The Neonatal Locus Coeruleus is a Differentiated and Complex Neuromodulatory System as Revealed by Local Field Potential Analysis

• Author / Creator

  Rawal, Bijal

• The locus coeruleus (LC) in the pons of the brainstem provides the sole source of noradrenergic afferent input to most brain structures including the cerebral cortex, hippocampus, cerebellum and spinal cord. The resulting modulation of activity is important for controlling behaviors like sleep-wake cycle, pain sensitization, memory formation or opioid (withdrawal) reactions. It is still unclear how this small nucleus modulates activity in these brain areas in a diverse fashion. The aim of this thesis was to study, in brain slices from neonatal rats, properties of spontaneous electrical LC activity with emphasis on the involvement of subtypes of ionotropic glutamatergic receptors (iGluR) in modulation of both network discharge and cellular firing patterns.It was firstly found with single unit recording that LC neurons discharge with a jitter of 30-100 ms at a rate of ~1 Hz single spikes that summate to a ~ 0.2 s-lasting local field potential (LFP) burst and that each neuron preferentially discharges in a particular phase of this network response. Elevating superfusate K+ from 3 to 7 mM either increased LFP rate or transformed its pattern from a bell-shaped signal into multi-peak bursts lasting several seconds. The latter LFP pattern was also seen during recovery from inhibition of rhythm by µ-opioid receptor activation with DAMGO.It was next investigated with simultaneous LFP and whole-cell membrane potential (Vm) recording whether the spontaneous jittered, yet phase-locked LC neuronal spiking and LFP pattern are altered by bath-applied glutamate or the iGluR agonists AMPA, KA, QUI and NMDA and whether a complex of the AMPA receptor (AMPAR) with TARP (auxiliary transmembrane AMPAR regulatory proteins) is functional. TARP-AMPAR complex activation via bath-application of the partial agonist CNQX increased LFP rate via neuronal depolarization that accelerated spiking to increase the free cytosolic Ca2+ concentration (Cai). The Cai rise was blocked by the L-type Ca2+ channel blocker nifedipine and the electrophysiological CNQX effects were abolished by the non-competitive AMPAR blocker GYKI. AMPA and KA accelerated LFP rate and transformed the pattern to faster sinusoidally-shaped oscillatory events of shorter event duration with fluctuations of signal amplitude. Both agents also increased the regularity of LFP bursting and decreased cellular spike jitter, but did not increase network synchronization. Glutamate made the network rhythm more irregular and increased burst duration with decreased network synchronization whereas NMDA caused faster oscillatory events of shorter duration with rhythmic pauses and enhanced network synchronicity. Pattern transformation by QUI was similar to that evoked by glutamate, but without decreasing synchronicity, and this effect was mediated by iGluR activation as judged by the countering effect of the nonselective iGluR antagonist kynurenic acid. This study is the first demonstration that spiking in the neonatal LC is not synchronous, but rather jittered, yet phase-locked to the population burst and that the pattern of this bursting is transformed by changes in network excitability evoked by K+, opioids and iGluR agonists. These findings provide the basis for future studies aiming at understanding the causal link between LC firing patterns and resulting modulation of activities in the targeted brain areas and thus in their functions.

• Subjects / Keywords

  • Locus coeruleus

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-cx81-8702

• License

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