Richard Zigmond, PhD

Professor
Department of Neurosciences
School of Medicine
Professor
Department of Neurological Surgery
School of Medicine
Professor
Department of Pathology
School of Medicine

Research Information

Research Interests

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 plays 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 preventation 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, plays an important role in clearing myelin after a peripheral nerve lesion. 

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In one of the very early examples of activity dependent gene expression, we showed that stimulation of the cervical sympathetic trunk led to an increase in the activity of protein level, and mRNA level of tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step in the synthesis of the neurotransmitter norepinephrine in the superior cervical ganglion (SCG). Interestingly, antidromic stimulation of the superior cervical ganglion did not mimic the effect of synaptic stimulation.

 

two line graphs with days as x-axis and % Contralateral Contol as y-axis, with bottom y-axis Protien content and top y-axis Enzyme specific activity. Time course of the effects of preganglionic nerve stimulation on TH, dopamine beta hydroxylase (DBH) and dopa decarboxylase (DDC) in the SCG. The cervical sympathetic trunk (CST) was stimulated for 90 min with trains of 40 Hz for 250 out of every 750 msec. TH and DBH activity reached a maximum at 3 days. Neither DDC nor total protein changed significantly.

Fig. 1. Time course of the effects of preganglionic nerve stimulation on tyrosine hydroxylase (TH), dopamine beta hydroxylase (DBH) and dopa decarboxylase (DDC) in the SCG. The cervical sympathetic trunk (CST) was stimulated for 90 min with trains of 40 Hz for 250 out of every 750 msec. TH and DBH activity reached a maximum at 3 days. Neither DDC nor total protein changed significantly. The data are the means +/- S.E.M. from 8-10 SCG except for day 5 on which N=5.

In studies on a second mechanism of TH regulation, namely the acute activation of this enzyme by phosphorylation, we made the unexpected discovery that synapses in the rat SCG use a second transmitted in addition to acetlylcholine (Fig. 2), and we presented evidence suggesting that this molecule could be a peptide of the secretin-glucagon family (Fig. 3). Currently evidence suggests that the transmitter is pituitary adenylate cyclase activating peptide (PACAP).

bar graph with x-axis Atropine, Hex & Hex + Atropine, and y-axis pmol DOPA/ganglion/hr at 0,200,400,600, 800. The preganglionic trunk of the scg was stimilated at 10 Hz for 30 mins. Atropie, Hexamethonium (Hex) or both antagonists were added 10 mins prior to the beginning of stimulation. Hatched bars stimulated ganglia, open bars, control ganglia.

Fig 2. The preganglionic trunk of the SCG was stimilated at 10 Hz for 30 min. Atropine, Hexamethonium (Hex) or both antagonists were added 10 min prior to the beginning of stimulation. Hatched bars stimulated ganglia, open bars control ganglia. 

graph with x-axis peptide concentration (M) from 0 to 10 to the power of -9,-8,-7,-6,-5,-4. y-axis pmol DOPA/ganglion/15min from 20,40,60,80,100 with 2 lines, one Secretin, other VIP. Concentration-response curve for the stimulation of TH activity by secretin and VIP. Ganglia were preincubated with peptide for 60 min prior to addition of a dopa decarboxylase inhibition. Dopa accumulation was measured during the subsequent 15 min.

Fig. 3. Concentration-response curve for the stimulation of TH activity by secretin and VIP. Ganglia were preincubated with peptide for 60 min prior to addition of a dopa decarboxylase inhibitor. Dopa accumulation was measured during the subsequent 15 min.

An exciting consequence of the discovery that there is cotransmission in this ganglion was the finding that the extent to which transmission in the SCG is cholinergic or non-cholinergic (peptidergic) depends on the pattern of impulse activity (Fig. 4).

bar graph with x-axis 10 Hz (Continuous) and 10 Hz (1/6), and y-axis pmol DOPA/ganglion/30min from 100,200,300,400. Effect of cholinergic antagonists on the increase in TH activity produced by preganglionic nerve stimulation. Stimulation was for 30 min at 10 Hz continuously or at 10 Hz for 1 out of every 6 sec. Hexamethonium (3mM) and atropine (6µM) were added to some groups prior to stimulation. The presence of a cholinergic component in the transsynaptic effect depends on the stimulation pattern.

Fig. 4. Effect of cholinergic antagonists on the increase in TH activity produced by preganglionic nerve stimulation. Stimulation was for 30 min at 10 Hz continuously or at 10 Hz for 1 out of every 6 sec. Hexamethonium (3mM) and atropine (6µM) were added to some groups prior to stimulation. The presence of a cholinergic component in the transsynaptic effect depends on the stimulation pattern.

In a second neuronal system, we showed that the 40-fold circadian rhythm in activity of pineal serotonin N-acetyltransferase (NAT), a regulatory enzyme in the pathway for melatonin synthesis, could be mimicked by electrical stimulation of the sympathetic innervation of the gland (producing a night time effect) followed by cessation of stimulation (producing a day time effect). While studying the pineal gland, we recognized that the rhythm in NAT provided a unique bioassay which could be used for measuring recovery of function following lesions in the sympathetic nervous system. These studies lead us to two important discoveries. The first finding was that of a novel mechanism of neural plasticity, which we termed “heteroneuronal uptake”, in which a nerve ending (even one that is itself electrically silent) can take up transmitter released by another ending and thereby modulate the latter’s postsynaptic efficacy (Fig. 5).

three diagrams with nerves with black and white arrow of directionality and NE above. first labelled normal, second unilateral decentralization, and third unilateral denervation. A model to account for the recovery of pineal NAT activity after unilateral denervation (cutting the postganglionic internal carotid nerve) but not after unilateral decentralization (cutting the preganglionic CST). Two sympathetic nerves, one from the left and one from the right SCG are pictured innervating the same pinealocyte.

Fig. 5. A model to account for the recovery of pineal NAT activity after unilateral denervation (cutting the postganglionic internal carotid nerve) but not after unilateral decentralization (cutting the preganglionic CST). Two sympathetic nerves, one from the left and one from the right SCG are pictured innervating the same pinealocyte. In the normal animal, both neurons are electrophysiologically active and are releasing NE as shown by the white arrows. In addition, both neurons take up NE as shown by the black arrows. The situation in unilaterally decentralized pineal glands is depicted in the middle panel. In this diagram, a neuron from one SCG is shown as electrophysiologically inactive and therefore as not releasing NE. However the uptake capacity of this neuron is intact. Therefore the net effect of such a neuron is to inhibit the postsynaptic effectiveness of the active neurons from the contralateral ganglion. In the right panel, the situation in the unilaterally denervated pineal gland is shown. Sometime between 9 and 32 h after cutting one postganglionic trunk, the terminals of these nerve degenerate, thus decreasing the number of varicosities taking up NE. The loss of these NE uptake sites increases the postsynaptic effective of the neurons from the contralateral intact ganglion.

The second finding was that, although preganglionic sympathetic nerves can regenerate after a lesion and can effectively reinnervate neurons in the SCG, normal pineal function is not restored (Fig. 6). This finding conflicts with the prediction from a classical study by John Langley in the early 1900’s on regeneration of these neurons. We hypothesize that many of the neurons that reinnervate neurons in the SCG that project to the pineal gland are different from the original neurons and do not get the needed input from the circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus which directs the normal rhythm in NAT activity (Fig. 7).

bar graph with x-axis in days 30, 60, 100, and 100 double lesion, and y-axis NAT Activity pmol/ug protien/20min at 20, 40, 60, with key box in white Sham and lined Crush. Peak night pineal NAT activity after crushing both CSTs and the effect of a double lesion on this recovered activity.

Fig. 6. Peak night pineal NAT activity after crushing both CSTs and the effect of a double lesion on this recovered activity.

Model of misrouting of fibers during reinnervation of the SCG. fist labelled normal with fibers labelled Iris, in blue, Pineal, in red, and Eyelid, in green radiating form bottom cone named CST into circle named SCG. second labelled crushed with same sturcture except fibers are severed. last labelled Regenerated with model similar to first except Iris, Pineal & Eyelid each have blue, red, green fibers.

Fig. 7. Model of misrouting of fibers during reinnervation of the SCG.

Another unexpected discovery was the finding that the snake venom from which bungarotoxin is purified contains a second toxin (“neuronal bungarotoxin”) which blocks synaptic transmission in autonomic ganglia. After purifying this toxin, we used it to quantify the density of nicotinic receptors at ganglionic synapses. Autoradiographic grains from 125 I-labeled neuronal bungarotoxin were concentrated at synapses in the chick ciliary ganglion as shown in Fig. 8. We also used this labeled toxin to localize a class of nicotinic receptors on SCG neurons in culture and in the rat brain.

micrograph of Preganglionic nerve terminals (nt) and post-ganglionic cell bodies (cb) in the chick ciliary ganglion. The black autoradiographic grains from radioactive neuronal bungarotoxin are concentrated at synapses within the ganglion. two different images, one labelled A with small black arrows, and one labelled B with small black area in bottom left.

Fig. 8. Preganglionic nerve terminals (nt) and post-ganglionic cell bodies (cb) in the chick ciliary ganglion. The black autoradiographic grains from radioactive neuronal bungarotoxin are concentrated at synapses within the ganglion.

In 1989, I moved to Case Western Reserve University to join its newly formed Department of Neurosciences. During the first year, we made a serendipitous discovery that when the SCG is placed in organ culture levels of vasoactive intestinal peptide (VIP) increase dramatically (i.e., ~30-fold; Fig. 9), rather than decreasing as we expected, since we assumed the peptide was present in preganglionic nerve terminals.

bar graph with a-axis t=0, t=24, t-46, and y-axis pg VIP-IR per SCG from 0,100,200,300, with bars denoting increase in VIP-like immunoreactivity in adult SCG maintained in organ culture.

Fig. 9. Increase in VIP-like immunoreactivity in adult SCG maintained in organ culture.

This finding led to the second major theme of our research, namely, the molecular and cellular responses of neurons to injury. When we started these studies, neuropeptide regulation in postganglionic SCG neurons was thought to be regulated primarily by afferent nerve activity, which is abolished in organ culture, the idea being that activity suppressed the peptide phenotype. However, we demonstrated in vivo that it was axotomy of the SCG, not deafferentation, which mimicked the effects seen in organ culture. A trivial reason for this finding would have been that axotomy, by blocking transport of the peptide, led to a buildup in the cell body. However, we found that axotomy also leads to an increase in VIP mRNA. We went on to find that the cytokine leukemia inhibitory factor (LIF) is induced in non-neuronal cells in the ganglion both after axotomy and after explantation. Conditioned medium from ganglion non-neuronal cells stimulates VIP expression and this effect is blocked by an antibody to LIF (Fig. 10).

LIF, but not CNTF, from non-neuronal cells increase neuronal VIP expression.

two bar graphs, one above the other, illegible, with title LIF, but not CNTF, from non-neuronal cells (up arrow) neuronal VIP expression. VIP levels in dissociated SCG neurons with and without addition of ganglion non-neuronal cell conditioned medium (GNCM).

Fig. 10. VIP levels in dissociated SCG neurons with and without addition of ganglion non-neuronal cell conditioned medium (GNCM).

In vivo the axotomy-induced increase in VIP is reduced, but not completely abolished, in LIF knockout mice (Fig. 11). This finding was the first demonstration of an effect of LIF on the nervous system in vivo. Also we found that galanin and substance P were regulated similarly.

bar graph with a-axis sham(+/+), axotomy(x,x), sham(-/-), axotomy(-,-), and y-axis VIP-IR (pg/SCG) from 0,100,200. the graph reflects Axotomy-induced VIP expression in the SCG is reduced in LIF -/- mice.

Fig. 11. Axotomy-induced VIP expression in the SCG is reduced in LIF -/- mice.

Interestingly, unlike the case with the SCG, in the dorsal root ganglion (DRG), LIF was not induced after axotomy; however, the cytokine was induced in the lesioned sciatic nerve. We believe this is the first demonstration of an oft hypothesized relationship between changes in cytokine and growth factor expression in the distal segment of a lesioned nerve and the expression of certain genes by the axotomized neurons. In addition, using galanin knockout mice, we demonstrated that the induction of galanin after axotomy plays an important role in the conditioning lesion response of sensory neurons.

We have evidence that LIF is only one of a number of molecules that influence the response of sympathetic and sensory neurons to axotomy. LIF is a member of a family of cytokines, called the gp130 family. Also, we have shown that removal of the influence of the target derived neurotrophic factor nerve growth factor (NGF) is an important signaling event. Injection of animals with a nerve growth factor antiserum produces an increase in galanin expression in both the SCG and DRG and triggers a conditioning lesion-like effect in sympathetic neurons.

It has long been known that macrophages play a role in neural regeneration after axotomy; however, this influence has been viewed as occurring solely via an effect on Wallerian degeneration in the distal nerve segment. Some years ago, we discovered that, in addition to accumulating in the distal nerve, macrophages also accumulate around axotomized neuronal cell bodies. We have examined macrophage infiltration into DRGs and SCGs in two mutant strains of mice: the slow Wallerian degeneration mouse (Wlds) and a knockout for the receptor CCR2, the receptor on which the macrophage chemokine CCL2 acts. In both mouse strains, macrophage infiltration into the DRG was abolished and macrophage infiltration into the SCG was diminished. We then demonstrated that these macrophages within peripheral ganglia play an important role in peripheral nerve regeneration by activating neurite out-growth in response to a conditioning lesion (Fig. 12).

two bar graphs DRG a and b, a-axis WT and CCR2-/- and y-axis Mean length (um) of 20 longest neurites-24hr on first and Mean length (um) of 20 longest neurites -48hr from 0-700 with white box key as Contralateral, and black box key Conditioned.  two images c and d below of cell ganglion with outgrowth from explants of adult L5 DRGs ipsilateral (black bars) and contralateral (white bars) to a unilateral sciatic nerve transection 7 days previously in (WT) and CCR-/- mice.

Fig. 12. Neurite outgrowth from explants of adult L5 DRGs ipsilateral (black bars) and contralateral (white bars) to a unilateral sciatic nerve transection 7 days previously in wild type (WT) and CCR2-/- mice. Growth of the 20 longest neurites was measured at 24 h (left hand histogram) and 48 h (right hand histograms) after placement in culture on a growth permissive substrate. A conditioning lesion effect was seen in the contralateral but not the ipsilateral ganglia.

Another quite unexpected finding from these experiments came when we looked at Wallerian degeneration in the two mouse strains 7 days after unilateral transection using luxol fast blue staining. As expected the clearance of myelin in the Wlds mice was severely impeded; however, quite dramatically the results for the CCR2-/- mice were indistinguishable from controls, in spite of the fact that we found no infiltration of macrophages into the sciatic nerve in these animals (Fig. 13). These results raise the question of what cell type is the predominant phagocyte in the absence of infiltrating macrophage. Current work in the lab indicate an important role for neutrophils.

bar graph a with a-axis WT, Wlds, CCR2-/-, and y-axis Percent Area Stained-Sciatic from 0-100, with key box white Contralateral and black Axotomy, with 6 nerve micrographs below, b-g, in blue. Quantitation of the myelin in the distal sciatic nerve after unilateral transection 7 days earlier and in the contralateral nerve. The micrographs represent sections from the ipsilateral (e– g) and contralateral (b– d) nerves from WT, Wlds, and CCR2-/-mice. *p<0.05, **p<0.001. Scale bar, 20 µm.

Fig. 13. (a). Quantitation of the myelin in the distal sciatic nerve after unilateral transection 7 days earlier and in the contralateral nerve. The micrographs represent sections from the ipsilateral (e– g) and contralateral (b– d) nerves from WT, Wlds, and CCR2-/-mice. *p<0.05, **p<0.001. Scale bar, 20 µm.

 

We next examined whether over expression of the macrophage chemokine CCL2 stimulated neurite outgrowth. Control (uninjured) mice were injected intrathecally with an adeno-associated virus coding for CCL2. The virus infected neurons in the dorsal root ganglia and caused them to express CCL2. As a consequence, macrophages invaded the ganglia in spite of the fact that they had not been injured. 

two bar graphs DRG a and b, a-axis WT and CCR2-/- and y-axis Mean length (um) of 20 longest neurites-24hr on first and Mean length (um) of 20 longest neurites -48hr from 0-700 with white box key as Contralateral, and black box key Conditioned.  two images c and d below of cell ganglion with outgrowth from explants of adult L5 DRGs ipsilateral (black bars) and contralateral (white bars) to a unilateral sciatic nerve transection 7 days previously in (WT) and CCR-/- mice.

Fig. 14. Wild type mice were inject intrathecally with AAV5-CCL2 or a control virus coding for YFP. Three weeks later when CCL2 expression and macrophage accumulation were at their maximum, DRGs were removed and placed in organ culture (A-C) or dissociated cell culture(D-F). Neurite outgrowth was enhanced neurons from AAC5-CCL2 treated mice. Addition of recombinant CCL2 directly to control neurons produced no effect on neurite outgrowth (G-L)

Three weeks later when the ganglia were placed in organ culture or dissociated cell culture, neurite outgrowth was enhanced (Fig. 14). When the same protocol was performed in CCR2 knockout animals, no effect on neurite outgrowth occurred. Addition of CCL2 recombinant protein to control cultures also produced no effect on neurite outgrowth (Fig. 14), suggesting that the viral stimulation of neurite outgrowth depended on macrophage accumulation in the ganglia.

Publications

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Graduate Students' First Author Publications (Since 1992)

  • Talsma AD, Niemi JP, Pachter JS, Zigmond RE. The primary macrophage chemokine, CCL2, is not necessary after a peripheral nerve injury for macrophage recruitment and activation or for conditioning lesion enhanced peripheral regeneration. J Neuroinflammation. 2022 Jul 12;19(1):179. doi: 10.1186/s12974-022-02497-9.
  • Lindborg JA, Niemi JP, Howarth MA, Liu KW, Moore CZ, Mahajan D, Zigmond RE. Molecular and cellular identification of the immune response in peripheral ganglia following nerve injury. J Neuroinflammation. 2018 Jun 26;15(1):192. doi: 10.1186/s12974-018-1222-5.
  • Lindborg JA, Mack M, Zigmond RE. (2017) Neutrophils are critical for myelin removal in peripheral nerve injury model of Wallerian degeneration. J Neurosci 37(43): 10258-10277. PMID: 28912156
  • Niemi JP, Filous AR, DeFrancesco A, Lindborg JA, Malhotra NA, Wilson GN, Zhou B, Crish SD, Zigmond RE. (2017) Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus. Exp Neurol 296: 1-15. PMID: 28645526
  • Niemi JP, DeFrancesco-Lisowitz A, Cregg JM, Howarth M, Zigmond RE. (2016) Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. Exp Neurol 275: 25-37.
  • Niemi JP, DeFrancesco-Lisowitz A, Roldan-Hernandez L, Lindborg JA, Mandell D, Zigmond RE (2013) A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve renegration. J Neurosci 41:16236-16248.
  • Shoemaker SE, Sachs HH, Vacariello SA, Zigmond RE (2006) Reduction in nerve growth factor availability leads to a conditioning lesion-like effect in sympathetic neurons. J Neurobiol 66:1322-1337.
  • Shoemaker SE, Sachs HH, Vaccariello SA, Zigmond RE (2005) A conditioning lesion enhances sympathetic neurite outgrowth. Exp Neurol 194:432-443.
  • Zhou Y, Deneris E, Zigmond RE (2001) Nicotinic acetylcholine receptor subunit proteins alpha7 and beta4 decrease in the superior cervical ganglion after axotomy. J Neurobiol 46:178-192.
  • Bibevski S, Zhou Y, McIntosh JM, Zigmond RE, Dunlap ME (2000) Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J Neurosci 20:5076-5082.
  • Ip NY, Zigmond RE (2000) Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons. J Neurobiol 42:14-21.
  • Boeshore KL, Luckey CN, Zigmond RE, Large TH (1999) TrkB isoforms with distinct neurotrophin specificities are expressed in predominantly nonoverlapping populations of avian dorsal root ganglion neurons. J Neurosci 19:4739-4747.
  • Mohney RP, Zigmond RE (1999) Galanin expression is decreased by cAMP-elevating agents in cultured sympathetic ganglia. Neuroreport 10:1221-1224.
  • Mohney RP, Zigmond RE (1998) Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J Neurosci 18:5285-5293.
  • Zhou Y, Deneris E, Zigmond RE (1998) Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol 34:164-178.
  • Sun Y, Zigmond RE (1996) Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons. Eur J Neurosci 8:2213-2220.
  • Sun Y, Zigmond RE (1996) Involvement of leukemia inhibitory factor in the increases in galanin and vasoactive intestinal peptide mRNA and the decreases in neuropeptide Y and tyrosine hydroxylase mRNA in sympathetic neurons after axotomy. J Neurochem 67:1751-1760.
  • Sun Y, Landis SC, Zigmond RE (1996) Signals triggering the induction of leukemia inhibitory factor in sympathetic superior cervical ganglia and their nerve trunks after axonal injury. Mol Cell Neurosci 7:152-163.
  • Sun Y, Rao MS, Zigmond RE, Landis SC (1994) Regulation of vasoactive intestinal peptide expression in sympathetic neurons in culture and after axotomy: the role of cholinergic differentiation factor/leukemia inhibitory factor. J Neurobiol 25:415-430.
  • Mohney RP, Siegel RE, Zigmond RE (1994) Galanin and vasoactive intestinal peptide messenger RNAs increase following axotomy of adult sympathetic neurons. J Neurobiol 25:108-118.
  • Rao MS, Sun Y, Escary JL, Perreau J, Tresser S, Patterson PH, Zigmond RE, Brulet P, Landis SC (1993) Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron 11:1175-1185.
  • Rao MS, Sun Y, Vaidyanathan U, Landis SC, Zigmond RE (1993) Regulation of substance P is similar to that of vasoactive intestinal peptide after axotomy or explantation of the rat superior cervical ganglion. J Neurobiol 24:571-580.
  • Piszczkiewicz S, Zigmond RE (1992) Is the vasoactive intestinal peptide-like immunoreactivity in the rat pineal gland present in fibers originating in the superior cervical ganglion? Brain Res 598:327-331.
  • Sun Y, Rao MS, Landis SC, Zigmond RE (1992) Depolarization increases vasoactive intestinal peptide- and substance P-like immunoreactivities in cultured neonatal and adult sympathetic neurons. J Neurosci 12:3717-3728.

Postdocs' First Author Publications (Since 1993)

  • Boeshore KL, Schreiber RC, Vaccariello SA, Sachs HH, Salazar R, Lee J, Ratan RR, Leahy P, Zigmond RE (2004) Novel changes in gene expression following axotomy of a sympathetic ganglion: a microarray analysis. J Neurobiol 59:216-235.
  • Shadiack AM, Sun Y, Zigmond RE (2001) Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurobiol 21:363-371.
  • Ip NY, Zigmond RE (2000) Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons. J Neurobiol 42:14-21.
  • Rittenhouse AR, Zigmond RE (1999) Role of N- and L-type calcium channels in depolarization-induced activation of tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and nerve terminals. J Neurobiol 40:137-148.
  • Nagamoto-Combs K, Vaccariello SA, Zigmond RE (1999) The levels of leukemia inhibitory factor mRNA in a Schwann cell line are regulated by multiple second messenger pathways. J Neurochem 72:1871-1881.
  • Shadiack AM, Zigmond RE (1998) Galanin induced in sympathetic neurons after axotomy is anterogradely transported toward regenerating nerve endings. Neuropeptides 32:257-264.
  • Shadiack AM, Vaccariello SA, Sun Y, Zigmond RE (1998) Nerve growth factor inhibits sympathetic neurons' response to an injury cytokine. Proc Natl Acad Sci U S A 95:7727-7730.
  • Shadiack AM, Vaccariello SA, Zigmond RE (1995) Galanin expression in sympathetic ganglia after partial axotomy is highly localized to those neurons that are axotomized. Neuroscience 65:1119-1127.
  • Schulz DW, Kuchel GA, Zigmond RE (1993) Decline in response to nicotine in aged rat striatum: correlation with a decrease in a subpopulation of nicotinic receptors. J Neurochem 61:2225-2232.
  • McKeon TW, Zigmond RE (1993) Vasoactive intestinal peptide and secretin produce long-term increases in tyrosine hydroxylase activity in the rat superior cervical ganglion. Brain Res 607:345-348

 

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