Principles of Intrinsic Motor Cortex Connectivity in Primates.

The forelimb representation in motor cortex (M1) is an important model system in contemporary neuroscience. Efforts to understand the organization of the M1 forelimb representation in monkeys have focused on inputs and outputs. In contrast, intrinsic M1 connections remain mostly unexplored, which is surprising given that intra-areal connections universally outnumber extrinsic connections. To address this knowledge gap, we first mapped the M1 forelimb representation with intracortical microstimulation (ICMS) in male squirrel monkeys. Next, we determined the connectivity of individual M1 sites with ICMS + intrinsic signal optical imaging (ISOI). Every stimulation site activated a distinctive pattern of patches (∼0.25 to 1.0 mm radius) that we quantified in relation to the motor map. Arm sites activated patches that were mostly in arm zones. Hand sites followed the same principle, but to a lesser extent. The results collectively indicate that preferential connectivity between functionally matched patches is a prominent organizational principle in M1. Connectivity patterns for a given site were conserved across a range of current amplitudes, train durations, pulse frequencies, and microelectrode depths. In addition, we found close correspondence in somatosensory cortex between connectivity that we revealed with ICMS+ISOI and connections known from tracers. ICMS+ISOI is therefore an effective tool for mapping cortical connectivity and is particularly advantageous for sampling large numbers of sites. This feature was instrumental in revealing the spatial specificity of intrinsic M1 connections, which appear to be woven into the somatotopic organization of the forelimb representation. Such a framework invokes the modular organization well-established for sensory cortical areas.SIGNIFICANCE STATEMENT Intrinsic connections are fundamental to the operations of any cortical area. Surprisingly little is known about the organization of intrinsic connections in motor cortex (M1). We addressed this knowledge gap using intracortical microstimulation (ICMS) concurrently with intrinsic signal optical imaging (ISOI). Quantifying the activation patterns from dozens of M1 sites allowed us to uncover a fundamental principle of M1 organization: M1 patches are preferentially connected with functionally matched patches. Relationship between intrinsic connections and neurophysiological map is well-established for sensory cortical areas, but our study is the first to extend this framework to M1. Microstimulation+imaging opened a unique possibility for investigating the connectivity of dozens of tightly spaced M1 sites, which was the linchpin for uncovering organizational principles.

Optical imaging reveals functional domains in primate sensorimotor cortex.

Motor cortex (M1) and somatosensory cortex (S1) are central to arm and hand control. Efforts to understand encoding in M1 and S1 have focused on temporal relationships between neural activity and movement features. However, it remains unclear how the neural activity is spatially organized within M1 and S1. Optical imaging methods are well-suited for revealing the spatio-temporal organization of cortical activity, but their application is sparse in monkey sensorimotor cortex. Here, we investigate the effectiveness of intrinsic signal optical imaging (ISOI) for measuring cortical activity that supports arm and hand control in a macaque monkey. ISOI revealed spatial domains that were active in M1 and S1 in response to instructed reaching and grasping. The lateral M1 domains overlapped the hand representation and contained a population of neurons with peak firing during grasping. In contrast, the medial M1 domain overlapped the arm representation and a population of neurons with peak firing during reaching. The S1 domain overlapped the hand representations of areas 1 and 2 and a population of neurons with peak firing upon hand contact with the target. Our single unit recordings indicate that ISOI domains report the locations of spatial clusters of functionally related neurons. ISOI is therefore an effective tool for surveilling the neocortex for "hot zones" of activity that supports movement. Combining the strengths of ISOI with other imaging modalities (e.g., fMRI, 2-photon) and with electrophysiological methods can open new frontiers in understanding the spatio-temporal organization of cortical signals involved in movement control.

Cortical neuron response properties are related to lesion extent and behavioral recovery after sensory loss from spinal cord injury in monkeys.

Lesions of the dorsal columns at a mid-cervical level render the hand representation of the contralateral primary somatosensory cortex (area 3b) unresponsive. Over weeks of recovery, most of this cortex becomes responsive to touch on the hand. Determining functional properties of neurons within the hand representation is critical to understanding the neural basis of this adaptive plasticity. Here, we recorded neural activity across the hand representation of area 3b with a 100-electrode array and compared results from owl monkeys and squirrel monkeys 5-10 weeks after lesions with controls. Even after extensive lesions, performance on reach-to-grasp tasks returned to prelesion levels, and hand touches activated territories mainly within expected cortical locations. However, some digit representations were abnormal, such that receptive fields of presumably reactivated neurons were larger and more often involved discontinuous parts of the hand compared with controls. Hand stimulation evoked similar neuronal firing rates in lesion and control monkeys. By assessing the same monkeys with multiple measures, we determined that properties of neurons in area 3b were highly correlated with both the lesion severity and the impairment of hand use. We propose that the reactivation of neurons with near-normal response properties and the recovery of near-normal somatotopy likely supported the recovery of hand use. Given the near-completeness of the more extensive dorsal column lesions we studied, we suggest that alternate spinal afferents, in addition to the few spared primary axon afferents in the dorsal columns, likely have a major role in the reactivation pattern and return of function.

Effects of muscimol inactivations of functional domains in motor, premotor, and posterior parietal cortex on complex movements evoked by electrical stimulation.

Parietal and frontal cortex are central to controlling forelimb movements. We previously showed that movements such as reach, grasp, and defense can be evoked from primary motor (M1), premotor (PMC), and posterior parietal (PPC) cortex when 500-ms trains of electrical pulses are delivered via microelectrodes. Stimulation sites that evoked a specific movement clustered into domains, which shared a topographic pattern in New World monkeys and prosimian galagos. Matched functional domains in parietal and frontal cortex were preferentially interconnected. We reasoned that matched functional domains form parallel networks involved in specific movements. To test the roles of domains in M1, PMC, and PPC, we systematically inactivated with muscimol domains in one region and determined if functional changes occurred in matching domains in other regions. The most common changes were higher current thresholds for stimulation-evoked movements and shorter, not fully developed, trajectories of movements. Inactivations of an M1 functional domain greatly reduced or abolished movements evoked from the matching domains in PMC or PPC, whereas movements evoked from nonmatching domains remained mostly unaffected. In contrast, inactivating PMC or PPC domains did not consistently abolish the ability to evoke movements from matching M1 domains. However, inactivation of PMC domains suppressed or altered the movements evoked from PPC domains. Thus movement sequences evoked from PMC depend on M1 and movement sequences evoked from PPC depend on both M1 and PMC. Overall, the results support the conclusion that PPC, PMC, and M1 are subdivided into functional domains that are hierarchically related within parallel networks.

Optical imaging in galagos reveals parietal-frontal circuits underlying motor behavior.

The posterior parietal cortex (PPC) of monkeys and prosimian galagos contains a number of subregions where complex, behaviorally meaningful movements, such as reaching, grasping, and body defense, can be evoked by electrical stimulation with long trains of electrical pulses through microelectrodes. Shorter trains of pulses evoke no or simple movements. One possibility for the difference in effectiveness of intracortical microstimulation is that long trains activate much larger regions of the brain. Here, we show that long-train stimulation of PPC does not activate widespread regions of frontal motor and premotor cortex but instead, produces focal, somatotopically appropriate activations of frontal motor and premotor cortex. Shorter stimulation trains activate the same frontal foci but less strongly, showing that longer stimulus trains do not produce less specification. Because the activated sites in frontal cortex correspond to the locations of direct parietal-frontal anatomical connections from the stimulated PPC subregions, the results show the usefulness of optical imaging in conjunction with electrical stimulation in showing functional pathways between nodes in behavior-specific cortical networks. Thus, long-train stimulation is effective in evoking ethologically relevant sequences of movements by activating nodes in a cortical network for a behaviorally relevant period rather than spreading activation in a nonspecific manner.

Cortical networks for ethologically relevant behaviors in primates.

Parietal-frontal networks in primate brains are central to mediating actions. Physiological and anatomical investigations have shown that the parietal-frontal network is consistently organized across several branches of primate evolution that include prosimian galagos, New World owl and squirrel monkeys, and Old World macaque monkeys. Electrical stimulation with 0.5-sec trains of pulses delivered via microelectrodes evoked ethologically relevant actions from both posterior parietal cortex (PPC) and frontal motor cortex (FMC). Reaching, grasping, defensive, and other complex movement patterns were evoked from domains that had a characteristic organization in both FMC and PPC. Although a PPC domain (e.g. reaching) may be connected with other PPC domains (e.g. grasping and defensive), its connections with FMC are preferential for a matching domain (reaching). Similarly, electrical stimulation of a PPC domain and concurrent optical imaging of FMC, showed activation patterns consistent with the preferential connectivity of PPC and FMC domains. The evidence for similar arrangements of interconnected functional domains in PPC and FMC of members of three major branches of the primate radiation suggests that the parietal-frontal networks emerged early in the evolution of primates. The small size of PPC in the close relatives of primates including lagomorphs, rodents, and tree shrews, suggests a limited involvement of PPC in motor behavior before archaic primates emerged. However, functional domains may have evolved in motor cortex before the emergence of archaic primates.

Motor actions are spatially organized in motor and dorsal premotor cortex.

Frontal motor areas are central to controlling voluntary movements. In non-human primates, the motor areas contain independent, somatotopic, representations of the forelimb (i.e., motor maps). But are the neural codes for actions spatially organized within those forelimb representations? Addressing this question would provide insight into the poorly understood structure-function relationships of the cortical motor system. Here, we tackle the problem using high-resolution optical imaging and motor mapping in motor (M1) and dorsal premotor (PMd) cortex. Two macaque monkeys performed an instructed reach-to-grasp task while cortical activity was recorded with intrinsic signal optical imaging (ISOI). The spatial extent of activity in M1 and PMd was then quantified in relation to the forelimb motor maps, which we obtained from the same hemisphere with intracortical microstimulation. ISOI showed that task-related activity was concentrated in patches that collectively overlapped <40% of the M1 and PMd forelimb representations. The spatial organization of the patches was consistent across task conditions despite small variations in forelimb use. Nevertheless, the largest condition differences in forelimb use were reflected in the magnitude of cortical activity. Distinct time course profiles from patches in arm zones and patches in hand zones suggest functional differences within the forelimb representations. The results collectively support an organizational framework wherein the forelimb representations contain subzones enriched with neurons tuned for specific actions. Thus, the often-overlooked spatial dimension of neural activity appears to be an important organizing feature of the neural code in frontal motor areas.

Expression of the excitatory opsin ChRERα can be traced longitudinally in rat and nonhuman primate brains with PET imaging.

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner. ChRERα consists of the prototypical excitatory opsin channelrhodopsin-2 (ChR2) and the ligand-binding domain (LBD) of the human estrogen receptor α (ERα). ChRERα showed conserved ChR2 functionality and high affinity for [18F]16α-fluoroestradiol (FES), an FDA-approved PET radiopharmaceutical. Experiments in rats demonstrated that adeno-associated virus (AAV)-mediated expression of ChRERα enables neural circuit manipulation in vivo and that ChRERα expression could be monitored using FES-PET imaging. In vivo experiments in nonhuman primates (NHPs) confirmed that ChRERα expression could be monitored at the site of AAV injection in the primary motor cortex and in long-range neuronal terminals for up to 80 weeks. The anatomical connectivity map of the primary motor cortex identified by FES-PET imaging of ChRERα expression overlapped with a functional connectivity map identified using resting state fMRI in a separate cohort of NHPs. Overall, our results demonstrate that ChRERα expression can be mapped longitudinally in the mammalian brain using FES-PET imaging and can be used for neural circuit modulation in vivo.

Multiple parietal-frontal pathways mediate grasping in macaque monkeys.

The nodes of a parietal-frontal pathway that mediates grasping in primates are in anterior intraparietal area (AIP) and ventral premotor cortex (PMv). Nevertheless, multiple somatosensory and motor representations of the hand, in parietal and frontal cortex, respectively, suggest that additional pathways remain unrealized. We explored this possibility in macaque monkeys by injecting retrograde tracers into grasp zones identified in primary motor cortex (M1), PMv, and area 2 with long train electrical stimulation. The M1 grasp zone was densely connected with other frontal cortex motor regions. The remainder of the connections originated from somatosensory areas 3a and second somatosensory cortex/parietal ventral area (S2/PV), and from the medial bank and fundus of the intraparietal sulcus (IPS). The PMv grasp zone was also densely connected with frontal cortex motor regions, albeit to a lesser extent than the M1 grasp zone. The remainder of the connections originated from areas S2/PV and aspects of the inferior parietal lobe such as PF, PFG, AIP, and the tip of the IPS. The area 2 grasp zone was densely connected with the hand representations of somatosensory areas 3b, 1, and S2/PV. The remainder of the connections was with areas 3a and 5 and the medial bank and fundus of the IPS. Connections with frontal cortex were relatively weak and concentrated in caudal M1. Thus, the three grasp zones may be nodes of parallel parietal-frontal pathways. Differential points of origin and termination of each pathway suggest varying functional specializations. Direct and indirect connections between those parietal-frontal pathways likely coordinate their respective functions into an accurate grasp.

Cortical connections of functional zones in posterior parietal cortex and frontal cortex motor regions in new world monkeys.

We examined the connections of posterior parietal cortex (PPC) with motor/premotor cortex (M1/PM) and other cortical areas. Electrical stimulation (500 ms trains) delivered to microelectrode sites evoked movements of reach, defense, and grasp, from distinct zones in M1/PM and PPC, in squirrel and owl monkeys. Tracer injections into M1/PM reach, defense, and grasp zones showed dense connections with M1/PM hand/forelimb representations. The densest inputs outside of frontal cortex were from PPC zones. M1 zones were additionally connected with somatosensory hand/forelimb representations in areas 3a, 3b, and 1 and the somatosensory areas of the upper bank of the lateral sulcus (S2/PV). Injections into PPC zones showed primarily local connections and the densest inputs outside of PPC originated from M1/PM zones. The PPC reach zone also received dense inputs from cortex caudal to PPC, which likely relayed visual information. In contrast, the PPC grasp zone was densely connected with the hand/forelimb representations of areas 3a, 3b, 1, and S2/PV. Thus, the dorsal parietal-frontal network involved in reaching was preferentially connected to visual cortex, whereas the more ventral network involved in grasping received somatosensory inputs. Additional weak interlinks between dissimilar zones (e.g., PPC reach and PPC grasp) were apparent and may coordinate actions.

Cortical connectivity is embedded in resting state at columnar resolution.

Resting state (RS) fMRI is now widely used for gaining insight into the organization of brain networks. Functional connectivity (FC) inferred from RS-fMRI is typically at macroscale, which is too coarse for much of the detail in cortical architecture. Here, we examined whether imaging RS at higher contrast and resolution could reveal cortical connectivity with columnar granularity. In longitudinal experiments (~1.5 years) in squirrel monkeys, we partitioned sensorimotor cortex using dense microelectrode mapping and then recorded RS with intrinsic signal optical imaging (RS-ISOI, 20 µm/pixel). FC maps were benchmarked against microstimulation-evoked activation and traced anatomical connections. These direct comparisons showed high correspondence in connectivity patterns across methods. The fidelity of FC maps to cortical connections indicates that granular details of network organization are embedded in RS. Thus, for recording RS, the field-of-view and effective resolution achieved with ISOI fills a wide gap between fMRI and invasive approaches (2-photon imaging, electrophysiology). RS-ISOI opens exciting opportunities for high resolution mapping of cortical networks in living animals.

Thalamocortical connections of functional zones in posterior parietal cortex and frontal cortex motor regions in New World monkeys.

Posterior parietal cortex (PPC) links primate visual and motor systems and is central to visually guided action. Relating the anatomical connections of PPC to its neurophysiological functions may elucidate the organization of the parietal-frontal network. In owl and squirrel monkeys, long-duration electrical stimulation distinguished several functional zones within the PPC and motor/premotor cortex (M1/PM). Multijoint forelimb movements reminiscent of reach, defense, and grasp behaviors characterized each functional zone. In PPC, functional zones were organized parallel to the lateral sulcus. Thalamocortical connections of PPC and M1/PM zones were investigated with retrograde tracers. After several days of tracer transport, brains were processed, and labeled cells in thalamic nuclei were plotted. All PPC zones received dense inputs from the lateral posterior nucleus and the anterior pulvinar. PPC zones received additional projections from ventral lateral (VL) divisions of motor thalamus, which were also the primary source of input to M1/PM. Projections to PPC from rostral motor thalamus were sparse. Dense projections from ventral posterior (VP) nucleus of somatosensory thalamus distinguished the rostrolateral grasp zone from the other PPC zones. PPC connections with VL and VP provide links to cerebellar nuclei and the somatosensory system, respectively, that may integrate PPC functions with M1/PM.

Mapping mesoscale cortical connectivity in monkey sensorimotor cortex with optical imaging and microstimulation.

To map in vivo cortical circuitry at the mesoscale, we applied a novel approach to map interareal functional connectivity. Electrical intracortical microstimulation (ICMS) in conjunction with optical imaging of intrinsic signals (OIS) was used map functional connections in somatosensory cortical areas in anesthetized squirrel monkeys. ICMS produced activations that were focal and that displayed responses which were stimulation intensity dependent. ICMS in supragranular layers of Brodmann Areas 3b, 1, 2, 3a, and M1 evoked interareal activation patterns that were topographically appropriate and appeared consistent with known anatomical connectivity. Specifically, ICMS revealed Area 3b connections with Area 1; Area 1 connections with Areas 2 and 3a; Area 2 connections with Areas 1, 3a, and M1; Area 3a connections with Areas M1, 1, and 2; and M1 connections with Areas 3a, 1, and 2. These somatosensory connectivity patterns were reminiscent of feedforward patterns observed anatomically, although feedback contributions are also likely present. Further consistent with anatomical connectivity, intra-areal and intra-areal patterns of activation were patchy with patch sizes of 200-300 µm. In summary, ICMS with OIS is a novel approach for mapping interareal and intra-areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity are discussed.

Transient middle cerebral artery occlusion disrupts the forelimb movement representations of rat motor cortex.

Infarcts from proximal middle cerebral artery (MCA) stroke can produce impairments in motor function, particularly finger movements in humans and digit flexion in rats. In rats, the extent of neural damage may be limited to basal ganglia structures or may also include portions of the frontal and parietal cortex in severe cases. Although the primary motor cortex (M1) is anatomically spared in proximal MCA occlusion, its functional integrity is suspect because even a small subcortical infarct can damage neural circuits linking M1 with basal ganglia, brainstem, and spinal cord. This motivated the present study to investigate the neurophysiological integrity of M1 after transient proximal MCA occlusion. Rats, preoperatively trained and non-preoperatively trained to reach for food, received extensive reach training/testing with the contralateral-to-lesion paw for several weeks after MCA occlusion. The forelimb movement representations were assayed from the ipsilateral-to-lesion M1 with intracortical microstimulation approximately 10 weeks after MCA occlusion. Digit flexion was impaired during food grasping in rats with relatively small subcortical infarcts and was completely abolished in rats that sustained at least moderate subcortical damage. Corresponding forelimb movement representations ranged from abnormally small to absent. The results suggest that ischemia in subcortical territories of the MCA does not spare the neurophysiological properties of M1 despite its apparent anatomical intactness, probably because of damage sustained to its descending fibers. Thus, M1 dysfunction contributes to the impairments that ensue from proximal MCA occlusion, even when the infarct is limited to subcortical regions.

Attempt-dependent decrease in skilled reaching characterizes the acute postsurgical period following a forelimb motor cortex lesion: an experimental demonstration of learned nonuse in the rat.

The notion that shock or diaschisis is a distinctive stage in the recovery process following brain damage has played a formative role in the characterization of brain injury. For example, damage to the forelimb region of motor cortex results in an acute period of behavioural depression in skilled reaching and other skilled actions followed by improved performance mediated by compensatory movements. Whereas the progression of improvement and the use of compensatory movements in the chronic period of recovery is well-documented, temporal aspects of behaviour during the acute period of depression of behaviour are relatively unstudied. The present study examined the temporal scheduling of reach-attempts by rats attempting to gain single pellets of food from a shelf in a skilled reaching task. Pretrained rats received contralateral-to-the-pretrained limb forelimb motor cortex lesions. Control lesions included contralateral-to-the-pretrained limb parietal cortex lesions, or ipsilateral-to-the-pretrained limb motor cortex lesions. Frame-by-frame video analysis of behaviour showed a decrease in reaching attempts as a function of successive approaches and attempts to grasp the food over the first few postsurgical days in rats with contralateral-to-the-pretrained limb motor cortex lesions. A similar approach-dependent decrease in attempts did not occur after parietal or ipsilateral-to-the-pretrained limb motor cortex lesions. The decrease in responding occurred only during acute testing and was not observed in rats first tested after 8 days of postoperative recovery. The findings are discussed in relation to the ideas that: (1) the stroke subject is an active participant in modifying behaviour to cope with injury; (2) learned nonuse contributes to behaviour in the acute postinjury period following motor cortex injury; (3) diaschisis inadequately accounts for poststoke behaviour.

Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats.

The current study examines the effects of chronic administration of nicotine on motor behavior after focal stroke in rats. Animals were trained in a tray-reaching task for 2weeks and then they were divided into: (1) control+saline (2) control+nicotine (3) stroke+saline, and (4) stroke+nicotine groups. Lesions were produced by devascularization of the surface blood vessels of the sensorimotor cortex contralateral to the forepaw used for reaching. Forty-eight hours after the lesions, and for a total of 12days, animals received two daily injections of either nicotine (0.3mg/kg) or saline (0.9%). Animals were tested in a motor battery 1week after the lesions and every other week for a total of 7weeks. Pyramidal cells in forelimb and cingulate areas were then examined for dendritic length and branching using a Golgi-Cox procedure. Behavioral results demonstrated that by the end of the testing stroke+nicotine animals showed significant behavioral improvement relative to stroke+saline animals. Stroke+nicotine animals showed an increase in dendritic length and branching in pyramidal cells of the forelimb and cingulate areas. The results suggest that the behavioral enhancement in the stroke+nicotine group might be attributable to the enhanced dendritic growth in residual cortical motor regions.

Parallel stages of learning and recovery of skilled reaching after motor cortex stroke: "oppositions" organize normal and compensatory movements.

Forelimb/hand motor cortex injury in rodents and primates causes impairments in skilled paw/hand movements that includes a period of movement absence followed by functional recovery/compensation. Although the postsurgical period of movement absence has been attributed to "shock" or "diaschisis", the behavior of animals during this period has not been fully described. Here, rats were trained to reach for single food pellets from a shelf and then the vasculature of the forelimb region of the sensorimotor cortex contralateral to the reaching limb was removed. A control group received a posterior parietal cortex devasularization. Frame-by-frame video analysis of reaching behavior showed that the stages of the acquisition of skilled reaching and the stages of recovery after motor cortex stroke were similar. The animals sequentially learn three relationships or "oppositions" between a body part and the food target. The oppositions are invariant relationships but each can be achieved with movements that can vary from reach to reach and between rats. A snout-pellet opposition organizes the movements of orienting, a paw-pellet opposition organizes limb transport and grasping the pellet in the digits, and a mouth-pellet opposition organizes limb withdrawal and the release of the food into the mouth. The three oppositions and the movements that they recruit were disrupted after motor cortex damage, but not parietal cortex damage. The oppositions were reestablished after stroke in the order in which they were acquired prior to stroke. Enduring impairments were more noticeable in transport and withdrawal oppositions. That the stages of recovery from motor cortex stroke parallel those of initial acquisition are discussed in relation to contemporary explanations of diaschisis and the contribution of motor cortex to motor learning.

The exploratory behavior of rats in an open environment optimizes security.

When given a locomotor/exploratory test in the laboratory, rats form one or more home bases, operationally defined as places where they spend a disproportionate period of their time and from which they make excursions. Because exploratory tests in the laboratory necessarily restrict the animals' movements, the cause of exploration (e.g., fear, curiosity, innate disposition) and the extent to which organization is imposed by the restriction of the testing environment has not been fully examined. In the present study, rats received exploratory tests in environments in which restrictions were remote; in a parking lot or on a playing field. Each rat began a test in one of three conditions: in a small refuge, within a transparent open home cage, or beside a landmark. In the parking lot, the rats failed to leave the small refuge, made excursions from the home cage, and left the landmark, usually at a gallop, and made no movements of returning. On the playing field they remained in the small refuge, left and returned to the open home cage, and were more likely to permanently leave the landmark at a gallop. Rats that displayed a strong preference for the landmark over three test sessions in a laboratory, also immediately left the same landmark when tested on the playing field. The pattern of behavior, in which the rats failed to explore from a secure starting position and were increasingly likely to run away as security decreased, suggests that a primary function of locomotor behavior in a novel environment is to optimize security. The results are discussed in relation to the advantages of investigating the influence of neural processes on exploration in terms optimization theory versus motivational theory.

The origins of thalamic inputs to grasp zones in frontal cortex of macaque monkeys.

The hand representation in primary motor cortex (M1) is instrumental to manual dexterity in primates. In Old World monkeys, rostral and caudal aspects of the hand representation are located in the precentral gyrus and the anterior bank of the central sulcus, respectively. We previously reported the organization of the cortico-cortical connections of the grasp zone in rostral M1. Here we describe the organization of thalamocortical connections that were labeled from the same tracer injections. Thalamocortical connections of a grasp zone in ventral premotor cortex (PMv) and the M1 orofacial representation are included for direct comparison. The M1 grasp zone was primarily connected with ventral lateral divisions of motor thalamus. The largest proportion of inputs originated in the posterior division (VLp) followed by the medial and the anterior divisions. Thalamic inputs to the M1 grasp zone originated in more lateral aspects of VLp as compared to the origins of thalamic inputs to the M1 orofacial representation. Inputs to M1 from thalamic divisions connected with cerebellum constituted three fold the density of inputs from divisions connected with basal ganglia, whereas the ratio of inputs was more balanced for the grasp zone in PMv. Privileged access of the cerebellothalamic pathway to the grasp zone in rostral M1 is consistent with the connection patterns previously reported for the precentral gyrus. Thus, cerebellar nuclei are likely more involved than basal ganglia nuclei with the contributions of rostral M1 to manual dexterity.

Skilled reaching impairments from the lateral frontal cortex component of middle cerebral artery stroke: a qualitative and quantitative comparison to focal motor cortex lesions in rats.

The classical approach to investigating brain contributions to behavior has been to localize function to a region. In clinical investigations, however, injury is frequently multifocal, raising the question of how individual brain regions contribute to a resulting behavioral syndrome. For example, middle cerebral artery (MCA) ischemia in humans can concurrently damage a number of cortical and subcortical areas and the same areas are damaged in rat models of MCA stroke. In the rat, MCA occlusion produces severe motor deficits, but the cortical area of damage is the lateral neocortex, sparing motor cortex. This anatomical finding raises the question of whether the rat lateral neocortex contributes to MCA-related motor impairments, a question that was investigated in the present study. Rats received unilateral neocortical lesions via electrocoagulation of the MCA and were compared to rats with standard motor cortex lesions produced by devascaulrization of the overlaying blood vessels. The MCA group was as impaired as the motor cortex group in skilled reaching movements as assessed by quantitative measures of the contralateral-to-lesion forelimb in a single pellet task and in a tray-reaching task. Although there was improvement in success scores over a 2-week period in both groups, the groups were characterized by distinctive and enduring qualitative impairments. The motor cortex deficit was exemplified by use of trunk musculature and head movements to assist the reaching limb while the MCA impairment included sensory abnormalities. The results are discussed in relation to the contribution of lateral frontal cortex injury to MCA stroke sensorimotor syndromes.