Norepinephrine (NE)-induced, long-lasting facilitation of the perforant path evoked population spike amplitude in the dentate gyrus (DG) has been reported to occur following iontophoresis of norepinephrine in the DG in vivo and following application of 10 or 20 microM NE to the hippocampal slice in vitro. The present study employs glutamatergic activation of the locus coeruleus (LC) to induce NE release in the DG. Thirty-three female rats served as subjects. The perforant path-evoked potential was elicited once every 10 s and monitored in the DG cell body layer. Following appropriate control periods, 100-150 nL of 0.5 M l-glutamate were pressure ejected in the vicinity of the LC. All placements in or within 300 microM of the LC produced significant facilitation (140%) of the population spike amplitude. Facilitation lasted more than 20 min in 37% of the animals tested. The facilitation effects on population spike amplitude were replicated with up to four ejections of glutamate at the same site. Propranolol (30 mg/kg i.p.) blocked this facilitation of population spike amplitude. Changes in EPSP slope were variable. Glutamate-activation of LC was not accompanied by blood pressure increases. These data suggest that physiological NE release via LC activation induces a beta receptor mediated facilitation of the perforant path-evoked population spike which parallels that obtained with direct application of NE to the DG in vivo or in vitro. LC-NE may provide one mechanism in the mammalian brain for long-lasting heterosynaptic modulation of neural inputs.

Theta and gamma oscillations are thought to provide signal sets that promote neural coding of cognitive processes. Over 40 yrs ago, Jeffrey Gray reported event-related changes in a narrow band of hippocampal theta (7.5-8.5 Hz) which appeared to involve norepinephrine (NE) release from, the noradrenergic nucleus, the locus coeruleus (LC). These event-related alterations in EEG were elicited by novelty, attentional changes, the use of preparatory signals, and signal-mismatch events. Gray et al. have since provided indirect evidence that supports the role of NE in the modulation of 7.5- to 8.5-Hz oscillations in the hippocampus, but studies investigating the effects of direct LC activation in awake rats have been lacking. In the present study, dentate gyrus EEG was examined during glutamatergic activation of the LC in awake male rats in relation to plasticity effects on simultaneously recorded perforant path-evoked field potentials. Glutamate-injected animals were divided into three groups based on histological and plasticity outcomes; perforant path stimulated controls were also included. The three injected groups were: (1) rats with positive LC placements, demonstrating NE-LTP of the dentate gyrus evoked potential, (2) rats with positive LC placements, without NE-LTP, and (3) Non-LC injected controls. Activation of the LC in awake rats demonstrating NE-LTP increased the relative power of 7- to 9-Hz theta, a result masked in broader 4- to 12-Hz analysis. Comparatively, urethane-anesthetized rats showed an increase in 5-7 Hz, but not 7- to 9-Hz theta with LC activation. Discriminative analysis in the approximate theta band predicted by Gray (7.4-8.5 Hz) revealed that awake rats demonstrating NE-LTP had increased relative power in this narrow frequency compared to rats receiving perforant path only (noninjected) and Non-LC injected rats. Transiently reduced gamma (20-40 Hz) relative power was most commonly observed in rats with verified LC placements failing to express NE-LTP. Given current theories of LC function, these results suggest oscillatory tuning within the theta and gamma range may facilitate shifts in cognitive set.

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