I Can’t Sleep - Long-term Potentiation | Gentle Bedtime Reading

Episode Date: September 5, 2024

Ease into rest with this calm bedtime reading about long-term potentiation, a fascinating process in neuroscience that explains how our brains strengthen connections and form lasting memories. Benjamin’s soothing narration explores the science, discovery, and importance of this concept, all delivered in a steady and peaceful cadence. With fact-filled storytelling—no whispers, no hypnosis—this episode helps quiet restless thoughts, ease insomnia, and reduce stress while you gently learn. Perfect for sleepless nights or calming the mind after a long day. Press play, relax, and drift into sleep with long-term potentiation. Want More? Request a Topic: https://www.icantsleeppodcast.com/request-a-topic Ad-Free Episodes: https://icantsleep.supportingcast.fm/ Shop Sleep-Friendly Products: https://www.icantsleeppodcast.com/sponsors Join the Discussion on Discord: https://discord.gg/myhGhVUhn7 This content is derived from the Wikipedia article on Long-term Potentiation, available under the Creative Commons Attribution-ShareAlike (CC BY-SA) license. Read the full article: Wikipedia – Long-term Potentiation. Happy sleeping! Learn more about your ad choices. Visit megaphone.fm/adchoices

You're listening to a Glassbox media podcast. What if I told you that most of the modern day self-help advice you've been hearing could actually make you worse? The key to a better life isn't about feel-good gimmicks that sound catchy. The Mentally Stronger Podcast gives you access to a licensed therapist who shares science-backed tools that will actually change your life. Hi, I'm Amy Morin, psychotherapist, mental strength trainer, and international best-selling author. In each episode, we cover research-back strategies, like how to stop relying on willpower and start creating habits for lasting change. And the five mental strength-building exercises you can do from your couch.

I also speak to world-class experts like Dr. Nicole Kane, who shares how to permanently heal anxiety by addressing the root cause. With over 200 episodes in our catalog, this podcast is for you if you're ready to crush self-doubt, conquer challenges, and become stronger than ever with therapist-approved strategies that can change your life. Listen to Mentally Stronger with Therapist Amy Morin, wherever you get your podcasts. Welcome to the I Can't Sleep Podcast, where I read random articles from across the web to bore you to sleep with my soothing voice. I'm your host, Benjamin Boster. Today's episode is from a Wikipedia article titled Long-Term Potential.

In neuroscience, long-term potentiation, LTP, is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength. As 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. LTPE was discovered in the rabbit hippocampus by Teriolomo in 1966.

and has remained a popular subject of research since. Many modern LTP studies seek to better understand its basic biology, while others aim to draw a causal link between LTP and behavioral learning. Still, others try to develop methods, pharmacologic or otherwise, of enhancing LTP to improve learning and memory. LTP is also a subject of clinical research, for example, in the areas of Alzheimer's disease and addiction medicine. At the end of the 19th century, scientists generally recognize

that the number of neurons in the adult brain, roughly 100 billion, did not increase significantly with age. Having neurobiologists, good reason to believe that memories were generally not the result of new neuron production. With this realization came the need to explain how memories could form, in the absence of new neurons. The Spanish neuroanatomist Santiago Romon Icahal was among the first to suggest a mechanism of learning

that did not require the formation of new neurons. In his 1894 Crunian lecture, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. Hebbian theory, introduced by Donald Hebb in 1949, echoed Ramon Icahal's ideas, further proposing that cells may grow new connections or undergo metabolic and synaptic changes that enhance their ability to communicate and create a neural network of experiences.

Let us assume that the persistence of repetition of a reverberatory activity, or trace, tends to induce lasting cellular changes that add to its stability. When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells, such that A's efficiency, as one of the cells firing B, is increased. Eric Candell, 1964, and associates were some of the first researchers to discover long-term potentiation during their work with C-slug aplegia.

They attempted to apply behavioral conditioning to different cells in the slug's neural network. Their results showed synaptic strength changes, and researchers suggested that this may be due to a basic form of learning occurring within the slug. though these theories of memory formation are now well established, they were far-sighted for their time. Late 19th and early 20th century neuroscientists and psychologists were not equipped with the neurophysiological techniques necessary

for elucidating the biological underpinions of learning and animals. These skills could not come until the later half of the 20th century had about the same time as the discovery of long-term potentiation. LTP was first observed by Terje Lomo in 1966 in the Oslo-Norway Laboratory of Per Anderson. There, Lomo conducted a series of neurophysiological experiments on anesthetized rabbits to explore the role of hippocampus in short-term memory. Lomo's experiments focused on connections or synapses from the Perfront pathway to the dentate gyrus. These experiments were carried out by stimulating presynaptic fibers of the perfron pathway

and recording responses from a collection of post-synaptic cells of the dentate gyrus. As expected, a single pulse of electrical stimulation to fibers of the perforin pathway caused exitory post-synaptic potentials, EPSPs, and cells of the dentate gyrus. What Lomo unexpectedly observed was that the post-synaptic cells' response to these single-pulse stimuli could be enhanced for a long period of time if he first delivered a high-frequency train of stimuli to the pre-synaptic fibers. When such a train of stimuli was applied, subsequent single-pulls stimuli excited stronger prolonged EPSPs in the post-synaptic cell population. This phenomenon whereby a high-frequency stimulus could produce a long-lived enhancement in the post-synactic cells response to subsequent single-pulse stimuli

was initially called long-lasting potentiation. Timothy Bliss, who joined the Anderson Laboratory in 1968, collaborated with Lomo, and in 1973, the two published the first characterizations of long-lasting potentiation in the Rabahippe. a campus. Bliss and Tony Gardner Medwin published a similar report of long-lasting potentiation and the awake animal which appeared in the same issue as the Bliss and Loma report. In 1975, Douglas and Goddard proposed long-term potentiation as a new name for the phenomenon of long-lasting potentiation. Anderson suggested that the authors chose long-term potentiation, perhaps because of its easily pronounced acronym, LTP. The physical and biological mechanism of LTP is still not understood,

but some successful models have been developed. Studies of dendritic spines, protruding structures on dendrites that physically grow and retract over the course of minutes or hours, have suggested a relationship between the electrical resistance of the spine and the effective synapse strength due to their relationship with intracellular calcium transients. Mathematical models such as BCM theory, which depends also on intracellular calcium in relation to NMDA receptor voltage gates, have been developed since the 1980s and modify the traditional a priori Hebian learning model, with both biological and experimental justification. Still, others have proposed rearranging or synchronizing the relationship between receptor regulation,

LTP, and synaptic strength. Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the cerebral cortex, cerebellum, amygdala, and many others. Robert Malenka, prominent LTP researcher, has suggested that LBelhoea, LTP may even occur at all exotory synapses in the mammalian brain. Different areas of the brain exhibit different forms of LTP. The specific type of LTP exhibited between neurons depends on a number of factors.

One such factor is the age of the organism when LTP is observed. For example, the molecular mechanisms of LTP in the immature hippocampus differ from those mechanisms that underlie LTP of the adult hippocampus. The signaling pathways used by a particular cell also contribute to the specific type of LTP present. For example, some types of hippocampal LTPE depend on the NMDA receptor. Others may depend upon the metabotropic glutamate receptor, M-G-L-U-R. While still others depend upon a non-M-M-M-D-A-R, other molecule altogether. The variety of signaling pathways that contribute to LTP and the wide

distribution of these various pathways in the brain are reasons that the type of LTP exhibited between neurons depend only in part upon the anatomic location in which LTP is observed. For example, LTPE in the Schaffer collateral pathway of the hippocampus is NMDA receptor dependent. This was proved by the application of AP5, an antagonist to the NMDA receptor, which prevented LTP in this pathway. Conversely, LTP in the mossy fiber pathway is NMDA receptor independent, even though both pathways are in the hippocampus. The pre- and post-synaptic activity required to induce LTP are often criteria by which LTP is classified.

Broadly, this allows classification of LTP into Hebbian, non-Hebion, and anti-Hebion mechanisms. Borrowing its name from Hebb's postulate, summarized by the maxim that cells that fire together wire together, Hebbian LTPureization for its induction. Non-Hebion LTP is a type of LTP that does not require such simultaneous depolarization. of pre- and post-synaptic cells. An example of this occurs in the mossy fiber hippocampal pathway. A special case of non-Hibbean LTP, anti-Hubian LTP explicitly requires simultaneous pre-synaptic depolarization

and relative post-synaptic hyperpolarization for its induction. Owing to its predictable organization and readily inducible LTP, the CA1 hippocampus has become the prototypical site of mammalian LTP study. In particular, NMDA receptor-dependent LTP in the adult CA1 hippocampus is the most widely studied type of LTP and is therefore the focus of this article. NMDA receptor-dependent LTP exhibits several properties, including input specificity, associativity, cooperativity, and persistence. Input specificity.

Once induced, LTP at one synapse does not spread to other synapses. Rather, LTP is input-specific. Long-term potentiation is only propagated to those synapses according to the rules of associativity and cooperativity. However, the input specificity of LTPicity of LTPICT. may be incomplete at short distances. One model to explain the input specificity of LTP was presented by Frey and Morris in 1997

and is called the synaptic tagging and capture hypothesis. Associativity Associativity refers to the observation that when weak stimulation of a single pathway is insufficient for the induction of LTP, Simultaneous strong stimulation of another pathway will induce LTP at both pathways. Cooperativity LTP can be induced either by strong titanic stimulation of a single pathway to a synapse or cooperatively via the weaker stimulation of many.

When one pathway into a synapse is stimulated weakly, it produces insufficient post-Synaptic depolarization to induce LTP. In contrast, when weak stimuli are applied to many pathways that converge on a single patch of post-synaptic membrane, the individual post-synaptic depolarizations generated may collectively depolarize the post-synaptic cell enough to induce LTPortively. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and cooperativity. Bruce McNaughton argues that any difference between associativity and cooperativity is strictly semantic. Experiments performed by stimulating an array of individual dendritic spines have shown that synaptic cooperativity by as few as two adjacent dendritic spines

prevents long-term depression, LTT, allowing only LTP. Persistence LTP is persistent. lasting from several minutes to many months, and it is this persistence that separates LTP from other forms of synaptic plasticity. Maintenance While induction entails a transient activation of CAMKI and PKC, maintenance of E LTP, early form LTP, is characterized by their persistent activation. During this stage, PKM Zeta, which does not have dependence on calcium, become autonomously active.

Consequently, they are able to carry out the phospholation events that underlie ELTP expression. Phospholation is a chemical reaction in which a small phosphate group is added to another molecule to change that molecule's activity. Autonomously active CAMKI and PKC use phospholation to carry out the two major mechanisms underlying the expression of ELTP. First and most importantly, they phosphorylate existing AMPA receptors to increase their activity. Second, they mediate or modulate the insertion of additional AMPA receptors into the posts, synaptic membrane. Importantly, the delivery of AMPA receptors to the synapse during ELTP is independent of protein synthesis. This is achieved by having a non-synaptic pool of AMPA receptors adjacent to the post-synaptic membrane. When the appropriate LTP-inducing stimulus arrives, non-synaptic AMPA

receptors are rapidly trafficked into the post-synaptic membrane under the influence of protein kinasis. As mentioned previously, AMPA receptors are the brain's most abundant glutamate receptors and mediate the majority of its excitatory activity. By increasing the efficiency and number of AMPA receptors at the synapse, future exotory stimuli generate larger post-synaptic responses. While the above model of ELTP describes entirely post-synaptic mechanisms for induction, maintenance, and expression. An additional component of expression may occur presynaptically. One hypothesis of this pre-synaptic facilitation is that persistent CAMK-I-I activity in the post-synaptic cell during ELTP may lead to the synthesis of a retrograde messenger, according to this hyperstic.

hypothesis, the newly synthesized messenger travels across the synaptic cleft from the post-synaptic to the presynaptic cell, leading to a chain of events that facilitate the presynaptic response to subsequent stimuli. Such events may include an increase in neurotransmitter vesicle number, probability of vesicle release, or both. In addition to the retrograde messenger underlying pre-synaptic expression in early LTP, the retrograde messenger may also play a role in the expression of late LTP. Late LTP is the natural extension of ELTP. Unlike ELTP, which is independent of protein synthesis, LLP requires gene transcription and protein synthesis in the post-synaptic cell. Two phases of LLP exist. The first depends upon protein synthesis, while the second depends

upon both gene transcription and protein synthesis. These phases are occasionally called LTP2 and LTP3 respectively, with E LTP referred to as LTP1 under this nomenclature. Induction. Late LTP is induced by changes in gene expression and protein synthesis brought about by the persistent activation of protein kinasis activated during ELTP such as MAPK. In fact, MAPK specifically the extracellular signal regulated kinase, ERK, subfamily of MAPKs, may be the molecular link between ELTPPP and H. LLTP, since many signaling cascades involved in ELTP, including CAMKII and PKC, can converge on ERK. Recent research has shown that the induction of LLTP can depend on coincident molecular events, namely P-K-A activation and calcium influx that converge on CRT-C-1, T-O-R-C-C-1, a potent transcriptional co-activator for CAMP response element binding protein, Kreb.

This requirement for a molecular coincidence accounts perfectly for the associative nature of LTP, and presumably for that of learning. Maintenance Upon activation, ERK may phosphorlate a number of cytoplasmic and nuclear molecules that ultimately result in the protein synthesis and morphological changes observed in LLTP. These cytoplasmic and nuclear molecules may include transcription factors such as Kreb. ERK mediated changes in transcription factor activity may trigger the synthesis of proteins that underlie the maintenance of LLTP. One such molecule may be protein kinase, a persistently active kinase,

whose synthesis increases following LTP induction. Retrograde signaling is a hypothesis that attempts to explain that while LTP is induced and expressed post-synaptically, some evidence suggests that it is expressed pre-synaptically as well. The hypothesis gets its name because normal synaptic transmission is directional and proceeds from the pre-synaptic to the post-synaptic cell. For induction to occur post-synaptically and be partially expressed pre-synaptically, a message must travel from the post-synaptic cell to the pre-synaptic cell in a retrograde, reverse direction. Once there, the message presumably initiates a cascade of events that leads to a pre-synaptic component of expression,

such as the increased probability of neurotransmitter vesicle release. Retrograde signaling is currently a contentious subject, as some investigators do not believe the presynaptic cell contributes at all to the expression of LTP. Even among proponents of the hypothesis, there's controversy over the identity of the messenger. Early thoughts focused on nitric oxide, while most recent evidence points to cell adhesion proteins. Before the local protein synthesis hypothesis gained significant support, there was general agreement that the protein synthesis underlying LLP occurred in the cell body. Further, there was thought that the products of this synthesis were shipped cell-wide in a non-specific manner. It thus became necessary to explain how protein synthesis could occur in the cell body

without compromising LTP's input specificity. The synaptic tagging hypothesis attempts to solve the cell's difficult problem of synthesizing proteins in the cell body, but ensuring they only reach synapses that have received LTP inducing stimuli. The synaptic tagging hypothesis proposes that a synaptic tag is synthesized

at synapses that have received LTP inducing stimuli. and that this synaptic tag may serve to capture plasticity-related proteins shipped cell-wide from the cell body. Studies of LTP in the marine snail Applegia, California, have implicated synaptic tagging as a mechanism for the input specificity of LTP. There is some evidence that given two widely separated synapses, and LTP inducing stimulus at one synapse drives several signaling cascades that initiates gene expression in the cell nucleus. At the same synapse, but not the unstimulated synapse, local protein synthesis creates a short-lived, less than three hours, synaptic tag.

The products of gene expression are shipped globally throughout the cell, but are only captured by synapses that express the synaptic tag. Thus, only the synapse receiving LTP-inducing stimuli is potentated, demonstrating LTP's input specificity. The synaptic tag hypothesis may also account for LTP's associativity and cooperativity. Associativity is observed when one synapse is excited with LTP inducing stimulation, while a separate synapse is only weakly stimulated. Whereas one might expect only the strongly stimulated synapse to undergo LTP,

both synapses will in fact undergo LTP. While weak stimuli are unable to induce protein synthesis in the cell body, they may prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, of inducing cell-body protein synthesis, then may prompt the production of plasticity-related proteins, which are shipped cell-wide. With both synapses expressing the synaptic tag,

both would capture the protein products resulting in the expression of LTP and both the strongly stimulated and weakly stimulated pathways. Co-operativity is observed when two synapses are activated, by weak stimuli, incapable of inducing LTP, when stimulated individually. But upon simultaneous weak stimulation, both synapses undergo LTP in a cooperative fashion. Synaptic tagging does not explain how multiple weak stimuli can result in a collective stimulus sufficient to induce LTP. Rather, synaptic tagging explains the ability of the ability of,

of weakly stimulated synapses, none of which are capable of independently generating LTP to receive the products of protein synthesis initiated collectively. As before, this may be accomplished through the synthesis of a local synaptic tag following weak synaptic stimulation. As described previously, the molecules that underlie LTP can be classified as mediators or modulators. A mediator of LTP is a molecule, such as the NMDA receptor or calcium, whose presence and activity is necessary for generating LTP under nearly all conditions.

By contrast, a modulator is a molecule that can alter LTP, but is not essential for its generation or expression. In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the steroid hormone estradial may enhance LTP by driving crab phospholation and subsequent dendritic spine growth. Nitric oxide synthase activity may also result in the subsequent activation of guanolocytes and PKG. Similarly, activation of dopamine receptors enhance LTPs. through the Camp PKA signaling pathway.