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MEMORY: WHERE AND HOW MEMORIES STORED?
Mohammad Hanafi
ABSTRACT
Human brain is considered to be the most complex structure in the universe. Research in memory began in early of nineteenth cen- tury. After more than forty years of study, they found where memory is stored temporarily, i.e. in the hippocampal formation and adjacent, anatomically related cortex: the perirhinal and parahippocampal cortices. Serotonin acts as neurotransmitter in implicit short-term memory storage, while glutamate involves in explicit short-term memory storage. For long-term memory storage, both implicit and explicit used the same core-signaling pathway, PKA, MAPK, and CREB-1. Short-term memory storage, either implicit or explicit does not required new protein synthesis, but undergone covalent modification of preexisting protein which cause increase synaptic strength, while the long term memory storage involve activation of gene expression, new protein synthesis and the formation of new connection.
Keywords : memory, implicit, explicit, hippocampus.
INTRODUCTION
Human brain is considered the most complex structure in the universe (Woolley, 2001). The brain weighs about 3 pounds, comprises about 97% of the central nervous system, 2% of body weight, and consumes 20% of body’s energy. It is estimated that the brain is a collec- tion of some 30 to 100 billion neurons with one trillion connections (Greengard, 2001; Anonymous1, 2003).
Hermann Ebbinghans performed the first human simple experimental method for studying learning and memory in 1885, followed a few years later in experimental ani- mals by Ivan Pavlov and Edgar Thorndike. This ex- perimental method of studying learning and memory lead to the development of empirical school of psychol- ogy called behaviorism. Behaviorists concentrated on examining objectively and precisely the relationship between specific physical stimuli and observable re- sponses in intact animal, but largely ignored mental processes. By the 1960’s, emerges new discipline of science named cognitive psychology. Unlike behavior- ists, it was also concerned on the flow of sensory recep- tors to its eventual use in memory and action. The neu- roscience has grown rapidly over the last half century. This has provided a new framework for the study of memory, perception, action, language, and conscious awareness. Cognitive neuroscience emerges as fusion of two disciplines, psychology and neurobiology. The fu- sion of these two disciplines was facilitated as well by the emergence of coherent neuroscience. In the cogni- tive neuroscience, an interdisciplinary approach to the nervous system might be usefully applied to the analysis of cognition (Miller, 1998).
Department of Biochemistry Airlangga University School of Medicine, Surabaya.
Within the discipline of cognitive neuroscience this pa- per is written focusing on memory and learning, as in- troduction, especially on where, and how in the molecu- lar level memory is stored. Very important definition must be introduced here; firstly, implicit memory – a memory for precept and motor skills – involves a vari- ety of anatomical systems (Schacter, 1994). Implicit memory is expressed through performance, without conscious recall of past episode. For example, one form of implicit memory, that for conditioned fear, involves the amygdale. Secondly, explicit memory (declarative memory) – a memory for facts, places, and events – requires the hippocampus and related medial temporal lobe structures. Explicit memory requires conscious recall ( Kandels, 2001).
WHERE ARE MEMORIES STORED?
At the beginning of the 19 th^ century, F.J. Gall studied the surface of the skulls of individuals, and divided the brain underneath into at least 27 regions. Each region corresponds to a specific mental faculty. He thought that even the most abstract and complex of human traits, such as generosity and secretiveness, are localized to discrete areas of the brain. Gall called this anatomically oriented approach to personality organology. Later it was evident that he misidentified the function of most parts of the cortex.
P.Flourens (1820) subjected Gall’s ideas into experi- mental analysis. From this experiments Flourens con- cluded that individual site in the brain are not sufficient for specific behaviors such as sexual behavior and ro- mantic love and that all regions of the brain especially the cerebral hemispheres of the fore brain participate in every mental function. He proposed that any part of the cerebral hemisphere is able to perform all the functions of the hemisphere.
In the period from 1920 to 1950, the debate between cortical localization and equipotentiality in cognitive function dominated thinking about mental process, in- cluding memory. Lashley (1929) explored the cerebral cortex in the rat, systematically removing different cor- tical areas. He found that there was no particular any brain region involved specifically in memory storage. Hebb (1949) in his book the organization of behaviors suggested that memory storage involves many parts of the brain. There was no apparent single memory center exists, and many parts of the nervous system participate in the representation of any single event. B. Milner (1957) was Hebb students who described the remark- able patient H.M. H.M. had sustained a bilateral resec- tion of the medial structures of the temporal lobe in 1953 to relieve severe epilepsy. Following the surgery H.M. had a very profound impairment of recent memory in the apparent absence of other intellectual loss. The works of W. Penfield in association with Milner from 1955 until 1964 on their patients and further proven by an autopsy finally showed that when both side of hippo- campus were deprived the patient suffered a severe, persistent, and generalized impairment of recent mem- ory.
In the year of 1991, Mort Mishkin and Zola Morgan established an animal model of human amnesia in the monkey. With the model, the question of precisely which structures within the medial temporal lobe were important could be systematically explored. The impor- tant structures are the hippocampus proper, the dentate gyres, the subicular complex, and the enthorhinal cortex (which together comprise the hippocampal formation) and adjacent, anatomically related cortex: the perirhinal and parahippocampal cortices.
A key feature of medial temporal lobe function is that the medial temporal lobe is involved in memory for a limited period after learning. The medial temporal lobe structures direct a gradual process of organization of cortical representations, for examples, by gradually binding together the multiple, geographically separate cortical regions that together store memory for a whole event. After sufficient time has passed, the hippocampal formation is not needed to support storage or retrieval of declarative memory and long-term memory is fully de- pendent on neocortex.
The different components of the medial temporal lobe need not have equivalent roles in declarative memory; different structures within the medial temporal lobe are likely to carry out different sub functions. As damage increase, fewer strategies may be available for storing memory, with the result that memory impairment be- come more severe.
LEARNING AND MEMORY
Learning is the process by which we acquire new knowledge, whereas memory is the process by which we retain that knowledge over time. Memory is the out come of learning. It is not possible to consider learning without memory or conversely, memory without learn- ing (Anonymous 2).
In Aplysia, simple reflex could be modified by three different form of learning: habituation, sensitization, and conditioning. Memory storage for each type of learning in Aplysia has two phases: a transient memory that lasts minutes and enduring memory that last days (other term used are short-term and long-term memory). Conversion of short term to long-term memory storage requires spaced repetition (Kandel, 2001).
The simple reflex in Aplysia is in fact a simple learning behavior and is called implicit learning, as a result ac- quires an implicit memory or non-declarative memory. Explicit (declarative) learning/memory involves knowl- edge about people, facts, places, and events. Many stud- ies in mice confined to memory for space, a complex form of explicit memory storage. There are at least two theories proposed on how memory stored. First, mem- ory is stored in the growth of new connections. Second, memory is stored dynamically by self-reexciting chain of neuron.
To explore the molecular basic of learning and memory is in fact to examine the change in the area close to syn- apses, either pre or postsynaptic area. Synapses can convert electrical impulse into chemical signals and back again, as well as modulate the strength of the transmitted signals. This ability to modify the strength of transmission known as synaptic plasticity is thought to be the cellular basis of the brain’s ability to compute, learn, and remember (Dorunz, 2002).
IMPLICIT LEARNING AND MEMORY
E.R. Kandel (2001) searches the molecular basic of learning and memory in Aplysia by focusing initially on one type of learning i.e. sensitization. It is a form of learning of fear where by Aplysia on receiving an aver- sive shock to a part of the body such as the tail, it rec- ognizes the stimulus as aversive and learns to enhance its defensive reflex responses to variety of subsequent stimulus applied to the siphon, even innocuous stimulus. A single shock gives rise to a memory last only minutes; this short-term memory does not require the synthesis of new protein. In contrast, four or five spaced shock to the tail give rise to a memory lasting several days, the long-
critical for the short-term process, is made persis- tently active for days by repeated training, without requiring a continuous signal. The kinase becomes autonomous, and does not require serotonin, cAMP or PKA).
- C/EBP (CAAT Enhancer Binding Protein): tran- scription factor that binds to the DNA response
element CAAT, which activates genes that encode proteins important for the growth of new synaptic connections. (Kandel, 2001; Anonymous 2, 2002).
Figure 1B. Effect of Short and Long Term sensitization on the monosynap- tic component of the gill-withdrawal reflex of Aplasia (Re- drawn from Kandel, 2001).
EXPLICIT LEARNING AND MEMORY
Explicit memory unlike implicit memory requires con- scious recall and concerned with memory for people, places, and event. Explicit memory involve in special- ized anatomical system in the medial temporal lobes and structure deep to it, the hippocampus. The hippocampus contains a cellular representation of extra-personal space, a cognitive map of space, and lesion of hippo- campus interfere with spatial task. More over, within the hippocampus the perforant path, a major path way ex- hibits activity dependent plasticity, a change now called long-term potentiation (LTP) (Kandel, 2001).
LTP of synaptic transmission in the hippocampus is the leading experimental model for the synaptic change that may underlie learning and memory (Malenka, 1999; Wooley, 2001). How ever LTP occur not only in hippo- campus, and it function probably not only related to memory stored, but it is a fundamental property of the majority of exitory synapses in the mammalian brain, and as such, is likely to serve many function. The ex- perimental design at present mostly carried out in rat and recorded in the hippocampal CA1 region following
stimulation of CA3 Schaffer collateral (Sch) (Figure 3A).
Early phase LTP obtained with a single train of stimuli given for one second at 100 Hz. Early LTP lasts 2- hours.Late phase of LTP occurs with four trains of stimuli separated by 10 min. The late LTP lasts 24 or more hours (Figure 3B).
Molecular Mechanisms
a. Early phase LTP (E-LTP) (Figure 2)
A single train of high-frequency tetanus stimulation results in: (1) an increase Ca2+^ -dependent exocytosis of glutamate presynapticly. In postsynaptic neuron it will (2) increase activation of AMPA (α amino 3 hydroxy 5 methyl 4 isoxazole propionic acid) receptors result in (3) increase depolarization that relieves Mg2+^ blockage of the NMDA (N Methyl D Aspartate) receptors chan- nel, allowing Ca2+^ entry into the postsynaptic cell. Stimulation also (4) activates metabo-tropic glutamate receptors (mGluR), which can cause phosphorylation of NMDAR, results in further increase in intracellular Ca2+ level. In addition it (5) activate voltage dependent Ca2+
channels, and increase Ca2+^ intra cellular even further. The rise in Ca 2+^ triggers Ca2+^ -dependent kinases (Ca2+^ /calmodulin dependent kinase, CK and PKC) as well as the protein tyrosine kinase, Fyn that together induces LTP. Some suggestion of (6) activation of
nNOS, result in release of NO, a retrograde messenger that increase synaptic transmission. (Kandel, 2001; Anonymous 2, 2002; Duty, 2002.)
Figure 2. Cellular Basis of LTP Induction (Adapted from Anonymous 2, 2002: Duty, 2002)
b. Late phase LTP (L-LTP) (Figure 3 A B C)
With repeated trains of stimuli, the Ca2+^ influx also re- cruits an adenylyl cyclase, leading to the activation of PKA that plays a critical role in the transformation of short-term explicit memory into long-term memory. L- LTP, like long-term storage of implicit memory, re- quires pathways involving PKA, MAPK and CREB. PKA and MAPK are transported to the nucleus to acti- vate CREB, which, in turn, activates effectors for growth (tPA= tissue plasminogen activator, BDNF= brain-derived neurotrophic factor) and regulators (C/EBPβ=CAAT Enhancer Binding Protein), resulting in the synthesis of new proteins and structural changes, including the formation of new connections.
The balance between protein phosphorylation governed by PKA and dephosphorylation determines the thresh- old for hippocampal synaptic plasticity and memory storage. It has been proven that endogenous Ca2+^ - sensitive phosphatase calcineurin acts as a constraint on this balance. It might be worthwhile to mention here that other modulator inputs, such as dopamine signaling pathway, may also regulate the adenylyl cyclase activ- ity, thereby participating in the processes of long-term memory. However, the detail mechanism of it still to be describes (Greengard, 2001).
Figure 3C. A model for late LTP in the Schaffer collateral pathway (Redrawn fro Kandel 2001)
CONCLUDING REMARKS
The study so far led to the conclusion that memory stor- age involves in the synaptic changes. The short term memory result in covalent modification of preexisting protein, which cause increase synaptic strength, while the long term memory storage involve activation of gene expression, new protein synthesis and the forma- tion of new connection. The study of memory will con- tinue for many years to come, since there are so many questions seeking the answers. For instances, how do different parts of the brain interact. Why hippocampus needed only for short period in memory storage. What is the molecular mechanism in memory recall, and many others formidable task to be encountered.
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