Noradrenergic modulation of hippocampal CA1 and CA3 networks

Abstract

The release of neuromodulators within the hippocampus regulates the encoding of memories. The locus coeruleus (LC) is a brainstem nucleus that projects diffusely throughout the cortex, releasing noradrenaline (NA) and – within the hippocampus – this release acts as a novelty signal, with the LC switching from tonic firing in familiar spaces to burst firing when an animal enters a novel environment.

To explore the relatively understudied modulatory effects of NA on hippocampal synaptic inputs and post-synaptic firing properties we used a combination of whole-cell patch-clamp recordings in mouse ex vivo hippocampal slices, optogenetic manipulations and computational modelling.

Bath application of NA attenuated both excitatory and feed-forward inhibitory responses at the Schaffer collateral-CA1 (SC-CA1) synapse, resulting in a reduced spike output in response to synaptic stimulation. However, high-frequency inputs were able to overcome this attenuation and shift the excitatory/inhibitory (E/I) ratio towards excitation – a novel result consistent with a role of NA in prioritising high frequency (perhaps salient) drives.

At mossy fibre-CA3 (MF-CA3) synapses NA decreased feed-forward inhibition but spared excitatory inputs. The effect of NA on naturalistic granule cell firing patterns was further examined using a Tsodyks-Markram model of the MF-CA3 synapse, which suggested that a reduction in the ability of feed-forward inhibitory interneurons to recover from depression underscored the enhanced E/I ratio.

In contrast to the effects of high concentrations of bath-applied NA, optogenetically-evoked NA augmented CA1 spike output through a β-AR mechanism and a potential inhibition of transient voltage-gated K+ channels. These effects were recapitulated with a sub-micromolar concentration of bath-applied NA, highlighting the importance of concentration and spatiotemporal release patterns of neuromodulators when investigating their effects in ex vivo slices. Utilising fast-scan voltammetry and a genetically-encoded fluorescent NA sensor, we show that optically-evoked physiological release of NA is much lower than the bath-applied concentrations used in the literature.

Date of Award	24 Mar 2020
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jack R Mellor (Supervisor) & Anthony Edward Pickering (Supervisor)