Ventricular fold oscillations lower the vocal pitch in rhesus macaques.

We carried out ex vivo and in vivo experiments to explore the functional role of the ventricular folds in sound production in macaques. In the ex vivo experiments, 29 recordings out of 67 showed that the ventricular folds co-oscillated with the vocal folds. Transitions from normal vocal fold oscillations to vocal-ventricular fold co-oscillations as well as chaotic irregular oscillations were also observed. The in vivo experiments indicated that the vocal-ventricular fold co-oscillations were also observed in two macaque individuals. In both ex vivo and in vivo experiments, the vocal-ventricular fold co-oscillations significantly lowered the fundamental frequency. A mathematical model revealed that the lowering of the fundamental frequency was caused by a low oscillation frequency inherent in the ventricular folds, which entrained the vocal folds to their low-frequency oscillations. From a physiological standpoint, the macaques may utilize the ventricular fold oscillations more frequently than humans. The advantages as well as disadvantages of using the ventricular folds as an additional vocal repertory are discussed.

Elimination of the Cortico-Subthalamic Hyperdirect Pathway Induces Motor Hyperactivity in Mice.

The substantia nigra pars reticulata (SNr) is the output station of the basal ganglia and receives cortical inputs by way of the following three basal ganglia pathways: the cortico-subthalamo (STN)-SNr hyperdirect, the cortico-striato-SNr direct, and the cortico-striato-external pallido-STN-SNr indirect pathways. Compared with the classical direct and indirect pathways via the striatum, the functions of the hyperdirect pathway remain to be fully elucidated. Here we used a photodynamic technique to selectively eliminate the cortico-STN projection in male mice and observed neuronal activity and motor behaviors in awake conditions. After cortico-STN elimination, cortically evoked early excitation in the SNr was diminished, while the cortically evoked inhibition and late excitation, which are delivered through the direct and indirect pathways, respectively, were unchanged. In addition, locomotor activity was significantly increased after bilateral cortico-STN elimination, and apomorphine-induced ipsilateral rotations were observed after unilateral cortico-STN elimination, suggesting that cortical activity was increased. These results are compatible with the notion that the cortico-STN-SNr hyperdirect pathway quickly conveys cortical excitation to the output station of the basal ganglia, resets or suppresses the cortical activity related to ongoing movements, and prepares for the forthcoming movement.SIGNIFICANCE STATEMENT The basal ganglia play a pivotal role in the control of voluntary movements, and their malfunctions lead to movement disorders, such as Parkinson's disease and dystonia. Understanding their functions is important to find better treatments for such diseases. Here we used a photodynamic technique to selectively eliminate the projection from the motor cortex to the subthalamic nucleus, the input station of the basal ganglia, and found greatly reduced early excitatory signals from the cortex to the output station of the basal ganglia and motor hyperactivity. These results suggest that the neuronal signals through the cortico-subthalamic hyperdirect pathway reset or suppress ongoing movements and that blockade of this pathway may be beneficial for Parkinson's disease, which is characterized by oversuppression of movements.

Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism.

BACKGROUND: Parkinson's disease is caused by dopamine deficiency in the striatum, which is a result of loss of dopamine neurons from the substantia nigra pars compacta. There is a consensus that a subpopulation of nigral dopamine neurons that expresses the calcium-binding protein calbindin is selectively invulnerable to parkinsonian insults. The objective of the present study was to test the hypothesis that dopamine neuron degeneration might be prevented by viral vector-mediated gene delivery of calbindin into the dopamine neurons that do not normally contain it. METHODS: A calbindin-expressing adenoviral vector was injected into the striatum of macaque monkeys to be conveyed to cell bodies of nigral dopamine neurons through retrograde axonal transport, or the calbindin-expressing lentiviral vector was injected into the nigra directly because of its predominant uptake from cell bodies and dendrites. The animals in which calbindin was successfully recruited into nigral dopamine neurons were administered systemically with MPTP. RESULTS: In the monkeys that had received unilateral vector injections, parkinsonian motor deficits, such as muscular rigidity and akinesia/bradykinesia, appeared predominantly in the limbs corresponding to the non-calbindin-recruited hemisphere after MPTP administration. Data obtained from tyrosine hydroxylase immunostaining and PET imaging for the dopamine transporter revealed that the nigrostriatal dopamine system was preserved better on the calbindin-recruited side. Conversely, on the non-calbindin-recruited control side, many more dopamine neurons expressed α-synuclein. CONCLUSIONS: The present results indicate that calbindin recruitment into nigral dopamine neurons protects against the onset of parkinsonian insults, thus providing a novel approach to PD prevention. © 2018 International Parkinson and Movement Disorder Society.

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.

Dorsal area 46 is a major target of disynaptic projections from the medial temporal lobe.

The medial temporal lobe (MTL) is responsible for various mnemonic functions, such as association/conjunction memory. The lateral prefrontal cortex (LPFC) also plays crucial roles in mnemonic functions and memory-based cognitive behaviors, for example, decision-making. Therefore, it is considered that the MTL and LPFC connect with each other and cooperate for the control of cognitive behaviors. However, there exist very weak, if any, direct inputs from the MTL to the LPFC. Employing retrograde transsynaptic transport of rabies virus, we investigated the organization of disynaptic bottom-up pathways connecting the MTL and the inferotemporal cortex to the LPFC in macaques. Three days after rabies injections into dorsal area 46, a large number of labeled neurons were observed in the MTL, such as the hippocampal formation (including the entorhinal cortex), the perirhinal cortex, and the parahippocampal cortex. In contrast, a majority of the labeled neurons were located in the inferotemporal cortex following rabies injections into ventral area 46 and lateral area 12. Rabies injections into lateral area 9/area 8B labeled only a small number of neurons in the MTL and the inferotemporal cortex. The present results indicate that, among the LPFC, dorsal area 46 is the main target of disynaptic inputs from the MTL.

Color vision test for dichromatic and trichromatic macaque monkeys.

Dichromacy is a color vision defect in which one of the three cone photoreceptors is absent. Individuals with dichromacy are called dichromats (or sometimes "color-blind"), and their color discrimination performance has contributed significantly to our understanding of color vision. Macaque monkeys, which normally have trichromatic color vision that is nearly identical to humans, have been used extensively in neurophysiological studies of color vision. In the present study we employed two tests, a pseudoisochromatic color discrimination test and a monochromatic light detection test, to compare the color vision of genetically identified dichromatic macaques (Macaca fascicularis) with that of normal trichromatic macaques. In the color discrimination test, dichromats could not discriminate colors along the protanopic confusion line, though trichromats could. In the light detection test, the relative thresholds for longer wavelength light were higher in the dichromats than the trichromats, indicating dichromats to be less sensitive to longer wavelength light. Because the dichromatic macaque is very rare, the present study provides valuable new information on the color vision behavior of dichromatic macaques, which may be a useful animal model of human dichromacy. The behavioral tests used in the present study have been previously used to characterize the color behaviors of trichromatic as well as dichromatic new world monkeys. The present results show that comparative studies of color vision employing similar tests may be feasible to examine the difference in color behaviors between trichromatic and dichromatic individuals, although the genetic mechanisms of trichromacy/dichromacy is quite different between new world monkeys and macaques.

Rhythm information represented in the fronto-parieto-cerebellar motor system.

Rhythm is an essential element of human culture, particularly in language and music. To acquire language or music, we have to perceive the sensory inputs, organize them into structured sequences as rhythms, actively hold the rhythm information in mind, and use the information when we reproduce or mimic the same rhythm. Previous brain imaging studies have elucidated brain regions related to the perception and production of rhythms. However, the neural substrates involved in the working memory of rhythm remain unclear. In addition, little is known about the processing of rhythm information from non-auditory inputs (visual or tactile). Therefore, we measured brain activity by functional magnetic resonance imaging while healthy subjects memorized and reproduced auditory and visual rhythmic information. The inferior parietal lobule, inferior frontal gyrus, supplementary motor area, and cerebellum exhibited significant activations during both encoding and retrieving rhythm information. In addition, most of these areas exhibited significant activation also during the maintenance of rhythm information. All of these regions functioned in the processing of auditory and visual rhythms. The bilateral inferior parietal lobule, inferior frontal gyrus, supplementary motor area, and cerebellum are thought to be essential for motor control. When we listen to a certain rhythm, we are often stimulated to move our body, which suggests the existence of a strong interaction between rhythm processing and the motor system. Here, we propose that rhythm information may be represented and retained as information about bodily movements in the supra-modal motor brain system.

Multisynaptic projections from the ventrolateral prefrontal cortex to the dorsal premotor cortex in macaques - anatomical substrate for conditional visuomotor behavior.

Lines of evidence indicate that both the ventrolateral prefrontal cortex (vlPFC) (areas 45/12) and dorsal premotor cortex (PMd) (rostral F2 in area 6) are crucially involved in conditional visuomotor behavior, in which it is required to determine an action based on an associated visual object. However, virtually no direct projections appear to exist between the vlPFC and PMd. In the present study, to elucidate possible multisynaptic networks linking the vlPFC to the PMd, we performed a series of neuroanatomical tract-tracing experiments in macaque monkeys. First, we identified cortical areas that send projection fibers directly to the PMd by injecting Fast Blue into the PMd. Considerable retrograde labeling occurred in the dorsal prefrontal cortex (dPFC) (areas 46d/9/8B/8Ad), dorsomedial motor cortex (dmMC) (F7 and presupplementary motor area), rostral cingulate motor area, and ventral premotor cortex (F5 and area 44), whereas the vlPFC was virtually devoid of neuronal labeling. Second, we injected the rabies virus, a retrograde transneuronal tracer, into the PMd. At 3 days after the rabies injections, second-order neurons were labeled in the vlPFC (mainly area 45), indicating that the vlPFC disynaptically projects to the PMd. Finally, to determine areas that connect the vlPFC to the PMd indirectly, we carried out an anterograde/retrograde dual-labeling experiment in single monkeys. By examining the distribution of axon terminals labeled from the vlPFC and cell bodies labeled from the PMd, we found overlapping labels in the dPFC and dmMC. These results indicate that the vlPFC outflow is directed toward the PMd in a multisynaptic fashion through the dPFC and/or dmMC.

Evolutionary loss of complexity in human vocal anatomy as an adaptation for speech.

Human speech production obeys the same acoustic principles as vocal production in other animals but has distinctive features: A stable vocal source is filtered by rapidly changing formant frequencies. To understand speech evolution, we examined a wide range of primates, combining observations of phonation with mathematical modeling. We found that source stability relies upon simplifications in laryngeal anatomy, specifically the loss of air sacs and vocal membranes. We conclude that the evolutionary loss of vocal membranes allows human speech to mostly avoid the spontaneous nonlinear phenomena and acoustic chaos common in other primate vocalizations. This loss allows our larynx to produce stable, harmonic-rich phonation, ideally highlighting formant changes that convey most phonetic information. Paradoxically, the increased complexity of human spoken language thus followed simplification of our laryngeal anatomy.

Origins of multisynaptic projections from the basal ganglia to rostrocaudally distinct sectors of the dorsal premotor area in macaques.

We examined the organization of multisynaptic projections from the basal ganglia (BG) to the dorsal premotor area in macaques. After injection of the rabies virus into the rostral sector of the caudal aspect of the dorsal premotor area (F2r) and the caudal sector of the caudal aspect of the dorsal premotor area (F2c), second-order neuron labeling occurred in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Labeled GPi neurons were found in the caudoventral portion after F2c injection, and in the dorsal portion at the rostrocaudal middle level after F2r injection. In the SNr, F2c and F2r injections led to labeling in the caudal or rostral part, respectively. Subsequently, third-order neuron labeling was observed in the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the striatum. After F2c injection, labeled neurons were observed over a broad territory in the GPe, whereas after F2r injection, labeled neurons tended to be restricted to the rostral and dorsal portions. In the STN, F2c injection resulted in extensive labeling over the nucleus, whereas F2r injection resulted in labeling in the ventral portion only. After both F2r and F2c injections, labeled neurons in the striatum were widely observed in the striatal cell bridge region and neighboring areas, as well as in the ventral striatum. The present results revealed that the origins of multisynaptic projections to F2c and F2r in the BG are segregated in the output stations of the BG, whereas intermingling rather than segregation is evident with respect to their input station.

Motor and non-motor projections from the cerebellum to rostrocaudally distinct sectors of the dorsal premotor cortex in macaques.

In the caudal part of the dorsal premotor cortex of macaques (area F2), both anatomical and physiological studies have identified two rostrocaudally separate sectors. The rostral sector (F2r) is located medial to the genu of the arcuate sulcus, and the caudal sector (F2c) is located lateral to the superior precentral dimple. Here we examined the sites of origin of projections from the cerebellum to F2r and F2c. We applied retrograde transsynaptic transport of a neurotropic virus, CVS-11 of rabies virus, in macaque monkeys. Three days after rabies injections into F2r or F2c, neuronal labeling was found in the deep cerebellar nuclei mainly of the contralateral hemisphere. After the F2r injection, labeled cells were distributed primarily in the caudoventral portion of the dentate nucleus, whereas cells labeled after the F2c injection were distributed in the rostrodorsal portion of the dentate nucleus, and in the interpositus and fastigial nuclei. Four days after rabies injections, Purkinje cells were densely labeled in the lateral part of the cerebellar cortex. After the F2r injection, Purkinje cell labeling was confined to Crus I and II, whereas the labeling seen after the F2c injection was located broadly from lobules III to VIII, including Crus I and II. These results have revealed that F2c receives inputs from broader areas of the cerebellum than F2r, and that distinct portions of the deep cerebellar nuclei and the cerebellar cortex send major projections to F2r and F2c, suggesting that F2c and F2r may be under specific influences of the cerebellum.

Laminar Pattern of Projections Indicates the Hierarchical Organization of the Anterior Cingulate-Temporal Lobe Emotion System.

The anterior cingulate cortex (ACC), surrounding the genu of the corpus callosum, plays important roles in emotional processing and is functionally divided into the dorsal, perigenual, and subgenual subregions (dACC, pgACC, and sgACC, respectively). Previous studies have suggested that the pgACC and sgACC have distinctive roles in the regulation of emotion. In order to elicit appropriate emotional responses, these ACC regions require sensory information from the environment. Anatomically, the ACC has rich connections with the temporal lobe, where the higher-order processing of sensory information takes place. To clarify the organization of sensory inputs into the ACC subregions, we injected neuronal tracers into the pgACC, sgACC, and dACC and compared the afferent connections. Previously, we analyzed the afferent projections from the amygdala and found a distinct pattern for the sgACC. In the present study, the patterns of the afferent projections were analyzed in the temporal cortex, especially the temporal pole (TP) and medial temporal areas. After tracers were injected into the sgACC, we observed labeled neurons in the TP and the subiculum of the hippocampal formation. The majority of the labeled cell bodies were found in the superficial layers of the TP ("feedforward" type projections). The pgACC received afferent projections from the TP, the entorhinal cortex (EC), and the parahippocampal cortex (PHC), but not from the hippocampus. In each area, the labeled cells were mainly found in the deep layers ("feedback" type projection). The pattern for the dACC was similar to that for the pgACC. Previous studies suggested that the pgACC, but not the sgACC receive projections from the dorsolateral prefrontal cortex (DLPFC). These data suggest that the sgACC plays crucial roles for emotional responses based on sensory and mnemonic inputs from the anterior temporal lobe, whereas the pgACC is more related to the cognitive control of emotion.

Afferent connections of the dorsal, perigenual, and subgenual anterior cingulate cortices of the monkey: Amygdalar inputs and intrinsic connections.

The anterior cingulate cortex (ACC) is crucial for emotional processing, and its abnormal activities contributes to mood disorders. The ACC is divided into three subregions: the dorsal ACC (dACC), perigenual ACC (pgACC), and subgenual ACC (sgACC). Although these regions have been implicated in emotional processing, the dACC is more involved in cognitive functions, while the other two regions are important in the pathophysiology underlying mood disorders. Recent studies have suggested that the sgACC and pgACC exhibit opposite emotion-related activity patterns and that an interaction of the ACC with the amygdala is crucial for emotion-related ACC functions. Here, we injected neuronal tracers into the sgACC, pgACC, and dACC of macaques and quantitatively compared the distributions of the retrogradely labeled neurons in the amygdalar nuclei. For both the dACC and pgACC, about 90% of the labeled neurons were found in the basal nucleus, about 10% were in the accessory basal nucleus, and the lateral nucleus had almost no neuronal labeling. However, after sgACC injections, nearly half of the labeled neurons were found in the accessory basal nucleus, and a moderate number of labeled neurons were found in the lateral nucleus. These differences in amygdalar inputs might underlie the functional differences in the sgACC and pgACC. Moreover, after tracer injections in the sgACC, labeled neurons were observed in the pgACC and not the dACC, suggesting that the pgACC directly influences the activity of the sgACC.

Efficient gene transfer via retrograde transport in rodent and primate brains using a human immunodeficiency virus type 1-based vector pseudotyped with rabies virus glycoprotein.

The primate lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) has been used for a wide range of gene therapy trials in animal models. Axonal transport in the retrograde direction, which is observed with some viral vectors, confers a considerable advantage to gene transfer into neuronal cell bodies that are localized in regions remote from the injection site of the vectors. However, retrograde axonal transport of the HIV-1-based lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein is reported to be inefficient. In the present study, we developed an efficient gene transfer system through retrograde transport in the brain with the HIV-1-based vector pseudotyped with rabies virus glycoprotein (RV-G). Injection of the RV-G-pseudotyped HIV-1 vector into the dorsal striatum of mice yielded an increase in gene transfer into neuronal populations in the cerebral cortex, thalamus, and ventral midbrain, each of which innervates the striatum. In addition, injection of the RV-G-pseudotyped vector into the monkey striatum (putamen) resulted in highly efficient transfer into neurons in the ventral midbrain (nigrostriatal dopamine neurons). Our results indicate that pseudotyping of the HIV-1 vector with RV-G enhances the efficiency of gene transfer through retrograde axonal transport in both mouse and monkey brains. This primate lentiviral vector system will provide a powerful approach to gene therapy for neurological and neurodegenerative diseases by means of enhanced retrograde transport.

Differential characteristics of HIV-based versus SIV-based lentiviral vector systems: Gene delivery to neurons and axonal transport of expressed gene.

The differential characteristics of lentiviral vectors based on human and simian immunodeficiency viruses (HIV and SIV) were investigated in rats and monkeys. Each vector was injected into the striatum, and the expression patterns of the marker gene green fluorescent protein (GFP) were analyzed in the basal ganglia. With respect to the capability of gene delivery to neural cells, the HIV-based vector exhibited a higher tropism to neurons than to astroglias in the striatum, and vice versa for the SIV-based vector. The preferential direction of axonal transport of striatally expressed GFP was also examined in the present study. The HIV-based vector allowed for both anterograde transport via the striatopallidal and striatonigral pathways and retrograde transport via the nigrostriatal pathway. The GFP labeling of axon terminals through anterograde transport was apparent regardless of the animal species, while that of neuronal cell bodies through retrograde transport was much more prominent in monkeys than in rats. As for the SIV-based vector, on the other hand, evidence for anterograde transport was obtained much more markedly in monkeys than in rats, and only weak or no retrograde transport occurred in either monkeys or rats. Our results indicate that HIV-based, but not SIV-based, lentiviral vectors possess the high tropism to neurons and permit retrograde transport of an expressed gene, especially in primates. The latter property might carry a potential benefit in gene therapy for Parkinson's disease, as stereotaxic injections of the vectors could be performed into the striatum, spatially larger than the substantia nigra, with greater certainty.

Organization of multisynaptic inputs from prefrontal cortex to primary motor cortex as revealed by retrograde transneuronal transport of rabies virus.

The organization of multisynaptic projections from the prefrontal cortex to the primary motor cortex (MI) was examined in macaque monkeys by retrograde transneuronal transport of rabies virus. In the first series of experiments, the virus was injected into the MI forelimb region, and the time-dependent distribution patterns of transsynaptic labeling were analyzed in the frontal lobe with various survivals (2-4 d). Two days after the viral injection, neuronal labeling emerged in the caudal aspects of the nonprimary motor-related areas that are known to project to the MI directly. At the same time, the motor thalamus contained labeled neurons. On the third day, cortical labeling extended into the rostral motor-related areas and, also, prearcuate area 8. Moreover, a number of labeled neurons were located in the internal pallidum and the cerebellar nuclei. At the 4 d postinjection period, neuronal labeling occurred widely in prefrontal areas as well as in the putamen and the cerebellar cortex. In the second series of experiments, the viral injection was made into the MI hindlimb region, and the distribution pattern of prefrontal labeling on the fourth day was compared with that in the forelimb-injection case. The labeled neurons in each prefrontal area were much fewer in the hindlimb-injection case than in the forelimb-injection case. Whereas ventral area 46 was most densely labeled from the forelimb region, only sparse labeling from the hindlimb region was observed in this prefrontal area. The present results suggest the importance of ventral area 46 in the cognitive control of forelimb movements.

Somatotopically arranged inputs from putamen and subthalamic nucleus to primary motor cortex.

Employing retrograde transsynaptic transport of rabies virus, we investigated the organization of basal ganglia inputs to hindlimb, proximal and distal forelimb, and orofacial representations of the macaque primary motor cortex (MI). Four days after rabies injections into these MI regions, neuronal labeling occurred in the striatum and the subthalamic nucleus (STN) through the cortico-basal ganglia loop circuits. In the striatum, two distinct sets of the labeling were observed: one in the dorsal putamen, and the other in the ventral striatum (ventromedial putamen and nucleus accumbens). The dorsal striatal labeling was somatotopically arranged and its distribution pattern was in good accordance with that of the corticostriatal inputs, such that the hindlimb, orofacial, or forelimb area was located in the dorsal, ventral, or intermediate zone of the putamen, respectively. The distribution pattern of the ventral striatal labeling was essentially the same in all cases. In the STN, the somatotopic arrangement of labeled neurons was in register with that of corticosubthalamic inputs. The present results suggest that the cortico-basal ganglia motor circuits involving the dorsal putamen and the STN may constitute separate closed loops based on the somatotopy, while the ventral striatum provides common multisynaptic projections to all body-part representations in the MI.

D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase.

Dopamine effects in the striatum are mediated principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons. After degeneration of the nigrostriatal dopamine system, direct pathway neurons display a supersensitive response to D1 dopamine receptor agonists, which is demonstrated by the induction of immediate early genes (IEGs), such as c-fos. Here we show, using analysis of receptor-mediated signal transduction, including protein phosphorylation and induction of IEGs, that D1 dopamine receptor supersensitivity is attributable to a switch to ERK1/2/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) in direct pathway neurons. Normally, in the dopamine-intact striatum, activation of ERK1/2/MAP kinase is shown to be restricted to indirect and not direct pathway neurons in response to stimulation of corticostriatal afferents. Moreover, in the dopamine-intact striatum, treatment with full D1 dopamine receptor agonists or stimulation of nigrostriatal dopaminergic afferents, both of which result in the induction of IEGs in direct striatal projection neurons, does not activate ERK1/2/MAP kinase. However, after degeneration of the nigrostriatal dopaminergic pathway, ERK1/2/MAP kinase is activated in direct pathway neurons in response to D1 dopamine receptor agonists either alone or when combined with stimulation of corticostriatal afferents. Inhibitors of MEK (MAP kinase kinase), which is responsible for phosphorylation of ERK1/2/MAP kinase, blocks D1 dopamine receptor agonist activation of ERK1/2/MAP kinase in the dopamine-depleted striatum, as well as the supersensitive induction of IEGs. These results demonstrate that dopamine input to the striatum maintains distinct forms of protein kinase-mediated gene regulation in the direct and indirect striatal projection neurons.

Responses of monkey prefrontal neurons during the execution of transverse patterning.

Recent functional imaging studies have suggested that the prefrontal cortex (PF) is engaged in the performance of transverse patterning (TP), which consists of 3 conflicting discriminations (A+/B-, B+/C-, C+/A-). However, the roles of PF in TP are still unclear. To address this issue, we examined the neuronal responses in 3 regions [the principal sulcus (PS), dorsal convexity (DC), and medial prefrontal cortex (MPF)] of the macaque PF during the performance of an oculomotor version of TP. A delayed matching-to-sample (DMS) task was used as a control task. The TP task-responsive neurons were most abundant in MPF. We analyzed the dependency of each neuronal response on the task type (TP or DMS), target shape (A, B, or C), and target location (left or right). Immediately after the choice cue presentation, many MPF neurons showed task dependency. Interestingly, some of them already exhibited differential activity between the 2 tasks before the choice cue presentation. Immediately before the saccade, the number of target location-dependent neurons increased in MPF and PS. Among them, many MPF neurons were also influenced by the task type, whereas PS neurons tended to show location dependency without task dependency. These results suggest that MPF and PS are involved in the execution of TP: MPF appears to be more important in the target selection based on the TP rule, whereas PS is apparently more related to the response preparation. In addition, some neurons showed a postsaccadic response, which may be related to the feedback mechanism.

Input-output organization of the rostral part of the dorsal premotor cortex, with special reference to its corticostriatal projection.

Until recently, little was known about the rostral part of the dorsal premotor cortex (PMdr). In the present study, somatotopical representations of the PMdr were electrophysiologically identified in the macaque monkey, and the distribution of corticostriatal input from the forelimb region of the PMdr was analyzed in relation to its thalamocortical and intracortical (with the frontal lobe) connections. Results have revealed that (1) the forelimb is represented predominantly in the PMdr, while only a few sites representing other body parts are distributed as embedded within the forelimb representation; (2) the corticostriatal input zone is located in the striatal cell bridges and their surroundings; (3) the cells of origin of the thalamocortical projections to the PMdr are located mainly in the parvicellular division of the ventroanterior nucleus, the oral divison of the ventrolateral nucleus, area X, the caudal divison of the ventrolateral nucleus, the mediodorsal nucleus, and the intralaminar nuclear group; (4) the PMdr is interconnected primarily with higher-order motor-related areas and dorsal area 46. These data indicate that the input-output pattern of the PMdr resembles those of the presupplementary motor area and the rostral cingulate motor area, and that the PMdr may play critical roles in higher-order motor functions.