Download TOT Phenomenon 1 Running Head: TOT Phenomenon Neural

TOT Phenomenon 1
Running Head: TOT Phenomenon
Neural Mechanism of the TOT phenomenon and its correlation with bilinguals
Ji Yoon Park
Bugil Academy GLP
The tip-of-the-tongue phenomenon is the feeling that a currently inaccessible item
will be recalled. In other words, it is a state in which there is evidence of knowledge but no
imminent retrieval for items. The TOT phenomenon has been actively researched for its
psychological origins such as the effects of emotion and lexical based studies on memory.
Molecules and cellular based studies have not been widely researched because it is hard to
precisely capture the moment when TOT phenomenon is occurring and it is even harder to
conduct a neural analysis at that moment. However, this paper aims to integrate the
mechanisms of long-term memory, organization of recent and remote memories, the
molecules involved in maintaining and inhibiting long-term memory, and the proposed
theories of system consolidation to posit a comprehensive hypothesis of how malfunctions in
long-term memory contribute to the TOT phenomenon. It is hypothesized that system
consolidation, a systemic memory mechanism different from a synaptic point of view, is
correlated with memory precision and PKM zeta, CaMKII, NMDAR, and AMDAR induces
memory reorganization and helps maintain long term memory. The following literature
reviews attempt to support the hypothesis.
In a review of the organization of recent and remote memories by Bontempi and
Frankland (2005), the cellular correlation of memory reactivation was shown. Memory
reactivation is the core mechanism in memory consolidation model. Reactivation of the
hippocampal memory leads to the reinstatement of experience-dependent patterns of neural
activity in the cortex. Subsequent stabilization and iterative refinement of cortical traces store
completely on the cortex, which becomes independent of the hippocampus. Baars and Gage
agree with the consolidation hypothesis as it relates to stabilization of long-term memory by
transferring temporary synapse connections to permanent traces. System consolidation is now
known to be triggered by the interaction between temporal lobe and neocortex activity.
Immediate memories are encoded as neurons in the neocortex that make new connections.
However, for permanent memories, RNA or protein synthesis is required. In this process,
dendrite spines grow and develop to a stabilized and rigid structure.
Long term potentiation (LTP) and long term depression (LTD) are also central to the
consolidation model since both only refers to consolidation at cellular level and local change
in synapse connection efficiency. Synapse mechanism, gene transcription, and protein
synthesis occur in order during the rapid consolidation process. According to the molecular
switch hypothesis proposed by Lisman, calcium ions (Ca2+) enter into a postsynaptic cell and
activate CaMKII in the CA1 region of the hippocampus before LTP occurs. Each subunit of
CaMKII catalyzes phosphorylation of substrate proteins in response to the increase of Ca2+calmodulin complex. The catalytic region performs a phosphorylation reaction. The
regulatory region normally covers the catalytic region which keeps the enzyme off. The hinge
opens on activation of the molecule by Ca2+-bound calmodulin, freeing the catalytic region to
add phosphate group to other proteins. Large increase in Ca2+ can cause autophosphorylation
(phosphorylation of one subunit by another), and enables the catalytic region to stay on
permanently. Persistent activity of CaMKII can contribute to maintaining the synaptic
potentiation by keeping postsynaptic AMPA receptors phosphorylated. α-CaMKII signaling
enzymes are expressed in excitatory forebrain neurons and have a crucial role in neuronal
plasticity. Therefore, under sudden pressure or stressful situations like when experimental
mice are in a “freezing” status, neuronal and cortical plasticity are more vulnerable to being
hindered to form remote hippocampus-independent memories, and result in premature
memory loss at extended retention delays. These deficits in cortical plasticity observed in
hippocampus-independent memories also show an overexpression of PAK (p21-activated
kinase) that regulates spinogenesis in neuronal cultures, which can serve as proof to the
occurrence of TOT phenomenon as well. These abnormalities are limited to the cortex, where
neurons have fewer dendritic spines and increased proportion of larger synapses. These
alterations are known to be associated with enhanced LTP but decreased LTD as well.
However, it is important to note that not only CaMKII molecules, but also MAPK (mitogenactivated protein kinase), PKA (protein kinase A), NMDAR neurotransmitters and CREB
(cyclic AMP-responsive element-binding protein) are involved in the initial stabilization of
memory and are not interrupted by those inhibitor agents. Lisman demonstrated that the role
of persistent signaling of molecules in memory maintenance but did not account the
morphology of synaptic connections into consideration.
Dudai, Shema, and Sacktor (2007) demonstrated from an experiment conducted on a
rat cortex that long-term associative memories vanished rapidly after local application of an
inhibitor of the protein kinase C isoform, PKM zeta. In the neocortex, which is assumed to be
the repository of multiple types of long-term memory, persistence of memory is dependent
ongoing activity of a protein kinase long after that memory is considered to have consolidated
into a long-term stable form. The main question this article addresses is whether persistent
phosphorylation by PKM zeta is critical for storage of long-term memory in cortex. Dudai,
Sacktor, and Shema investigated taste memory in the insular cortex, which contains the
gustatory cortex in an experimental rat’s brain and microinfused ZIP (selective PKM zeta
pseudosubstrate inhibitor) bilaterally into the insular cortex after three days and seven days.
The PKM zeta inhibitor blocked memory at all times showed difference between ZIP groups
at 3 days and 7 days and the controls and it demonstrated that the effect of ZIP on long-term
memory is rapid and is not eliminated by intensifying training. In this experiment done in
latent inhibition (LI), familiarity with the tastant attenuated its potency to serve as
conditioned stimulus in subsequent conditioned taste aversion (CTA) training and
microinfusion of ZIP into the insular cortex after exposure to the tastant in the LI protocol
had no effect on familiarity. Although it may be far-fetched to connect this experiment to
semantic and lexical memory within the TOT phenomenon because this experiment is only
limited to long term memory gustatory memory consolidation, it may be safe to conclude that
because PKM zeta inhibitor in the hippocampus did not impair CTA memory, the effect of
ZIP that could affect inhibiting a sudden recall of semantic memory is thus region-specific.
Sacktor (2011) raises several questions in his review paper are addressed: How does
a brief exposure to PKM zeta inhibitor (ZIP groups) rapidly disrupt a stable memory? After
inhibitors are removed, how can new memories be learned and stored with retraining? Lastly,
how does transiently inhibiting PKM zeta produce persistent retrograde memory erasure, with
no anterograde effect? PKM zeta is a constitutively active protein kinase C isoform,
expressed exclusively in neural tissue and enriched in the forebrain. It enhances postsynaptic
AMPAR responses, which mediate fast excitatory synaptic transmission in the brain through
continual phosphorylation. Sacktor posits that AMPAR-mediated synaptic transmission is
directly related to why LTP maintenance and memories that were stable become fragile with
the loss of PKM zeta activity. Agents that block the trafficking to the synapse-such as zeta
inhibitory peptide (ZIP) which inhibits PKM zeta and pep 2m which blocks NSF binding to
GluR2 prevent and reverse long-term potentiation (LTP) reverse. In LTP maintenance, PKM
zeta continues to decrease receptor endocytosis and enhances the action of NSF that prevents
PICK1-mediated postsynaptic removal of GluR2, thus stabilizing the increased number of
receptors at postsynaptic sites. In contrast, during LTP reversal of memory erasure by ZIP,
PKM zeta activity is inhibited and extra receptors from the synapse are removed. This review
supports the hypothesis that PKM zeta functions to maintain long-term memory and
temporary inhibition may hinder recall of certain memories. However, there is necessity for
more research on the substrates of PKM zeta phosphorylation that mediate synaptic
potentiation and how new information may be incorporated into PKM zeta-mediated memory
traces by reconsolidation. If the molecular mechanism of memory storage can be reduced to
the presence of absence of PKM zeta at specific synaptic regions, a memory trace can be
possibly quantified after humans learn and remember, such as by counting the number of
dendritic spines containing PKM zeta.