Lynch et al. Cognition enhancement in normal subjects reason to assume that these efforts will ultimately narrow the et al.,2001;Plath et al.,2006;Katche et al.,2010,2012).However gap in cross-species comparisons.But there is a more funda- the basic idea that new protein synthesis is critical to memory for- mental issue from comparative biology that could underlie the mation has been controversial since its introduction more than failure-to-predict problem:humans are enormously encephalized 50 years ago (Abraham and Williams,2008;Gold,2008).Much of animals and rodents aren't (neocortex makes up at least 77%of the dispute revolves around the necessary prediction that protein brain volume in human and just 31%in rat;Stephan et al.,1981;synthesis inhibitors will selectively block recently acquired mem- Swanson,1995).Encephalization is hypothesized to result in a ory;most papers report this result but others do not,or argue that shift of functions from lower brain to cortex;from this perspec- observed disruptions to encoding are due to factors unrelated to tive,humans may be using networks of a very different kind than synthesis(Routtenberg,2008;Gold and Wrenn,2012). those employed by rodents to solve similar problems. Beyond this,the protein synthesis argument faces certain con- An alternative to behaviorally based approaches to developing ceptual problems.Learning is a continuous process in humans, enhancers would be to focus on the neurobiological substrates of and likely other mammals,with new encoding occurring many memory and cognition.This seems feasible in the case of mem- times a minute,as is evident with episodic memory.People recog- ory because of the tremendous progress that has been made in nize or recall a remarkable number of serial events when queried identifying synaptic mechanisms that encode information.There after a 90 min movie.Unless we make the very unlikely assump- is no good reason to think that these processes differ significantly tion that each item of information is encoded on a different between mammalian species and indeed comparative studies sug- neuron,it is difficult to see why,after hours of producing pro- gest that certain essential elements are evolutionarily ancient teins needed for consolidation,a given cell would need further (Crystal and Glanzman,2013).It follows from this that treat- synthesis to stabilize a now forming memory.Along this line,it ments acting on memory substrates in rodents are likely to have has been argued that animals exposed to an enriched environ- similar actions in human brain.Cognition again represents a ment which would entail constitutively elevated basal activity,and much more challenging problem.However,the universally held thus activity-driven protein synthesis,may not require additional assumption that cognitive operations arise from the transient synthesis to support LTP(Abraham and Williams,2008)and the formation of telencephalic networks points to a relatively sim- related encoding of hippocampus-dependent memories.There is, ple idea for enhancement.Communication within and between however,a special case in which transcription and/or broadly cortical regions is mediated by glutamatergic transmission;if distributed translation could be required to securely encode a so,then agents that augment the release of glutamate,or the specific memory;namely,a circumstance in which continuous post-synaptic response to it,should facilitate the formation of learning of similar material does not precede the new instance. cognition's substrates. Under these conditions,consolidation could depend upon pro- The following sections consider attempts to develop enhancers teins generated by the isolated learning episode.Note that this via actions on (i)different aspects of the complex machinery scenario loosely describes the great majority of animal studies underlying learning-related synaptic modifications,or(ii)com- testing for the contributions of protein synthesis.Certain of these munication within and between cortical networks. arguments make relatively straightforward,readily tested predic- tions.For example,animals with a well-developed learning set MEMORY ENHANCEMENT could be given protein synthesis inhibitors after learning a single Most research on memory enhancement deals with psychological problem with or without having dealt with many such problems events that precede the actual encoding of information.There is in the preceding hours.Such a paradigm can be achieved for rats for example a very large literature describing attempts,typically using two-odor discriminations.If continual learning obviates the using chemical agents,to increase the speed of learning by mod- need for problem-specific synthesis,then the blockers should have ulating arousal and attention (Lynch et al.,2011).It has become no effect in a group given many trials prior to being introduced common to refer to resultant improvements as cognitive enhance- to the new test items ment,presumably because key elements of cognition are being There is a variant of the translation hypothesis that addresses manipulated,but there are reasons to question this assumption the problem of why prior synthesis doesn't provide a sufficient (see below).There is a smaller,but rapidly growing,body of work supply of proteins for current learning.This involves the ample directed at the machinery responsible for converting patterns of evidence for dendritic (local)translation from already in place afferent activity into the long lasting increases in synaptic strength mRNAs.One could posit a set of conditions in which new synthe- assumed to encode specific information.This section evaluates sis,even after recent experience,needs to occur post-acquisition the latter material. for transfer into long-term storage;e.g.,(1)translation occurs within very small dendritic compartments;(2)such active regions GENE EXPRESSION AND PROTEIN SYNTHESIS are only found in the immediate vicinity of recently modified Work in this area begins with the hypothesis that learning triggers synapses;and(3)newly formed proteins do not diffuse to any the transcription or local translation of proteins that serve to con- great degree.These circumstances would reduce the probabil- solidate the newly acquired memories,something that can take ity that proteins from earlier learning would be present at the anywhere from many minutes to hours.Compounds that facili-large majority of current sites.But"synaptic tagging"experi- tate production of the pertinent RNAs or proteins could accord- ments,conducted for instances where LTP in hippocampal slices ingly increase the likelihood that recent learning will lead to stable is blocked by protein synthesis inhibitors,describe results that are memory,and there are many reports of such effects (Guzowski not consistent with these postulates.Specifically,LTP induction at Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8 Article 90 2Lynch et al. Cognition enhancement in normal subjects reason to assume that these efforts will ultimately narrow the gap in cross-species comparisons. But there is a more funda￾mental issue from comparative biology that could underlie the failure-to-predict problem: humans are enormously encephalized animals and rodents aren’t (neocortex makes up at least 77% of brain volume in human and just 31% in rat; Stephan et al., 1981; Swanson, 1995). Encephalization is hypothesized to result in a shift of functions from lower brain to cortex; from this perspec￾tive, humans may be using networks of a very different kind than those employed by rodents to solve similar problems. An alternative to behaviorally based approaches to developing enhancers would be to focus on the neurobiological substrates of memory and cognition. This seems feasible in the case of mem￾ory because of the tremendous progress that has been made in identifying synaptic mechanisms that encode information. There is no good reason to think that these processes differ significantly between mammalian species and indeed comparative studies sug￾gest that certain essential elements are evolutionarily ancient (Crystal and Glanzman, 2013). It follows from this that treat￾ments acting on memory substrates in rodents are likely to have similar actions in human brain. Cognition again represents a much more challenging problem. However, the universally held assumption that cognitive operations arise from the transient formation of telencephalic networks points to a relatively sim￾ple idea for enhancement. Communication within and between cortical regions is mediated by glutamatergic transmission; if so, then agents that augment the release of glutamate, or the post-synaptic response to it, should facilitate the formation of cognition’s substrates. The following sections consider attempts to develop enhancers via actions on (i) different aspects of the complex machinery underlying learning-related synaptic modifications, or (ii) com￾munication within and between cortical networks. MEMORY ENHANCEMENT Most research on memory enhancement deals with psychological events that precede the actual encoding of information. There is for example a very large literature describing attempts, typically using chemical agents, to increase the speed of learning by mod￾ulating arousal and attention (Lynch et al., 2011). It has become common to refer to resultant improvements as cognitive enhance￾ment, presumably because key elements of cognition are being manipulated, but there are reasons to question this assumption (see below). There is a smaller, but rapidly growing, body of work directed at the machinery responsible for converting patterns of afferent activity into the long lasting increases in synaptic strength assumed to encode specific information. This section evaluates the latter material. GENE EXPRESSION AND PROTEIN SYNTHESIS Work in this area begins with the hypothesis that learning triggers the transcription or local translation of proteins that serve to con￾solidate the newly acquired memories, something that can take anywhere from many minutes to hours. Compounds that facili￾tate production of the pertinent RNAs or proteins could accord￾ingly increase the likelihood that recent learning will lead to stable memory, and there are many reports of such effects (Guzowski et al., 2001; Plath et al., 2006; Katche et al., 2010, 2012). However, the basic idea that new protein synthesis is critical to memory for￾mation has been controversial since its introduction more than 50 years ago (Abraham and Williams, 2008; Gold, 2008). Much of the dispute revolves around the necessary prediction that protein synthesis inhibitors will selectively block recently acquired mem￾ory; most papers report this result but others do not, or argue that observed disruptions to encoding are due to factors unrelated to synthesis (Routtenberg, 2008; Gold and Wrenn, 2012). Beyond this, the protein synthesis argument faces certain con￾ceptual problems. Learning is a continuous process in humans, and likely other mammals, with new encoding occurring many times a minute, as is evident with episodic memory. People recog￾nize or recall a remarkable number of serial events when queried after a 90 min movie. Unless we make the very unlikely assump￾tion that each item of information is encoded on a different neuron, it is difficult to see why, after hours of producing pro￾teins needed for consolidation, a given cell would need further synthesis to stabilize a now forming memory. Along this line, it has been argued that animals exposed to an enriched environ￾ment which would entail constitutively elevated basal activity, and thus activity-driven protein synthesis, may not require additional synthesis to support LTP (Abraham and Williams, 2008) and the related encoding of hippocampus-dependent memories. There is, however, a special case in which transcription and/or broadly distributed translation could be required to securely encode a specific memory; namely, a circumstance in which continuous learning of similar material does not precede the new instance. Under these conditions, consolidation could depend upon pro￾teins generated by the isolated learning episode. Note that this scenario loosely describes the great majority of animal studies testing for the contributions of protein synthesis. Certain of these arguments make relatively straightforward, readily tested predic￾tions. For example, animals with a well-developed learning set could be given protein synthesis inhibitors after learning a single problem with or without having dealt with many such problems in the preceding hours. Such a paradigm can be achieved for rats using two-odor discriminations. If continual learning obviates the need for problem-specific synthesis, then the blockers should have no effect in a group given many trials prior to being introduced to the new test items. There is a variant of the translation hypothesis that addresses the problem of why prior synthesis doesn’t provide a sufficient supply of proteins for current learning. This involves the ample evidence for dendritic (local) translation from already in place mRNAs. One could posit a set of conditions in which new synthe￾sis, even after recent experience, needs to occur post-acquisition for transfer into long-term storage; e.g., (1) translation occurs within very small dendritic compartments; (2) such active regions are only found in the immediate vicinity of recently modified synapses; and (3) newly formed proteins do not diffuse to any great degree. These circumstances would reduce the probabil￾ity that proteins from earlier learning would be present at the large majority of current sites. But “synaptic tagging” experi￾ments, conducted for instances where LTP in hippocampal slices is blocked by protein synthesis inhibitors, describe results that are not consistent with these postulates. Specifically, LTP induction at Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 2