Lynch et al. Cognition enhancement in normal subjects levels,early stage Huntington Disease,and Angelman syndrome introduction of the word "synapse"(Cajal,1894).The idea is (Rex et al.,2006;Simmons et al.,2009;Baudry et al.,2012;Kramar intuitively attractive since such increases would clearly alter the et al.,2012a).When tested,daily injections also reduced or elimi- operation of cortical networks and thus behavior.In essence,it nated memory impairments(Simmons et al.,2009;Baudry et al., describes microscopic events that,when implemented at many 2012).Several weeks of daily ampakine treatment were shown sites,could be the physical instantiation of the macroscopic phe- to be well tolerated.They also markedly reduced pathology and nomenon of memory.From this perspective,the most direct improved motor functioning in a mouse model of early onset route to memory enhancement would involve facilitating physi- Huntington Disease (Simmons et al.,2011);subsequent work ologically produced,long lasting increases in synaptic responses. with systemic administration of a TrkB agonist obtained similar Developing what is still only an outline of the machinery that results (Simmons et al.,2013). induces,expresses,and consolidates LTP then shaped ideas about Although it is apparent that semi-chronic ampakine treat- how to produce facilitation.To some extent,it also led to a uni- ment increases BDNF protein levels,and has potent brain effects fication that is perhaps under-appreciated:an unrelated array of predicted from this,there appear to be no studies testing for enhancement candidates such as steroids,trophic factors,posi- influences of up-regulating BDNF on learning in normal,high tive modulators of glutamate receptors,and channel blockers can functioning animals.This likely reflects an assignment of greater now be seen to operate at specific levels within the same cell bio- importance to treatment than to enhancement with regard logical framework (Lynch et al.,2013).Optimistically,we may to drug development.But the exciting results obtained with be approaching a reductionistic (simplifying)conceptual event up-regulation and receptor agonists with regard to brain dis- with regard to enhancing encoding of specific pieces of infor- orders make BDNF-based strategies one of the more promis- mation.Notably,something of this kind may also be going on ing mechanism-grounded approaches to achieving memory for appreciating shared mechanistic impairments present in quite enhancement. different disorders that interfere with learning:work with a sizable The substrate map for LTP consolidation includes estrogen number of rodent models suggests that conditions with disparate receptor beta as a second membrane agent that exerts a powerful etiologies result in a common endpoint failure in cytoskeletal modulatory influence over the actin signaling leading to LTP con- reorganization(Lynch and Gall,2013). solidation.Thirty minute infusions of estrogen,at physiological But there are warning signs with regard to the possibility that concentrations,cause a modest increase in baseline transmis- the current substrate model may be overly tailored to a spe- sion in hippocampus but a striking facilitation of LTP(Cordoba cific instance of learning-related plasticity,and in particular to Montoya and Carrer,1997;Foy et al.,1999;Bi et al,2000;Kramar that found in a particular dendritic lamina(stratum radiatum) et al.,2009).Recent work showed that these effects are due to of a particular hippocampal subfield(CAl).Even within that activation of one of the actin regulatory cascades initiated by subfield,there is good evidence that the basal dendritic field theta bursts (i.e.,RhoA>ROCK>LIMK>cofilin-see Figure 3)exhibits a different form of LTP (Arai et al.,1994;Kramar and and the assembly of new filamentous actin in spine heads(Kramar Lynch,2003).And it is now well established that the peculiar et al.,2009).Unlike the case for BDNE,there are several reports mossy fiber connections between dentate gyrus and field CA3 that estrogen improves memory scores in high functioning sub- use a form of long lasting potentiation that bears little resem- jects across tasks and species (Frye et al.,2007;Liu et al.,blance to that found in apical field CAl(Staubli,1992;Schmitz 2008;Hara et al.,2014).Evidence for similar effects in humans et al.,2003).It is not unreasonable to expect that additional appears to be lacking(Grodstein,2013)although several stud- plasticity variants will be discovered as parametric studies are ies describe a decline in verbal memory with surgical menopause carried out for other telencephalic connections;e.g.,the cortico- and improvements with hormone replacement (Brinton,2009). striatal glutamatergic synapses (Jia et al.,2010)or the olfactory Beyond needing further evidence for effects in cognitively normal and associational afferents to piriform cortex (Jung et al,1990). individuals,a primary barrier to development of an estrogen- While these observations greatly complicate predictions about the based enhancement strategy lies in the fact that the steroid affects behavioral effects of putative enhancers,they also offer intrigu- many fundamental cellular processes in brain and the periphery, ing possibilities concerning specificity of action.That is,there and is known to facilitate certain types of cancer.More restricted are reasons to think that different forms of synaptic potentiation actions can be had using agonists selective for the hormone's beta may underlie different types,or aspects,of memory.An explicit receptor which is,to a degree,concentrated in brain;such agonists proposal of this type has been advanced for the basal and api- are highly effective in LTP studies (Kramar et al.,2009).Evidence cal dendrites of field CAl (Arai et al.,1994;Kramar and Lynch, that estrogen is synthesized by hippocampal neurons and that 2003):The easily induced,readily erased LTP in the basal den- hormone of local origin contributes significantly to hippocampal dritic field seems well suited for transient encoding while the synaptic plasticity(Ooishi et al.,2012;Vierk et al.,2012)should higher threshold and more rapidly stabilized form in the apical also be noted here.Thus,it may be possible to find means to field is more appropriate for long term memory.An arrangement promote normal,likely activity-dependent,estrogen actions in a of this type would be useful in addressing the problem of how regionally restricted manner. to accomplish,through repeated sampling,low noise extraction of constancies from a novel environment (apical dendrites)while INTEGRATION:MANY PATHS TO THE SAME END at the same time transiently storing a great deal of information Brain scientists had proposed increases in the strength of con- much of which can be discarded as being irrelevant(basal den- nections between neurons as the substrate of memory before the drites).In any event,testing experimental compounds on various Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8 Article 90|8Lynch et al. Cognition enhancement in normal subjects levels, early stage Huntington Disease, and Angelman syndrome (Rex et al., 2006; Simmons et al., 2009; Baudry et al., 2012; Kramar et al., 2012a). When tested, daily injections also reduced or elimi￾nated memory impairments (Simmons et al., 2009; Baudry et al., 2012). Several weeks of daily ampakine treatment were shown to be well tolerated. They also markedly reduced pathology and improved motor functioning in a mouse model of early onset Huntington Disease (Simmons et al., 2011); subsequent work with systemic administration of a TrkB agonist obtained similar results (Simmons et al., 2013). Although it is apparent that semi-chronic ampakine treat￾ment increases BDNF protein levels, and has potent brain effects predicted from this, there appear to be no studies testing for influences of up-regulating BDNF on learning in normal, high functioning animals. This likely reflects an assignment of greater importance to treatment than to enhancement with regard to drug development. But the exciting results obtained with up-regulation and receptor agonists with regard to brain dis￾orders make BDNF-based strategies one of the more promis￾ing mechanism-grounded approaches to achieving memory enhancement. The substrate map for LTP consolidation includes estrogen receptor beta as a second membrane agent that exerts a powerful modulatory influence over the actin signaling leading to LTP con￾solidation. Thirty minute infusions of estrogen, at physiological concentrations, cause a modest increase in baseline transmis￾sion in hippocampus but a striking facilitation of LTP (Cordoba Montoya and Carrer, 1997; Foy et al., 1999; Bi et al., 2000; Kramar et al., 2009). Recent work showed that these effects are due to activation of one of the actin regulatory cascades initiated by theta bursts (i.e., RhoA>ROCK>LIMK>cofilin—see Figure 3) and the assembly of new filamentous actin in spine heads (Kramar et al., 2009). Unlike the case for BDNF, there are several reports that estrogen improves memory scores in high functioning sub￾jects across tasks and species (Frye et al., 2007; Liu et al., 2008; Hara et al., 2014). Evidence for similar effects in humans appears to be lacking (Grodstein, 2013) although several stud￾ies describe a decline in verbal memory with surgical menopause and improvements with hormone replacement (Brinton, 2009). Beyond needing further evidence for effects in cognitively normal individuals, a primary barrier to development of an estrogen￾based enhancement strategy lies in the fact that the steroid affects many fundamental cellular processes in brain and the periphery, and is known to facilitate certain types of cancer. More restricted actions can be had using agonists selective for the hormone’s beta receptor which is, to a degree, concentrated in brain; such agonists are highly effective in LTP studies (Kramar et al., 2009). Evidence that estrogen is synthesized by hippocampal neurons and that hormone of local origin contributes significantly to hippocampal synaptic plasticity (Ooishi et al., 2012; Vierk et al., 2012) should also be noted here. Thus, it may be possible to find means to promote normal, likely activity-dependent, estrogen actions in a regionally restricted manner. INTEGRATION: MANY PATHS TO THE SAME END Brain scientists had proposed increases in the strength of con￾nections between neurons as the substrate of memory before the introduction of the word “synapse” (Cajal, 1894). The idea is intuitively attractive since such increases would clearly alter the operation of cortical networks and thus behavior. In essence, it describes microscopic events that, when implemented at many sites, could be the physical instantiation of the macroscopic phe￾nomenon of memory. From this perspective, the most direct route to memory enhancement would involve facilitating physi￾ologically produced, long lasting increases in synaptic responses. Developing what is still only an outline of the machinery that induces, expresses, and consolidates LTP then shaped ideas about how to produce facilitation. To some extent, it also led to a uni- fication that is perhaps under-appreciated: an unrelated array of enhancement candidates such as steroids, trophic factors, posi￾tive modulators of glutamate receptors, and channel blockers can now be seen to operate at specific levels within the same cell bio￾logical framework (Lynch et al., 2013). Optimistically, we may be approaching a reductionistic (simplifying) conceptual event with regard to enhancing encoding of specific pieces of infor￾mation. Notably, something of this kind may also be going on for appreciating shared mechanistic impairments present in quite different disorders that interfere with learning: work with a sizable number of rodent models suggests that conditions with disparate etiologies result in a common endpoint failure in cytoskeletal reorganization (Lynch and Gall, 2013). But there are warning signs with regard to the possibility that the current substrate model may be overly tailored to a spe￾cific instance of learning-related plasticity, and in particular to that found in a particular dendritic lamina (stratum radiatum) of a particular hippocampal subfield (CA1). Even within that subfield, there is good evidence that the basal dendritic field exhibits a different form of LTP (Arai et al., 1994; Kramar and Lynch, 2003). And it is now well established that the peculiar mossy fiber connections between dentate gyrus and field CA3 use a form of long lasting potentiation that bears little resem￾blance to that found in apical field CA1 (Staubli, 1992; Schmitz et al., 2003). It is not unreasonable to expect that additional plasticity variants will be discovered as parametric studies are carried out for other telencephalic connections; e.g., the cortico￾striatal glutamatergic synapses (Jia et al., 2010) or the olfactory and associational afferents to piriform cortex (Jung et al., 1990). While these observations greatly complicate predictions about the behavioral effects of putative enhancers, they also offer intrigu￾ing possibilities concerning specificity of action. That is, there are reasons to think that different forms of synaptic potentiation may underlie different types, or aspects, of memory. An explicit proposal of this type has been advanced for the basal and api￾cal dendrites of field CA1 (Arai et al., 1994; Kramar and Lynch, 2003): The easily induced, readily erased LTP in the basal den￾dritic field seems well suited for transient encoding while the higher threshold and more rapidly stabilized form in the apical field is more appropriate for long term memory. An arrangement of this type would be useful in addressing the problem of how to accomplish, through repeated sampling, low noise extraction of constancies from a novel environment (apical dendrites) while at the same time transiently storing a great deal of information much of which can be discarded as being irrelevant (basal den￾drites). In any event, testing experimental compounds on various Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 8