Local-circuit modulation in the dentate gyrus induced by increased norepinephrine following orexin-A infusion into the locus coeruleus

The present thesis was designed to probe the local-circuit effects in the dentate gyrus following orexin-A infusion in or near the locus coeruleus as a manipulation to transiently increase norepinephrine levels. The study evaluated excitation and inhibition in the dentate gyrus as reflected in closely spaced pairs of perforant path evoked potentials in urethane-anesthetized rats. A paired pulse perforant path stimulation paradigm using three interstimulus intervals, in conjunction with a frequency dependent inhibition test was used to probe local-circuit activity for early inhibition, facilitation and late inhibition. Measures of both the conditioning and test perforant path evoked potential excitatory post-synaptic potential (EPSP) slope and population spike amplitude were taken. -- Orexin-A infusion, in or near the locus coeruleus, resulted in a gradually developing, significant enhancement of population spike amplitude and EPSP slope. Based a comparison of input-output data taken to prior to orexin-A infusion there were no differences in early GABA-A mediated inhibition or in midrange facilitation effects. The input-output data, however, supported an increase in late, GABA-B mediated inhibition following locus coeruleus activation. This was the first demonstration of a possible noradrenergic-induced enhancement of late paired pulse inhibition. -- Frequency dependent inhibition results were disparate; interpreting the between group measures suggested that frequency dependent inhibition was reduced, whereas more sensitive within group measures were consistent with no change. -- The increase of GABA-B mediated late inhibition initiated by norepinephrine may contribute to the ability of norepinephrine to reduce epileptic seizures and supports its role in promoting theta activity. Increased theta power has been implicated in learning and memory and would be consistent with norepinephrine's role in promoting plasticity