Despite advances in our understanding of the cellular actions of norepinephrine (NE) in the CNS, we do not know how the LC-NE system modulates neural network function. The main olfactory bulb (MOB) is a relatively simple, well characterized cortical network that functions to process olfactory information. LC densely innervates this network with a higher degree of laminar specificity than in any other forebrain target. This laminar organization leads to specific predictions about the neurons targeted by NE synapses and to equally specific predictions, supported by new pilot studies, of LC-NE actions on olfactory bulb network function. We propose in vivo and in vitro electrophysiological experiments to characterize the action of the LC-NE system on the MOB at both the cellular and circuit levels. Research during the present funding cycle demonstrated that LC activation in vivo has a dramatic 'modulatory' action increasing mitral cells (MCs) responses to weak but not strong olfactory nerve (ON) shocks. This modulatory action can be reproduced in vitro, where it is mimicked by a1 agonists and blocked by a1 antagonists. We also found that MCs exhibit bistability, alternating between two membrane potentials separated by 10 mV which seems to be determined by the balance between an outward K+ current and a non-inactivating Na* current. MC responses to ON input or current injection differ dramatically between these to states. Preliminary findings suggest that NE, via a1 receptors depolarizes MCs by reducing the outward K+ current. This effect is """"""""amplified' by bistability making the MCs more likely to discharge in response to weak ON inputs. Tufted (T) cells, by contrast, exhibit a """"""""bursting"""""""" firing pattern and are not bistable. If NE has a similar a1 effect on T as MCs, the depolarization would not be amplified by bistability. Thus, NE may differentially modulate the responses of M and T cells - the two output neurons of the bulb. We will test this hypothesis using whole cell current/voltage-clamp studies. Synapses from M/T cell lateral dendrites excite granule (G) cell dendrites, which in turn, provide GABAergic inhibition back onto M/T cell dendrites. NE fibers heavily target the granule cell layer but nothing is known about the actions of NE on G cells. We will test hypothetical sites of NE modulation of M/T-to-G and G-to-M/T synapses using patch clamping and Ca2+ imaging. Finally, we wifi determine how NE modulates the primary function of the bulb, odor sensory processing. The influence of synaptically released NE on odor processing is unknown. We wifi close this gap. Since LC activation in vivo increases mitral cell responses to weak ON shocks. Therefore, we predict that LC activation will selectively increases mitral cell responses evoked by low concentrations of odors. We will directly test this prediction by measuring the effect of LC activation on MC responses to odors in anesthetized rats.
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