Do We Really Forget? Fathoming The Esoteric Realms of Memory

“Smells like teen spirit”, but it could be true that we never really loose any memory in our lifetime. Our memories are stored in the synapses (junction, more specifically, gaps between adjoining neurons) as a function of synaptic strength, in the nerve cells like dendrites as proteins, and some other processes which mostly encompasses a chemical interaction. I am excluding memories such as T cell or B cell memories here; memory, here, will refer to neural ones that occur in the CNS.

We know that in dementias such as global multi infarct dementia, Alzheimer’s disease; there are diffuse losses of neurons and losses of cholinergic neurons in particular, respectively. In surgical cases of epilepsy or brain tumor, there are losses of neurons too. In these cases, memory loss may be irrecoverable, though cases are on record which points to shifting of those memories into some other safe havens. But what about the rest of the population? Does an established long term memory vanish completely?

Let’s consider some facts. The numbers of synapses and their strengths are finite, though both can change in response to stimuli. Even the number of neuron themselves can increase, contrary to the belief held earlier. Neuronal stem cell pool has been identified in the brain. Memories stored in the brain are finite too. Memories are inherently dynamic in nature. Even long term memory stored in the neocortex (medial temporal lobe, on the other hand, stores memories as a buffer, like a D RAM chip, a temporary storage) can change location, as much as transferring itself to the other hemisphere (intercortical transfer), when needed; via the optic chiasm and corpus callosum. So, we see that the number of synapses, though finite, can rise to the demand of an enhanced input from sensory cues which are finite too, leading to memories that can jump across their own allocated territories. A finite brain capacity (say C) can certainly contain a finite memory (say M) as long as C is greater than/ equal to M. Certain computer softwares even trespass this limit; a zip file of 2 MB may deliver 3MB of contents on unzipping! Who knows if the brain isn't using this for the past thousand years.

Synapses, simplistically, may be thought of in binary terms: 1, when it is on; 0, when it is off. Both 1 and 0 is a bit in Boolean terms. We leave aside the synaptic strength part here for the sake of simplicity. In addition, memories may shuttle between synapses in such a way so that it is present in the brain, but not represented by any synapse. I will explain. We all have seen those jugglers juggling those colorful balls too many at a time using only their two hands. A similar thing like dipole dynamics may occur in the brain. Added to this is quantum superposition, which allows the situation of BOTH 1 and 0 state at the same time at the synapse. That the brain can be in a quantum state at the core body temperature and the brain can effectively avoid ‘decoherence’ in the background thermal noise has been discussed by Roger Penrose and Stuart Hameroff. We also know that memories aren’t kept as such, but they are fragmented into individual elements, which are mostly matched to existing elements and are associated. This is economic as it saves space, and useful for indexing and contextual retrieval.

Thus it seems that we ought to have immense memory storage. Haven’t we encountered long forgotten memories in our dreams? Electrical stimulations in some parts of the hippocampus (deep brain stimulation or DBS, figure shown) during routine surgical procedures have given rise to ‘deja vu’ phenomena. The patients remembered things considered long forgotten. We may not be aware of the vast database of memories and are liable to infer that we have “killed ‘em all”, but in reality this may not be the case as Norio Ota et al clearly points it out in their paper. It smells like another chapter from your favorite science fiction novel, but it could be true.

Last modified: never; N.B.There is a substantial amount of speculation in this paper. Please exercise your own judgment and enlighten me about any possible error.
Reference: hyper-links, unless specifically mentioned.

LTP Ensures That Memories Are Forever

LTP or Long term potentiation is a process that may explain how memory gets stored in the brain for long term use. When you stimulate the presynaptic neuron by giving a brief (of transient duration) but rapid train of stimulus, the post synaptic neuron adjusts its ‘weight of association’ with respects to the presynaptic one, in the form of a chemical reaction. Though LTP occurs throughout the brain, it has been studied mostly in the hippocampus. If we are to understand the underlying molecular mechanism of memory, we can not do without LTP.

Two different types of LTP are known: mossy fiber LTP and Schaffer collateral type LTP. While the basis of mossy fiber LTP is not clearly known; it involves modification of the presynaptic terminal, and is independent of NMDA. A schematic and functional diagram for Schaffer collateral LTP is presented here. But before that, allow me to digress a little bit.

Your computer has a DRAM (Dynamic Random Access Memory) memory chip: memory because it can store and retrieve information; Random access as it allows you to search anywhere within the memory at random (it does not have to reach D via A through B, and then through C, sequentially), and dynamic, since the memory needs to be refreshed from time to time. To store a bit of data in memory, your computer charges devices called ‘capacitors’ within the chip, which retain their charge; and all your computer have to do is to read the data in the form of those stored charges for later retrieval. But these capacitors lose their charge over time and hence dynamic refreshing is necessary to maintain their memory.

You’ll now understand why this digital analogy as we discuss LTP. The picture on the left portrays a presynaptic neuron which discharges glutamate, the main excitatory neurotransmitter of the brain and the spinal cord. Glutamate after being released upon the stimulation of the presynaptic terminal, binds with their ‘receptors’ in the postsynaptic neuron. The post synaptic neuron, downstream, has 2 types of Glutamate receptors: NMDA (N methyl D Aspartate) and AMPA (alpha Amino 3 hydroxy 5 Methyl isoxazole 4 Propionate). Glutamate binds with both NMDA and AMPA receptors. NMDA receptors have a Magnesium ion, guarding at its channel entry. So, for NMDA receptors to act, it needs to be partially depolarized first, so that this magnesium block is removed. This is achieved by the AMPA receptors, which upon binding with glutamate, allows the entry of Sodium ions inside, thereby raising the cell voltage. NMDA receptors now swing into action as it now allows huge amounts of Calcium ions (and Sodium ions) to enter inside.

These Ca++ then bind with Calmodulin present within the cell to form a complex, which then activates calcium-calmodulin kinase 2 (Ca/Cam k2). This newly formed compound then activates (phosphorylates) AMPA receptors, resulting in: 1) increased activity conductance of the already existing AMPA receptors in the cell membrane 2) Recruitment of AMPA receptors from within the cell to the cell membrane. So we can see that the synaptic strength is increased with each firing by both AMPA recruitment and increased AMPA conductance. The synapse stops at not only this, the postsynaptic neuron also discharges a ‘diffusible’ messenger, nitric oxide (NO), which 'tells' the presynaptic neuron to discharge more quantal release of glutamate next time. The phenomenon epitomizes Hebbian learning: Cells that fire together, wire together.

But the memories so formed need to be stabilized as in the case of DRAM. In the central nervous system, dendritic spines are the main postsynaptic sites. These tiny protrusions form and change over a few hours. In hippocampal slice cultures it was shown, by De Roo and colleagues, that application of theta burst remodeled the dendritic spines; unused ones were shed (trimmed) while used ones were stabilized and new spines were formed. LTP was the chemical basis of all these modifications. They used GFP or green fluorescent protein for visualizing these changes of neural plasticity. However, they (physical units of memory) can also be seen by restorative deconvolution microscopy, in the form of flattened synapses (as if the ohmic resistance getting diminished in their electronic cousins) and hence more area for contact between the pre and postsynaptic neurons. So like DRAM chips, our memory chips too need to be constantly refreshed, even long term memories need maintenance.

Last modified: Jun 26, 2010
Reference:Dominique Muller, Morgan Sheng, Mathias De Roo, Paul Klauser, & Morgan Sheng (2008). LTP Promotes a Selective Long-Term Stabilization and Clustering of Dendritic Spines PLoS Biology

The Binding Of Memory And Hebbian Learning

Imagine this. Your physics professor is taking his regular class, and a boy sneezes. The professor is startled and the chalk falls from his hand. The whole class breaks into laughter. The memory of this particular incident gets stored in your head.

The whole process is somewhat like this. The visual scenes (your teacher’s attire, the chalk and the blackboard etc) are analyzed and processed in the visual association areas; the sounds (sneeze, laughter) get processed in the sound processed in their respective association areas and so on. Thus memory seems to be broken down to its individual elements; and these elements confine themselves in the areas in the neocortex where they were first processed.


Hippocampus (means sea horse in Greek) is a small banana shaped structure inside the brain. It gets its input from these association areas via another structure called the parahippocampal cortex. Hippocampus, as if, queries those areas: ‘what happened’, ‘when did it happen’ and ‘where did it happen’? Then the hippocampus binds all those information in the form of an event. For this particular episodic memory (classroom drama); the hippocampus wires together the respective areas so that the whole event is now bound together into an ‘engram’, the proposed neuro-anatomical representative of a particular memory.

While all these are happening in the medial temporal lobe (MTL), more specifically the hippocampus, the actual memory elements are still in the neocortex. With each recapitulation, voluntary (by thinking about the incident) or involuntary (someone else’s sneezing reminds you of that event), the association gets stronger. Thinking of sneezing (memory stored in neuron A) reminds you of chalk falling (neuron B). This way as A becomes active (fires), B is associated too, and this leads to wiring them. This is known as 'Hebb’s rule', after Donald Hebb, a Canadian scientist. Simply put, it says, ‘cells that fire together, wire together’.

The strengthening of synapses as a basis of learning were later found to have been mediated in part to LTP or long term potentiation, a chemical process. While the memories are being strengthened this way, the neocortical areas become more and more inter-connected. This releases the MTL connection, as the memory finally gets settled in the neocortex. This 'plasticity' is important. The neocortex stores memories effectively, has a large storage space, but it learns slowly. The MTL learns quickly, but has little storage space. One can think of neocortex as the ‘hard disk’ and MTL as the ‘RAM’ of a computer. Freeing the MTL would enable it to acquire memory more efficiently.

No wonder my teacher said, ‘Read once, write twice, think thrice’. Its time we consolidated our memories by recap.  

Last modified: never
Reference: hyper-links, unless specifically mentioned

Dendrites and Memories

In my previous post 'Spiny Dendrites', I discussed about dendrites' role in learning and memory as well as its role in evoking consciousness. Exactly how these dendrites learn and more importantly memorize, has not been clearly understood, but they are being discovered at a rapid pace.

On the dendritic cell membrane, nerve endings from various other neurons converge at the synapse, the gap between those neuronal processes and the neurone on which it is converging upon. The synapses are generally chemically coupled (by neurotransmitters), but they may also be electrically coupled (as in the lateral vestibular nucleus) or both electrical and chemical coupling may be found (conjoint). Chemical coupling is the most common. In this mode of signal transmission, whenever a presynaptic nerve gets an electrical signal (in the form of an action potential), it releases a neurotransmitter (the chemical coupler) into the synaptic cleft. The post-synaptic nerve (the nerve it verges upon, downstream) senses these chemicals (acetylcholine, adrenaline, glutamic acid, GABA etc) by virtue of 'receptors', located mostly in the 'post synaptic densities' (thickened portions of post-synaptic dendritic/neuronal cell membranes, adjacent to that part of the presynaptic membranes releasing the neurotransmitters, i.e. the synaptic vesicles).

Recently, it has been discovered that PSD-95 (post synaptic density-95), a key protein constituent (of postsynaptic densities), on which other proteins are assembled, needed to be phosphorylated, for it to act correctly (as a scaffold, for other proteins to act). Researchers suggested that this (phosphorylation) could help improve cognitive function in schizophrenia, autism and depression. I, personally, think that they will be of use as nootropics too.

In another development in neurobiology, it was shown that memories were burned into the neurons (as you burn 'memories' into a CD using Nero or other programs), and these basic units of memories had to be constantly recycled so that the memories remained there. These memory units, in the form of 'receptors' (of the neurotransmitters; which were located in the postsynaptic neuronal membranes), were in constant motion within the 'fluid' cell membranes. This 'recycling' might explain how the dendritic spines maintain their characteristic identity despite constant molecular turnover. This research might help us fight neurological disorders, such as Alzheimer's disease, schizophrenia, or learning disorders like autism.