Insights into the effects of norepinephrine on memory: studies of noradrenergic modulation of synaptic plasticity in the dentate gyrus of the rat

Walling, Susan G. (2003) Insights into the effects of norepinephrine on memory: studies of noradrenergic modulation of synaptic plasticity in the dentate gyrus of the rat. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Norepinephrine (NE) is known to increase memory for emotional events. This catacholamine, applied exogenously or through natural release mechanisms, increases memory in rats and humans, and increases cell excitability in areas of the rat brain (NE-induced potentiation), in a manner congruent with other models of long-lasting memory support. The purpose of this dissertation is to investigate the effects of NE on synaptic efficacy in rat dentate gyrus, a component of the memory structure, the hippocampus. Three chapters are presented, each utilizing a different method of intensifying the synaptic levels of NE in the dentate gyrus, and investigating the ensuing effects on the perforant path-dentate gyrus evoked potential. -- In the first chapter, exogenous NE and noradrenergic agents were applied in the lateral ventricle of the awake rat, a technique used to meld in vitro bath application of drugs, with in vivo whole animal recording in the absence of anesthetic. Here it was found that NE, infused ventricularly reliably increased the synaptic contribution of the evoked potential (EPSP slope), a result characteristic of bath application of NE in the hippocampal slice. NE also increased dentate granule cell firing as indexed by the population spike amplitude of the evoked response. Though these initial increases returned to baseline within 30 min, a subset of animals monitored 24 hr after NE infusion, demonstrated long-term potentiation of the EPSP slope and population spike amplitude. Both the short-term and long-term potentiation were dependent on β-adrenergic receptor activation. The data suggest NE can mediate multiple phases of synaptic plasticity and long-term potentiation may not reflect an uninterrupted progression from short-term potentiation, a widely held theory of how long-term memories are formed. -- In the second chapter, the evoked population activity in the dentate gyrus of the anesthetized rat was monitored while the recently discovered neuropeptide orexin-A (OREX-A) was infused directly into the LC as a method of discretely activating LC neurons to evoke NE release in the hippocampus. Application of OREX-A at 3 concentrations (1, 10, and 100 nM) produced a robust potentiation of the population spike amplitude lasting for greater than 3 hr. This potentiation was reduced by intradentate application of the β-adrenergic receptor antagonist propranolol. Infusion of vehicle into the LC failed to produce changes in the evoked activity. LC infusion of the α₂₋adrenergic receptor agonist clonidine prior to OREX-A infusion, a method of pharmacologically inactivating LC neurons, blocked the effect of OREX-A. Lastly, hippocampal levels of NE were monitored to confirm that infusion of OREX-A into the LC produced a transient elevation of NE levels in the hippocampus. This is the first study to investigate hippocampal synaptic effects of orexinergic activation of LC neurons and the first to suggest that OREX-A can produce changes in synaptic activity reminiscent of memory formation. -- The third study takes advantage of a technique developed in the anesthetized preparation whereby endogenous release of NE is initiated by the application of the excitatory amino acid transmitter glutamate to the noradrenergic neurons of the LC. As anesthetized preparations are limited by the duration over which effects can be monitored, this technique was used in the awake rat to assess the effects of NE on the dentate gyrus evoked potential at periods 24 hr after LC activation. Glutamatergic activation of the LC neurons produced a robust facilitation of the dentate gyrus population spike and EPSP slope, an increase more sizable than that seen within the first 3 hr following LC activation. This effect is unusual in that short-term potentiation of the evoked potential was not a necessary requirement for the NE-induced long-term potentiation observed at 24 hr. Though this effect is novel in the mammalian nervous system, there are behavioral studies that are in keeping with this finding and similar synaptic effects have been seen in an invertebrate. These effects were dependent on the activation of β-adrenergic receptors and on the synthesis of de novo protein. -- Taken together these studies suggest locus coeruleus activation has a special role in the initiation of long-term increases in synaptic strength and cell responses in circuitry known to be critical for memory formation and, further, that short-term and long-term synaptic plasticity may be supported by distinct and independent processes.

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