The cortico-motoneuronal (CM) [I think it is a subset or alternative of corticospinal tract, CST] system is unique to dexterous primates. It provides a direct pathway from motor cortex to the alpha motoneuron (a special neuron type reside at brainstem and spinal cord, with local innvervation or regulation of nearby muscle contraction). It has long been associated with skilled use of the hands and with tool-making in particular.
CM connections are particularly well developed in dexterous, tool-using primates. In a recent study, Quallo et al demonstrated that macaque corticospinal neurons, including some CM cells, were just as active during tool use, involving use of a rake to retrieve food rewards, as they were during a precision grip.
Rodents do not possess CM connections, and their manipulative skills have developed along quite different lines, well suited to their ecological niche. Because of the methodological advantages of using the rat (and particularly the mouse) for the genetic dissection of neural control systems, a number of studies have sought to model grasp in rats or mice by training them to retrieve small pellets with the forepaw. These studies generally show that, even after training, rodents generally achieve quite low levels of success on such tasks, often around 50 to 60%. It is important to stress the fundamental difference between precision grip in the Old World primate, such as the macaque, and the grasp executed by rodents. It is noteworthy that macaques can be trained to perform precision grip at success rates close to 100%.
Of course, it would be very interesting if ‘dexterity’ in rodents could be improved by supplementing their forepaw control system with CM connections. A fascinating piece of recent research has achieved just this. This study took advantage of the fact that CM connections, though absent in adult rodents, are transiently present in the neonatal animal, before being withdrawn in the early postnatal period 54, 56. Gu et al. 54 sought to interfere genetically with the plexin-based signalling system involved in withdrawal of CM projections. They developed a PlexA1 mutant in which CM connections established at birth are maintained into adulthood. Other descending pathways were not affected. Using ICMS, the authors demonstrated that these mutants had a fast motor pathway from motor cortex to forelimb muscles, which was lacking in the wild-type mouse. They also showed that the mutant mice could be trained to perform a pellet-grasping task at higher levels of success than wild-type animals. Because other descending pathways were not changed in the mutants, this lends further support to a main role for the corticospinal system in enhancing skilled grasp.
A further fascinating part of this discovery was to demonstrate the existence of a CIS-regulatory system in layer V of motor cortex that inhibits the Plexin signalling and thereby allows CM connections, all of which are derived from layer V corticospinal neurons, to be maintained into adulthood. The authors showed that this inhibitory system is strongly expressed in motor cortex of dexterous primates such as human, chimpanzee, orangutan and baboon but is not present in other less dexterous primates, such as marmoset and bushbaby, or in rats or mice 54 (decribed below).
Here is the paper of 54
Superior manual dexterity in higher primates emerged together with the appearance of cortico-motoneuronal (CM) connections during the evolution of the mammalian corticospinal (CS) system. Previously thought to be unique to higher primates, we identified transient CM connections in early postnatal mice (detectable at P2, decrease at P10 and undetectable at P14), which are eventually eliminated by Sema6D-PlexA1 signaling. PlexA1 mutant mice maintain CM connections into adulthood and exhibit superior manual dexterity compared to controls. Finally, differing PlexA1 expression in layer 5 of the motor cortex, which is strong in wild-type mice but weak in humans, may be explained by FEZF2-mediated cis-regulatory elements that are found only in higher primates. Thus, species-dependent regulation of PlexA1 expression may have been crucial in the evolution of mammalian CS systems that improved fine motor control in higher primates.
To determine whether species-dependent cis-regulatory elements might define PLEXA1 expression levels in layer 5, we first identified and compared putative orthologous enhancer regions between humans and mice. Enhancers were identified based on features indicative of active regulatory regions, including H3K4me3 and H3K27ac histone marks, DNase hypersensitivity, and DNA conservation across mammals. This resulted in a ~5 kilobase putative orthologous enhancer in humans and mice (fig. S22). Within the putative human enhancer, we identified a total of 28 putative FEZF2 binding sites. FEZF2 (also known as FEZL and ZFP312), encoding a zinc-finger transcription repressor required for CS tract development, was expressed in the putative layer 5 of the 22 pcw human brain (fig. S26A). Three FEZF2 binding sites correspond to the typical “CTNCANCN” Fezf2 binding site (figs. S23–S25, blue bars) (16), with the remaining 25 resembling a recently described “CGCCGC” element (figs. S23–S25, green and red bars) (17). 5 of the total 28 sites were conserved in both humans and mice (fig. S24, green bars), while 23 of them were only found in humans, resulting in a putative homotypic cluster of 23 human FEZF2 binding sites (Fig. 4B, figs. S22A, S23–S25) (18, 19). Humans, chimpanzees, gorillas, orangutans, and baboons, which all have CM connections (2), all possess these FEZF2 binding sites in their putative PlexA1 cis-regulatory elements (Fig. 4B, and figs. S23–S25). In contrast, mice, rats, and rabbits, as well as some primates, such as marmosets and bushbabies that lack CM connections (2), either lack these FEZF2 binding sites completely or have nucleotide mismatches that are predicted to decrease FEZF2 binding (Fig. 4B, figs. S23–S25). Electrophoretic mobility shift assays (EMSAs) demonstrated binding of FEZF2 to the human FEZF2 binding site, but weaker binding to the homologous mouse sequence and human sequence with point mutations (making it identical to the mouse sequence) (fig. S26B).
