In vivo optogenetic activation of locus coeruleus and consequent effects on perforant path evoked potentials in dentate gyrus

Quinlan, Meghan Anne Laura (2017) In vivo optogenetic activation of locus coeruleus and consequent effects on perforant path evoked potentials in dentate gyrus. Masters thesis, Memorial University of Newfoundland.

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Abstract

Locus coeruleus (LC) is a nucleus composed of noradrenergic neurons, with extensive forebrain connections. Within hippocampus, the dentate gyrus (DG) receives its input predominantly from entorhinal cortex through glutamatergic fibers of the perforant pathway (PP). LC activation prompts norepinephrine (NE) release onto DG granule cells, which consequently potentiates the cellular response to glutamate. Previous research using electrical and/or chemical LC activation revealed NE-induced long-term potentiation (NE-LTP) in the DG, when paired with PP electrical stimulation. The current study investigates whether previous models of in vivo NE-LTP can be replicated with optogenetic manipulation of LC neurons in anesthetized rats. Transgenically modified rats (TH-CRE) were first infused with a virus (AAV8), containing photosensitive channels (ChR2h134r) and recovered for a minimum of 4-weeks. Recording and stimulating (.1Hz, 0.2ms pulse) electrodes were then situated in the DG and PP respectively, to monitor the evoked potentials. The evoked response was monitored for a 30-min period prior to optogenetic activation, using 10Hz trains of 150mA (60-70mW), 30ms pulses of blue light from a laser diode directed at LC to initiate NE release. A recording electrode was assembled with the laser diode to simultaneously monitor cellular responses to light. Successful infusions of AAV8 showed colocalization of LC neurons and virus uptake. The introduction of the light into LC increased neuronal firing, and when paired with PP electrical stimulation, induced enduring changes in the DG-PP evoked response, as measured by population spike amplitude. These results occurred despite the limited duration of LC firing, revealed by our concurrent recording, and are consistent with the effects of chemical and electrical LC activation. They argue convincingly that PP-evoked potential spike potentiation is selectively related to a relatively brief period of LC-NE release. Developments in optogenetic technologies are promising steps toward a highly selective, reversible technique for nerve excitation and silencing. Light stimulation offers the potential for relating selective activation patterns of specific neurons to functional outcomes and for understanding the consequences of specific temporal interactions among neuronal networks.

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