Lynch et al. Cognition enhancement in normal subjects forms of plasticity could lead to agents that target particular forms a third stimulation train produces still more potentiation but of memory. only if it is applied at least 60 min after the second.Additional work suggested that this LTP "spaced trials effect"reflects the COGNITIVE ENHANCEMENT presence of a large population of synapses with high plasticity DOES AUGMENTING MEMORY ENHANCE COGNITION? thresholds that are "primed"by the first theta episode and then Memory is such a prominent part of cognition that it seems obvi- shifted into the potentiated state by the second(Kramar et al., ous that enhancing the one will improve the other.However, 2012b).These effects fit naturally within the above described sub- there may be good computational reasons that cognitive benefit strate map for LTP:activation of synaptic integrins by a first is gained when acquisition is less than optimal in terms of speed theta burst train was followed by an approximately one hour and strength.Animals faced with new and complex circumstances period before these receptors could be re-engaged by additional need to encode regular features without storing variable,low stimulation (Babayan et al.,2012).They also set the stage for a information elements.Otherwise,as noted earlier,the resultant first test of how a drug that enhances memory affects a phys- memories will be noisy and less predictive of future encounters. iological analogue of the spaced trials effect.The results were The spaced trials effect-wherein,temporally separated train- clear:infusion of an ampakine prior to theta train #1 produced ing trials more efficiently support encoding than does a single the expected enhancement in the amplitude of LTPI but also "massed"session-can be seen as one adaptation toward better occluded further increases in the level of potentiation following capture of regularities in the learning environment(Hintzman,a second,delayed theta train administered in the absence of the 1976;Commins et al.,2003;Cepeda et al.,2006).That is,spac- drug(Kramar et al.,2012b).Thus,the ampakine enhanced ini- ing ensures that only elements that are regularly present will be tial encoding(as multiply reported)but did so at the expense of incorporated into memory while transient features will not.An effects of spaced stimulation,and presumably the computational enhancer could obviate the need for spacing by producing strong advantages associated with spacing(Lynch and Gall,2013 for a memory on an initial trial but would be expected to result in a discussion). noisy representation. The preceding example describes a situation in which phar- Tests of the above point are lacking but LTP experiments have macologically augmenting memory would likely not result in produced what may be pertinent results.The original descrip-enhanced cognition,at least in complex environments lacking tions of links between theta burst afferent stimulation and LTP explicit guidelines for effective performance.These are routine showed that,absent other manipulations,trains of ten bursts pro- circumstances in which demands on cognition are high.But a duced near maximal potentiation (Larson et al.,1986),a result great deal of cognition involves instances in which significant that led to what has become a standard paradigm.Recently,how- cues and appropriate responses are salient and predetermined, ever,it was found that a second theta train doubles the level of and irrelevant information is minimized.Under these conditions, potentiation but only if it is delayed by about 60 min(Figure 5); enhanced encoding could be of great use in building or expanding 3.2- o control path experimental path (n=7) 2.4 Ploj) 1.6 0.8 ↑TBS 0 % 80 120 160 200 240 280 320 B 3.2 个TBS1↑TBS2 (n=6) (n=5 (n=6 2.4 1.6 0.8 ↑年10min ←30min ◆40min ↑60min 0 20406080 03060901200 30 60 90 306090120 minutes FIGURE 5 A "spaced trials effect"for LTP (A)Theta burst stimulation decay over 5h of recording (means +s.e.m.s for seven slices);traces at right (TBS)produces stable LTP A single train of ten bursts was delivered to one show representative baseline (black)and potentiated (gray)responses. input to the CA1b recording field after 20 min of collecting baseline synaptic (B)Effect of a second theta train (TBS2)applied at various times after TBS1. responses to 3/min stimulation pulses in adult rat hippocampal slices.A TBS2 produced no further increases in the slopes of the responses when second input to the same dendritic region received 3/min pulses throughout delayed by 10,30,or 40 min after TBS1,but doubled the magnitude of LTP the session.Note that the potentiation of the experimental input did not when applied after a 60 min interval.Modified from Kramar et al.(2012b). Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8 Article 909Lynch et al. Cognition enhancement in normal subjects forms of plasticity could lead to agents that target particular forms of memory. COGNITIVE ENHANCEMENT DOES AUGMENTING MEMORY ENHANCE COGNITION? Memory is such a prominent part of cognition that it seems obvi￾ous that enhancing the one will improve the other. However, there may be good computational reasons that cognitive benefit is gained when acquisition is less than optimal in terms of speed and strength. Animals faced with new and complex circumstances need to encode regular features without storing variable, low information elements. Otherwise, as noted earlier, the resultant memories will be noisy and less predictive of future encounters. The spaced trials effect—wherein, temporally separated train￾ing trials more efficiently support encoding than does a single “massed” session—can be seen as one adaptation toward better capture of regularities in the learning environment (Hintzman, 1976; Commins et al., 2003; Cepeda et al., 2006). That is, spac￾ing ensures that only elements that are regularly present will be incorporated into memory while transient features will not. An enhancer could obviate the need for spacing by producing strong memory on an initial trial but would be expected to result in a noisy representation. Tests of the above point are lacking but LTP experiments have produced what may be pertinent results. The original descrip￾tions of links between theta burst afferent stimulation and LTP showed that, absent other manipulations, trains of ten bursts pro￾duced near maximal potentiation (Larson et al., 1986), a result that led to what has become a standard paradigm. Recently, how￾ever, it was found that a second theta train doubles the level of potentiation but only if it is delayed by about 60 min (Figure 5); a third stimulation train produces still more potentiation but only if it is applied at least 60 min after the second. Additional work suggested that this LTP “spaced trials effect” reflects the presence of a large population of synapses with high plasticity thresholds that are “primed” by the first theta episode and then shifted into the potentiated state by the second (Kramar et al., 2012b). These effects fit naturally within the above described sub￾strate map for LTP: activation of synaptic integrins by a first theta burst train was followed by an approximately one hour period before these receptors could be re-engaged by additional stimulation (Babayan et al., 2012). They also set the stage for a first test of how a drug that enhances memory affects a phys￾iological analogue of the spaced trials effect. The results were clear: infusion of an ampakine prior to theta train #1 produced the expected enhancement in the amplitude of LTP1 but also occluded further increases in the level of potentiation following a second, delayed theta train administered in the absence of the drug (Kramar et al., 2012b). Thus, the ampakine enhanced ini￾tial encoding (as multiply reported) but did so at the expense of effects of spaced stimulation, and presumably the computational advantages associated with spacing (Lynch and Gall, 2013 for a discussion). The preceding example describes a situation in which phar￾macologically augmenting memory would likely not result in enhanced cognition, at least in complex environments lacking explicit guidelines for effective performance. These are routine circumstances in which demands on cognition are high. But a great deal of cognition involves instances in which significant cues and appropriate responses are salient and predetermined, and irrelevant information is minimized. Under these conditions, enhanced encoding could be of great use in building or expanding FIGURE 5 | A “spaced trials effect” for LTP. (A) Theta burst stimulation (TBS) produces stable LTP. A single train of ten bursts was delivered to one input to the CA1b recording field after 20 min of collecting baseline synaptic responses to 3/min stimulation pulses in adult rat hippocampal slices. A second input to the same dendritic region received 3/min pulses throughout the session. Note that the potentiation of the experimental input did not decay over 5 h of recording (means ± s.e.m.s for seven slices); traces at right show representative baseline (black) and potentiated (gray) responses. (B) Effect of a second theta train (TBS2) applied at various times after TBS1. TBS2 produced no further increases in the slopes of the responses when delayed by 10, 30, or 40 min after TBS1, but doubled the magnitude of LTP when applied after a 60 min interval. Modified from Kramar et al. (2012b). Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 9