Chondroitinase ABC promotes selective reactivation of somatosensory cortex in squirrel monkeys after a cervical dorsal column lesion

Abstract

After large but incomplete lesions of ascending dorsal column afferents in the cervical spinal cord, the hand representation in the contralateral primary somatosensory cortex (area 3b) of monkeys is largely or completely unresponsive to touch on the hand. However, after weeks of spontaneous recovery, considerable reactivation of the hand territory in area 3b can occur. Because the reactivation process likely depends on the sprouting of remaining axons from the hand in the cuneate nucleus of the lower brainstem, we sought to influence cortical reactivation by treating the cuneate nucleus with an enzyme, chondroitinase ABC, that digests perineuronal nets, promoting axon sprouting. Dorsal column lesions were placed at a spinal cord level (C5/C6) that allowed a portion of ascending afferents from digit 1 to survive in squirrel monkeys. After 11-12 wk of recovery, the contralateral forelimb cortex was reactivated by stimulating digit 1 more extensively in treated monkeys than in control monkeys. The results are consistent with the proposal that the treatment enhances the sprouting of digit 1 afferents in the cuneate nucleus and that this sprouting allowed these preserved inputs to activate cortex more effectively.plasticity | primates I mmediately after a major loss of sensory inputs from an arm or other part of the body in primates and other mammals, most or all of the corresponding part of the somatotopic representation in the primary somatosensory cortex no longer responds to touch (1-3). However, preserved inputs may activate some of the deprived cortex, and over weeks of recovery more and more of the deprived cortex responds to remaining inputs. When somatosensory inputs from the hand have been largely removed in monkeys by cutting ascending branches of cutaneous afferents in the dorsal column pathways of the spinal cord (2, 4, 5) or by selectively cutting the dorsal roots of peripheral nerves subserving a part of the hand (3), most of the territory of the representation of the hand in the contralateral primary somatosensory cortex (area 3b) initially fails to respond to touch on the hand. In food-retrieval tasks, hand use is impaired, and the monkeys look for food pellets already in their hand as although unsure whether they have grasped the food object (5, 6). However, hand use rapidly recovers over days to weeks as the remaining inputs from the hand reactivate more and more of the cortical territory for the hand. Thus, the reactivation of cortex by preserved afferents from the hand appears to be important in the behavioral recovery.The mechanisms of the reactivation are not understood completely, but at least some of the reactivation occurs at the first relay of information from the preserved dorsal column afferents in the cuneate nucleus of the lower brainstem and upper spinal cord (7,8). It appears that preserved axon terminals of primary afferents, and possibly second-order neurons in the spinal cord (5), sprout in the cuneate nucleus to activate neurons more effectively (9, 10). Similar amplifications of ...

Chondroitinase Enhances Cortical Map Plasticity and Increases Functionally Active Sprouting Axons after Brain Injury

“…cABC-induced enlargement of the cortical map responsive to afferents at 11-12 weeks after dorsal column lesions in the squirrel monkey was suggested, though not validated, to occur as a result of sprouting at three different sites along the CNS axis. 5 Increased axon sprouting may well underlie map plasticity after brain trauma, because the current c-Fos map enlargement coincides temporally with the peak of the sprouting response in this model after cABC intervention. 23 Spatially, the ipsi-and contralateral increases in gray-and white-matter c-Fos cell density observed were consistent with the contralateral spread of enzyme that we recorded.…”

“…Interventions after central nervous system (CNS) injury aimed at readjusting the balance toward growth promotion by reduction of inhibitory proteins using digestive enzymes and/or in combination with other therapies report enhanced axon sprouting, which mostly leads to improved outcome. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] However, at least after TBI, the degree of functional-behavioral improvements do not always follow the magnitude of the anatomical response. 1 It is difficult to directly determine whether newly sprouting axons support function and do, in fact, connect and contribute to the circuitry within which they are growing.…”

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

“…Digestion of CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), following local delivery to the spinal cord, has led to axon regeneration, plastic neuronal rearrangements and functional recovery following section or crush injury in laboratory animal SCI models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Encouragingly, these findings have also been found using clinically relevant contusive injury rodent models (22,23) and large animal models such as cats and squirrel monkeys (19,24,25). Despite these advances, a major limitation for the use of ChABC in humans is the rapid decay of enzymatic activity at body temperature, within 24 to 72 hours (26).…”

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

“…With brain maturation, juvenile plasticity of so-called critical or sensitive periods is decreased and is accompanied by the appearance of the brain's extracellular matrix (ECM) and its specialized compact form named "perineuronal net" (PNN) enwrappping cell bodies and synaptic contacts (2,3). Enzymatic degradation of the ECM in adult animals has been demonstrated to restore such forms of developmental (juvenile) plasticity with respect to topographical map plasticity in the visual cortex (4), fearresponse-mediating circuits in the amygdala (5), spinal cord injuries (6,7), and song learning circuits of zebra finches (8). In addition, enzymatic ECM removal altered several forms of synaptic plasticity in vitro and in vivo (9)(10)(11)(12).…”