Metrifonate improves associative learning and retention in aging rabbits.

Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive deficits associated with normal aging and aging-related dementias. Trace eyeblink conditioning (EBC), a hippocampusand forebrain-dependent learning paradigm, is impaired in both aged rabbits and aged humans, attributable in part to cholinergic dysfunction. In the present study, we examined the effects of galantamine (3 mg/kg), a cholinesterase inhibitor and nAChR allosteric potentiating ligand, on the acquisition of trace EBC in aged (30-33 months) and young (2-3 months) female rabbits. Trace EBC involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), separated by a stimulus-free trace interval. Repeated CS-US pairings results in the development of the conditioned eyeblink response (CR) prior to US onset. Aged rabbits receiving daily injections of galantamine (Aged/Gal) exhibited significant improvements compared with age-matched controls in trials to eight CRs in 10 trial block criterion (P = 0.0402) as well as performance across 20 d of training [F(1,21) = 5.114, P = 0.0345]. Mean onset and peak latency of CRs exhibited by Aged/Gal rabbits also differed significantly [F (1,21) = 6.120/6.582, P = 0.0220/0.0180, respectively] compared with age-matched controls, resembling more closely CR timing of young drug and control rabbits. Galantamine did not improve acquisition rates in young rabbits compared with age-matched controls. These data indicate that by enhancing nicotinic and muscarinic transmission, galantamine is effective in offsetting the learning deficits associated with decreased cholinergic transmission in the aging brain.

Section: Discussionmentioning

confidence: 96%

Section: Drug Treatment and Trainingmentioning

confidence: 99%

Galantamine Facilitates Acquisition of Hippocampus-Dependent Trace Eyeblink Conditioning in Aged Rabbits

Weible¹,

Oh²,

Lee³

et al. 2004

“…Acquisition of either trace EBC (rats and rabbits) or WMZ (rats) results in a reduction of the post-burst AHP in CA1 pyramidal neurons (Moyer Jr. et al 1996;Oh et al 2003;Kuo et al 2004). In addition, systemic administration of compounds that reduce the AHP result in an enhancement of learning hippocampus-dependent tasks (Kronforst-Collins et al 1997;Weiss et al 2000). Based on these findings, we hypothesized that training rats on two hippocampus-dependent tasks would result in facilitation of the second task.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

Kuo¹,

Lee²,

Disterhoft³

2006

A common cellular alteration, reduced post-burst afterhyperpolarization (AHP) in CA1 neurons, is associated with acquisition of the hippocampus-dependent tasks trace eyeblink conditioning and the Morris water maze. As a similar increase in excitability is correlated with these two learning paradigms, we sought to determine the interactive behavioral effects of training animals on both tasks by using either a consecutive or simultaneous training design. In the consecutive design, animals were trained first on either the trace eyeblink conditioning task for six sessions, followed by training on the water maze task for six sessions, or vice versa. The simultaneous design consisted of six or 11 training days; animals received one session/day of both trace eyeblink conditioning and water maze training. Separate groups were used for consecutive and simultaneous training. Animals trained on both tasks simultaneously were significantly facilitated in their ability to acquire the trace eyeblink conditioning task; no effect of simultaneous training was seen on the water maze task. No effect was seen on acquisition for either task when using the consecutive training design. Taken together, these findings provide insight into how the hippocampus processes information when animals learn multiple hippocampus-dependent tasks.The importance of the hippocampus in learning is well established (Berger et al. 1976;Berger and Thompson 1978;Disterhoft et al. 1999). A number of studies have demonstrated the necessity of the hippocampus in learning spatial and nonspatial tasks, as well as those requiring the association of temporally remote events (Morris et al. 1982;Moyer Jr. et al. 1990;Davidson and Jarrard 1993;McEchron et al. 1998;Bannerman et al. 1999;Weiss et al. 1999a). Two such tasks are trace eyeblink conditioning (EBC) and Morris water maze (WMZ).A common cellular mechanism that underlies learning, increased membrane excitability, has been observed by several investigators. This mechanism is conserved across species, tasks, and brain regions. Trains of action potentials in both hippocampal and cortical neurons are followed by a prolonged post-burst afterhyperpolarization (AHP), which decreases neuronal excitability and inhibits further firing to a sustained depolarizing input (Schwindt et al. 1988;Storm 1990). A reduction in the AHP occurred in both rat and rabbit CA1 pyramidal neurons after acquisition of trace EBC (Moyer Jr. et al. 1996;Kuo et al. 2004). This reduction also occurred in rat CA1 pyramidal neurons after acquisition of another type of hippocampus-dependent task, the spatial Morris WMZ (Oh et al. 2003). Alterations in the AHP with learning have also been observed in rat piriform cortical neurons after acquisition of an odor discrimination task (Saar et al. 1998). In both hippocampus and piriform cortex, the reduced AHP followed a similar time course after learning, with a maximal reduction 24 h after task acquisition and a return to baseline within 7 d of acquisition (Moyer Jr. et al. 1996;Saar et al. 1998).In a...

“…The long-lasting post-burst AHP is reduced in hippocampal cells from animals that have learned a hippocampus-dependent task (Moyer Jr. et al 1996;Oh et al 2003), and increased in aging animals that have difficulty learning. Pharmacologically reducing the post-burst AHP in vivo with calcium channel blockers (nimodipine) (Deyo et al 1989), acetylcholine agonists (CI-1017) (Weiss et al 2000), or cholinesterase inhibitors (galantamine and metrifonate) (Kronforst-Collins et al 1997;Weible et al 2004) leads to improved learning in aging animals. Thus, the finding that blocking the BK channel results in slowed learning is somewhat surprising, given the previous report of a reduction in the BK-mediated fast AHP after learning tEBC (Matthews et al 2008).…”

mentioning

confidence: 99%

Blocking the BK channel impedes acquisition of trace eyeblink conditioning

Matthews¹,

Disterhoft²

2009

Big-K+ conductance (BK)-channel mediated fast afterhyperpolarizations (AHPs) following action potentials are reduced after eyeblink conditioning. Blocking BK channels with paxilline increases evoked firing frequency in vitro and spontaneous pyramidal activity in vivo. To examine how increased excitability after BK-channel blockade affects learning, rats received bilateral infusions of paxilline, saline, or nothing into hippocampal CA1 prior to trace eyeblink conditioning. The drug group was slower to acquire the task, but learning was not completely impaired. This suggests that nonspecific increases in excitability and baseline neuronal firing rates caused by in vivo blockade of the BK channel may disrupt correct processing of inputs, thereby impairing hippocampus-dependent learning.Learning and increased neuronal intrinsic excitability are strongly correlated, although a causal relationship has not yet been definitively established (Disterhoft and Oh 2006). One of the mechanisms of increased excitability is through reduction of potassium currents, which cause afterhyperpolarizations (AHP). Afterhyperpolarizations in pyramidal cells can be divided into three categories based upon their timing and duration. The fast AHP lasts only 2-5 ms, follows the depolarizing phase of individual action potentials, and is mediated largely by the big-K + conductance (BK) channel. The post-burst AHP has a medium (50-100 ms) and a slow (1-2 s) component, and follows trains or bursts of action potentials. The medium AHP is carried by apamin sensitive small-K + conductance (SK) channels, but the channel(s), which carry the slow AHP, are still unknown (Storm 1987;Disterhoft and Oh 2006).Learning-related reductions in the post-burst AHP are well documented (for review see Disterhoft and Oh 2006). Additionally, pharmacological modulators of the post-burst AHP alter learning in an expected manner-compounds that reduce the AHP improve learning (galantamine [Simon et al. 2004] and nimodopine [Deyo et al. 1989]). Learning-related reductions of the fast AHP are also seen in prefrontal cortex pyramidal neurons after extinction of fear conditioning (Santini et al. 2008) and in CA1 hippocampal pyramidal neurons after learning trace eyeblink conditioning (tEBC) (Matthews et al. 2008). In vitro whole-cell recordings show that blocking the BK channel with either paxilline or iberiotoxin increases the firing rate to a step current injection (Nelson et al. 2003). Likewise, injection of paxilline into the hippocampus increases the in vivo spontaneous firing frequency of hippocampal CA1 neurons of awake freely moving rats up to 2.5-fold over saline injections (Matthews et al. 2008), indicating that the BK-mediated fast AHP plays an important role in intrinsic excitability. The current study was undertaken to determine whether pharmacologically reducing the fast AHP during training would improve trace eyeblink conditioning.Experimental subjects were 3-to 4-mo old Fisher 344 X Brown Norway F1-hybrid rats. Animals were housed in pairs, in a climate-con...