Lynch et al. Cognition enhancement in normal subjects cognitive structures.Thus,the effects of memory enhancement important roles played by adenosine in the periphery,including on cognition could prove to be situationally dependent with clear actions on the heart and lungs. benefits in some cases and neutral or even negative influence in Nicotinic receptors for acetylcholine are also found on glu- others. tamatergic terminals where they promote release (Wonnacott, 1997)and there is evidence that this increases network through- NETWORKS AND COGNITIVE ENHANCEMENT put (Gioanni et al.,1999).Alpha7-containing and alpha4/beta2 Discussions of neurobiological processes underlying cognition subtypes of the receptors both appear to be effective in this regard inevitably begin with the immensely complicated networks (Dickinson et al.,2008).However,the situation is complicated formed by cortical neurons,if for no other reason than a lack by the likelihood that compounds targeting nicotinic receptors of realistic alternatives.This fundamental idea suggests two paths act on cholinergic and GABAergic neurons as well (Wonnacott, to acute enhancement.First,improving throughput within estab- 1997;Alkondon and Albuquerque,2001);moreover,it is not clear lished networks should lead to faster computation and better that these receptors are present throughout glutamatergic net- utilization of cognitive time.Second,augmented synaptic com- works.In all,nicotinic receptor agonists and positive allosteric munication could allow for the transient assembly of larger modulators can be assumed to affect portions of excitatory cir- than normal networks (e.g.,incorporation of additional corti- cuitry in the telencephalon while at the same time modifying local cal regions)to deal with a particular problem,and thus the processing-via modulation of cholinergic input,interneurons, opportunity to execute more complex or even entirely novel com- and glutamatergic collaterals-at individual relays.Net effects putations.In this sense better throughput would add capabilities, will be complex but there is good evidence that the compounds perhaps the surest measure of cognitive enhancement.Increased acting on frontal networks enhance "top-down"mechanisms for plasticity might add a third route to enhanced cognition by allow- focusing attention (Sarter et al.,2009).Since pertinent drugs ing for construction of functional networks that would not likely are already in clinical trials(Holmes et al.,2011;Demeter and emerge under normal conditions;however,as noted in the pre- Sarter,2013),nicotinic compounds,and especially those target- ceding section,positive versions of such effects may be limited to ing the alpha4/beta2 receptor subtype concentrated in brain,have particular circumstances. to be seen as one of the most promising of current approaches to There are multiple manipulations that should result in cognitive enhancement. improved throughput.Communication between collections of The ampakine compounds described in the earlier section on neurons is greatly improved by synchronizing their activity,memory enhancement seem particularly appropriate for improv- something that is accomplished in the cortical telencephalon ing communication within and between cortical regions.Their by system-wide rhythms.These patterns are induced by diffuse mode of action has the virtue of relative simplicity:an exten- ascending projections from the lower brain and drugs that affect sive body of research from many laboratories has not uncovered these have predictable strong effects on rhythmic activity(Staubli any evidence for effects on targets other than AMPA receptors. and Xu,1995;Kowalczyk et al.,2013).But,as mentioned in And they produce the same facilitation of fast,excitatory trans- the discussion of memory,the diffuse systems influence a broad mission after peripheral administration as seen with infusions range of brain functions including ones that are vital to survival. into brain slices.Indeed,ampakines appear to be the only agents And so,as in the case of memory,they do not represent a promis- so far shown to cause comparable in vitro/in vivo facilitation ing avenue toward enhancement in high functioning individuals. of EPSPs.These points lead to two critical experimental ques- A more likely approach would be to increase transmitter release tions.First,does increasing monosynaptic transmission result in or post-synaptic responses to transmitter binding at the gluta- greater output from a polysynaptic network?This might seem to matergic connections used for the great bulk of intra-cortical be a foregone conclusion but each step in a series of neuronal communication. stations has local processing mechanisms (relays are not passive Adenosine,which depresses glutamate release via presynap- transferal points)dominated by an impressive collection of dif- tic Al receptors (Dunwiddie and Haas,1985),is increased in ferent types of inhibitory interneurons.These inhibitory elements the extracellular environment during repetitive firing by two respond both to inputs directly and to discharges from principle mechanisms:rapid release from post-synaptic neurons followed (glutamatergic)neurons;they also form complex local networks by slower release of ATP from glia which is then converted to among themselves.It is therefore possible that strong inputs are adenosine by ecto-5'-nucleotidase,an enzyme located on glial dampened and normalized to a degree such that the second stage membranes (Klyuch et al.,2012;Wall and Dale,2013).These of a network may not pass on a larger than normal signal in observations represent a significant part of the tripartite model the presence of an ampakine.Second,assuming augmentation (terminal bouton,spine,astrocyte)of fast,excitatory transmis- of the signal does occur,what are the functional consequences of sion (Araque et al.,1999).Selective antagonists of the Al receptor enhanced network throughput? increase glutamate release in slices and these compounds do Brain slices provide for the simplest and most compelling indeed reverse impairments in LTP in slices of middle-aged rat tests for circuit behavior because anatomically precise stimulation hippocampus (Rex et al.,2005).However,despite evidence that and recording is possible and extrinsic modulatory (cholinergic, the compounds enter the brain (Wall and Dale,2013),there etc.)inputs(cholinergic,serotonergic,etc.)that might influence has been surprisingly little work on in vivo effects after periph- downstream responses are excluded.Work of this kind has estab- eral administration.Perhaps the lack of interest with regard to lished that weak facilitation of monosynaptic transmission with network operations reflects understandable concern about the an ampakine results in a greatly amplified response from the Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8|Article 90 10Lynch et al. Cognition enhancement in normal subjects cognitive structures. Thus, the effects of memory enhancement on cognition could prove to be situationally dependent with clear benefits in some cases and neutral or even negative influence in others. NETWORKS AND COGNITIVE ENHANCEMENT Discussions of neurobiological processes underlying cognition inevitably begin with the immensely complicated networks formed by cortical neurons, if for no other reason than a lack of realistic alternatives. This fundamental idea suggests two paths to acute enhancement. First, improving throughput within estab￾lished networks should lead to faster computation and better utilization of cognitive time. Second, augmented synaptic com￾munication could allow for the transient assembly of larger than normal networks (e.g., incorporation of additional corti￾cal regions) to deal with a particular problem, and thus the opportunity to execute more complex or even entirely novel com￾putations. In this sense better throughput would add capabilities, perhaps the surest measure of cognitive enhancement. Increased plasticity might add a third route to enhanced cognition by allow￾ing for construction of functional networks that would not likely emerge under normal conditions; however, as noted in the pre￾ceding section, positive versions of such effects may be limited to particular circumstances. There are multiple manipulations that should result in improved throughput. Communication between collections of neurons is greatly improved by synchronizing their activity, something that is accomplished in the cortical telencephalon by system-wide rhythms. These patterns are induced by diffuse ascending projections from the lower brain and drugs that affect these have predictable strong effects on rhythmic activity (Staubli and Xu, 1995; Kowalczyk et al., 2013). But, as mentioned in the discussion of memory, the diffuse systems influence a broad range of brain functions including ones that are vital to survival. And so, as in the case of memory, they do not represent a promis￾ing avenue toward enhancement in high functioning individuals. A more likely approach would be to increase transmitter release or post-synaptic responses to transmitter binding at the gluta￾matergic connections used for the great bulk of intra-cortical communication. Adenosine, which depresses glutamate release via presynap￾tic A1 receptors (Dunwiddie and Haas, 1985), is increased in the extracellular environment during repetitive firing by two mechanisms: rapid release from post-synaptic neurons followed by slower release of ATP from glia which is then converted to adenosine by ecto-5 -nucleotidase, an enzyme located on glial membranes (Klyuch et al., 2012; Wall and Dale, 2013). These observations represent a significant part of the tripartite model (terminal bouton, spine, astrocyte) of fast, excitatory transmis￾sion (Araque et al., 1999). Selective antagonists of the A1 receptor increase glutamate release in slices and these compounds do indeed reverse impairments in LTP in slices of middle-aged rat hippocampus (Rex et al., 2005). However, despite evidence that the compounds enter the brain (Wall and Dale, 2013), there has been surprisingly little work on in vivo effects after periph￾eral administration. Perhaps the lack of interest with regard to network operations reflects understandable concern about the important roles played by adenosine in the periphery, including actions on the heart and lungs. Nicotinic receptors for acetylcholine are also found on glu￾tamatergic terminals where they promote release (Wonnacott, 1997) and there is evidence that this increases network through￾put (Gioanni et al., 1999). Alpha7-containing and alpha4/beta2 subtypes of the receptors both appear to be effective in this regard (Dickinson et al., 2008). However, the situation is complicated by the likelihood that compounds targeting nicotinic receptors act on cholinergic and GABAergic neurons as well (Wonnacott, 1997; Alkondon and Albuquerque, 2001); moreover, it is not clear that these receptors are present throughout glutamatergic net￾works. In all, nicotinic receptor agonists and positive allosteric modulators can be assumed to affect portions of excitatory cir￾cuitry in the telencephalon while at the same time modifying local processing—via modulation of cholinergic input, interneurons, and glutamatergic collaterals—at individual relays. Net effects will be complex but there is good evidence that the compounds acting on frontal networks enhance “top-down” mechanisms for focusing attention (Sarter et al., 2009). Since pertinent drugs are already in clinical trials (Holmes et al., 2011; Demeter and Sarter, 2013), nicotinic compounds, and especially those target￾ing the alpha4/beta2 receptor subtype concentrated in brain, have to be seen as one of the most promising of current approaches to cognitive enhancement. The ampakine compounds described in the earlier section on memory enhancement seem particularly appropriate for improv￾ing communication within and between cortical regions. Their mode of action has the virtue of relative simplicity: an exten￾sive body of research from many laboratories has not uncovered any evidence for effects on targets other than AMPA receptors. And they produce the same facilitation of fast, excitatory trans￾mission after peripheral administration as seen with infusions into brain slices. Indeed, ampakines appear to be the only agents so far shown to cause comparable in vitro/in vivo facilitation of EPSPs. These points lead to two critical experimental ques￾tions. First, does increasing monosynaptic transmission result in greater output from a polysynaptic network? This might seem to be a foregone conclusion but each step in a series of neuronal stations has local processing mechanisms (relays are not passive transferal points) dominated by an impressive collection of dif￾ferent types of inhibitory interneurons. These inhibitory elements respond both to inputs directly and to discharges from principle (glutamatergic) neurons; they also form complex local networks among themselves. It is therefore possible that strong inputs are dampened and normalized to a degree such that the second stage of a network may not pass on a larger than normal signal in the presence of an ampakine. Second, assuming augmentation of the signal does occur, what are the functional consequences of enhanced network throughput? Brain slices provide for the simplest and most compelling tests for circuit behavior because anatomically precise stimulation and recording is possible and extrinsic modulatory (cholinergic, etc.) inputs (cholinergic, serotonergic, etc.) that might influence downstream responses are excluded. Work of this kind has estab￾lished that weak facilitation of monosynaptic transmission with an ampakine results in a greatly amplified response from the Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 10