To investigate the effects of postlesion training on motor recovery, we compared the motor recovery of macaque monkeys that had received intensive motor training with those that received no training after a lesion of the primary motor cortex (M1). An ibotenic acid lesion in the M1 digit area resulted in impairment of hand function, with complete loss of digit movement. In the monkeys that had undergone intensive daily training (1 h/day, 5 days/wk) after the lesion, behavioral indexes used to evaluate manual dexterity recovered to the same level as in the prelesion period after 1 or 2 mo of postlesion training period. Relatively independent digit movements, including precision grip (prehension of a small object with finger-to-thumb opposition), were restored in the trained monkeys. Although the behavioral indexes of manual dexterity recovered to some extent in the monkeys without the postlesion training, they remained lower than those in the prelesion period until several months after M1 lesion. The untrained monkeys frequently used alternate grip strategies to grasp a small object with the affected hand, holding food pellets between the tip of the index finger and the dorsum of the thumb. These results suggest that the recovery after M1 lesion includes both use-dependent and use-independent processes and that the recovery of precision grip can be promoted by intensive use of the affected hand in postlesion training.

To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.

The question of how intensive motor training restores motor function after brain damage or stroke remains unresolved. Here we show that the ipsilesional ventral premotor cortex (PMv) and perilesional primary motor cortex (M1) of rhesus macaque monkeys are involved in the recovery of manual dexterity after a lesion of M1. A focal lesion of the hand digit area in M1 was made by means of ibotenic acid injection. This lesion initially caused flaccid paralysis in the contralateral hand but was followed by functional recovery of hand movements, including precision grip, during the course of daily postlesion motor training. Brain imaging of regional cerebral blood flow by means of H 2 15O-positron emission tomography revealed enhanced activity of the PMv during the early postrecovery period and increased functional connectivity within M1 during the late postrecovery period. The causal role of these areas in motor recovery was confirmed by means of pharmacological inactivation by muscimol during the different recovery periods. These findings indicate that, in both the remaining primary motor and premotor cortical areas, time-dependent plastic changes in neural activity and connectivity are involved in functional recovery from the motor deficit caused by the M1 lesion. Therefore, it is likely that the PMv, an area distant from the core of the lesion, plays an important role during the early postrecovery period, whereas the perilesional M1 contributes to functional recovery especially during the late postrecovery period.

By using the developing monkey brain as a model for human development, we investigated the expression pattern of the FOXP2 gene, a member of the FOX family of transcription factors in the developing monkey brain, and compared its expression pattern with transcription factors PBX3, MEIS2, and FOXP1. We observed FOXP2 mRNA expression in several brain structures, including the striatum, the islands of Calleja and other basal forebrain regions, the cerebral cortex, and the thalamus. FOXP2 mRNA was preferentially expressed in striosomal compartments during striatal development. The striosomal expression was transient and developmentally down-regulated in a topographical order. Specifically, during the perinatal state, striosomal FOXP2 expression was detected in both the caudate nucleus and the putamen, although expression was more prominent in the caudate nucleus than in the putamen. Striosomal FOXP2 expression declined during the postnatal period, first in the putamen and later in the caudate nucleus. During the same period, we also detected PBX3 mRNA in the striosomal compartment of the developing monkey striatum. FOXP2, as well as PBX3 and MEIS2, was expressed in the islands of Calleja and other cell clusters of the basal forebrain. FOXP2, in combination with PBX3 and MEIS2, may play a pivotal role in the development of striosomal neurons of the striatum and the islands of Calleja.

Brain damage such as stroke is a devastating neurological condition that may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic maleate, facilitated experience-driven synaptic glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptor delivery and resulted in the acceleration of motor function recovery after motor cortex cryoinjury in mice in a training-dependent manner through cortical reorganization. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2) and failed to augment recovery in CRMP2-deficient mice. Edonerpic maleate enhanced motor function recovery from internal capsule hemorrhage in nonhuman primates. Thus, edonerpic maleate, a neural plasticity enhancer, could be a clinically potent small compound with which to accelerate rehabilitation after brain damage.