Nobuhiko Hatanaka

Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey

The cingulate motor areas reside within regions lining the cingulate sulcus and are divided into rostral and caudal parts. Recent studies suggest that the rostral and caudal cingulate motor areas participate in distinct aspects of motor function: the former plays a role in higher‐order cognitive control of movements, whereas the latter is more directly involved in their execution. Here, we investigated the organization of cingulate motor areas inputs to the basal ganglia in the macaque monkey. Identified forelimb representations of the rostral and caudal cingulate motor areas were injected with different anterograde tracers and the distribution patterns of labelled terminals were analysed in the striatum and the subthalamic nucleus. Corticostriatal inputs from the rostral and caudal cingulate motor areas were located within the rostral striatum, with the highest density in the striatal cell bridges and the ventrolateral portions of the putamen, respectively. There was no substantial overlap between these input zones. Similarly, a certain segregation of input zones from the rostral and caudal cingulate motor areas occurred along the mediolateral axis of the subthalamic nucleus. It has also been revealed that corticostriatal and corticosubthalamic input zones from the rostral cingulate motor area considerably overlapped those from the presupplementary motor area, while the input zones from the caudal cingulate motor area displayed a large overlap with those from the primary motor cortex. The present results indicate that a parallel design underlies motor information processing in the cortico‐basal ganglia loop derived from the rostral and caudal cingulate motor areas.

Thalamocortical and intracortical connections of monkey cingulate motor areas

Although there has been an increasing interest in motor functions of the cingulate motor areas, data concerning their input organization are still limited. To address this issue, the patterns of thalamic and cortical inputs to the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas were investigated in the macaque monkey. Tracer injections were made into identified forelimb representations of these areas, and the distributions of retrogradely labeled neurons were analyzed in the thalamus and the frontal cortex. The cells of origin of thalamocortical projections to the CMAr were located mainly in the parvicellular division of the ventroanterior nucleus and the oral division of the ventrolateral nucleus (VLo). On the other hand, the thalamocortical neurons to the CMAd/CMAv were distributed predominantly in the VLo and the oral division of the ventroposterolateral nucleus‐the caudal division of the ventrolateral nucleus. Additionally, many neurons in the intralaminar nuclear group were seen to project to the cingulate motor areas. Except for their well‐developed interconnections, the corticocortical projections to the CMAr and CMAd/CMAv were also distinctively preferential. Major inputs to the CMAr arose from the presupplementary motor area and the dorsal premotor cortex, whereas inputs to the CMAd/CMAv originated not only from these areas but also from the supplementary motor area and the primary motor cortex. The present results indicate that the CMAr and the caudal cingulate motor area (involving both the CMAd and the CMAv) are characterized by distinct patterns of thalamocortical and intracortical connections, reflecting their functional differences. J. Comp. Neurol. 462:121–138, 2003.

Kinase-Dead Knock-In Mouse Reveals an Essential Role of Kinase Activity of Ca2+/Calmodulin-Dependent Protein Kinase IIα in Dendritic Spine Enlargement, Long-Term Potentiation, and Learning

Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) is an essential mediator of activity-dependent synaptic plasticity that possesses multiple protein functions. So far, the autophosphorylation site-mutant mice targeted at T286 and at T305/306 have demonstrated the importance of the autonomous activity and Ca2+/calmodulin-binding capacity of CaMKIIα, respectively, in the induction of long-term potentiation (LTP) and hippocampus-dependent learning. However, kinase activity of CaMKIIα, the most essential enzymatic function, has not been genetically dissected yet. Here, we generated a novel CaMKIIα knock-in mouse that completely lacks its kinase activity by introducing K42R mutation and examined the effects on hippocampal synaptic plasticity and behavioral learning. In homozygous CaMKIIα (K42R) mice, kinase activity was reduced to the same level as in CaMKIIα-null mice, whereas CaMKII protein expression was well preserved. Tetanic stimulation failed to induce not only LTP but also sustained dendritic spine enlargement, a structural basis for LTP, at the Schaffer collateral–CA1 synapse, whereas activity-dependent postsynaptic translocation of CaMKIIα was preserved. In addition, CaMKIIα (K42R) mice showed a severe impairment in inhibitory avoidance learning, a form of memory that is dependent on the hippocampus. These results demonstrate that kinase activity of CaMKIIα is a common critical gate controlling structural, functional, and behavioral expression of synaptic memory.

Organization of prefrontal outflow toward frontal motor-related areas in macaque monkeys

Linkage between the prefrontal cortex and the primary motor cortex is mediated by nonprimary motor‐related areas of the frontal lobe. In an attempt to analyse the organization of the prefrontal outflow from area 46 toward the frontal motor‐related areas, we investigated the pattern of projections involving the higher‐order motor‐related areas, such as the presupplementary motor area (pre‐SMA) and the rostral cingulate motor area (CMAr). Tracer injections were made into these motor‐related areas (their forelimb representation) on the medial wall that had been identified electrophysiologically. The following data were obtained from a series of tract‐tracing experiments in Japanese monkeys. (i) Only a few neurons in area 46 were retrogradely labelled from the pre‐SMA and CMAr; (ii) terminal labelling from area 46 occurred sparsely in the pre‐SMA and CMAr; (iii) a dual labelling technique revealed that the sites of overlap of anterograde labelling from area 46 and retrograde labelling from the pre‐SMA and CMAr were evident in the rostral parts of the dorsal and ventral premotor cortices (PMdr and PMvr); (iv) and tracer injections into the PMdr produced neuronal cell labelling in area 46 and terminal labelling in the pre‐SMA and CMAr. The present results indicate that a large portion of the prefrontal signals from area 46 is not directly conveyed to the pre‐SMA and CMAr, but rather indirectly by way of the PMdr and PMvr. This suggests that area 46 exerts its major influence on the cortical motor system via these premotor areas.

Input–output organization of jaw movement-related areas in monkey frontal cortex

The brain mechanisms underlying mastication are not fully understood. To address this issue, we analyzed the distribution patterns of cortico–striatal and cortico–brainstem axon terminals and the origin of thalamocortical and intracortical fibers by injecting anterograde/retrograde tracers into physiologically and morphologically defined jaw movement‐related cortical areas. Four areas were identified in the macaque monkey: the primary and supplementary orofacial motor areas (MIoro and SMAoro) and the principal and deep parts of the cortical masticatory area (CMaAp and CMaAd), where intracortical microstimulation produced single twitch‐like or rhythmic jaw movements, respectively. Tracer injections into these areas labeled terminals in the ipsilateral putamen in a topographic fashion (MIoro vs. SMAoro and CMaAp vs. CMaAd), in the lateral reticular formation and trigeminal sensory nuclei contralaterally (MIoro and CMaAp) or bilaterally (SMAoro) in a complex manner of segregation vs. overlap, and in the medial parabranchial and Kölliker‐Fuse nuclei contralaterally (CMaAd). The MIoro and CMaAp received thalamic projections from the ventrolateral and ventroposterolateral nuclei, the SMAoro from the ventroanterior and ventrolateral nuclei, and the CMaAd from the ventroposteromedial nucleus. The MIoro, SMAoro, CMaAp, and CMaAd received intracortical projections from the ventral premotor cortex and primary somatosensory cortex, the ventral premotor cortex and rostral cingulate motor area, the ventral premotor cortex and area 7b, and various sensory areas. In addition, the MIoro and CMaAp received projections from the three other jaw movement‐related areas. Our results suggest that the four jaw movement‐related cortical areas may play important roles in the formation of distinctive masticatory patterns. J. Comp. Neurol. 492:401–425, 2005.

Somatotopic arrangement and corticocortical inputs of the hindlimb region of the primary motor cortex in the macaque monkey

Using Japanese monkeys, we examined the somatotopic organization of the hindlimb region of the primary motor cortex (MI) with intracortical microstimulation. In the hindlimb region of the MI, areas representing distal movements (digits and ankle joints) were basically surrounded by those representing proximal movements (knee and hip joints). Thus, the hindlimb region of the MI has a nested or horseshoe-like somatotopic representation. We then examined the topographic organization of corticocortical projections to the hindlimb region of the MI by the retrograde double-labeling technique: one monkey received paired injections of Fast blue (FB) and Diamidino yellow (DY) into hindlimb or forelimb representation of the MI, respectively, while two monkeys received those of FB and DY into proximal or distal representation of the hindlimb region of the MI, respectively. The neurons projecting to the hindlimb region of the MI were located in cortical areas largely separate from those projecting to the forelimb region of the MI. On the other hand, we found a substantial overlap of corticocortical neurons projecting to the proximal and distal parts of the hindlimb region of the MI in the dorsal division of the premotor cortex and the cingulate motor areas.

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.

B-mode and color Doppler ultrasound imaging for localization of microelectrode in monkey brain

Using alert monkeys, we attempted ultrasound imaging after partial craniotomy to localize a metal microelectrode in the brain. B-mode ultrasonography provided images of sulcus and gyrus patterns of the cerebral cortex, and locations of the ventricles and subarachnoid cisterns. As the microelectrode proceeded in the brain, the position of the microelectrode was clearly identified. Electrolytic microlesions generated by delivering direct currents via the microelectrode could also be detected. Color Doppler imaging of blood vessels of the brain was helpful to demarcate deep brain structures and to avoid accidental injury of the blood vessels by the microelectrode. The ultrasonography will make it possible to place recording microelectrodes or injection needles accurately in target regions of the brain in physiological, anatomical or behavioral experiments.

Distribution of median, ulnar and radial motoneurons in the monkey spinal cord : a retrograde triple-labeling study

Topographic distribution of motoneurons innervating hand muscles through the median (Mn), ulnar (Ul), or radial (Rd) nerves was examined using a retrograde multiple-labeling technique in the macaque monkey. The Mn and Ul motoneurons, i.e. flexor motoneurons, were distributed from C6 to T2 and from C7 to T2 segments of the spinal cord, respectively, while the Rd motoneurons, i.e. extensor motoneurons, were distributed from C4 to T2. The present study further revealed partial intermingling of the cell bodies and partial overlap of the dendritic fields among the motoneurons projecting through different nerves, indicating that subregions of motoneuronal pool participate in coordination between the flexor and extensor, or among the flexor muscles. It was suggested that there exists a control mechanism for precise hand movements in the spinal cord.

A cortical motor region that represents the cutaneous back muscles in the macaque monkey

A cortical motor region that represented the cutaneous muscles on the back was identified on the medial wall of the frontal lobe in the macaque monkey. In this region, neurons responded to somatosensory stimuli such as light touch or squeezing of the back skin, and intracortical microstimulation elicited contraction of the back skin. Such a region was located primarily on the dorsal bank of the cingulate sulcus, corresponding to the dorsal cingulate motor area.