My laboratory studies neurochemical plasticity in adult neurons. 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 the electrical 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 rat 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 peptide and mRNA 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 at least in part by the induction of cytokines of the gp130 family, including leukemia inhibitory factor (LIF), and by the reduction of the target-derived trophic factor nerve growth factor (NGF) both of which occur after transection of sympathetic axons. Strikingly, changes in both of 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 an increase in the intrinsic growth capacity of these neurons. We study this effect by using the conditioning lesion response, which we have shown occurs in sympathetic neurons, as it has been shown to occur in sensory and motor neurons.

Another change which occurs in sympathetic and sensory ganglia after axotomy is the influx of macrophages. While macrophage infiltration 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.

1. Hyatt Sachs H, Rohrer H, Zigmond RE. (2010)
   The conditioning lesion effect on sympathetic neurite outgrowth is dependent on gp130 cytokines. Exp Neurol. 223:516-22.
   
2. Habecker BA, Sachs HH, Rohrer H, Zigmond RE. (2009)
   The dependence on gp130 cytokines of axotomy induced neuropeptide expression in adult sympathetic neurons. Dev Neurobiol. 69:392-400.
   
3. Hyatt Sachs H, Schreiber RC, Shoemaker SE, Sabe A, Reed E, Zigmond RE. (2007)
   Activating transcription factor 3 induction in sympathetic neurons after axotomy: response to decreased neurotrophin availability. Neuroscience. 150:887-97.
   
4. Sachs HH, Wynick D, Zigmond RE. (2007)
   Galanin plays a role in the conditioning lesion effect in sensory neurons. Neuroreport. 18:1729-33.
   
5. Zigmond RE, Vaccariello SA. (2007)
   Activating transcription factor 3 immunoreactivity identifies small populations of axotomized neurons in rat cervical sympathetic ganglia after transection of the preganglionic cervical sympathetic trunk. Brain Res. 1159:119-23.
   
6. 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.
   
7. Shoemaker SE, Sachs HH, Vaccariello SA, Zigmond RE. (2005)
   A conditioning lesion enhances sympathetic neurite outgrowth. Exp Neurol. 2005 Aug; 194(2):432-443.
   
8. Schreiber RC, Boeshore KL, Laube G, Veh RW, Zigmond RE. (2004)
   Polyamines increase in sympathetic neurons and non-neuronal cells after axotomy and enhance neurite outgrowth in nerve growth factor-primed PC12 cells. Neuroscience. 2004; 128(4):741-749.
   
9. 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. 2004 May; 59(2):216-235.
   
10. Nielsen KM, Chaverra M, Hapner SJ, Nelson BR, Todd V, Zigmond RE, Lefcort F. (2004)
    PACAP promotes sensory neuron differentiation: blockade by neurotrophic factors. Mol Cell Neurosci. 2004 Apr; 25(4):629-641.
    
11. Schreiber RC, Vaccariello SA, Boeshore K, Shadiack AM, Zigmond RE. (2002)
    A comparison of the changes in the non-neuronal cell populations of the superior cervical ganglia following decentralization and axotomy. J Neurobiol. 2002 Oct; 53(1):68-79.
    
12. Takasu MA, Dalva MB, Zigmond RE, Greenberg ME. (2002)
    Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science. 2002 Jan 18; 295(5554):491-495. 2001/12/20 [aheadofprint].
    
13. Zigmond RE. (2001)
    Can galanin also be considered as growth-associated protein 3.2? Trends Neurosci. 2001 Sep; 24(9):494-6; discussion 496.
    
14. Schreiber RC, Krivacic K, Kirby B, Vaccariello SA, Wei T, Ransohoff RM, Zigmond RE. (2001)
    Monocyte chemoattractant protein (MCP)-1 is rapidly expressed by sympathetic ganglion neurons following axonal injury. Neuroreport. 2001 Mar 5; 12(3):601-606.
    
15. Zigmond RE. (2000)
    Neuropeptide action in sympathetic ganglia. Evidence for distinct functions in intact and axotomized ganglia. Ann N Y Acad Sci. 2000; 921:103-108.
    
16. 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. 2001 Feb 15; 46(3):178-192.
    
17. 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 Neurosci. 2001 Jan 15; 21(2):363-371.
    
18. 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. 2000 Jul 1; 20(13):5076-5082.
    
19. 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. 1999 Aug; 40(2):137-148.
    
20. 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. 1999 May; 72(5):1871-1881.
    
21. Mohney RP, Zigmond RE. (1998)
    Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J Neurosci. 1998 Jul 15; 18(14):5285-5293.
    
22. 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. 1998 Jun 23; 95(13):7727-7730.
    
23. Zhou Y, Deneris E, Zigmond RE. (1998)
    Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol. 1998 Feb 5; 34(2):164-178.
    
24. 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. 1996 Oct; 8(10):2213-2220.
    
25. Zigmond RE, Hyatt-Sachs H, Mohney RP, Schreiber RC, Shadiack AM, Sun Y, Vaccariello SA. (1996)
    Changes in neuropeptide phenotype after axotomy of adult peripheral neurons and the role of leukemia inhibitory factor. Perspect Dev Neurobiol. 1996; 4(1):75-90.
    

1. 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.
   
2. Shoemaker SE, Sachs HH, Vaccariello SA, Zigmond RE. (2005)
   A conditioning lesion enhances sympathetic neurite outgrowth. Exp Neurol. 2005 Aug; 194(2):432-443.
   
3. 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. 2001 Feb 15; 46(3):178-192.
   
4. 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. 2000 Jul 1; 20(13):5076-5082.
   
5. 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. 2000 Jan; 42(1):14-21.
   
6. 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. 1999 Jun 15; 19(12):4739-4747.
   
7. Mohney RP, Zigmond RE. (1999)
   Galanin expression is decreased by cAMP-elevating agents in cultured sympathetic ganglia. Neuroreport. 1999 Apr 26; 10(6):1221-1224.
   
8. Mohney RP, Zigmond RE. (1998)
   Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J Neurosci. 1998 Jul 15; 18(14):5285-5293.
   
9. Zhou Y, Deneris E, Zigmond RE. (1998)
   Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol. 1998 Feb 5; 34(2):164-178.
   
10. 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. 1996 Oct; 8(10):2213-2220.
    
11. 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. 1996 Oct; 67(4):1751-1760.
    
12. 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. 1996 Feb; 7(2):152-163.
    
13. 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. 1994 Apr; 25(4):415-430.
    
14. Mohney RP, Siegel RE, Zigmond RE. (1994)
    Galanin and vasoactive intestinal peptide messenger RNAs increase following axotomy of adult sympathetic neurons. J Neurobiol. 1994 Feb; 25(2):108-118.
    
15. 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. 1993 Dec; 11(6):1175-1185.
    
16. 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. 1993 May; 24(5):571-580.
    
17. 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. 1992 Dec 11; 598(1-2):327-331.
    
18. 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. 1992 Oct; 12(10):3717-3728.
    

1. 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. 2004 May; 59(2):216-235.
   
2. 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 Neurosci. 2001 Jan 15; 21(2):363-371.
   
3. 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. 2000 Jan; 42(1):14-21.
   
4. 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. 1999 Aug; 40(2):137-148.
   
5. 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. 1999 May; 72(5):1871-1881.
   
6. Shadiack AM, Zigmond RE. (1998)
   Galanin induced in sympathetic neurons after axotomy is anterogradely transported toward regenerating nerve endings. Neuropeptides. 1998 Jun; 32(3):257-264.
   
7. 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. 1998 Jun 23; 95(13):7727-7730.
   
8. 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. 1995 Apr; 65(4):1119-1127.
   
9. 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. 1993 Dec; 61(6):2225-2232.
   
10. 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. 1993 Apr 2; 607(1-2):345-348.