Zalman Abraham Kekst Professor in Neuroscience
Modulatory neurotransmitter systems profoundly influence circuit function and behavior with effects on processes ranging from learning and memory to the control of peripheral organ function. Developmental signals play critical roles in the establishment of normal adult function of these modulatory systems in both the central and peripheral nervous systems, and can also contribute to the progression of pathological states such as heart disease and developmental disorders.
We are interested in understanding the molecular and cellular interactions that direct the development of the noradrenergic and cholinergic systems, including those that innervate the heart and modulate cardiac function. We have identified neurotrophic factors and members of the bone morphogenetic protein family as regulators of a series of sequential and overlapping developmental events during sympathetic neuron development. These factors promote neurite growth, axonal arborization, and synapse formation, leading to functional maturation of sympathetic drive to heart cells. Neurotrophic and glial signals also modulate sympathetic synaptic transmission and co-transmission, suggesting a new role for local glial interactions within the mammalian sympathetic ganglia.
Cholinergic neurons in the central nervous system also provide modulatory control of target function through long-range projections to major brain areas involved in learning, emotion, and response to sensory information. We have shown that neurotrophin signaling within the basal forebrain contributes to the acquisition of cholinergic neurotransmitter properties and to the establishment of cholinergic innervation of cortical targets. These projections also modulate sensory behaviors and these interactions can be explored by using transgenic mice and other manipulations that perturb the level of cholinergic innervation and function.
Within these areas of interest, we use molecular, cellular, transgenic and electrophysiological approaches to investigate:
- The neurotrophic factors and glial-dependent pathways that drive developing noradrenergic and cholinergic neurons to acquire their unique neurotransmitter and synaptic properties;
- The reciprocal interactions between sympathetic neurons and their cardiac targets that lead to innervation and maturation of the heart and the mechanisms by which developmental changes affect mature properties and pathological processes, including hypertension;
- The development and function of cholinergic projections from the basal forebrain to the cortex and amygdala and the effects of cholinergic transmission on cortical circuits and behavior.
- Habecker BA, Anderson ME, Birren SJ, Fukuda K, Herring N, Hoover DB, Kanazawa H, Paterson DJ, Ripplinger CM. (2016) "Molecular and cellular neurocardiology: Development, cellular and molecular adaptations to heart disease." J Physiol. 2016 Apr 6. doi: 10.1113/JP27184.
- Kreipke, R.E. and Birren, S.J. 2015. "Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal." J. Physiol. 593:5057-73.
- Rosado M, Barber CF, Berciu C, Feldman S, Birren SJ, Nicastro D, Goode BL. (2014) "Critical roles for multiple formins during cardiac myofibril development and repair." Mol Biol Cell. 2014 Mar;25(6):811-27.
- Birren SJ, Marder E. (2013) "Plasticity in the neurotransmitter repertoire." Science. 2013 Apr 26;340(6131):436-7.
- Luther JA, Enes J, Birren SJ. (2013) "Neurotrophins regulate cholinergic synaptic transmission in cultured rat sympathetic neurons through a p75-dependent mechanism." J Neurophysiol. 2013 Jan;109(2):485-96.
- Neseliler S, Narayanan D, Fortis-Santiago Y, Katz DB, Birren SJ. (2011) "Genetically induced cholinergic hyper-innervation enhances taste learning." Front Syst Neurosci. 2011;5:97.
- Luther JA, Birren SJ. (2009) "Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties." Auton Neurosci. 2009 Nov 17;151(1):46-60.
- Luther JA, Birren SJ. (2009) "p75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents." J Neurosci. 2009 Apr 29;29(17):5411-24.
- Dore JJ, Dewitt JC, Setty N, Donald MD, Joo E, Chesarone MA, Birren SJ. (2009) "Multiple Signaling Pathways Converge to Regulate Bone-Morphogenetic-Protein-Dependent Glial Gene Expression." Dev Neurosci. 2009;31(6):473-86.
- Habecker BA, Bilimoria P, Linick C, Gritman K, Lorentz CU, Woodward W, Birren SJ. (2008) "Regulation of cardiac innervation and function via the p75 neurotrophin receptor." Auton Neurosci. 2008 Jun;140(1-2):40-8.
- Moon JI, Birren SJ. (2008) "Target-dependent inhibition of sympathetic neuron growth via modulation of a BMP signaling pathway." Dev Biol. 2008 Mar 15;315(2):404-17.
- Lin PY, Hinterneder JM, Rollor SR, Birren SJ. (2007) "Non-cell-autonomous regulation of GABAergic neuron development by neurotrophins and the p75 receptor." J Neurosci. 2007 Nov 21;27(47):12787-96.
- Slonimsky JD, Mattaliano MD, Moon JI, Griffith LC, Birren SJ. (2006) "Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission." Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2915-9.
- Luther JA, Birren SJ. (2006) "Nerve growth factor decreases potassium currents and alters repetitive firing in rat sympathetic neurons." J Neurophysiol. 2006 Aug;96(2):946-58.
- Dore JJ, Crotty KL, Birren SJ. (2005) "Inhibition of glial maturation by bone morphogenetic protein 2 in a neural crest-derived cell line." Dev Neurosci. 27:37-48.
- Slonimsky, J.D., Yang, B., Hinterneder, J.M., Nokes, E.B. and Birren, S.J. (2003) "BDNF and CNTF regulate cholinergic properties of sympathetic neurons through independent mechanisms." Mol. Cell. Neurosci. 23:648-660.
- Yang B, Slonimsky JD, Birren SJ. (2002) "A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor." Nat Neurosci 5:539-545.
- Bharmal, S, Slonimsky, J.D., Mead, J.N., Sampson, C.P.B., Tolkovsky, A.M, Yang, B., Bargman, R., and Birren, S.J. (2001) "Target interactions promote the functional maturation of neurons derived from a sympathetic precursor cell line." Dev. Neurosci.23:153-164.
- Worley, D.S., Pisano J.M., Choi, E.D., Walus, L., Hession, C.A., Cate, R.L., Sanicola, M., and Birren, S.J. (2000) "Developmental regulation of GDNF response and receptor expression in the enteric nervous system." Development. 127:4383-93.
- Pisano JM, Colon-Hastings F, Birren S.J. (2000) "Postmigratory enteric and sympathetic neural precursors share common, developmentally regulated, responses to BMP2." Dev Biol. 227:1-11.
- Lockhart, S.T., Mead, J.N., Pisano, J.M., Slonimsky, J.D., and Birren, S.J. (2000) "Nerve growth factor collaborates with myocyte-derived factors to promote development of presynaptic sites in cultured sympathetic neurons." J. Neurobiol. 42:460-476.
- Pisano, J.M. and Birren, S.J. (1999) "Restriction of developmental potential during divergence of the enteric and sympathetic neuronal lineages." Development. 126:2855-2868.
- Lockhart, S.T., Turrigiano, G.G., and Birren, S.J. (1997) "Nerve growth factor modulates synaptic transmission between sympathetic neurons and cardiac myocytes." J. Neurosci. 17:9573-9582.