Reorganization of motor cortex and impairment of motor performance induced by hindlimb unloading are partially reversed by cortical IGF-1 administration.

Immobilization, bed rest, or sedentary lifestyle, are known to induce a profound impairment in sensorimotor performance. These alterations are due to a combination of peripheral and central factors. Previous data conducted on a rat model of disuse (hindlimb unloading, HU) have shown a profound reorganization of motor cortex and an impairment of motor performance. Recently, our interest was turned towards the role of insulin-like growth factor 1 (IGF-1) in cerebral plasticity since this growth factor is considered as the mediator of beneficial effects of exercise on the central nervous system, and its cortical level is decreased after a 14-day period of HU. In the present study, we attempted to determine whether a chronic subdural administration of IGF-1 in HU rats could prevent deleterious effects of HU on the motor cortex and on motor activity. We demonstrated that HU induces a shrinkage of hindlimb cortical representation and an increase in current threshold to elicit a movement. Administration of IGF-1 in HU rats partially reversed these changes. The functional evaluation revealed that IGF-1 prevents the decrease in spontaneous activity found in HU rats and the changes in hip kinematics during overground locomotion, but had no effect of challenged locomotion (ladder rung walking test). Taken together, these data clearly indicate the implication of IGF-1 in cortical plastic mechanisms and in behavioral alteration induced by a decreased in sensorimotor activity.

Role of IGF-1 in cortical plasticity and functional deficit induced by sensorimotor restriction.

In the adult rat, sensorimotor restriction by hindlimb unloading (HU) is known to induce impairments in motor behavior as well as a disorganization of somatosensory cortex (shrinkage of the cortical representation of the hindpaw, enlargement of the cutaneous receptive fields, decreased cutaneous sensibility threshold). Recently, our team has demonstrated that IGF-1 level was decreased in the somatosensory cortex of rats submitted to a 14-day period of HU. To determine whether IGF-1 is involved in these plastic mechanisms, a chronic cortical infusion of this substance was performed by means of osmotic minipump. When administered in control rats, IGF-1 affects the size of receptive fields and the cutaneous threshold, but has no effect on the somatotopic map. In addition, when injected during the whole HU period, IGF-1 is interestingly implied in cortical changes due to hypoactivity: the shrinkage of somatotopic representation of hindlimb is prevented, whereas the enlargement of receptive fields is reduced. IGF-1 has no effect on the increase in neuronal response to peripheral stimulation. We also explored the functional consequences of IGF-1 level restoration on tactile sensory discrimination. In HU rats, the percentage of paw withdrawal after a light tactile stimulation was decreased, whereas it was similar to control level in HU-IGF-1 rats. Taken together, the data clearly indicate that IGF-1 plays a key-role in cortical plastic mechanisms and in behavioral alterations induced by a decrease in sensorimotor activity.

Hypoactivity affects IGF-1 level and PI3K/AKT signaling pathway in cerebral structures implied in motor control.

A chronic reduction in neuromuscular activity through prolonged body immobilization in human alters motor task performance through a combination of peripheral and central factors. Studies performed in a rat model of sensorimotor restriction have shown functional and biochemical changes in sensorimotor cortex. However, the underlying mechanisms are still unclear. Interest was turned towards a possible implication of Insulin-like Growth Factor 1 (IGF-1), a growth factor known to mediate neuronal excitability and synaptic plasticity by inducing phosphorylation cascades which include the PI3K-AKT pathway. In order to better understand the influence of IGF-1 in cortical plasticity in rats submitted to a sensorimotor restriction, we analyzed the effect of hindlimb unloading on IGF-1 and its main molecular pathway in structures implied in motor control (sensorimotor cortex, striatum, cerebellum). IGF-1 level was determined by ELISA, and phosphorylation of its receptor and proteins of the PI3K-AKT pathway by immunoblot. In the sensorimotor cortex, our results indicate that HU induces a decrease in IGF-1 level; this alteration is associated to a decrease in activation of PI3K-AKT pathway. The same effect was observed in the striatum, although to a lower extent. No variation was noticed in the cerebellum. These results suggest that IGF-1 might contribute to cortical and striatal plasticity induced by a chronic sensorimotor restriction.