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

Locus coeruleus (LC) is a nucleus composed of noradrenergic neurons, with \nextensive forebrain connections. Within hippocampus, the dentate gyrus (DG) receives its \ninput predominantly from entorhinal cortex through glutamatergic fibers of the perforant \npathway (PP). LC activation prompts norepinephrine (NE) release onto DG granule cells, \nwhich consequently potentiates the cellular response to glutamate. Previous research \nusing electrical and/or chemical LC activation revealed NE-induced long-term \npotentiation (NE-LTP) in the DG, when paired with PP electrical stimulation. The current \nstudy investigates whether previous models of in vivo NE-LTP can be replicated with \noptogenetic manipulation of LC neurons in anesthetized rats. Transgenically modified \nrats (TH-CRE) were first infused with a virus (AAV8), containing photosensitive \nchannels (ChR2h134r) and recovered for a minimum of 4-weeks. Recording and \nstimulating (.1Hz, 0.2ms pulse) electrodes were then situated in the DG and PP \nrespectively, to monitor the evoked potentials. The evoked response was monitored for a \n30-min period prior to optogenetic activation, using 10Hz trains of 150mA (60-70mW), \n30ms pulses of blue light from a laser diode directed at LC to initiate NE release. A \nrecording electrode was assembled with the laser diode to simultaneously monitor \ncellular responses to light. Successful infusions of AAV8 showed colocalization of LC \nneurons and virus uptake. The introduction of the light into LC increased neuronal firing, \nand when paired with PP electrical stimulation, induced enduring changes in the DG-PP \nevoked response, as measured by population spike amplitude. These results occurred \ndespite 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 \nconvincingly that PP-evoked potential spike potentiation is selectively related to a \nrelatively brief period of LC-NE release. Developments in optogenetic technologies are \npromising steps toward a highly selective, reversible technique for nerve excitation and \nsilencing. Light stimulation offers the potential for relating selective activation patterns of \nspecific neurons to functional outcomes and for understanding the consequences of \nspecific temporal interactions among neuronal networks.