Insular Cortical Grafts: Factors Affecting the Recovery of Learning

The insular cortex (IC), or visceral neocortex, is known to be involved in aversive related learning and memory processes. The IC receives taste and visceral information from the thalamus and sends direct projections to the nucleus of the tractus solitarius (the first-order relay for visceral information). The IC also has connections with limbic structures, including the amygdala and medial prefrontal cortex. Lesions of the IC region in adult rats impair the acquisition and retention of conditioned taste aversion (CTA). Recent findings showing that N-methylD-aspartate lesions of the IC disrupt the acquisition of inhibitory (passive) avoidance tasks, indicate that the IC is also involved in exteronociceptive-based learning. Our research has focused on the recovery of the acquisition of conditioned taste aversion and inhibitory avoidance learning task, by fetal brain grafts in IC-lesioned animals. In a first series of experiments, we have shown that cortical brain grafts produced a significant recovery in the ability to learn in IC-lesioned animals. The recovery induced by fetal brain grafts was related to the origin of the graft tissue used. That is, animals that received homotopic (IC), but not occipital cortical tissue recovered the capability to learn the CTA task. The IC-grafts produced a significant recovery in the ability to learn at 60 days post-graft. Biochemical analyses revealed that IC fetal grafts released GABA, ACh and glutamate in response to K+ depolarization. In contrast, occipital grafts released GABA and glutamate, but not ACh. Results with a horseradish peroxidase (HRP) retrograde tracing technique revealed that cortical, but not brainstem, grafts established connections with amygdala and ventromedial nucleus of the thalamus. In further experiments, rats with lesions of IC showing disrupted taste aversions received neocortical grafts and were retrained at 15, 30, 45 and 60 days after transplantation. The behavioral results showed almost complete functional recovery at 60 days, slight recovery at 30 and 45 days and a poor recovery at 15 days postgraft. HRP histochemistry revealed that at 15 days there were no HRP labeled cells in the ventromedial nucleus or in the amygdala. At 30, 45 and 60 days post-graft, there were an increasing number of HRP labeled cells, almost as many as those seen in the controls, in the thalamus and the amygdala. The behavioral recovery was correlated with increased acetylcholinesterase activity, detected histochemically, and with morphological maturation, revealed by Golgi staining. The possibility that neurotrophic factors alone may be involved in the functional recovery is unlikely, because it is necessary to wait at least 30 days to see any recuperation. Therefore, such findings suggest that if neurotrophic factors are involved, they need to be associated with cortical homotopic grafts and/or with some time dependent factor essential for producing functional recovery. These series of experiments also suggest that cortical grafts’ maturation and/or ACh activity may play a role in graft-mediated behavioral recovery. Recently, we have evaluated the role of nerve growth factor (NGF) in the recovery of CTA and inhibitory avoidance induced by cortical grafts. The behavioral results showed that IC, but not occipital, grafts plus NGF promote recovery of learning at 15 days post-graft, 30 days earlier than without NGF. Biochemical analyses showed that ChAT activity in the homotopic grafts+NGF was similar to the intact control animals. The IC-grafts with vehicle showed a significantly reduced ChAT activity