Shors & Matzel (1997) suggest replacing the question “Is LTP a mechanism of learning?” with “Is LTP a mechanism of arousal and attention?” However, the failure of experiments to verify the LTP-learning hypothesis may arise not because it is untrue, but because in its current guise, it is not properly testable. If so, then the LTP-attention hypothesis is untestable, as well.

The problem of neural memory storage is discussed, based on the results of studies of memory impairment after hippocampal lesions, motor learning, and electrophysiological research on “spinal memory. ” I support Shors & Matzel's major statements. The absence of reliable evidence on the LTP memory storage function and other data cast doubt on the synaptic theory of memory.

LTP is thought to be an experimental model for studying the cellular mechanism of learning and memory. Shors & Matzel review some contradictory data concerning the linkage between LTP and memory and suggest that LTP does not underlie learning and memory. LTP is a cellular and synaptic process and cannot be a memory mechanism. In fact, it is a cellular information storage mechanism.

Preoccupation with LTP as a putative memory mechanism may have retarded the consideration of pathological modulation of synaptic plasticity in clinical disorders where memory dysfunction is not a primary feature. Encouraged by Shors & Matzel's review, we consider the relationship between stress, synaptic plasticity, and depressive disorder.

The hypothesis that there is a 1:1 correspondence between LTP and learning is simplistic, and the correlation approach to testing it is therefore too limited. The alternative hypothesis that LTP plays a role in arousal is consistent with activity-dependent neuromodulation, but ignores the Hebbian properties of LTP. LTP may involve both types of mechanisms, suggesting a possible synthesis of the two hypotheses.

The absence of a clear influence of the responses modified by new connections created by LTP on the development of these connections casts doubt on an essential role of LTP in learning and memory formation without any association with reinforcement. The evidence for the involvement of the monoaminergic systems in synaptic potentiation in the cerebral cortex during learning is adduced, and their role in reinforcement system function is discussed.

Since learning emerges from a circuit mediating behavior it is unrealistic to require LTP to be a sufficient explanation of it; however, LTP is a necessary component of some learning circuits. The properties of that component bear a closer formal relationship to the acquisition of associative strength than to the modulation of attention.

Changes in synaptic strength are described as a unifying hypothesis for memory formation and storage, leading philosophers to consider the ‘synaptic efficacy hypothesis’ as a paradigmatic explanation in neuroscience. Craver’s mosaic view has been influential in understanding synaptic efficacy by presenting long-term potentiation as a multi-level mechanism nested within a multi-level structure. This paper argues that the mosaic view fails to fully capture the explanatory power of the synaptic efficacy hypothesis due to assumptions about multi-level mechanisms. I present an alternative (...) approach that emphasizes the explanatory function of unification, accounting for the widespread consensus in neuroscience regarding synaptic efficacy by highlighting the stability of synaptic causal variables across different multi-level mechanisms. (shrink)

The neurophysiological phenomenon of LTP (long term potentiation) is considered by many to represent an adequate mechanism for acquiring or storing memories in the mammalian brain. In our target article, we reviewed the various arguments put forth in support of the LTP/memory hypothesis. We concluded that these arguments were inconsistent with the purported data base and proposed an alternative interpretation that we suggested was at least as compatible with the available data as the more widely held view. In doing so, (...) we attempted to illustrate that the inadequacy of present experimental designs did not permit us to distinguish between equally viable hypotheses. In the four years since we wrote the first draft of our target article, hundreds of additional studies on LTP have been published and their results have been incorporated into current theories about memory. A diverse group of commentators responded to our target article with their own theories of how memories might be stored in the brain, some of which rely on LTP. Some commentators doubted whether memories can be stored through modifications of synaptic strength. Some assert that it will never be possible to understand the neural mechanisms of memory; still others remain hopeful that we will accomplish some semblance of a resolution, provided we appreciate LTP's role in a subset of seemingly amorphous memory systems. In summary, although it is commonly written that “LTP is a memory storage device,” the divergence of views among the commentators suggests, at least as strongly as our target article, that such conviction is unwarranted and fails to acknowledge both the lack of consensus regarding the role of LTP in memory and the complexity of the phenomenon of memory itself. (shrink)

Shors & Matzel's conclusion that LTP is not related to learning is similar to one we reached several years ago. We discuss some methodological advances that have relevance to the issue and applaud the authors for challenging existing dogma.

Shors and Matzel's evaluation of approaches to the behavioural function of LTP is welcome, and should encourage a widening of conceptual approaches to this problem. In addition to their call for increased sophistication in thinking about LTP, there needs to be a parallel increase in sophistication in the study of behaviour. Changes in emotional state or tone may be a better function for LTP than attention mechanisms.

Gene targeting has generated a great deal of data on the molecular mechanisms of long-term potentiation and its potential role in learning and memory. However, the interpretation of some results has been questioned. Compensatory mechanisms and the contribution of genetic background may make it difficult to unequivocally prove the existence of a causal (genetic) link between LTP and learning.

Shors & Matzel provide compelling arguments against a role for hippocampal long-term potentiation (LTP) in mammalian learning and memory. As an alternative, they suggest that LTP is an arousal mechanism. I will argue that this view is not a satisfactory alternative to current conceptions of LTP function.

In the developing and adult cortex, just as in the adult hippocampus, LTP is unable to account for a variety of types of functional plasticity.

This commentary argues that (1) arousal is not sufficient to induce LTP in the hippocampus, (2) learning can profoundly modulate synaptic plasticity in a state-dependent manner without affecting baseline synaptic efficacy, and (3) unilateral, synapse-specific LTP induction triggers an interhippocampal communication manifested as bilateral increases in gene expression at multiple sites in the hippocampal network.

Long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy that many consider the best candidate currently available for a neural mechanism of memory formation and/or storage in the mammalian brain. In our target article, LTP: What's learning got to do with it?, we concluded that there was insufficient data to warrant such a conclusion. In their commentaries, Jeffery and Zhadin raise a number of important issues that we did not raise, both for and against the hypothesis. Although we agree (...) with a number of these issues, we maintain that there remains insufficient evidence that LTP is a memory mechanism. (shrink)

A fundamental assumption in Shors & Matzel's target article is that brain activity can be related to the traditional categories of mentalistic psychology. This has led them to make numerous further assumptions that are contradicted by the available evidence.

The structuralist program has developed a useful metascientific resource: ontological reductive links (ORLs) between the constituents of the potential models of reduced and reducing theories. This resource was developed initially to overcome an objection to structuralist ``global'' accounts of the intertheoretic reduction relation. But it also illuminates the way that concepts at a higher level of scientific investigation (e.g., cognitive psychology) become ``structured through reduction'' to lower-level investigations (e.g., cellular/molecular neuroscience). After (briefly) explaining this structuralist background, I demonstrate how this (...) resource illuminates an actual, emerging scientific example: the link between the psychological concept of a ``consolidation switch'' from short-term to long-term memory and the cellular/molecular mechanisms of the transition from early- to late-phases of long-term potentiation (LTP) (an important type of synaptic plasticity in mammalian hippocampus and cortex). (shrink)

Despite close scrutiny in recent years, the traditional properties of LTP are holding up remarkably well, and they remain a credible influence on the belief that LTP has something to do with learning and information storage.

Recent evidence from our lab indicates that LTP shares an important property with memory consolidation: it is consolidated by natural reinforcement. Nevertheless, the hypothesis, that LTP-like mechanisms or other forms of enhanced synaptic efficacy are basic elements in learning is not unequivocally supported. Skepticism aside, LTP is an accessible experimental model that is optimally equipped for the investigation of the cellular and molecular machinery involved in synaptic weight changes.

In this commentary, I review the articles by CrPEL et al.; LINDEN; Vincent].

We argue in this paper that so-called new wave reductionism fails to capture the nature of the interlevel relations between psychology and neuroscience. Bickle (1995, Psychoneural reduction of the genuinely cognitive: some accomplished facts, Philosophical Psychology, 8, 265-285; 1998, Psychoneural reduction: the new wave, Cambridge, MA: MIT Press) has claimed that a (bottom-up) reduction of the psychological concepts of learning and memory to the concepts of neuroscience has in fact already been accomplished. An investigation of current research on the phenomenon (...) of long-term potentiation reveals that this claim overstates the facts. Both the psychological and the neural concepts involved have not yet stabilized and face further correction under the influence of both bottom-up and top-down selection pressures. In addition, psychological concepts often refer to functions, and functions are indispensable and irreducible. Function ascriptions pick out objective patterns involving historical factors and distal goals. This view of functions implies that psychological facts cannot be simply read off from the neurophysiological facts. Although psychological theorizing is constrained by neurophysiology (and vice versa), psychology remains distinct at least to some degree. (shrink)

Shors & Matzel somewhat lightly dismiss the evidence that a process like LTP may underlie the learning-induced increase in neuronal activity in the hippocampus in eyeblink conditioning. I provide some 12 lines of evidence supporting this hypothesis and the further hypothesis that this learning-induced LTP-like hippocampal plasticity can play a critical role in certain aspects of learned behavior.

The regulatory properties of the neurospecific, type I adenylyl cyclase and its distribution within brain have suggested that this enzyme may be important for neuroplasticity. To address this issue, the murine, Ca2+ -stimulated adenylyl cyclase (type I), was inactivated by targeted mutagenesis. Ca2+ -stimulated adenylyl cyclase activity was reduced 40% to 60% in the hippocampus, neocortex, and cerebellum. Long term potentiation in the CA1 region of the hippocampus from mutants was perturbed relative to controls. Both the initial slope and maxim (...) um extent of changes in synaptic response were reduced. Although mutant mice learned to find a hidden platform normally in the Morris water task, they did not display a preference for the region where the platform had been when it was removed. The behavioral phenotype of these mice is very similar to that exhibited by mice which have been surgically lesioned in the hippocampus. These results indicate that disruption of the gene for the type I adenylyl cyclase produces changes in spatial memory and indicate that the cAMP signal transduction pathway may play an important role for synaptic plasticity. (shrink)

Our results on hippocampal long-term potentiation are considered in the context of Xia et al.'s hypothesis. Whereas the target article proposes presynaptic PKC involvement in adenylyl cyclase activation by phosphorylation of nenromodulin, we suggest an additional postsynaptic role involving RC3/nenrogranin. Finally, we examine the possibility that the adenylyl cyclase mutant mouse may display normal learning with a selective impairment of memory.

Long-Term Potentiation (LTP) is a kind of synaptic plasticity that many contemporary neuroscientists believe is a component in mechanisms of memory. This essay describes the discovery of LTP and the development of the LTP research program. The story begins in the 1950's with the discovery of synaptic plasticity in the hippocampus (a medial temporal lobe structure now associated with memory), and it ends in 1973 with the publication of three papers sketching the future course of the LTP research program. The (...) making of LTP was a protracted affair. Hippocampal synaptic plasticity was initially encountered as an experimental tool, then reported as a curiosity, and finally included in the ontic store of the neurosciences. Early researchers were not investigating the hippocampus in search of a memory mechanism; rather, they saw the hippocampus as a useful experimental model or as a structure implicated in the etiology of epilepsy. The link between hippocampal synaptic plasticity and learning or memory was a separate conceptual achievement. That link was formulated in at least three different ways at different times: reductively (claiming that plasticity is identical to learning), analogically (claiming that plasticity is an example or model of learning), and mechanistically (claiming that plasticity is a component in learning or memory mechanisms). The hypothesized link with learning or memory, coupled with developments in experimental techniques and preparations, shaped how researchers understood LTP itself. By 1973, the mechanistic formulation of the link between LTP and memory provided an abstract framework around which findings from multiple perspectives could be integrated into a multifield research program. (shrink)

Examples of how LTP and LTD can control adaptively-timed learning that modulates attention and motor control are given. It is also suggested that LTP/LTD can play a role in storing memories. The distinction between match-based and mismatch-based learning may help to clarify the difference.

Long‐term potentiation (LTP) in the hippocampus is accompanied by a number of changes on both sides of the synapse. It is now generally considered that the trigger for initiating LTP is the entry of calcium into the postsynaptic area through the NMDA‐associated channel while the mechanism(s) underlying the maintenance of LTP are less well understood and probably involve contributions from both sides of the synapse.

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with descriptions of memory formation. Other characteristics (...) of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms, provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism. (shrink)

Philosophy and Neuroscience: A Ruthlessly Reductive Account is the first book-length treatment of philosophical issues and implications in current cellular and molecular neuroscience. John Bickle articulates a philosophical justification for investigating "lower level" neuroscientific research and describes a set of experimental details that have recently yielded the reduction of memory consolidation to the molecular mechanisms of long-term potentiation (LTP). These empirical details suggest answers to recent philosophical disputes over the nature and possibility of psycho-neural scientific reduction, including the multiple realization (...) challenge, mental causation, and relations across explanatory levels. Bickle concludes by examining recent work in cellular neuroscience pertaining to features of conscious experience, including the cellular basis of working memory, the effects of explicit selective attention on single-cell activity in visual cortex, and sensory experiences induced by cortical microstimulation. (shrink)

Carl F. Craver investigates what we are doing when we use neuroscience to explain what's going on in the brain. When does an explanation succeed and when does it fail? Craver offers explicit standards for successful explanation of the workings of the brain, on the basis of a systematic view about what neuroscientific explanations are.

Prefrontal cerebral areas project to Purkinje cells, located in the most lateral part of the cerebellum, via mossy and climbing fibers. The latter olivary error signals reflect the attentional load of the prefrontal cortex. At the cerebral level, LTP-LTD plasticity allows these Purkinje cells to adaptively reinforce the active pyramidal cells involved in the motor sequence.

We agree with Shors & Matzel's general hypothesis that the proposed link between NMDA-dependent LTP and memory is weak. They suggest that NMDA-dependent LTP is important to arousal or attentional processes which influence learning in an anterograde manner. However, current evidence is also consistent with the view that NMDA receptors modulate memory consolidation retroactively, as occurs in several other receptor classes.

Marx thinks that capitalism is exploitative, and that is a major basis for his objections to it. But what's wrong with exploitation, as Marx sees it? (The paper is exegetical in character: my object is to understand what Marx believed,) The received view, held by Norman Geras, G.A. Cohen, and others, is that Marx thought that capitalism was unjust, because in the crudest sense, capitalists robbed labor of property that was rightfully the workers' because the workers and not the capitalists (...) produced it. This view depends on a Labor Theory of Property (LTP), that property rights are based ultimately on having produced something. (A view oddly enough shared with the libertarian right, though the LTP is better support for egalitarian or socialist views; see my From Libertarianism to Egalitarianism, 18 Social Theory & Prac. 259-288 (1992).) -/- I show that the idea that Marx's objection to exploitation is based on injustice or LTP-grounded theft is mistaken. Marx's real objection to exploitation is based on unfreedom, that capitalist relations of production, he thinks, unnecessarily limit human freedom. In the first place Marx is quite clear that he vehemently rejects the concepts of justice, fairness, or rights as bourgeois ideology. It is true that he uses the language of "theft" on occasion, but either a literal interpretation of that language must be abandoned, or his consistent, life-long objection to rights- and justice talk must be given up. Second, the structure, indeed the point, of his analysis of the laws of motion of capitalism, is that capitalists make profits through exploitation of labor -- without cheating -- by the normal "legitimate" operation of the system. Other arguments make the same point. -/- The unfreedom or force-based view, though not necessarily my specific arguments advocated so far is shared by a minority of other writers, such as Nancy Holmstrom and Richard Arneson. What my paper offers that is novel, part from arguments for the foregoing that are different and better than those found elsewhere (although Holmstrom and Arneson are excellent), is an account of in detail of what Marx regards as the real problem with exploitation. -/- I analyze Marx's objection that capitalist exploitation causes unnecessary unfreedom by distinguishing and spelling out three different kinds of freedom that he invokes: classic negative freedom, or noninterference; positive freedom, understood as control over or access to the resources enabling one to exercise one's negative freedom; and "real" freedom, as he puts it, the ability to "give the law to oneself," to regulate one's own activities under rules chosen by oneself, to develop one's capacities by autonomous choice. This puts Marx in the tradition going back through Hegel and Kant to Rousseau, the first express advocate of this idea. The opposite of real freedom, the unfreedom due to lack of autonomy, is alienation. -/- I conclude by stating that I think that justice-based objections to exploitation that avoid Marx's objections to the concept are possible. I do not attempt to spell these out here. I take up that task in my subsequently published paper Relativism, Reflective Equilibrium, and Justice, 17 Legal Stud.,128-168 (1997). -/- The present paper is related to and partly overlaps with my paper In Defense of Exploitation, 11 Econ. & Phil. 49-81 (1995), a critique of John Roemer's equality based account of the nature of exploitation and its wrongness. The research and writing of this paper was financially supported by the philosophy department of The Ohio State University. -/- Keywords: Exploitation, Justice, Unjustice, Theft, Labor Theory of Property, Marx, Freedom, Unfreedom, Rights, Fairness, Critique of Justice, Negative Freedom, Positive Freedom, Real Freedom, Alienation, G.A. Cohen, Norman Geras. (shrink)

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation. I suggest that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds as philosophers of science have traditionally conceived them.

Nitric oxide (NO) is involved in synaptic long-term potentiation (LTP) by multiple signaling pathways. Here, we show that LTP of synaptic transmission can be explained as a feature of signal transduction—bistable behavior in a chain of biochemical reactions with positive feedback, formed by diffusion of NO to the presynaptic site and facilitating the release of glutamate (Glu). The dynamics of Glu, calcium (Ca2+) and NO is described by a system of nonlinear reaction–diffusion equations with modified Michaelis–Menten (MM) kinetics. Numerical investigation (...) reveals that the chain of biochemical reactions analyzed can exhibit a bistable behavior under physiological conditions when production of Glu is described by MM kinetics and decay of NO is modeled by means of two enzymatic pathways with different kinetic properties. Our finding extends understanding of the role of NO in LTP: a short high-intensity stimulus is “memorized” as a long-lasting elevation of NO concentration. The conclusions obtained by analysis of the chain of biochemical reactions describing LTP can be generalized to other chains of interactions or for creating the logical elements for biological computers. (shrink)

Infants are sensitive to statistical regularities (i.e., transitional probabilities, or TPs) relevant to segmenting words in fluent speech. However, there is debate about whether tracking TPs results in representations of possible words. Infants show preferential learning of sequences with high TPs (HTPs) as object labels relative to those with low TPs (LTPs). Such findings could mean that only the HTP sequences have a word‐like status, and they are more readily mapped to a referent for that reason. But these findings could (...) also suggest that HTP sequences are easier to encode, just like any other predictable sequence. Here we aimed to distinguish between these explanations. To do so, we built on findings that infants become resistant to learning labels that are not typical of their native language as they approach 2 years of age and add words to their lexicons. If tracking TPs in speech results in identifying candidate words, at this age TPs may have reduced power to confer lexical status when they yield a unit that is very dissimilar to word forms that are typical of infants’ native language. Indeed, we found that at 20 months, English‐learning infants with relatively small vocabularies learned HTP Italian words (but not LTP words) as object labels, while infants with larger vocabularies resisted learning HTP Italian words. These findings suggest that the HTP sequences may be represented as candidate words, and more broadly, that TP statistics are relevant to word learning. (shrink)

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation (LTP). I argue that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds.

Several types of amygdala-dependent learning can be blocked by local infusion of NMDA antagonists into the amygdala. This blockade shows anatomical, pharmacological, temporal, and behavioral specificity, providing a pattern of data more consistent with a role for NMDA receptors in learning than in arousal or attention, and supporting the contention that an “LTP-like” process is a neural substrate for memory formation.

The type I CaM-sensitive adenylyl cyclase is in a position to integrate signals from multiple inputs, consistent with the requirements for mediating long term potentiation (LTP). Biochemical and genetic evidence supports the idea that this enzyme plays an important role inc LTP. However, more work is needed before we will be certain of the role that CaM-sensitive adenylyl cyclases play in LTP.

Plastic changes in spinal cord function like neuronal wind-up and increased receptive field are too short-lived to explain chronic pain without structural changes. It is possible that learning could be a mechanism for longlasting changes in nociceptive regulation. A learning process localized to the spinal cord has been shown to be important for the development of tolerance to the analgetic effect of ethanol, suggesting that nociceptive control systems may be changed by learning. Long term potentiation (LTP) is regarded as a (...) useful model of learning and memory. LTP-like changes have been observed in invitro preparations from the spinal cord and in spinal cord field potentials. Recently a long term increase in spinal A-[beta] and C-fibre evoked responses after painful stimulation has been observed. [coderre & katz, dickenson, wiesenfeld-hallin et al.]. (shrink)

This is an expository note on the Lascar group. We also study the Lascar group over hyperimaginaries and make some new observations on the strong types over those. In particular, we show that in a simple theory $\operatorname{Ltp}\equiv\operatorname{stp}$ in real context implies that for hyperimaginary context.

There is no general agreement as to the meaning of long-term potentiation, but this cannot be resolved by using it to explain additional phenomena. Increased attention to recently experienced stimuli is a form of learning known to neuropsychologists as repetition priming. As more is learned about the neurochemistry of synaptic change, the term LTP will wither.

Although it is not their fault, Shors & Matzel's attempt to review the LTP and learning hypothesis suffers from there being no clear published statement of the idea. Their summary of relevant evidence is not without error, however, and it oversimplifies fundamental issues relating to NMDA receptor function. Their attentional hypothesis is intriguing but requires a better systems-level understanding of how attention contributes to cognitive function.