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Long Term Potentiation Is A Speed-Dial Gizmo For Human Memory

Long term potentiation (LTP) is not the basis for human memory, but merely assists the speedy retrieval of critical memories. It is not LTP, but a galactic store of combinatorial codes, which power human memory. While LTP manages an elemental “Dial 100” aspect, combinatorial memories handle the whole phone directory.

Memory is not about responding to an emergency. It concerns the vast stores of human knowledge, including a normal person's ability to recognize each one of 10,000 images displayed to him at 1 second intervals. Visual memories involve the combinatorial arrangements of millions of pixels.

While a neuron can theoretically remember millions of combinations, its LTP memory can only be as large as the number of its dendrites. Yet, science continues to focus research on LTP, rather than on combinatorial coding. LTP acts merely as a sensitive loudspeaker for important news.

• The possible ways in which human memories can be stored in nerve cells have been extensively evaluated by science.
  
• With LTP, the postsynaptic cell continues to be excited for long periods on receiving just a single pulse stimuli from the presynaptic cell.
  
• Harvard scientists listed 117 molecules involved at the synaptic junctions which could increase LTP sensitivity.
  
• Persistent LTP is also associated with the presynaptic synthesis of an increase in the number of synaptic vesicles.
  
• LTP can be induced either by strong stimulation of a single pathway to a synapse, or cooperatively via the weaker stimulation of many.
  
• LTP converts a casual response into persisting distress.
  
• Enhanced NMDA receptor activity in the hippocampus produces enhanced LTP and improvement in spatial learning.
  
• LTP does not help us to remember what we had for dinner last week.
  

Long Term Potentiation
What Is The History Of Long Term Potentiation?
The possible ways in which human memories can be stored in nerve cells have been extensively evaluated by science. The 100 billion or so neurons in the adult brain do not increase significantly in number with age. Since there is a real increase in human data storage with age, memories are evidently not added by increasing the number of nerve cells. It was Cajal, who first proposed that memories might be stored across synapses, the junctions which enable communication between neurons. Hebb proposed that continuous excitation of one cell by another could trigger growth processes or metabolic changes, which improve such communication.

Terje Lomo first discovered that the responses of nerve cells to inputs from other cells could be enhanced over the long term by a suitable application of high frequency trains of stimuli. In 1975, Douglas and Goddard proposed "Long Term Potentiation" as the name of this phenomenon. Since the mechanism appeared to “remember” a neural event, LTP became the focus of research to discover the basis for human memory. But an LTP store of memory is physically limited by the number of synapses in the nervous system. Long term potentiation cannot account for the massive expansion of knowledge and experience with age. Only combinatorial codes can explain the significantly expandable scale and size of human memory.

Long Term Potentiation
How Does LTP Work?
In the nervous system, synapses are junctions, which enable one neuron to pass a signal to another cell. Information signals pass from the presynaptic neuron to the postsynaptic cell. Such signals are transmitted in the form of neurotransmitter molecules. Normally, a single pulse of electrical stimulation to fibers in the pathway to the presynaptic neuron will cause excitatory postsynaptic potentials (EPSPs) in the postsynaptic cells. In such a case, the response of the postsynaptic cell is normal and subdued.

But, such subdued cell responses change, when a high frequency train of stimuli is delivered to the presynaptic fibers. Then, the postsynaptic cells will keep firing for long periods of time in response to a single-pulse stimuli from the presynaptic cell. With LTP, the postsynaptic cell continues to be excited for long periods on receiving just a single pulse stimuli from the presynaptic cell. LTP creates a speed dial circuit, which becomes significantly more sensitive to faint neural messages. In essence, Long term potentiation is a facilitator for emergencies, not a store of memory.

Long Term Potentiation
What Is The Molecular Response?
Signals from the presynaptic cell are transmitted to the postsynaptic cell in the form of neurotransmitter (typically glutamate) molecules. These molecules bind to (mainly) AMPA neurotransmitter receptors on the surface of the postsynaptic cell. Glutamate binding to the AMPA receptor triggers the influx of positively charged sodium ions into the postsynaptic cell, causing the excitatory postsynaptic potential (EPSP).

AMPA receptors are the brain's most abundant glutamate receptors and mediate the majority of its excitatory activity. Repeated stimuli given at high frequency causes the postsynaptic cell to become progressively depolarized. LTP expression occurs through phosphorylation, which is a chemical reaction in which existing AMPA receptors increase their activity. They also mediate the insertion of additional AMPA receptors into the postsynaptic membrane. By increasing the efficiency and number of AMPA receptors at the synapse, future excitatory stimuli generate larger postsynaptic responses.

The process phosphorylates a number of molecules, which result in the protein synthesis. Harvard scientists listed 117 molecules involved at the synaptic junctions which could increase LTP sensitivity. One such molecule may be PKMz, which assists in the maintenance of long-term memory. Administration of a PKMz inhibitor into the hippocampi of rats results in retrograde amnesia with intact short-term memory. PKMz is not believed to play a role in the establishment of short-term memory.

Long Term Potentiation
How Does Persistent Activation Operate?
Protein receptors, which respond to events outside of the cell, enzymes, which trigger chemical reactions within the cell, along with signaling molecules enable the induction, maintenance and persisting expression of LTP. Repeated stimuli given at high frequency removes a magnesium ion, which prevents the entry of calcium into the postsynaptic cell and unblocks NMDA receptors present at postsynaptic membranes. While such induction entails transient activation, LTP is characterized by persistent activation.

Persistent activation is triggered by PKMz molecules, first discovered by Dr. Sacktorat. They are not dependent on calcium and increase the activity and number of of AMPA receptors. The PKMz molecules formed into precise fingerlike connections among brain cells that were strengthened. When a drug, which interferes with PKMzeta was injected directly into the brain, the animals forgot their induced fear. The animals even forgot a strong disgust they had developed for a taste after the administration of the drug. It was hoped that by disabling LTP, the drug could blunt painful memories and addictive urges.

Aside from PKMz, a few proteins synthesized during LTP contribute to an increase in dendritic spine number, surface area, and postsynaptic LTP sensitivity. Persistent LTP is also associated with the presynaptic synthesis of an increase in the number of synaptic vesicles. LTP enables the system to be sensitive to messages critical to survival.

Long Term Potentiation
How Is LTP Induced?
Once induced, LTP at one synapse does not spread to other synapses. While it is input specific, it associates and cooperates with other relevant inputs. While weak stimulation of a single pathway is insufficient for the induction of LTP, simultaneous strong stimulation of another pathway will induce associated LTP at both pathways. LTP can be induced either by strong stimulation of a single pathway to a synapse, or cooperatively via the weaker stimulation of many. Weak stimuli applied to many pathways converging on a single patch of postsynaptic membrane causes cooperative induction of LTP. LTP is persistent, lasting from several minutes to many months.

Long Term Potentiation
What Is The Speed Dial Effect?
The unique persistence of LTP is the main cause of much emotional discomfort. LTP has been observed in many regions, including the cerebral cortex, the hippocampus and the cerebellum. But, it is the process in the amygdala, which troubles you. This bundled network of neurons receive sensory inputs and trigger control responses. Nerve cells bring it inputs from sight, sound, touch, taste and pain systems. Combinatorial memories within the amygdala identify those signals, which threaten survival and trigger appropriate control impulses.

Impulses from the amygdalae to the brainstem trigger (typically jumpy) avoidance behaviors. They activate the sympathetic nervous system, raising blood pressure and heart beats. These impulses sent to the facial nerves generate expressions of anger, fear, or disgust. Those impulses release neurochemicals, which increase the intensity of fight, flight or freeze responses. Normally, the sensory inputs, which imply threats would only a momentary response from the system. But, LTP generates persisting control impulses. In the process, it converts a casual response into persisting distress. LTP is the main cause of acute emotional discomfort.

Long Term Potentiation
Does LTP Operate In The Hippocampus?
The hippocampus, a component of a region of the brain called the limbic system, is believed to be associated with the formation of human memory. Damage to the hippocampus is known to cause patients to forget ongoing events within a few seconds. But, incidents from childhood and early adult life were still remembered. Memory had faded from a couple of years prior to the event that caused damage to the hippocampus. Older memories were still retained by the patient even without the hippocampus. Evidently, the organ does not store such memories. It plays a role in recording durable memories into nervous system.

But regions called place fields in the hippocampus are believed to play a major role in storing spatial memories in mice. It is believed that groups of place cells form maps and become active only when the rat is in a particular location in the environment. The accuracy of these maps determines how well a rat can navigate. Susumu Tonegawa found that by impairing the NMDA receptor in the hippocampus in test animals, the place fields generated were substantially less specific than those of controls. Rats produced faulty spatial maps when their NMDA receptors were impaired and performed very poorly on spatial tasks compared to controls. Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning.

Long Term Potentiation
What Are The Effects Of High Frequency Stimulation & Stress?
LTP induced by high frequency stimulation appears to be the same as LTP induced by stress. The synapses potentiated during training could not be further potentiated through high frequency stimulation. Experimental spatial learning for rats is evaluated through the distressing possibility of foot shocks or drowning. For mice, a foot shock is a terrifying experience, which generates structural and electrical changes in its nervous system, preparing it for a swift response to future disaster. LTP is essentially a speed dial circuit for emergencies.

Long Term Potentiation
What Is Combinatorial Coding?
Combinatorial memories imply an ability by millions of nerve cells to individually recognize combinations of incoming nerve impulses. Such memories can store real time data regarding vision, taste, smell, touch and movement. Only such capabilities can justify the galactic range of real life neural memories. The mind stores visual memories of the thousands of places we have visited. It remembers our unique habitual movements, which require millions of motor events occurring thousands of times a second.

Combinatorial memories store the graceful moves of a ballet dancer, assembled through years of tedious practice. They store the vast inherited memories, which enable the flowing movements of centipedes and horses. LTP is merely a “Dial 100” circuit, which speeds up emergency messages. LTP does not help us to remember what we had for dinner last week. It is the mechanism, which will warn us tomorrow, if the meal caused us acute discomfort. 

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