Richard Zigmond, PhD

My laboratory studies plasticity in the adult nervous system. We are interested in the ways in which the chemistry of the adult nervous system can change and the functional consequences of such changes. We focus particularly on alterations that occur in response to 1) neural damage and 2) changes in neural activity.

Currently, we are focusing on the molecules and cells involved in altering neuronal gene expression in response to axonal injury and in changing the intrinsic growth capacity of these neurons. Our studies focus on sympathetic and sensory neurons. Previous research has established that, when a peripheral neuron’s axon is severed, it decreases its synthesis of a number of proteins involved in neurotransmission and increases its synthesis of other proteins involved in regeneration. We find that, following axotomy, sympathetic neurons in the superior cervical ganglion express vasoactive intestinal peptide (VIP), galanin, and pituitary adenylate cyclase-activating polypeptide, three neuropeptides not normally expressed by these neurons. These changes are detected both at the mRNA and peptide levels.

Similar changes occur if adult ganglia are placed in either explant or dissociated cultures, allowing us to use these in vitro systems to study the molecular mechanisms involved. Our studies have shown that these changes in neuropeptide expression are triggered by the induction of cytokines of the gp130 family, including leukemia inhibitory factor (LIF) and IL-6, and by the reduction of the target-derived trophic factor nerve growth factor (NGF) all of which occur after transection of sympathetic axons. Strikingly, changes in these peptides occur in two other types of peripheral neurons after axonal injury, namely, sensory and motor neurons.

These two signals also are involved in triggering a growth response of the neurons to a conditioning lesion. We have found that alterations in gp130 cytokine signaling play a role in the deficit in regeneration known to occur in diabetes.

Another change which occurs in sympathetic and sensory ganglia after axotomy is the influx of macrophages. While macrophage accumulation in the distal stump of a transected peripheral nerve plays an important role in phagocytosing myelin and axonal debris, their role within peripheral ganglia is unknown and this question is an important part of our current research focus. Using two mutant murine strains (the slow Wallerian degeneration mouse and a knockout for the chemokine receptors CCR2) we have found that prevention of macrophage accumulation in ganglia significantly inhibits the conditioning lesion response, suggesting that these macrophages play an important role in the response of neurons to injury. We also showed that neutrophils, the other major professional phagocytes, play an important role in clearing myelin after a peripheral nerve lesion. 

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