The sympathetic nervous system innervates a number of targets, including the heart, and sympathetic activity is a critical regulator of cardiac function. Sympathetic neurons form noradrenergic synapses onto heart cells resulting in excitation of myocyte function. Interestingly, these neurons also form cholinergic synapses onto themselves and are capable of releasing acetylcholine at neuron-myocyte synapses, which opposes the excitatory effects of noradrenergic transmission. The cholinergic and noradrenergic properties of these neurons are regulated by two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF promotes noradrenergic transmission via activation of Trk receptors. In contrast, BDNF acts through the p75 receptor to increase activity-dependent acetylcholine release. While extensive work has been done defining the co-transmission profile of sympathetic neurons, little is known about how co-transmission is established in the context of multiple targets or how selective availability of neurotrophic factors regulates the development of synaptic sites and the release of neurotransmitters in a target-specific manner. We will use electrophysiological and imaging approaches to examine the idea that the development of neurotransmitter properties of sympathetic neurons is locally regulated by the expression of neurotrophins at different targets and that individual neurons can maintain multiple release profiles at different synaptic sites. We will investigate the neurotrophin receptors that regulate the development of cholinergic and noradrenergic synaptic transmission and examine the role of neurotrophin signaling in the development of cholinergic synapses in vivo. By defining the developmental mechanisms that determine the level of sympathetic drive to the heart, these studies will provide a new understanding of the neural control of cardiovascular function.
Hypertension, myocardial hypertrophy and heart failure are all associated with increased sympathetic activity resulting in the disruption of normal homeostasis. This project investigates the ability target-derived neurotrophic factors to modulate neurotransmitter release from sympathetic neurons. The ability to modulate both excitatory and inhibitory components of sympathetic neurotransmission raises the possibility of interventions to limit the adverse effects of increased sympathetic drive in heart disease.
| Kreipke, R E; Birren, S J (2015) Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal. J Physiol 593:5057-73 |
| Luther, J A; Enes, J; Birren, S J (2013) Neurotrophins regulate cholinergic synaptic transmission in cultured rat sympathetic neurons through a p75-dependent mechanism. J Neurophysiol 109:485-96 |
| Neseliler, Selin; Narayanan, Darshana; Fortis-Santiago, Yaihara et al. (2011) Genetically induced cholinergic hyper-innervation enhances taste learning. Front Syst Neurosci 5:97 |
| Vega, A; Luther, J A; Birren, S J et al. (2010) Segregation of the classical transmitters norepinephrine and acetylcholine and the neuropeptide Y in sympathetic neurons: modulation by ciliary neurotrophic factor or prolonged growth in culture. Dev Neurobiol 70:913-28 |
