Cholinergic facilitation of trace eyeblink conditioning in aging rabbits

The hippocampus is importantly involved in learning and memory, and is seve rely impacted by aging. In in vitro hippocampal slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation are reduced in hippocampal pyramidal neurons after hippocampally-dependent trace eyebl ink conditioning, indications of increased cellular excitability. The AHP r esults from the activation of outward potassium currents, including sI(AHP) and muscarine-sensitive I-M. The AHP is significantly increased in aging h ippocampal neurons, potentially contributing to age-associated learning def icits. Compounds which reduce the AHP and spike-frequency accommodation cou ld facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances t race eyeblink conditioning by aging rabbits and reduces the AHP and accommo dation in hippocampal CAI neurons in a dose-dependent manner. These reducti ons are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippocampal neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of m etrifonate since the AHP and accommodation were further reduced when metrif onate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippocampally dependent tasks is mediated at least partially by increasing the baseline e xcitability of CAI pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholineste rase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M-1 agonist CI1017. A dose-dependent enhancement of acq uisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showi ng comparably improved learning rates as those receiving 0.5 mg/ml or vehic le. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective dose s of CI1017 were enhancing responsivity to the tone conditioned stimulus. T hese studies suggest that muscarinic cholinergic neurotransmission is impor tantly involved in associative learning; that learning in aging animals may be facilitated by enhancing cholinergic transmission; and that the facilit ation may be mediated through actions on hippocampal neurons.