Synaptic computation and neuromodulation in catecholaminergic neurons.

Our long-term focus is upon the integrative role of nicotinic, muscarinic and peptidergic synapses in sympathetic ganglia. 

In early work, we exploited bullfrog sympathetic ganglia as a model system. These ganglia have unique properties that simplify cell identification in isolated preparations of intact ganglia. In studies using electrophysiology, anatomical tract tracing, immunocytochemistry and novel preparations of ganglia isolated together with end-organs, we discovered neuropeptide markers for different cells types in the circuit, mapped their developmental expression, and firmly established the functional identity of B cells as secretomotor neurons that innervate cutaneous glands and of C cells as vasoconstrictor neurons. Important other experiments defined the distinct stimulus dependence of different slow muscarinic and peptidergic synaptic events, identified the cell specific expression of presynaptic muscarinic inhibition in the B cell system and ruled out the hypothesis that regulation of repetitive firing serves as the physiological output for slow synaptic transmission in ganglia.

In 2000, we began building computational models that predict paravertebral ganglia serve as activity-dependent synaptic amplifiers. The resulting theory posits that ganglionic gain is regulated by the convergence and strength of fast nicotinic synapses and is modulated by the cell-type specific expression of muscarinic and other G-protein coupled receptors. To test the model, we implemented dynamic clamp methodology that can reproduce in vivo patterns of virtual synaptic activity in living neurons under highly controlled in vitro conditions. We then transitioned to experiments that assess synaptic amplification in mammalian paravertebral sympathetic ganglia. These experiments exploit a new preparation that permits whole cell patch clamp recording of synaptic responses in rat sympathetic neurons in isolated intact ganglia. We are particularly interested in how ganglionic remodeling of synapses may contribute to the sympathetic hyperactivity seen in many cases of human hypertension.