Accounting for the valley of recovery during post-stroke rehabilitation training a model-based analysis of macaque manual dexterity.

Background: True recovery, in which a stroke patient regains the same precise motor skills observed in prestroke conditions, is the fundamental goal of rehabilitation training. However, a transient drop in task performance during rehabilitation training after stroke, observed in human clinical outcome as well as in both macaque and squirrel monkey retrieval data, might prevent smooth transitions during recovery. This drop, i.

Time- and area-dependent macrophage/microglial responses after focal infarction of the macaque internal capsule.

We quantitatively investigated temporal changes of macrophages and microglia (MΦ/MG) after focal infarction of the internal capsule using a macaque model we recently established. Immunoreactivity for Iba1, a general marker for MΦ/MG, in the periinfarct core gradually increased from 0 days to 2-3 weeks after infarction, and the increased immunoreactivity continued at least until 6 months; no study in rodents has reported increased Iba1-immunoreactive cells for so long. Retrograde atrophy or degeneration of neurons in layer V of the primary motor cortex, where the descending motor tract originates, was seen as secondary damage.

Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis.

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers.

The Ventral Striatum is a Key Node for Functional Recovery of Finger Dexterity After Spinal Cord Injury in Monkeys.

In a recent study, we demonstrated that the ventral striatum (VSt) controls finger movements directly during the early recovery stage after spinal cord injury (SCI), implying that the VSt may be a part of neural substrates responsible for the recovery of dexterous finger movements. The VSt is accepted widely as a key node for motivation, but is not thought to be involved in the direct control of limb movements. Therefore, whether a causal relationship exists between the VSt and motor recovery after SCI is unknown, and the role of the VSt in the recovery of dexterous finger movements orfinger movements in general after SCI remains unclear.

Premotor Cortical-Cerebellar Reorganization in a Macaque Model of Primary Motor Cortical Lesion and Recovery.

Neuromotor systems have the capacity for functional recovery following local damage. The literature suggests a possible role for the premotor cortex and cerebellum in motor recovery. However, the specific changes to interactions between these areas following damage remain unclear.

Hybrid Reaction Systems for the Synthesis of Alkylated Compounds Based upon Cu-Catalyzed Coupling of Radicals and Organometallic Species.

A transition metal catalyzed alkylation with an alkyl halide is one of the most difficult reactions to achieve, because of the difficult oxidative addition of an alkyl-halogen bond to a metal, and the tendency of the resulting alkylmetal intermediate to undergo a β-hydride elimination reaction to give an olefin. In this review, we discuss hybrid reaction systems involving Cu catalyzed combination of radicals and organometallic species, which enable facile alkylation reactions to construct C-C and C-heteroatom bonds. This paper highlights recent progress in arylation, alkenylation, alkynylation, cyclization, addition and introduction of heteroatoms via these hybrid reaction systems.

Ppm Cu Catalyst Enables -Alkylation Followed by C-H Cyclization To Synthesize Substituted Oxindoles.

In this paper, we established highly efficient Cu-catalyzed tandem -alkylation C-H cyclization of α-bromocarbonyls and methacrylamides to produce substituted oxindoles. The maximum turnover number was up to 48 000 with reasonable yield. Although the catalyst loadings were very low, the reaction was not involving radical chain reaction.

Neuronal and microglial localization of secreted phosphoprotein 1 (osteopontin) in intact and damaged motor cortex of macaques.

We previously reported that mRNA encoding secreted phosphoprotein 1 (SPP1), also known as osteopontin, is preferentially expressed in large neurons in layer V of the macaque motor cortex, most of which are presumed to be corticospinal tract neurons. As a first step to elucidating the cellular function of SPP1 in macaque neurons, we examined the localization of SPP1 in the primary motor cortex (M1) of the macaque by using immunohistochemistry. SPP1 immunoreactivity was found to be localized in the cell bodies of neurons, but not outside the cells, indicating that SPP1 was not secreted from these neurons.

CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage.

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.

Facile Synthesis of Single α-tert-Alkylated Acetaldehydes by Hydroxyalkylation of Enamides in Aqueous Solution.

In this work, we established a general protocol to synthesize single α-tert-alkylated acetaldehydes via Cu-catalyzed hydroxyalkylation of enamides in aqueous solutions. The yields of the products were very high and there was excellent functional group compatibility. Our reaction allows easy access to highly functionalized acetaldehydes that can be used to synthesize further useful compounds including spirocycles.

Comprehensive analysis of area-specific and time-dependent changes in gene expression in the motor cortex of macaque monkeys during recovery from spinal cord injury.

The present study aimed to assess the molecular bases of cortical compensatory mechanisms following spinal cord injury in primates. To accomplish this, comprehensive changes in gene expression were investigated in the bilateral primary motor cortex (M1), dorsal premotor cortex (PMd), and ventral premotor cortex (PMv) after a unilateral lesion of the lateral corticospinal tract (l-CST). At 2 weeks after the lesion, a large number of genes exhibited altered expression levels in the contralesional M1, which is directly linked to the lesioned l-CST.

Expression of Collagenase is Regulated by the VarS/VarA Two-Component Regulatory System in Vibrio alginolyticus.

Vibrio alginolyticus is an opportunistic pathogen in both humans and marine animals. Collagenase encoded by colA is considered to be one of the virulence factors. Expression of colA is regulated by multiple environmental factors, e.

Neural Activity during Voluntary Movements in Each Body Representation of the Intracortical Microstimulation-Derived Map in the Macaque Motor Cortex.

In order to accurately interpret experimental data using the topographic body map identified by conventional intracortical microstimulation (ICMS), it is important to know how neurons in each division of the map respond during voluntary movements. Here we systematically investigated neuronal responses in each body representation of the ICMS map during a reach-grasp-retrieval task that involves the movements of multiple body parts. The topographic body map in the primary motor cortex (M1) generally corresponds to functional divisions of voluntary movements; neurons at the recording sites in each body representation with movement thresholds of 10 μA or less were differentially activated during the task, and the timing of responses was consistent with the movements of the body part represented.

Development and Characterization of a Macaque Model of Focal Internal Capsular Infarcts.

Several studies have used macaque monkeys with lesions induced in the primary motor cortex (M1) to investigate the recovery of motor function after brain damage. However, in human stroke patients, the severity and outcome of motor impairments depend on the degree of damage to the white matter, especially that in the posterior internal capsule, which carries corticospinal tracts. To bridge the gap between results obtained in M1-lesioned macaques and the development of clinical intervention strategies, we established a method of inducing focal infarcts at the posterior internal capsule of macaque monkeys by injecting endothelin-1 (ET-1), a vasoconstrictor peptide.

Increased expression of the growth-associated protein-43 gene after primary motor cortex lesion in macaque monkeys.

We recently showed that changes of brain activity in the ipsilesional ventral premotor cortex (PMv) and perilesional primary motor cortex (M1) of macaque monkeys were responsible for recovery of manual dexterity after lesioning M1. To investigate whether axonal remodeling is associated with M1 lesion-induced changes in brain activity, we assessed gene expression of growth-associated protein-43 (GAP-43) in motor and premotor cortices. Increased expression was observed in the PMv during the period just after recovery and in the perilesional M1 during the plateau phase of recovery.

Temporal plasticity involved in recovery from manual dexterity deficit after motor cortex lesion in macaque monkeys.

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.

Differential expression of secreted phosphoprotein 1 in the motor cortex among primate species and during postnatal development and functional recovery.

We previously reported that secreted phosphoprotein 1 (SPP1) mRNA is expressed in neurons whose axons form the corticospinal tract (CST) of the rhesus macaque, but not in the corresponding neurons of the marmoset and rat. This suggests that SPP1 expression is involved in the functional or structural specialization of highly developed corticospinal systems in certain primate species. To further examine this hypothesis, we evaluated the expression of SPP1 mRNA in the motor cortex from three viewpoints: species differences, postnatal development, and functional/structural changes of the CST after a lesion of the lateral CST (l-CST) at the mid-cervical level.

Effects of early versus late rehabilitative training on manual dexterity after corticospinal tract lesion in macaque monkeys.

Dexterous hand movements can be restored with motor rehabilitative training after a lesion of the lateral corticospinal tract (l-CST) in macaque monkeys. To maximize effectiveness, the optimal time to commence such rehabilitative training must be determined. We conducted behavioral analyses and compared the recovery of dexterous hand movements between monkeys in which hand motor training was initiated immediately after the l-CST lesion (early-trained monkeys) and those in which training was initiated 1 mo after the lesion (late-trained monkeys).

Functional annotation of genes differentially expressed between primary motor and prefrontal association cortices of macaque brain.

DNA microarray-based genome-wide transcriptional profiling and gene network analyses were used to characterize the molecular underpinnings of the neocortical organization in rhesus macaque, with particular focus on the differences in the functional annotation of genes in the primary motor cortex (M1) and the prefrontal association cortex (area 46 of Brodmann). Functional annotation of the differentially expressed genes showed that the list of genes selectively expressed in M1 was enriched with genes involved in oligodendrocyte function, and energy consumption. The annotation appears to have successfully extracted the characteristics of the molecular structure of M1.

SPP1 expression in spinal motor neurons of the macaque monkey.

In the macaque cerebral cortex, the SPP1 (secreted phosphoprotein 1) gene is mainly expressed in corticospinal neurons. In this study, we found that SPP1 was principally expressed in motor neurons in lamina IX of the macaque spinal cord. The expression level varied among different spinal segments and correlated positively with neuron size.

SPP1 is expressed in corticospinal neurons of the macaque sensorimotor cortex.

The cellular distribution of SPP1, which we recently identified as a gene with greater expression in the macaque primary motor cortex than in the premotor or prefrontal cortices, was examined in rhesus macaque, common marmoset, and rat brains. In situ hybridization histochemistry revealed that SPP1 mRNA was expressed specifically in pyramidal neurons in layer V of the sensorimotor cortex of the rhesus macaque. These SPP1 mRNA-positive neurons were most abundant in the primary motor area, followed by Brodmann area 5 and the supplementary motor area, in accordance with the distribution of corticospinal neurons.

Increased expression of the growth-associated protein 43 gene in the sensorimotor cortex of the macaque monkey after lesioning the lateral corticospinal tract.

To investigate the neural basis for functional recovery of the cerebral cortex following spinal cord injury, we measured the expression of growth-associated protein 43 (GAP-43), which is involved in the process of synaptic sprouting. We determined the GAP-43 mRNA expression levels in the sensorimotor cortical areas of macaque monkeys with a unilateral lesion of the lateral corticospinal tract (l-CST) at the C4/C5 level of the cervical cord and compared them with the levels in the corresponding regions of intact monkeys. Lesioned monkeys recovered finger dexterity during the first months after surgery, and the GAP-43 mRNA levels increased in layers II-III in primary motor areas (M1), bilaterally.

Effects of motor training on the recovery of manual dexterity after primary motor cortex lesion in macaque monkeys.

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.

Expression of protein kinase-C substrate mRNA in the motor cortex of adult and infant macaque monkeys.

To understand the molecular and cellular bases of plasticity in the primate motor cortex, we investigated the expression of three protein kinase-C (PKC) substrates: GAP-43, myristoylated alanine-rich C-kinase substrate (MARCKS), and neurogranin, which are key molecules regulating synaptic plasticity. Prominent signals for the three mRNAs were primarily observed in pyramidal cells. Large pyramidal cells in layer V, from which the descending motor tract originates, contained weaker hybridization signals for GAP-43 and neurogranin mRNAs than did the smaller pyramidal cells.