This action is suppressed by serotonin receptor antagonists.
- Serotonin acts by facilitating, in vibrissae motoneurons, a persistent inward current which evokes rhythmic firing in whisking motoneurons. The magnitude of this persistent current is positively correlated with the motoneurons’ firing rate.
One interpretation of these findings is that, unlike conventional mammalian CPGs, vibrissa motoneurons actively participate in the rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae. Nevertheless, many of the nuclei that project to the lateral facial nucleus (see above) contain non-serotonergic neurons whose role in the regulation of whisking remains to be established. Within these nuclei may reside a more classically composed whisking CPG that delivers rhythmic inputs to the motoneurons
The motor cortex and rhythmic whisking
Although it is widely assumed that the vibrissal representation of motor cortex (vMCx) participates in voluntary whisking, the mechanisms by which this occurs remain to be established. One line of evidence suggests that whisking might be controlled by the vMCx on a cycle-by-cycle basis. Berg and Kleinfeld (Berg and Kleinfeld, 2003b) reported that stimulation of the vMCx at whisking frequencies evokes vibrissae movements entrained to the stimulation frequency. This result coupled with the recent findings that vibrissa motoneurons receive direct, albeit sparse, projections from vMCx (Grinevich et al., 2005) suggest that vMCx can, in principle, control whisking on a cycle-by-cycle basis.
In contrast, the data described above suggest that rhythmic whisking is generated by a subcortical CPG or rhythm generator, under modulatory control of the vMCx. Whisking persists after decerebration (Lovick, 1972), or cortical ablation (Semba and Komisaruk, 1984; Gao et al., 2003a), indicating that vMCx is not necessary for rhythmic whisking. Furthermore, recordings of cortical activity during voluntary whisking suggest vMCx does not directly generate whisking. Extracellular recordings from single vMCx neurons in awake behaving rats failed to identify covariations between task related neuronal discharges and vibrissae movements (Carvell et al., 1996). Additionally, vMCx activity precedes the onset of voluntary whisking and that rhythmic whisking outlasts vMCx activity, consistent with activation of a whisking CPG by vMCx (Friedman et al., 2006). ICMS of the rhythmic subregion of vMCx evokes whisking epochs that are preceded by relatively long onset latencies, occur at frequencies distinct from the stimulation frequency, and can outlast the stimulus (Haiss and Schwarz, 2005; Cramer and Keller, 2006). Taken together, these observations are consistent with the hypothesis that vMCx does not directly generate whisking but instead acts through a subcortical whisking CPG that contains an essential serotonergic component.
Obviously, the two control strategies are not mutually exclusive (Brecht, 2004). Indeed, Brecht et al. (Brecht et al., 2004) found that stimulation of layer V vMCx neurons evokes vibrissae movements entrained to the stimulation frequency, whereas stimulation of layer VI neurons produces bouts of whisking that are out of phase across trials. Thus vMCx might use different control strategies to produce or modulate rhythmic whisking
The superior colliculus and rhythmic whisking
The superior colliculus sends dense and direct projections to the facial nucleus, where the vibrissa motor neurons are located (Miyashita and Mori, 1995; Hattox et al., 2002), and stimulation of the superior colliculus produces movements of the vibrissae (McHaffie and Stein, 1982). These findings suggest that the superior colliculus may also have a role in controlling whisking kinematics. Indeed the superior colliculus may have a unique role in whisking behavior by functioning as a sensorimotor loop. Collicular neurons reliably respond to vibrissae contacts with short-latency spikes reflecting their direct and potent inputs from trigeminal nuclei (Hemelt and Keller, 2007) (and see Drager and Hubel, 1976). This, coupled with its direct projections to the facial nucleus, implies that the superior colliculus functions as part of a closed loop (Kleinfeld et al., 1999) through which vibrissae contacts reliably evoke vibrissae movements.
Consistent with this hypothesis, Hemelt and Keller (Hemelt and Keller, 2008) found that in anesthetized rats, microstimulation of the colliculus evoked a sustained vibrissa protraction. This suggests that the superior colliculus plays a pivotal role in vibrissa movement – regulating vibrissa set point and whisk amplitude. This result contrasted with the effects of stimulation of vMCx, which produced rhythmic protractions. Movements generated by the superior colliculus are independent of motor cortex and can be evoked at lower thresholds and shorter latencies than those generated by the motor cortex. Thus, with the motor cortex controlling the whisking frequency, the superior colliculus control of set point and amplitude would account for the main parameters of voluntary whisking.
Rhythm generation in the vibrissa system: Some unanswered questions
These relate primarily to mechanisms of synchronization and coordination of neuronal activity at several levels of the vibrissa sensorimotor system. They include (1) the simultaneous generation (in unison) of the whisking rhythm by all facial motoneurons on one side of the animal, (2) the coupling of whisking activity on the two sides of the face, (3) the coordination of retraction and protraction movements, (4) the contribution of motor cortex and other potential sources of descending motor control (e.g. superior colliculus; basal ganglia, cerebellum) and (5) the generation of and alternation between different types of whisking.
The currently available data provides only suggestive answers to these questions.
(1) Because the facial nucleus is thought not to contain interneurons, and its neurons do not have axon collaterals, Cramer, et al (Cramer et al., 2007) suggested that unilateral synchronization of whisking might result from coordinated discharge of electrically coupled vFMNs. However, gap junctions are present in the facial nucleus only between astrocytes (Rohlmann et al., 1993), and unpublished results (Y. Li and A. Keller) have thus far failed to identify gap junctions or electrical coupling among vFMNs. (2) While bilateral synchronization could be mediated by one of the numerous pre-motoneuron groups identified by Hattox et al (2002), its mechanism remains to be characterized. (3) Although earlier models of rhythm generation treated retraction as a passive, viscoelastic-relaxation process, the characterization of retraction as an active component of a triphasic neuromuscular mechanism led Kleinfeld et al (Kleinfeld, 2008) to conclude that the CPG underlying the biomechanics of whisking consists of three coupled oscillators corresponding to the three phases of muscle activity. However, the circuitry mediating this coupling remains undefined. Answers to these questions and to the question of whether there are multiple circuits for multiple forms of whisking will require neurobehavioral experiments in awake, behaving rodents analogous to those common with primates, combining unit recording, experimental control of the whisking response and high resolution, “online” monitoring of the vibrissae movements.
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