Learning-specific changes in long-term depression in adult perirhinal cortex

Abstract

Learning is widely believed to involve synaptic plasticity, using mechanisms such as those used in long-term potentiation (LTP). We assess whether the mechanisms used in alternative forms of plasticity, long-term depression (LTD) and depotentiation, play a role in learning. We have exploited the involvement of the perirhinal cortex in two different forms of learning to compare simultaneously, within the same brain region, their effects on LTD and depotentiation. Multiple-exposure learning but not single-exposure learning in vivo prevented, in a muscarinic receptor-dependent manner, subsequent induction of LTD and depotentiation, but not LTP, in perirhinal cortex in vitro. The contrast in the effects of the two types of learning under these particular experimental conditions indicate that the in vitro change is unlikely to be attributable to synapse-specific plastic changes registering the precise details of the individual learned associations. Instead, it is concluded that the lack of LTD and depotentiation arises from, and establishes the importance of, a learning-related generalized change in plasticity gain. The existence of this additional mechanism has important implications for interpretations of how plasticity relates to learning.

Figure 1.

Lack of effect of viewing novel or familiar stimuli on synaptic transmission or LTP. a, The paired viewing apparatus. The rat receives a juice reward for keeping its head in the observing hole. Pictures, novel on one side and familiar on the other, are shown simultaneously on two monitors, each visible to only one eye. In this way, information for novel stimuli is primarily delivered to one hemisphere (“novel”), and information for familiar stimuli is primarily delivered to the other (“familiar”). b, There is no difference in the input/output characteristics of fEPSPs when assessed as a function of novel versus familiar (left; p > 0.05; n = 13); right versus left hemisphere (middle; p > 0.05; n = 12); or comparison of the two stimulating electrodes (entorhinal vs temporal; right; p > 0.05; n = 12). The graphs illustrate increasing stimulus intensity versus synaptic strength. c, Pooled data showing that LTP that lasts at least 1 h is induced by HFS (100 Hz, 1 s stimulation, repeated 4 times, as indicated by the upward arrow). There is no difference in the magnitude of LTP between novel and familiar hemispheres (p > 0.05; n = 7). d, Repeated HFS (1 train of 100 Hz every 14 min) saturates LTP. Data show that there is no difference in the magnitude of potentiation between novel and familiar hemispheres (p > 0.05; n = 11; measured 15 min after HFS). In this and subsequent figures, the heterosynaptic pathway is not shown for the sake of clarity. Error bars represent SEM.

Figure 2.

Induction of depotentiation is prevented in familiar hemispheres. a, LTP, induced by HFS (indicated by the single upward arrow), is not different between novel and familiar hemispheres. Depotentiation, induced by 1 Hz stimulation for 15 min (indicated by the two joined arrows), occurs in novel hemispheres but not in familiar hemispheres. The traces illustrate fEPSPs taken from the time points indicated. Stimulus artifacts are blanked and replaced by arrows. b, Levels of depotentiation are renormalized to LTP levels to emphasize the lack of depotentiation in familiar hemispheres compared with the depotentiation in novel hemispheres. c, LTP and depotentiation were induced in slices from control animals (paired viewing procedure, no visual stimuli). Inset, Stimulus–response characteristics for control animals. Min, “Minimal” intensity (sufficient to produce an fEPSP discernable from the noise). Error bars represent SEM.

Figure 3.

The loss of depotentiation by viewing familiar stimuli is dependent on muscarinic receptor activation. a, c, LTP is induced by HFS, as indicated by the single upward arrow. a–d, Depotentiation is then induced by 1 Hz stimulation for 15 min, as indicated by the two joined arrows. a, The lack of depotentiation in familiar hemispheres when paired viewing was in the presence of methylscopolamine (controls). However, depotentiation occurred in familiar hemispheres when paired viewing was in the presence of scopolamine. b, Levels of depotentiation in familiar hemispheres renormalized to LTP levels, emphasizing the difference between the effects of scopolamine and methylscopolamine treatments. c, In novel hemispheres, depotentiation occurs regardless of prior treatment with scopolamine or methylscopolamine. d, Levels of depotentiation in novel hemispheres renormalized to LTP levels, demonstrating the lack of difference between scopolamine and methylscopolamine treatment. Error bars represent SEM.

Figure 4.

The prevention of LTD by prior viewing of familiar stimuli is muscarinic receptor dependent. a–c, LTD is induced by 5 Hz stimulation for 10 min, as indicated by the joined arrows. a, When paired viewing was performed in the presence of methylscopolamine (methylscop), LTD was induced by 5 Hz stimulation in novel hemispheres but was not induced in familiar hemispheres. b, Paired viewing in the presence of scopolamine prevents the loss of LTD in familiar hemispheres; the level of LTD in novel hemispheres is unaffected by scopolamine pretreatment. c, LTD is induced in control animals (paired viewing procedure, no visual stimuli).