Long-term-potentiation and memory. Where do we stand?

Long-term-potentiation and memory. Where do we stand?

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I was reading the answers to the question: How and where, in the human brain, are memories stored? and, as expected, LTP and LTD came out.

Every time I read about LTP/LTD there is always something that bugs me a lot.

When I read papers about LTP/LTD (OK, I should really say "when I browse", as I'm not exactly in that area of neurosciences, and that is probably the reason why I am confused by this) I always see these very neat experiments where stimulating a neuron in a certain way increases/decreases its further responses. Then, I look at the time axes on the graphs, or read the Methods, and I see that the LTP was induced and analysed few minutes after the stimulus.

So my questions are:

  1. Is there clear evidence that LTP is involved in long-term memory (not counting 1 hour as long-term… )?
  2. Has LTP/LTD been shown in vivo after long period of time (e.g. months).
  3. For those who work in the field, is there a strong belief that LTP/LTD are the only phenomena underlying memory?

Is there clear evidence that LTP is involved in long-term memory (not counting 1 hour as long-term… )? Has LTP/LTD been shown in vivo after long period of time (e.g. months).

This Journal of Neuroscience paper shows LTP in vivo measured out to one year: Abraham WC, Logan B, Greenwood JM, Dragunow M. 2002. Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 22: 9626-34.

Really good questions. As the guy who brought up LTP/LTD in the question you referenced, I thought I would weigh in.

There is the traditional definition of LTP/LTD as an increased/decreased synaptic efficacy at a single synapse or in a single cell. As you've noted, this is unlikely to be the only phenomena underlying memory and sometimes it's hard to see how some of these mechanisms can result in memory on behavioral timescales.

Let me propose, therefore, that the term long-term plasticity is more relevant these days, as it can refer to a variety of mechanisms that relate to the ability of the nervous system to change in stable ways over time. Physiological mechanisms involving changes in protein expression include traditional LTP/LTD at single synapses, but also homeostatic plasticity and long-term changes in intrinsic excitability where the tendency of the cell to fire changes independent of changes in synaptic weighting. Some structural mechanisms include the growth of new synapses, new spines, and new neurons--synaptogenesis, spinogenesis, and neurogenesis.

In the end, it is all of these mechanisms (and probably more) at play. Note, for instance, that the plasticity may move through structural changes in the system. This means that the lifetime of LTP in one cell or at one synapse does not necessarily have to be the same as the lifetime of the memory itself. All that said, I think all plasticity mechanisms ultimately reduce down to a change in the ability of an input to elicit an action potential somewhere in the brain (known as EPSP-spike coupling). This is likely to be the basic underlying mechanism of memory.

Good questions. I don't think that LTP has been (or will be) shown to be THE mechanism for long term memory. It is one of many mechanisms, all with different time courses, that contribute to the modification of synaptic efficiencies.

One mechanism not mentioned much anymore, but which I feel is absolutely crucial, is dendritic spine growth. Spines are malleable and formation/destruction of spines is probably very related to long term memory. But as always, the full picture is going to be a combination of mechanisms.

Here is a paper to have a look at: Engert F, Bonhoeffer T. 1999. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399: 66-70.

Long-term-potentiation and memory. Where do we stand? - Biology

Potentiation, habituation, and sensitization are three ways in which stimuli in the environment produce changes in the nervous system.

Learning Objectives

Differentiate among habituation, sensitization, and long-term potentiation

Key Takeaways

Key Points

  • “Potentiation” refers to a strengthening of a nerve synapse. Long-term potentiation is based on the principle that “cells that fire together, wire together,” and is widely considered one of the major cellular mechanisms that underlies learning and memory.
  • Habituation occurs when we learn not to respond to a stimulus that is presented repeatedly without change, punishment, or reward.
  • Sensitization occurs when a reaction to a stimulus causes an increased reaction to a second stimulus. It is essentially an exaggerated startle response and is often seen in trauma survivors.
  • During habituation, fewer neurotransmitters are released at the synapse. In sensitization, however, there are more pre-synaptic neurotransmitters, and the neuron itself is more excitable.

Key Terms

  • axon: A nerve fiber that is a long slender projection of a nerve cell, and which conducts nerve impulses away from the body of the cell to a synapse.
  • synapse: The junction between the terminal of a neuron and either another neuron or a muscle or gland cell, over which nerve impulses pass.
  • neurotransmitter: Any substance, such as acetylcholine or dopamine, responsible for sending nerve signals across a synapse between two neurons.
  • dendrite: A slender projection of a nerve cell that conducts nerve impulses from a synapse to the body of the cell.
  • stimuli: In psychology, any energy patterns (e.g., light or sound) that are registered by the senses.

Learning occurs when stimuli in the environment produce changes in the nervous system. Three ways in which this occurs include long-term potentiation, habituation, and sensitization.

Long-Term Potentiation

One way that the nervous system changes is through potentiation, or the strengthening of the nerve synapses (the gaps between neurons). Long-term potentiation (LTP) is the persistent strengthening of synapses based on recent patterns of activity: it occurs when a neuron shows an increased excitability over time due to a repeated pattern, behavior, or response. The opposite of LTP is long-term depression (LTD), which produces a long-lasting decrease in synaptic strength.

The structure of a neuron: Communication between neurons occurs when the neurotransmitter is released from the axon on one neuron, travels across the synapse, and is taken in by the dendrite on an adjacent neuron.

Because memories are thought to be encoded by modification of synaptic strength, LTP is widely considered one of the major cellular mechanisms that underlies learning and memory. The role of LTP in learning is still being researched, but studies on the hippocampus have found LTP to occur during associative learning (such as classical conditioning ). LTP is based on the Hebbian principle: “cells that fire together, wire together.” This principle attempts to explain associative learning, in which simultaneous activation of cells leads to pronounced increases in synaptic strength between those cells, and provides a biological basis for the pairing of stimulus and response in classical conditioning.


Recall that sensory adaptation involves the gradual decrease in neurological sensory response caused by the repeated application of a particular stimulus over time. Habituation is the “behavioral version” of sensory adaptation, with decreased behavioral responses over time to a repeated stimulus. In other words, habituation is when we learn not to respond to a stimulus that is presented repeatedly without change. As the stimulus occurs over and over (and as long as it is not associated with any reward or punishment), we learn not to focus our attention on it. It is a form of non-associative learning that does not require conscious motivation or awareness.

Habituation helps us to distinguish meaningful information from the background. For example, an animal may be startled when it hears a loud noise, but if it is repeatedly exposed to loud noises and experiences no associated consequence, such as pain, it will eventually stop being startled.

Habituation to stress: Habituation involves responding to stimuli and stress less over time—after our body’s initial natural resistance to the stimuli.


Sensitization is the strengthening of a neurological response to a stimulus due to the response to a secondary stimulus. For example, if a loud sound is suddenly heard, an individual may startle at that sound. If a shock is given following the sound, then the next time the sound occurs, the individual will subsequently react even more strongly to the sound. It is essentially an exaggerated startle response, and is often seen in trauma survivors. For example, the sound of a car backfiring might sound like a gunshot to a war veteran, and the veteran may drop to the ground in response, even if there is no threat present.

Neurological Differences

Habituation and sensitization work in different ways neurologically. In neural communication, a neurotransmitter is released from the axon of one neuron, crosses a synapse, and is then picked up by the dendrites of an adjacent neuron. During habituation, fewer neurotransmitters are released at the synapse. In sensitization, however, there are more pre-synaptic neurotransmitters, and the neuron itself is more excitable.

Neural communication: This image shows the way two neurons communicate by the release of the neurotransmitter from the axon, across the synapse, and into the dendrite of another neuron.

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function.

Conflict of interest statement

The authors declare no competing financial interests.


Fig. 1. CREB increases neuronal excitability

Fig. 1. CREB increases neuronal excitability

Fig. 2. Allocate-to-link hypothesis

Fig. 2. Allocate-to-link hypothesis

Fig. 3. CREB-dependent enhancement of excitability is…

Fig. 3. CREB-dependent enhancement of excitability is controlled both by dendritic LTP events and by…



All procedures were approved by the Animal Care Committee at the University of British Columbia (UBC) and conducted in accordance with the Canadian Council on Animal Care guidelines regarding humane and ethical treatment of animals. Ascl1 CreERT2 mice (Ascl1 tm1.1(Cre/ERT2)Jejo JAX 12882v [41]) and Ai14 reporter mice (Gt(ROSA)26Sor tm14(CAG-tdTomato)Hze JAX 7908 [42]) were purchased from The Jackson Laboratory, and were crossed to generate offspring that were heterozygous for Ascl1 CreERT2 and homozygous for the Cre-dependent tdTomato reporter, as described elsewhere [43] (hereafter, Ascl1 CreERT2 mice). Mice were maintained on a C57Bl/6J background, housed 5/cage (floor space 82 square inches), with ad lib access to food and water and a 12hr light-dark schedule with lights on at 7am. To induce tdTomato expression in Ascl1 + precursor cells and their progeny, mice were injected intraperitoneally with tamoxifen either neonatally (postnatal day zero or one

75 mg/kg, one injection) or during adulthood (6- to 8-weeks-old 150 mg/kg body weight, one injection/day for up to three days Fig 1) to permanently label newborn neurons. Adult mice of both sexes were used for electrophysiology experiments between 11- and 45- weeks of age.

(A) Timelines for labelling and recording from neonatal- and adult-born dentate granule neurons. (B) Fluorescence (left) and IR-DIC (middle) images of a tdTomato + adult-born granule cell (39 days post-tamoxifen injection) that was targeted for whole-cell recording. The right panel shows the low magnification view, where the stimulating electrode is placed in the outer molecular layer to target the lateral perforant path axons that arise from the lateral entorhinal cortex (gcl, granule cell layer hil, hilus mol, molecular layer). (C) Input resistance declines with time post-tamoxifen, consistent with the known age-related physiological maturation of adult-born granule cells (R 2 = 0.37, P < 0.0001). (D) Young adult-born granule cells had higher input resistance than older adult-born or neonatal-born cells (Kruskal Wallis test, P < 0.0001 4-6w vs 8 + w, ****P < 0.0001 4-6w vs neonatal, *P = 0.01 8 + w vs neonatal, P = 0.5). Bars reflect mean ± standard error.

Brain slice preparation

Mice were anesthetized with sodium pentobarbital (intraperitoneal injection, 50 mg/kg) immediately before cardiac perfusion with ice-cold cutting solution containing (in mM): 93 NMDG, 2.5 KCl, 1.2 NaH2PO4, 30 NaHCO3, 20 HEPES, 25 glucose, 5 sodium ascorbate, 3 sodium pyruvate, 10 n-acetyl cysteine, 0.5 CaCl2, 10 MgCl2 (pH-adjusted to 7.4 with HCl and equilibrated with 95% O2 and 5% CO2,

310 mOsm). Mice were then decapitated, brains removed, and transverse hippocampal slices prepared as described previously [44]. Slices from the right and/or left hemisphere were transferred to NMDG-containing cutting solution at 35°C for 20 minutes, before being transferred to a storage solution containing (in mM): 87 NaCl, 25 NaHCO3, 2.5 KCl, 1.25 NaH2PO4, 10 glucose, 75 sucrose, 0.5 CaCl2, 7 MgCl2 (equilibrated with 95% O2 and 5% CO2,

325 mOsm) for at least 40 minutes at 35°C before starting experiments.


Whole-cell patch-clamp recordings were made at near-physiological temperature (

32°C) from identified tdTomato + granule cells in the suprapyramidal blade of the dentate gyrus. Slices were superfused with an artificial cerebrospinal fluid (ACSF) containing (in mM): 125 NaCl, 25 NaHCO3, 2.5 KCl, 1.25 NaH2PO4, 25 glucose, 1.2 CaCl2, 1 MgCl2 (equilibrated with 95% O2 and 5% CO2,

320 mOsm). In all experiments GABAergic inhibition was blocked with bicuculline methiodide (10 uM [9]). Recording pipettes were fabricated from 2.0 mm/1.16 mM (OD/ID) borosilicate glass capillaries and had resistance

5 MOhm with an internal solution containing (in mM): 120 K-gluconate, 15 KCl, 2 MgATP, 10 HEPES, 0.1 EGTA, 0.3 Na2GTP, 7 Na2-phosphocreatine (pH 7.28 with KOH,

300 mOsm). Current-clamp and voltage-clamp recordings were performed at -80 mV. Only recordings with high seal resistance (several giga-ohms) and low holding current (less than 50 pA) were included in analyses. For current-clamp recordings, series resistance and pipette capacitance were compensated with the bridge balance and capacitance neutralization circuits of the amplifier. A bipolar electrode was placed in the outer 1/3 of the molecular layer to stimulate the lateral perforant path (LPP) fibers ([45,46] Fig 1B). Stimuli (0.1 ms) were delivered through a stimulus isolator (A-M Systems analog stimulus isolator model 2200) and intensity (range 50–500 μA, median 200 μA did not differ with cell age, correlation P = 0.95) was adjusted to evoke minimum excitatory postsynaptic currents (EPSCs -40 ± 4 pA, mean ± standard error (here and elsewhere)) and corresponding excitatory postsynaptic potentials (EPSPs)

5 mV (5.2 ± 0.5 mV). Paired-pulse facilitation was assessed using 50-Hz pairs of pulses. For LTP experiments, single EPSPs were evoked every thirty seconds before and after a single theta-burst stimulation (TBS) consisting of 10 trains of 10 pulses (100-Hz), delivered at 5-Hz, and repeated four times at 0.1 Hz, paired with postsynaptic current injection (100 pA, 100 ms) as previously described [8,9].

Data acquisition and analysis

Data were acquired with a Multiclamp 700B amplifier, low-pass filtered at 10 kHz, and digitized at 100 kHz with an Axon 1550B digitizer. Pulse generation and data acquisition were performed using pClamp 10 (Molecular Devices). EPSC and EPSP traces were analyzed offline using Clampfit (Molecular Devices) and Igor Pro (Wavemetrics) software. Input resistance was measured from a test pulse (10 mV) in voltage-clamp. Peak EPSC amplitudes were measured from average waveforms of 10 consecutive traces collected at 0.1 Hz, and from a baseline period immediately preceding each stimulus. LTP magnitude was measured as the mean peak EPSP amplitude during 40–50 minutes post-TBS normalized to the mean peak EPSP amplitude during ten minutes of baseline recording immediately preceding the TBS. Paired-pulse responses were collected immediately before and after each LTP experiment. Paired pulse ratios were calculated as the peak EPSC amplitude of the 2 nd response divided by the peak EPSC amplitude of the 1 st response. For some analyses, adult-born neurons were grouped into bins of 4–6 weeks and 8 + weeks post-tamoxifen injection, to specifically compare cohorts of cells that are within and beyond, respectively, the critical period for LTP at medial perforant path synapses [9]. Individual data points reflect cells only 1 cell was examined per slice and 1–2 cells were examined per animal. Since no differences were observed between adult-born cells from male vs female mice (LTP, input resistance and paired pulse ratio all P > 0.26), data from both sexes were pooled for all analyses. Total number of cells analyzed: 4-6w adult-born cells, n = 11 8 + w adult-born cells, n = 26 neonatal-born cells, n = 11, with the exception that sample sizes were slightly smaller for post-TBS paired pulse ratios: 4-6w adult-born cells, n = 8 8 + w adult-born cells, n = 22 neonatal-born cells, n = 10. Group data are expressed as means ± standard error.

Cell age-related physiological differences were analyzed by regression and group differences were identified by ANOVA and followed up with Holm-Sidak comparison tests. If data were non-normal, group differences were identified by a Kruskal-Wallis test with Dunn’s post-hoc test. Changes in paired pulse ratios were analyzed by t-test or, if the data were not normally distributed, Mann Whitney test. To facilitate comparison with data presented in graphs, most statistical analyses are described in the figure legends. For all analyses, statistical significance was defined as P < 0.05. The data for all graphs and analyses are provided as supporting information (S1 File).


During the last two decades of the last century, the locus of expression of NMDAR-dependent LTP was the focus of an intense debate (Malenka and Nicoll 1999 Nicoll 2003). Although in hindsight it seems difficult to understand how an apparently simple question could keep many researchers in the field busy, the confusion could largely be attributed to the lack of understanding of the basic physiology of excitatory synapses in the mammalian central nervous system. Although a minority of researchers in the field would argue that the question is still not fully answered, there is general agreement that the experiments that were performed to address this topic significantly furthered our understanding of the basic properties of synaptic transmission.

In theory, how LTP and LTD are expressed is a simple question. For LTP the increase in synaptic strength could be due either to more transmitter being released from the presynaptic axons being activated during the course of the experiment or to the same amount of transmitter being released but having a greater effect because the postsynaptic cell was more sensitive to the same amount of released neurotransmitter. It is important to note that if LTP (or LTD) is caused by enhanced (or decreased) transmitter release, it requires that the postsynaptic cell somehow communicate to the presynaptic terminals and modify their function. This is required because it is well established that NMDAR-dependent LTP and LTD are triggered in the postsynaptic cell. Indeed, during the debate about the locus of expression for LTP (and LTD), there was much discussion about the possible identity of so-called retrograde messengers, the substances that might be released from postsynaptic cells following appropriate activation of NMDARs and modify presynaptic function (Arancio et al. 1996 but see Williams et al. 1993).

To solve the pre- versus post- debate, which primarily focused on the locus of expression of LTP, a large number of experiments were performed. To assess whether presynaptic function changed, the assays included:

Using use-dependent open channel blockers of postsynaptic receptors to estimate the release probability. Most importantly, dizocilpine (MK-801) irreversibly blocks NMDARs once they are activated by glutamate. Thus, once glutamate is released from a single presynaptic terminal and activates its corresponding postsynaptic NMDARs, those NMDARs are irreversibly blocked. This means that application of MK-801 while activating a population of synapses leads to a gradual decrease of the postsynaptic currents generated by NMDARs, and the rate of this decrease directly correlates with the overall probability of release of the synapses being activated. Importantly, it was found that the rate of this decrease remains unaltered by LTP but is clearly affected by other manipulations that are known to influence the probability of transmitter release (Manabe and Nicoll 1994).

Monitoring short-term plasticity before and after the induction of LTP. Paired-pulse ratios and short-term facilitation or depression of synaptic responses during short, high-frequency bursts of stimulation reflect short-term changes in release probability. These ubiquitous forms of short-term synaptic plasticity are greatly influenced by the baseline release probability yet were unaffected by the generation of LTP (McNaughton 1982 Manabe et al. 1993 but see Schulz et al. 1995).

Monitoring glial glutamate transporter currents before and after LTP. The reuptake of glutamate by astrocytes is electrogenic, and thus currents can be measured from astrocytes that reflect the amount of transmitter released. There is, however, no change in the size of these currents after induction of LTP even though other manipulations that affect transmitter release have clear effects. These experiments are particularly convincing, because this approach relies on a readout that is independent of glutamate receptors and therefore unlikely to participate in the expression of LTP (Diamond et al. 1998 Lüscher et al. 1998).

Visualization of presynaptic exocytosis with styryl dyes such as FM1-43. These dyes stain presynaptic vesicles and are washed out once the vesicles fuse with the membrane in an activity-dependent fashion. Just as with MK-801, the destaining curves were superimposable before and after tetanic induction of NMDAR-dependent LTP in CA1 neurons at 50� Hz (Zakharenko et al. 2001).

Taken together, these findings (and additional experiments that are not covered because of space limitations) make it very unlikely that LTP is associated with an increase in release probability or the amount of glutamate released from a presynaptic vesicle. But they say nothing about what postsynaptic mechanisms contribute to LTP (and LTD). An important clue to this question came from the observation that in the hippocampi of very young animals, some synapses contain only NMDARs and no, or very few, AMPARs. Thus, these synapses are functionally silent under baseline conditions. After the application of an LTP induction protocol, these synapses “wake up” and become functional because of the insertion of AMPARs into their postsynaptic membrane (Isaac et al. 1995 Liao et al. 1995). This result immediately raised the possibility that at both silent synapses and synapses that already contain AMPARs, LTP involves the insertion of more AMPARs into the synapse, whereas conversely, LTD may involve the removal or endocytosis of synaptic AMPARs ( Fig. 3 ) (Lledo et al. 1998 Lüscher et al. 1999).

Postsynaptic expression mechanisms of LTP and LTD. (A) Weak activity of the presynaptic neuron leads to modest depolarization and calcium influx through NMDA receptors. This preferentially activates phosphatases that dephosphorylate AMPA receptors, thus promoting receptor endocytosis. Strong activity paired with strong depolarization triggers LTP in part via CaMKII, receptor phosphorylation, and exocytosis. (B) When endocytosis is blocked with a dynamin dominant-negative peptide, LTD is inhibited. Conversely, blocking exocytosis abolishes LTP. (Left panel: adapted and reprinted, with permission, from Lüscher et al. 1999 right panel: W Morishita and RC Malenka, unpubl.)

A large body of experimental evidence now supports this hypothesis (Lüscher et al. 2000 Lüscher and Frerking 2001 Malinow and Malenka 2002 Nicoll 2003 Collingridge et al. 2004 Malenka and Bear 2004). In fact, AMPARs can be quite mobile and recycle between the cytoplasm and the cell membrane even under baseline conditions within tens of minutes. This can be shown, for example, by interfering with endocytosis, which leads to a run-up of synaptic responses. It is presumably this mobile pool of AMPARs that allows for rapid but sustained changes in synaptic efficacy. The insertion and removal of AMPARs during LTP and LTD, respectively, is believed to involve classical mechanisms of SNARE protein–mediated exocytosis and dynamin-dependent endocytosis via clathrin-coated vesicles (Lüscher et al. 1999 Carroll et al. 2001 Kennedy and Ehlers 2011). Current evidence favors the idea that the endocytosis and exocytosis of AMPARs during LTD and LTP happens not directly at the synapse but at slightly perisynaptic locations, from where the receptors reach the postsynaptic density by lateral diffusion.

A large family of proteins associates with the AMPARs to regulate their mobility and biophysical properties as well as their stabilization within the PSD (see Sheng and Kim 2012). Different AMPAR subunits may play distinct roles in this redistribution process. Heteromeric GluA1/GluA2 receptors seem to be the primary subtype of AMPAR that is inserted into synapses during LTP (Adesnik and Nicoll 2007). In addition, there are also forms of synaptic potentiation that are expressed by an exchange of GluA2-containing AMPARs in the synapse for GluA2-lacking AMPARs (Liu and Zukin 2007). Because the latter have a higher conductance, this will potentiate the synapse even if the total number remains the same. It has also been suggested that during the very early phase of LTP (its first 10� min), there is a transient appearance of GluA2-lacking AMPARs at the synapse and this is required for the maintenance of LTP (Plant et al. 2006). However, this finding is controversial (Adesnik and Nicoll 2007). Of particular interest are members of the TARP family, which interact with all AMPA receptor subunits and control not only membrane insertion but also lateral redistribution (Chen et al. 2000 Tomita et al. 2005 see Blakely and Edwards 2012). If interactions with scaffolding proteins are manipulated through genetic interventions or the perfusion of dominant-negative proteins, LTP and LTD can be blocked (Lüscher et al. 1999 Lüthi et al. 1999 Collingridge and Isaac 2003).


The hippocampus in the medial temporal lobe plays important roles in learning and memory.

The clinical studies on Patient H.M in 1953 showed the significant functions of the medial temporal lobe. Patient H.M. underwent surgical removal of the medial temporal lobes. This resulted to anterograde amnesia (difficulty of forming new memories) and neologism (forming and/or using new words). However, procedural memories, semantic memories, speech, reading and writing were all left unaffected.

Situated in the medial temporal lobe, the hippocampus is responsible for the consolidation of short term memory and long term memory. In particular, the hippocampus is responsible for the formation of new memories related to experiences events, also known as autobiographical or episodic memories. Declarative memories, those that can be verbalized more explicitly than episodic memories, are formed but not stored in the hippocampus. These memories as well as past events are believed to be stored in the frontal and temporal lobes.

There are two hippocampi in the brain, one in the left hemisphere and the other one on the right. When one of these hippocampi are damaged and the other one is left intact, the person can still experience almost normal memory functioning. However, severe damage or removal of both hippocampi as in the case of Patient H.M. results to anterograde amnesia.

A process called long-term potentiation (LTP) occurs in the hippocampus. LTP refers to the increase in neural responsivity. Recent research studies proved that LTP is involved in spatial learning.

The Role of Attention in Memory

In order to encode information into memory, we must first pay attention, a process known as attentional capture.

Learning Objectives

Discuss the link between attentional capture and working memory

Key Takeaways

Key Points

  • Research suggests a close link between working memory and what is known as attentional capture, the process in which a person pays attention to specific information.
  • Attentional capture can happen either explicitly or implicitly.
  • Explicit attentional capture is when a stimulus that a person has not been attending to becomes salient enough that the person begins to attend to it and becomes cognizant of its existence.
  • Implicit attentional capture is when a stimulus that a person has not been attending to has an impact on the person’s behavior, whether or not they’re cognizant of that impact or the stimulus.
  • Working memory actively holds many pieces of information and manipulates them.

Key Terms

  • implicit: Implied indirectly, without being directly expressed.
  • explicit: Very specific, clear, or detailed.
  • working memory: The system that actively holds multiple pieces of information in the mind for execution of verbal and nonverbal tasks and makes them available for further information processing.

Attentional Capture

In order for information to be encoded into memory, we must first pay attention to it. When a person pays attention to a particular piece of information, this process is called attentional capture. By paying attention to particular information (and not other information), a person creates memories that could be (and probably are) different from someone else in the same situation. This is why two people can see the same situation but create different memories about it—each person performs attentional capture differently. There are two main types of attentional capture: explicit and implicit.

Explicit Attentional Capture

Explicit attentional capture is when a stimulus that a person has not been attending to becomes salient enough that the person begins to attend to it and becomes cognizant of its existence. Very simply, it’s when something new catches your focus and you become aware of and focused on that new stimulus. This is what happens when you are working on your homework and someone calls your name, drawing your complete attention.

Implicit Attentional Capture

Implicit attentional capture is when a stimulus that a person has not been attending to has an impact on the person’s behavior, whether or not they’re cognizant of that impact or the stimulus. If you are working on your homework and there is quiet but annoying music in the background, you may not be aware of it, but your overall focus and performance on your homework might be affected. Implicit attentional capture is important to understand when driving, because while you might not be aware of the effect a stimulus like loud music or an uncomfortable temperature is having on your driving, your performance will nevertheless be affected.

Implicit attentional capture: Even when you are focused on driving, your attention may still implicitly capture other information, such as movement on the GPS screen, which can affect your performance.

Working Memory and Attentional Capture

Working memory is the part of the memory that actively holds many pieces of information for short amounts of time and manipulates them. The working memory has sub-systems that manipulate visual and verbal information, and it has limited capacity. We take in thousands of pieces of information every second this is stored in our working memory. The working memory decides (based on past experiences, current thoughts, or information in long-term memory) if any particular piece of information is important or relevant. In other words, if the information is not used or deemed important, it will be forgotten. Otherwise, it is moved from the short-term memory and committed to long-term memory.

One famous example of attentional capture is the cocktail party effect, which is the phenomenon of being able to focus one’s auditory attention on a particular stimulus while filtering out a range of other stimuli, much the same way that a partygoer can focus on a single conversation in a noisy room. This effect is what allows most people to tune into a single voice and tune out all others.

Research suggests a close link between working memory and attentional capture, or the process of paying attention to particular information. A person pays attention to a given stimulus, either consciously (explicitly, with awareness) or unconsciously. This stimulus is then encoded into working memory, at which point the memory is manipulated either to associate it with another familiar concept or with another stimulus within the current situation. If the information is deemed important enough to store indefinitely, the experience will be encoded into long-term memory. If not, it will be forgotten with other unimportant information. There are several theories to explain how certain information is selected to be encoded while other information is discarded.

The Filter Model

The formerly accepted filter model proposes that this filtering of information from sensory to working memory is based on specific physical properties of stimuli. For every frequency there exists a distinct nerve pathway our attention selects which pathway is active and can thereby control which information is passed to the working memory. This way it is possible to follow the words of one person with a certain vocal frequency even though there are many other sounds in the surrounding area.

Attenuation Theory

The filter model is not fully adequate. Attenuation theory, a revision of the filter model, proposes that we attenuate (i.e., reduce) information that is less relevant but do not filter it out completely. According to this theory, information with ignored frequencies can still be analyzed, but not as efficiently as information with relevant frequencies.

Late-Selection Theory

Attenuation theory differs from late-selection theory, which proposes that all information is analyzed first and judged important or unimportant later however, this theory is less supported by research.

NMDA Receptor Function

The NMDA receptor is involved in the long-term potentiation of an action potential. Full activation of NMDA receptors is both voltage-gated and ligand-gated. The ion channels will only open if the post-synaptic membrane has already been depolarized, and the neurotransmitters glutamate and glycine are attached. There is a voltage-dependent Mg 2+ block that prevents the opening of the NMDA receptor ion channels when the membrane is not depolarized it acts as an antagonist. Membrane depolarization occurs when the neurotransmitter glutamate interacts with AMPA receptors in the membrane which then open ion channels that allow Na + and K + to enter the cell. This causes the resting membrane potential, which is negatively charged relative to outside of the neuron, to move closer to zero as the positive ions diffuse into the cell. When glutamate and glycine then bind to the NMDA receptors the conformation of the protein changes and Ca 2+ permeable ion channels open. As Ca 2+ enters the neuron it triggers phosphorylation of the AMPA receptors in the membrane, causing the AMPA receptors to become more responsive to neurotransmitters (glutamate). It also increases the number of AMPA receptors in the membrane, thus increasing the influx of positive Na + and K + ions and maintaining the membrane depolarization, and the action potential it produces.

Physiological Aspects of Long-term Memory

Previously, it was believed that only the cortex of the brain stores long-term information. Now we know that they are stored in different regions throughout the brain and other parts of the nervous system depending upon their type. Memories are not somewhat localized but stored through circuitry. Some types of memories may be stored throughout the body because receptors for chemicals in the brain are found everywhere.

When neurotransmitters are activated in the brain, a process called chemotaxis communicates the message to every part of the body. This communication is done basically through blood and cerebrospinal fluid. In this way, some memory may also get stored in muscles. People with organ transplants have reported the emotional reactions and feeling to certain events that they never had before.

NEURONAL MECHANISMS OF MEMORY FORMATION: CONCEPTS OF LONG-TERM POTENTIATION AND BEYOND. By Christian Hölscher. 2001. Cambridge: Cambridge University Press. Price £65. Pp. 528. ISBN 0-52177-067-X.

Zafar Bashir, NEURONAL MECHANISMS OF MEMORY FORMATION: CONCEPTS OF LONG-TERM POTENTIATION AND BEYOND. By Christian Hölscher. 2001. Cambridge: Cambridge University Press. Price £65. Pp. 528. ISBN 0-52177-067-X., Brain, Volume 124, Issue 11, November 2001, Pages 2335–2338,

The driving force behind this book is the enduring question of whether synaptic plasticity is a suitable model for understanding the basis of learning and memory. In this book synaptic plasticity is taken almost exclusively to mean long-term potentiation (LTP) and there is virtually no discussion of, for example, long-term depression or the cerebellum.

The book begins with an introduction by Holscher in which some of the main arguments contained within the rest of the book are rehearsed. This begins with an assessment of the validity of in vitro slice techniques and then questions whether in vitro studies are relevant to learning whether models of LTP are relevant to learning and whether knockout techniques and the employment of these are useful for understanding firstly LTP and then learning? This is followed by a critique of the different approaches that have attempted to correlate LTP with the cellular processes that may be involved with learning. Most people in this field will recognize the problems and limitations of the systems that we work with, be these in vivo or in vitro. Most realize that it is not a simple matter to relate synaptic plasticity in a dish or in anaesthetized animals to learning in animals or in humans. Nevertheless, the Introduction is a readable account and provides a useful summary of some of the main issues.

The rest of the book is divided into five sections. The first of these deals with `Long-term potentiation in vitro and in vivo'. Abraham discusses the different types of LTP that are found in different brain regions, the types of stimuli usually employed to induce LTP and the underlying mechanisms of induction in different regions. There is an interesting section on neurogenesis (unique to dentate gyrus) and how this may influence plasticity and function of this region. The, not unreasonable, conclusion is reached that different forms of plasticity may subserve different functions in different brain regions.

Perhaps some of the best evidence to date linking synaptic plasticity and learning is from work in the amygdala. This is discussed in two related chapters by Rogan and colleagues and by Maren. First, fear conditioning is described before a summary is given of the classical work illustrating that increases in evoked potentials occur following pairing of an unconditioned acoustic stimulus with an unconditioned aversive stimulus. This is followed by a description of work in vitro investigating the role of protein kinase A in synaptic plasticity in the amygdala. The chapter by Maren describes how an NMDA (N-methyl- d -aspartate) receptor-dependent phenomenon may play a role in contextual fear conditioning. Whilst the role of hippocampal plasticity per se has not been proven, Maren describes various attempts that provide a correlation between this and learning. The final chapter in this section by Jeffery discusses experience-dependent plasticity of hippocampal place cells. It is strongly argued that this is a valid, and perhaps one of the best, model(s) for identifying a role for plasticity in hippocampus.

Section two deals with `synaptic plasticity induced by natural stimulation frequencies'. The first of these chapters by Pike and colleagues argues that the use of such patterns of stimulation in the in vitro hippocampus will provide a greater understanding of both plasticity and learning. The authors propose that bursts of activity that resemble hippocampal spiking can facilitate the induction of LTP. They propose a model in which inputs into the hippocampus are encoded by complex spikes and the recall of information occurs through simple spike-like activity. Maroun and co-workers discuss plasticity of local circuits in hippocampus and amygdala, and how changes in the activity of a circuit may be more important than the simple phenomenon of LTP per se. The plasticity of local circuits relies on decrements in GABA inhibition. They suggest a correlation exists between age-related spatial memory abilities and local circuit plasticity, but not with LTP. Holscher argues that theta frequency induction of LTP is a better model for memory formation than LTP induced by tetanic stimulation. Theta oscillations set up temporal constraints on the induction of LTP and allow the induction of LTP with much `weaker' stimulation. Finally, Munk addresses gamma oscillations and suggests that networks firing together at high frequencies may be able to process complicated information in a parallel manner. Furthermore, it is shown that gamma oscillations can facilitate the induction of synaptic plasticity.

Section three deals with `models from data of synaptic plasticity'. Lisman and colleagues discuss whether NMDA receptor-dependent LTP and oscillations in the hippocampus provide a mechanism for functions of this region. They argue that the patterns of gamma and theta oscillations can explain some of the properties and capacity of short-term memory. Rolls argues that LTP-like phenomena are most likely to play a role in learning and memory and discusses several lines of evidence which support the notion that Pavlovian conditioning relies on Hebbian plasticity within networks of neurones. In the very next chapter, however, McEachern and Shaw argue very strongly that LTP is not a good model for learning. They base their discussion on various arguments. For example, that LTP is not permanent, LTP is not input specific under all conditions and that LTP associativity is just as likely to play a role in pathology as in learning. Finally they argue that the LTP literature is so full of contradictions between different laboratories that this in itself is a weakness. McEachern and Shaw suggest that LTP may provide a better understanding of pathology than of learning. In the final chapter in this section Matzel and Shors argue against the associative LTP = associative learning hypothesis. They suggest that an increase in synaptic transmission, even within a network, simply cannot provide for the complexities of learning. In addition, they also agree with the McEachern and Shaw view that many of the properties of LTP are simply not sufficient to provide for associative learning.

In section four, `Setting the stage for memory formation', Cain discusses the limitations of one of the most popular learning tasks (the Morris water maze) in which correlations are often made between the pharmacological block of LTP and pharmacological block of learning. However, Cain argues that interpreting results from the water maze is fraught with difficulty and cites the effects that non-spatial pretraining has on the NMDA receptor-dependence of the task. Rose and Diamond make the argument that simply finding a correlation between lack of LTP and lack of some form of learning is no good reason to suppose that the latter requires the former. They cite contradictory examples from studies in aged animals to suggest that the correlation between LTP and learning is not always very strong. McNaughton in the next chapter also argues that LTP may not be a good model upon which to base a mechanism of learning and memory. First, he suggests that the hippocampus, where most of the plasticity work is conducted, is not the repository of memory and is therefore not the place to study. The hippocampus, he argues, plays a role in fear and anxiety but not memory per se. In the last chapter in this section Diamond and co-workers also suggest that the hippocampus does not play a role in learning and memory but is important in regulating stress. They argue that the amygdala and hippocampus can thus form a system in which the amygdala functions to produce emotional memory that is in some way operated on by the hippocampus. LTP may affect this system but is not directly involved in producing the conditions for this system.

Section five, `transgenic mice as tools', consists of three chapters on in vivo recording of place cells from transgenics, synaptic plasticity in genetically modified animals and what gene activation can tell us about synaptic plasticity. Cho and Eichenbaum discuss work on place cells and how the development of place fields is affected by various gene deletions. They suggest that plasticity mechanisms are involved in the organization and development of hippocampal place fields. Chapman provides a review of some of the genetic manipulations that have been used in the study of synaptic plasticity and learning and memory. He also provides a critique of common problems and difficulties of interpretation of the results from such studies. Inevitably, until more targeted (spatial and temporal) techniques of manipulation are used, the problems associated with traditional gene knockouts will continue to haunt the field. Davis and Laroche also point out the various pitfalls of global gene deletion but are optimistic that the new techniques will overcome previous problems.

Overall, this book provides a useful and critical analysis of some of the underlying assumptions that LTP provides a good model for understanding mechanisms of learning and memory.

Long-term-potentiation and memory. Where do we stand? - Biology

Long-term potentiation, or LTP, is a process of synaptic strengthening that occurs over time between pre and post synaptic neuronal connections.

In one mechanism, when presynaptic neurons repeatedly fire and stimulate the postsynaptic cell, this action induces changes in the type and number of ion channels in the post synaptic membrane such as one class of glutamate receptors called N-methyl-D-aspartate, or NMDA.

NMDA receptors are usually inactivated by magnesium ions, however, with strong depolarization from repeated stimulation, the magnesium ions are displaced allowing calcium ions to enter.

This calcium influx initiates a signaling cascade that culminates in a second class of glutamate receptors. Alpha amino three hydroxy five methyl four isoxazolepropionic acid, AMPA for short, inserting into the membrane. In this case, more positive ions flow into the neuron making a stronger postsynaptic response to the same presynaptic stimulation.

LTP is essential for learning, and is one way to explain the adage practice makes perfect since the newly strengthened response can last from minutes to weeks or longer if the presynaptic stimulation persists.

18.10: Long-term Potentiation

Long-term potentiation, or LTP, is one of the ways by which synaptic plasticity&mdashchanges in the strength of chemical synapses&mdashcan occur in the brain. LTP is the process of synaptic strengthening that occurs over time between pre- and postsynaptic neuronal connections. The synaptic strengthening of LTP works in opposition to the synaptic weakening of long-term depression (LTD) and together are the main mechanisms that underlie learning and memory.

Hebbian LTP

LTP can occur when presynaptic neurons repeatedly fire and stimulate the postsynaptic neuron. This is called Hebbian LTP since it follows from Donald Hebb&rsquos 1949 postulate that &ldquoneurons that fire together wire together.&rdquo The repeated stimulation from presynaptic neurons induces changes in the type and number of ion channels in the postsynaptic membrane.

Two types of postsynaptic receptors of the excitatory neurotransmitter glutamate are involved in LTP: 1) N-methyl-D-aspartate or NMDA receptors and 2) &alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or AMPA receptors. Although NMDA receptors open upon glutamate binding, their pore is usually blocked by magnesium ions that prevent other positively charged ions from entering the neuron. However, glutamate released from presynaptic neurons can bind to postsynaptic AMPA receptors, causing an influx of sodium ions that results in membrane depolarization. When the postsynaptic membrane is depolarized by multiple frequent presynaptic inputs, the magnesium ion blocking the NMDA receptor pore is displaced, allowing sodium and calcium ions to flow into the neuron.

The increased calcium ion influx then initiates a signaling cascade that culminates in more AMPA receptors being inserted into the plasma membrane. Alternatively, the signaling cascade may phosphorylate glutamate receptors&mdashenabling them to stay open for a longer duration and enhancing the conductance of positively charged ions into the cell. As a result, the same presynaptic stimulation will now evoke a stronger postsynaptic response given that more glutamate receptors will be activated and more positively charged ions will enter the postsynaptic neuron. The amplification that occurs is known as synaptic strengthening or potentiation.

The adage &ldquopractice makes perfect&rdquo can be partly explained by LTP. When a novel task is being learned, new neural circuits are reinforced using LTP. After each iteration of practice, the synaptic strength in the neural circuits become stronger, and soon the task can be performed correctly and efficiently. The newly strengthened connections can last from minutes to weeks or longer if the presynaptic stimulation persists, meaning that each subsequent time the task is performed the LTP is maintained.

LTP and Disease

When LTP functions normally, we can learn and form memories with ease. However, abnormalities in LTP have been implicated in many neurological and cognitive disorders such as Alzheimer&rsquos disease, autism, addiction, schizophrenia, and multiple sclerosis. A better understanding of the mechanisms behind LTP could eventually lead to therapies.

Nicoll, Roger A. &ldquoA Brief History of Long-Term Potentiation.&rdquo Neuron 93, no. 2 (January 18, 2017): 281&ndash90. [Source]

Bliss, T. V. P., G. L. Collingridge, and R. G. M. Morris. &ldquoSynaptic Plasticity in Health and Disease: Introduction and Overview.&rdquo Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1633 (January 5, 2014). [Source]

Watch the video: Long Term Potentiation LTP basics (August 2022).