Aging and Learning-Specific Changes in Single-Neuron Activity in CA1 Hippocampus During Rabbit Trace Eyeblink Conditioning

Abstract

Aging and learning-specific changes in single-neuron activity in CA1 hippocampus during rabbit trace eyeblink conditioning. J Neurophysiol 86: 1839 -1857, 2001. Rabbit trace eyeblink conditioning is a hippocampus-dependent task in which the auditory conditioned stimulus (CS) is separated from the corneal airpuff unconditioned stimulus (US) by a 500-ms empty trace interval. Young rabbits are able to associate the CS and US and acquire trace eyeblink conditioned responses (CRs); however, a subset of aged rabbits show poor learning on this task. Several studies have shown that CA1-hippocampal activity is altered by aging; however, it is unknown how aging affects the interaction of CA1 single neurons within local ensembles during learning. The present study examined the extracellular activity of CA1 pyramidal neurons within local ensembles in aged (29 -34 mo) and young (3-6 mo) rabbits during 10 daily sessions (80 trials/session) of trace eyeblink conditioning. A single surgically implanted nonmovable stereotrode was used to record ensembles ranging in size from 2 to 12 separated single neurons. A total of six young and four aged rabbits acquired significant levels of CRs, whereas five aged rabbits showed very few CRs similar to a group of five young pseudoconditioned rabbits. Pyramidal cells (2,159 total) were recorded from these four groups during training. Increases in CA1 pyramidal cell firing to the CS and US were diminished in the aged nonlearners. Local ensembles from all groups contained heterogeneous types of pyramidal cell responses. Some cells showed increases while others showed decreases in firing during the trace eyeblink trial. Hierarchical clustering was used to isolate seven different classes of single-neuron responses that showed unique firing patterns during the trace conditioning trial. The proportion of cells in each group was similar for six of seven response classes. Unlike the excitatory modeling patterns reported in previous studies, three of seven response types (67% of recorded cells) exhibited some type of inhibitory decrease to the CS, US, or both. The singleneuron response classes showed different patterns of learning-related activity across training. Several of the single-neuron types from the aged nonlearners showed unique alterations in response magnitude to the CS and US. Cross-correlation analyses suggest that specific single-neuron types provide more correlated single-neuron activity to the ensemble processing of information. However, aged nonlearners showed a significantly lower level of coincident pyramidal cell firing for all cell types within local ensembles in CA1.

Age-Associated Alterations of Hippocampal Place Cells Are Subregion Specific

“…Past analyses of hippocampal information processing in aged animals have focused either exclusively on cells of the CA1 subregion Shen et al, 1997;McEchron et al, 2001; or have combined the data obtained from the CA1 and CA3 subregions for analytical purposes Oler and Markus, 2000;Wilson et al, 2003Wilson et al, , 2004Wilson et al, , 2005. In studies of aging that did analyze subregions separately (Mizumori et al, 1996;Mizumori and Kalyani, 1997), the experimental conditions for recordings were not suitable for detecting the distinctive features of CA1 and CA3 encoding in response to changes in the environment.…”

Small-Conductance Ca2+-Activated K+Channel Type 2 (SK2) Modulates Hippocampal Learning, Memory, and Synaptic Plasticity

“…Wholecell recordings revealed that the apamin-sensitive current in CA1 neurons, which contributes to the afterhyperpolarization, was significantly greater in SK2-overexpressing mice than in WT mice. The increase in the apamin-sensitive current in CA1 may affect neuronal excitability at the soma and subsequently affect learning and memory (Disterhoft et al, 1988;McEchron et al, 2001;Oh et al, 2003). A second and more direct mechanism by which SK2 channels may affect the induction of synaptic plasticity is via a Ca 2ϩ -mediated feedback loop between NMDARs and SK channels in the dendritic spines of CA1 neurons.…”

Deficits in Trace Cued Fear Conditioning in Galanin-Treated Rats and Galanin-Overexpressing Transgenic Mice

“…Furthermore, galanin specifically reduced freezing on the cued components of trace fear conditioning. Cued freezing in the trace fear conditioning test is thought to depend on the integrity of both the amygdala and the hippocampus (LeDoux et al 1990;Moyer et al 1990;Sutherland and McDonald 1990;Phillips and LeDoux 1992;McEchron et al 1998McEchron et al , 2000McEchron et al , 2001Weiss et al 1999;Davis and Whalen 2001;Ryou et al 2001;Schafe et al 2001). Specifically, both the galanin administered rats, and the galanin-overexpressing transgenic mice exhibited a deficit only in the particular aspect of the conditioning procedure that requires both amygdala and hippocampal mediation to a single discrete stimulus (trace cued fear).…”

“…These findings indicate that the cognitive impairments produced by galanin are consistent across two species, and across exogenous and endogenous manipulations, on specific components of fear conditioning. The addition of a delay between the CS and US has been used in a variety of investigations of hippocampal learning and memory (McEchron et al 1998(McEchron et al , 2001Weiss et al 1999;Huerta et al 2000;Ryou et al 2001). Delays ranging from 0.5 sec to >30 sec have been employed.…”

“…Phillips and LeDoux (1992) demonstrated that animals with hippocampal lesions exhibit normal cued fear in standard delay CCF training procedures, indicating an association of the CS and the US. Lesions of the hippocampus, however, severely disrupt cued fear conditioning in the trace CCF procedure (McEchron et al 1998;Weiss et al 1999;McEchron et al 2001;Ryou et al 2001). …”