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. The cholinergic and noradrenergic properties of these neurons are regulated by two neurotrophins, NGF and BDNF. NGF promotes noradrenergic transmission via activation of Trk receptors. In contrast, BDNF acts through the p75 receptor to increase activity-dependent ACh release. While extensive work has been done defining the co-transmission properties of sympathetic neurons, little is known about how co-transmission properties are established and maintained, how the release of multiple transmitters is regulated, or the physiological relevance of local and global regulation of sympathetic properties by neurotrophins. We will use electrophysiological and imaging approaches to examine the idea that the neurotransmitter properties of sympathetic neurons are 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 determine the pre- and postsynaptic actions of neurotrophins at neuronal and cardiac targets. We will investigate the receptors and mechanisms that underlie synaptic modulation by neurotrophins, and will examine the relationship between neurotrophin signaling and sympathetic function in vivo. These studies will define neurotrophic mechanisms that regulate 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 |
