Transneuronal Transport Of Rabies Virus Research Articles

A cerebro-cerebellar network for learning visuomotor associations

Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.

Volitional inspiration is mediated by two independent output channels in the primary motor cortex.

The diaphragm is a multifunctional muscle that mediates both autonomic and volitional inspiration. It is critically involved in vocalization, postural stability, and expulsive core-trunk functions, such as coughing, hiccups, and vomiting. In macaque monkeys, we used retrograde transneuronal transport of rabies virus injected into the left hemidiaphragm to identify cortical neurons that have multisynaptic connections with phrenic motoneurons. Our research demonstrates that representation of the diaphragm in the primary motor cortex (M1) is split into two spatially separate and independent sites. No cortico-cortical connections are known to exist between these two sites. One site is located dorsal to the arm representation within the central sulcus and the second site is lateral to the arm. The dual representation of the diaphragm warrants a revision to the somatotopic map of M1. The dorsal diaphragm representation overlaps with trunk and axial musculature. It is ideally situated to coordinate with these muscles during volitional inspiration and in producing intra-abdominal pressure gradients. The lateral site overlaps the origin of M1 projections to a laryngeal muscle, the cricothyroid. This observation suggests that the coordinated control of laryngeal muscles and the diaphragm during vocalization may be achieved, in part, by co-localization of their representations in M1. The neural organization of the two diaphragm sites underlies a new perspective for interpreting functional imaging studies of respiration and/or vocalization. Furthermore, our results provide novel evidence supporting the concept that overlapping output channels within M1 are a prerequisite for the formation of muscle synergies underlying fine motor control.

Hindlimb muscle representations in mouse motor cortex defined by viral tracing.

Descending pathways from the cortex to the spinal cord are involved in the control of natural movement. Although mice are widely used to study the neurobiology of movement and as models of neurodegenerative disease, an understanding of motor cortical organization is lacking, particularly for hindlimb muscles. In this study, we used the retrograde transneuronal transport of rabies virus to compare the organization of descending cortical projections to fast- and slow-twitch hindlimb muscles surrounding the ankle joint in mice. Although the initial stage of virus transport from the soleus muscle (predominantly slow-twitch) appeared to be more rapid than that associated with the tibialis anterior muscle (predominantly fast-twitch), the rate of further transport of virus to cortical projection neurons in layer V was equivalent for the two injected muscles. After appropriate survival times, dense concentrations of layer V projection neurons were identified in three cortical areas: the primary motor cortex (M1), secondary motor cortex (M2), and primary somatosensory cortex (S1). The origin of the cortical projections to each of the two injected muscles overlapped almost entirely within these cortical areas. This organization suggests that cortical projection neurons maintain a high degree of specificity; that is, even when cortical projection neurons are closely located, each neuron could have a distinct functional role (controlling fast- versus slow-twitch and/or extensor versus flexor muscles). Our results represent an important addition to the understanding of the mouse motor system and lay the foundation for future studies investigating the mechanisms underlying motor system dysfunction and degeneration in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy.

The mind-body problem: Circuits that link the cerebral cortex to the adrenal medulla

Which regions of the cerebral cortex are the origin of descending commands that influence internal organs? We used transneuronal transport of rabies virus in monkeys and rats to identify regions of cerebral cortex that have multisynaptic connections with a major sympathetic effector, the adrenal medulla. In rats, we also examined multisynaptic connections with the kidney. In monkeys, the cortical influence over the adrenal medulla originates from 3 distinct networks that are involved in movement, cognition, and affect. Each of these networks has a human equivalent. The largest influence originates from a motor network that includes all 7 motor areas in the frontal lobe. These motor areas are involved in all aspects of skeletomotor control, from response selection to motor preparation and movement execution. The motor areas provide a link between body movement and the modulation of stress. The cognitive and affective networks are located in regions of cingulate cortex. They provide a link between how we think and feel and the function of the adrenal medulla. Together, the 3 networks can mediate the effects of stress and depression on organ function and provide a concrete neural substrate for some psychosomatic illnesses. In rats, cortical influences over the adrenal medulla and the kidney originate mainly from 2 motor areas and adjacent somatosensory cortex. The cognitive and affective networks, present in monkeys, are largely absent in rats. Thus, nonhuman primate research is essential to understand the neural substrate that links cognition and affect to the function of internal organs.

Multiple areas of the cerebral cortex influence the stomach

The central nervous system both influences and is influenced by the gastrointestinal system. Most research on this gut-brain connection has focused on how ascending signals from the gut and its microbiome alter brain function. Less attention has focused on how descending signals from the central nervous system alter gut function. Here, we used retrograde transneuronal transport of rabies virus to identify the cortical areas that most directly influence parasympathetic and sympathetic control of the rat stomach. Cortical neurons that influence parasympathetic output to the stomach originated from the rostral insula and portions of medial prefrontal cortex, regions that are associated with interoception and emotional control. In contrast, cortical neurons that influence sympathetic output to the stomach originated overwhelmingly from the primary motor cortex, primary somatosensory cortex, and secondary motor cortex, regions that are linked to skeletomotor control and action. Clearly, the two limbs of autonomic control over the stomach are influenced by distinct cortical networks.

New Cerebello-Cortical Pathway Involved in Higher-Order Oculomotor Control.

The cerebellum and the basal ganglia play an important role in the control of voluntary eye movement associated with complex behavior, but little is known about how cerebellar projections project to cortical eye movement areas. Here we used retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to supplementary eye field (SEF) of the frontal cortex of macaques. After rabies injections into the SEF, many neurons in the restricted region, the ventral aspects of the dentate nucleus (DN), the caudal pole of the DN, and the posterior interpositus nucleus (PIN) were labeled disynaptically via the thalamus, whereas no neuron labeling was found in the anterior interpositus nucleus (AIN). The distribution of the labeled neurons was dorsoventrally different from that of DN and PIN neurons labeled from the motor cortex. In the basal ganglia, a large number of labeled neurons were confined to the dorsomedial portion of the internal segment of the globus pallidus (GPi) as more neurons were labeled in the inner portion of the GPi (GPii) than in the outer portion of the GPi (GPio). This is the first evidence of a projection between cerebellum/basal ganglia and the SEF that could enable the cerebellum to modulate the cognitive control of voluntary eye movement.

The mind–body problem: Circuits that link the cerebral cortex to the adrenal medulla

Which regions of the cerebral cortex are the origin of descending commands that influence internal organs? We used transneuronal transport of rabies virus in monkeys and rats to identify regions of cerebral cortex that have multisynaptic connections with a major sympathetic effector, the adrenal medulla. In rats, we also examined multisynaptic connections with the kidney. In monkeys, the cortical influence over the adrenal medulla originates from 3 distinct networks that are involved in movement, cognition, and affect. Each of these networks has a human equivalent. The largest influence originates from a motor network that includes all 7 motor areas in the frontal lobe. These motor areas are involved in all aspects of skeletomotor control, from response selection to motor preparation and movement execution. The motor areas provide a link between body movement and the modulation of stress. The cognitive and affective networks are located in regions of cingulate cortex. They provide a link between how we think and feel and the function of the adrenal medulla. Together, the 3 networks can mediate the effects of stress and depression on organ function and provide a concrete neural substrate for some psychosomatic illnesses. In rats, cortical influences over the adrenal medulla and the kidney originate mainly from 2 motor areas and adjacent somatosensory cortex. The cognitive and affective networks, present in monkeys, are largely absent in rats. Thus, nonhuman primate research is essential to understand the neural substrate that links cognition and affect to the function of internal organs.

How the mind controls the body

Brain Connections Can our brain influence our internal organs? Dum et al. used retrograde transneuronal transport of rabies virus to identify the brain regions that project to a part of the adrenal gland called the medulla. Two networks are the major sources of neuronal input to this organ, which

Motor, cognitive, and affective areas of the cerebral cortex influence the adrenal medulla

Modern medicine has generally viewed the concept of "psychosomatic" disease with suspicion. This view arose partly because no neural networks were known for the mind, conceptually associated with the cerebral cortex, to influence autonomic and endocrine systems that control internal organs. Here, we used transneuronal transport of rabies virus to identify the areas of the primate cerebral cortex that communicate through multisynaptic connections with a major sympathetic effector, the adrenal medulla. We demonstrate that two broad networks in the cerebral cortex have access to the adrenal medulla. The larger network includes all of the cortical motor areas in the frontal lobe and portions of somatosensory cortex. A major component of this network originates from the supplementary motor area and the cingulate motor areas on the medial wall of the hemisphere. These cortical areas are involved in all aspects of skeletomotor control from response selection to motor preparation and movement execution. The second, smaller network originates in regions of medial prefrontal cortex, including a major contribution from pregenual and subgenual regions of anterior cingulate cortex. These cortical areas are involved in higher-order aspects of cognition and affect. These results indicate that specific multisynaptic circuits exist to link movement, cognition, and affect to the function of the adrenal medulla. This circuitry may mediate the effects of internal states like chronic stress and depression on organ function and, thus, provide a concrete neural substrate for some psychosomatic illness.

Constrained spherical deconvolution provides evidence of extensive subcortical direct cerebellumbasal ganglia connections in human brain

Traditionally, the basal ganglia (BG) are thought to play a major role in the selection and inhibition of motor commands, while the cerebellum plays a role in tuning and reshaping on-going movement. In the past, the connections between the cerebellum and the cerebral cortex have been considered to be anatomically and functionally distinct from those linking the BG with the cerebral cortex. Evidences from recent anatomical experiments, using retrograde transneuronal transport of rabies virus in macaques, have challenged this old perspective demonstrating disynaptic subcortical pathways that directly link the cerebellum with the BG. Since the application of these techniques to the human brain remains elusive, due to the invasive nature of such methods, whether and to what extent these specific connections between the BG and cerebellum exist in the human brain remains unclear. However, recent developments in Diffusion Magnetic Resonance Imaging (dMRI) and diffusion tractography may allow for non-invasive and in vivo studies of the anatomical substrate of basal ganglia systems. Indeed, in our previous paper we studied the basal ganglia connectome providing strong evidences of a direct connection from cortex to Globus Pallidum (GPe and GPi) [1]. Thirteen normal subjects with no history of any overt neurological and/or psychiatric disorders were examined to test the hypotheses that substantial interactions, at least on the level shown in animal studies, also exist in the human brain. We demonstrated that it is feasible to disclose these cerebellar-subcortical connections by using constrained spherical deconvolution (CSD), an innovative approach which allows a reliable reconstruction of small- and long-fiber pathways, with subvoxel resolution in brain regions with multiple fiber orientations [2]. In particular we found evidences of subthalamic-cerebellar, dentate-thalamo-striatal, dentate-rubral-thalamic, dentate-rubral-pallidal and dentate-nigral connections. In addition to these connections, we found a direct cerebellar-dentate-pallidal connection never reported in literature to our knowledge; we identified and isolated two well-distinct tracts presenting an ipsilateral and contralateral component, converging mainly on the antero-medial part of the globus pallidus.

Anatomical evidence for the involvement of medial cerebellar output from the interpositus nuclei in cognitive functions

Although the cerebellar interpositus nuclei are known to be involved in cognitive functions, such as associative motor learning, no anatomical evidence has been available for this issue. Here we used retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to area 46 of the prefrontal cortex of macaques in comparison with the projections to the primary motor cortex (M1). After rabies injections into area 46, many neurons in the restricted region of the posterior interpositus nucleus (PIN) were labeled disynaptically via the thalamus, whereas no neuron labeling was found in the anterior interpositus nucleus (AIN). The distribution of the labeled neurons was dorsoventrally different from that of PIN neurons labeled from the M1. This defines an anatomical substrate for the contribution of medial cerebellar output to cognitive functions. Like the dentate nucleus, the PIN has dual motor and cognitive channels, whereas the AIN has a motor channel only.

The Motor Cortex Communicates with the Kidney

We used retrograde transneuronal transport of rabies virus from the rat kidney to identify the areas of the cerebral cortex that are potential sources of central commands for the neural regulation of this organ. Our results indicate that multiple motor and nonmotor areas of the cerebral cortex contain output neurons that indirectly influence kidney function. These cortical areas include the primary motor cortex (M1), the rostromedial motor area (M2), the primary somatosensory cortex, the insula and other regions surrounding the rhinal fissure, and the medial prefrontal cortex. The vast majority of the output neurons from the cerebral cortex were located in two cortical areas, M1 (68%) and M2 (15%). If the visceromotor functions of M1 and M2 reflect their skeletomotor functions, then the output to the kidney from each cortical area could make a unique contribution to autonomic control. The output from M1 could add precision and organ-specific regulation to descending visceromotor commands, whereas the output from M2 could add anticipatory processing which is essential for allostatic regulation. We also found that the output from M1 and M2 to the kidney originates predominantly from the trunk representations of these two cortical areas. Thus, a map of visceromotor representation appears to be embedded within the classic somatotopic map of skeletomotor representation.

The Cerebellum and Cerebello-Thalamo-Cortical Channels Contribute to New Learning and Long-Term Memory of Motor Skill

Lu and his research team used the retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to the cerebral cortex of macaques. In particular, projections from deep cerebellar nuclei to area 46 of the prefrontal cortex were compared with projections to the primary motor cortex (M1). They found that, after viral injections into area 46, many labeled neurons were observed in the ventral aspect of the Posterior Interpositus Nucleus (PIN), whereas no neuron labeling was found in the Anterior Interpositus Nucleus (AIN). In contrast, a number of labeled neurons were found in the dorsal portion of the PIN after viral injections into the M1. Additionally, neurons labeled from the M1 injections were also observed in the AIN [1-3]. These findings demonstrate that the cerebellar interpositus nuclei possess distinct outputs to the prefrontal cortex versus the M1, which potentially contribute to different aspects of behavioral functions such as different stages of the motor learning. Medial cerebellar outputs from the interpositus nuclei have been thought to be crucial for the associative motor learning. McCormick and Thompson have reported that lesions of the interpositus nuclei abolished the memorized eyeblink response; recordings from these nuclei have revealed neuronal activity to response learning [4]. Yet, clinical studies have reported that initial stage of trace eyeblink conditioning learning was impaired in patients with lesions in the PIN [5]. Imaging studies have also shown that the cerebellum play a key role in eyeblink conditioning [6-8]. Moreover, significant changes of positron emission tomography and regional cerebral blood flow in several areas, including the cerebellum and the prefrontal cortex, were observed during performance of associative motor learning task [9]. The above, taken together with the new medial cerebellar channels from the posterior interpositus nucleus to area 46 of the prefrontal cortex, it is reasonable to hypothesize that the cerebellum and cerebello-thalamocortical channels contribute to motor learning. The medial cerebellar output from the ventral PIN and the dorsal PIN/AIN play differential roles in various steps of the motor learning [5,10,11]. The dorsal aspect of the PIN has been thought to contribute to performance of memorized motor responses such as eyeblink and saccadic eye movements rather than to their initial learning [10, 11]. If this is the case, then impairment in the acquisition of the new learning by lesions of the PIN could be due to functional blockade of the ventral rather than dorsal portion of the PIN [5]. Furthermore, previous studies have shown evidence that the expression of representative motor memory formation genes was increased selectively in the AIN, but not in the PIN [12]. This finding strongly suggests that the AIN is involved in the storage and/or retrieval of long-term memory of motor learning. Moreover, many studies have indicated that the AIN is the site for long-term memory rather than new learning during practice of the eyeblink conditioning response. Examples include lesion [13-17]; inactivation [18,19]; electron microscopy [20]; functional magnetic resonance imaging [21]. Given the above, it is natural to raise a theory that the medial cerebellar output from the ventral PIN and the dorsal PIN/AIN plays a critical role in the new learning and long-term memory, respectively, during the motor learning processing. Interestingly, different cortical areas have been thought to be involved in these various steps of motor learning. A considerable theory for motor learning indicates that new learning is an explicit process originating in the prefrontal cortex, and that the long term memory for the learned motor skill becomes automatic and an implicit process formed in the motor cortex [22-24]. Thus, the disynaptic pathway from the ventral aspect of the PIN to area 46 may be involved in the initiation of the association of motor learning. After repeated practice, cerebellar channels to the M1 originating from the dorsal PIN/AIN turn to play a key role in the storage and/or retrieval of long-term memory, which makes the association automatic. Last, neuropsychological testing of patients with cerebellar lesions has revealed specific deficits in different faculties, including visual perception [25-31], short-term memory [32,33], or verbal fluency [34]. Moreover, clinical studies have shown that, in the brains of subjects with autism, the most consistent abnormalities are found in cerebellar Purkinje cells [35]. Accordingly, the questions of whether and how these cerebello-thalamo-cortical channels and their involvements in

Ascending multisynaptic pathways from the trigeminal ganglion to the anterior cingulate cortex

By means of retrograde transneuronal transport of rabies virus, ascending multisynaptic pathways from the trigeminal ganglion (TG) to the anterior cingulate cortex (ACC) were identified in the rat. After rabies injection into an electrophysiologically defined trigeminal projection region of the ACC, transsynaptic labeling of second-order neurons via the medial thalamus (including the parafascicular nucleus) was located in the spinal trigeminal nucleus pars caudalis. Third-order neuron labeling occurred in the TG. Most of these TG neurons were medium- or large-sized cells giving rise to myelinated Aδ or Aβ afferent fibers, respectively. By contrast, TG neurons labeled transsynaptically from the orofacial region of the primary somatosensory cortex contained many small cells associated with unmyelinated C afferent fibers. Furthermore, the TG neurons retrogradely labeled with fluorogold injected into the mental nerve were smaller in their sizes compared to those labeled with rabies. Our extracellular unit recordings revealed that a majority of ACC neurons responded to trigeminal nerve stimulation with latencies of shorter than 20ms. Thus, somatosensory information conveyed to the ACC by multisynaptic ascending pathways derived predominantly from myelinated primary afferents (i.e., the medial nociceptive system) and may be used to subserve affective-motivational aspects of pain. Lack of overlap with the lateral nociceptive system is notable and suggests that the medial and lateral nociceptive systems perform separate and non-overlapping functions.

Distribution of hypothalamic neurons with orexin (hypocretin) or melanin concentrating hormone (MCH) immunoreactivity and multisynaptic connections with diaphragm motoneurons

Prior work showed that neurons in the lateral, dorsal, and perifornical regions of the tuberal and mammillary levels of the hypothalamus participate in the control of breathing. The same areas also contain large numbers of neurons that produce either orexins (hypocretins) or melanin concentrating hormone (MCH). These peptides have been implicated in regulating energy balance and physiological changes that occur in transitions between sleep and wakefulness, amongst other functions. The goal of this study was to determine if hypothalamic neurons involved in respiratory control, which were identified in cats by the retrograde transneuronal transport of rabies virus from the diaphragm, were immunopositive for either orexin-A or MCH. In animals with limited rabies infection of the hypothalamus (< 10 infected cells/section), where the neurons with the most direct influences on diaphragm motoneurons were presumably labeled, a large fraction (28–75%) of the infected hypothalamic neurons contained orexin-A. In the same cases, 6–33% of rabies-infected hypothalamic cells contained MCH. However, in animals with more extensive infection, where rabies had presumably passed transneuronally through more synapses, the fraction of infected cells that contained orexin-A was lower. The findings from these experiments thus support the notion that hypothalamic influences on breathing are substantially mediated through orexins or MCH.

Subdivisions of primary motor cortex based on cortico-motoneuronal cells.

We used retrograde transneuronal transport of rabies virus from single muscles of rhesus monkeys to identify cortico-motoneuronal (CM) cells in the primary motor cortex (M1) that make monosynaptic connections with motoneurons innervating shoulder, elbow, and finger muscles. We found that M1 has 2 subdivisions. A rostral region lacks CM cells and represents an "old" M1 that is the standard for many mammals. The descending commands mediated by corticospinal efferents from old M1 must use the integrative mechanisms of the spinal cord to generate motoneuron activity and motor output. In contrast, a caudal region of M1 contains shoulder, elbow, and finger CM cells. This region represents a "new" M1 that is present only in some higher primates and humans. The direct access to motoneurons afforded by CM cells enables the newly recognized M1 to bypass spinal cord mechanisms and sculpt novel patterns of motor output that are essential for highly skilled movements.

Neural circuits controlling diaphragm function in the cat revealed by transneuronal tracing

Although a number of studies have considered the neural circuitry that regulates diaphragm activity, these pathways have not been adequately discerned, particularly in animals such as cats that utilize the respiratory muscles during a variety of different behaviors and movements. The present study employed the retrograde transneuronal transport of rabies virus to identify the extended neural pathways that control diaphragm function in felines. In all animals deemed to have successful rabies virus injections into the diaphragm, large, presumed motoneurons were infected in the C(4)-C(6) spinal segments. In addition, smaller presumed interneurons were labeled bilaterally throughout the cervical and upper thoracic spinal cord. While in short and intermediate survival cases, infected interneurons were concentrated in the vicinity of phrenic motoneurons, in late survival cases, the distribution of labeling was more expansive. Within the brain stem, the earliest infected neurons included those located in the classically defined pontine and medullary respiratory groups, the medial and lateral medullary reticular formation, the region immediately ventral to the spinal trigeminal nucleus, raphe pallidus and obscurus, and the vestibular nuclei. At longer survival times, infection appeared in the midbrain, which was concentrated in the lateral portion of the periaqueductal gray, the region of the tegmentum that contains the locomotion center, and the red nucleus. Considerable labeling was also present in the fastigial nucleus of the cerebellum, portions of the posterior and lateral hypothalamus and the adjacent fields of Forel known to contain hypocretin-containing neurons and the precruciate gyrus of cerebral cortex. These data raise the possibility that several parallel pathways participate in regulating the activity of the feline diaphragm, which underscores the multifunctional nature of the respiratory muscles in this species.

Topographic distribution of output neurons in cerebellar nuclei and cortex to somatotopic map of primary motor cortex

To investigate the somatotopic organization of the cerebellum, we analysed multisynaptic inputs to the primary motor cortex (MI) using retrograde transneuronal transport of rabies virus. At 3 days after rabies injections into proximal forelimb, distal forelimb and hindlimb representations of the macaque MI, second-order neurons via the thalamus were labeled in the deep cerebellar nuclei, including the dentate (DN), anterior interpositus (AIN) and posterior interpositus nuclei. In the DN, the labeling of both the forelimb and hindlimb was seen mainly in the dorsal aspect. The labeling of the hindlimb was located rostral to that of the forelimb and the labeling of the proximal forelimb was located slightly rostral to that of the distal forelimb. The same rostrocaudal arrangement was observed in the AIN. In the posterior interpositus nucleus, however, labeling from the MI hindlimb and forelimb representations largely overlapped. At the 4-day postinjection period, third-order labeling occurred in Purkinje cells of the cerebellar hemisphere. The Purkinje cell labeling from the forelimb representation, including the proximal and distal regions, was observed primarily in lobules IV-VI and crus I. The proximal forelimb labeling was both rostral and lateral to that of the distal forelimb within lobules IV-VI. However, the hindlimb labeling was seen both rostral and lateral to that of the proximal forelimb within lobules III-VI. These results indicate that the hindlimb, proximal forelimb and distal forelimb are arranged rostrocaudally in the DN and AIN, whereas there is dual somatotopy along the rostrocaudal and lateromedial axes in the cerebellar cortex.

Muscle representation in the macaque motor cortex: An anatomical perspective

How are the neurons that directly influence the motoneurons of a muscle distributed in the primary motor cortex (M1)? To answer this classical question we used retrograde transneuronal transport of rabies virus from single muscles of macaques. This enabled us to define cortico-motoneuronal (CM) cells that make monosynaptic connections with the motoneurons of the injected muscle. We examined the distribution of CM cells that project to motoneurons of three thumb and finger muscles. We found that the CM cells for these digit muscles are restricted to the caudal portion of M1, which is buried in the central sulcus. Within this region of M1, CM cells for one muscle display a remarkably widespread distribution and fill the entire mediolateral extent of the arm area. In fact, CM cells for digit muscles are found in regions of M1 that are known to contain the shoulder representation. The cortical territories occupied by CM cells for different muscles overlap extensively. Thus, we found no evidence for a focal representation of single muscles in M1. Instead, the overlap and intermingling among the different populations of CM cells may be the neural substrate to create a wide variety of muscle synergies. We found two additional surprising results. First, 15-16% of the CM cells originate from area 3a, a region of primary somatosensory cortex. Second, the size range of CM cells includes both "fast" and "slow" pyramidal tract neurons. These observations are likely to lead to dramatic changes in views about the function of the CM system.

The cerebellum communicates with the basal ganglia

The cerebral cortex is interconnected with two major subcortical structures: the basal ganglia and the cerebellum. How and where cerebellar circuits interact with basal ganglia circuits has been a longstanding question. Using transneuronal transport of rabies virus in macaques, we found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal ganglia processing, the striatum.