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SUCCINCT CONSIDERATIONS ABOUT MEMORY
Ferchmin 2016
Table of Content
1] Different types of memory. The two main forms of memory:
Declarative (explicit) and non-declarative (implicit).
2] Memory and cognitive impairment in Alzheimer’s and Parkinson’s
diseases.
3]Memory consolidation, the role of the medial temporal lobe,
amygdala, adrenals.
4] The hippocampus, its anatomy and use as experimental model to
study memory.
5]Long-Term Potentiation (LTP) and Long-Term Depression (LTD).
6] Interaction with cortex and memory storage.
5] Neurogenesis and memory
6] Synaptic transmission, NMDA and non-NMDA glutamate receptors.
7] Cell signaling involvement in memory consolidation and forgetting.
8] Aversive memory and its regulation.
9] Factors that cause memory loss.
10] Nutrition and memory
The following is a non-exhaustive list of modalities of learning and memory
The items of this list are loosely related among themselves. Some categories
overlap while others are exclusive.
1)
2)
3)
4)
Habituation and sensitization are the simplest non-associative forms of learning.
Classical conditioning: Pavlov's dogs learned to associate the bell (CS) with food (US).
Operant conditioning: Shock avoidance or reward seeking learning.
Aversion learning: One trial association between taste and texture of food and
visceral malaise. The nucleus of the solitary tract is involved.
The taste (cranial nerve VII, IX, X) and texture (cranial nerve VII) of food is sensed
by the tongue. The intestinal malaise (cranial nerve X) becomes associated with
the type of food (taste and texture) and the one trial aversion memory lasts for years.
Recall your personal aversion learning event.
5) Conditioned fear: Can be an exaggerated fear.
Is measured in animals as fear potentiated startle response.
6) Latent learning: effect of previous exposure on later learning.
7) Observational learning: learning by observing but without an opportunity to perform.
8) Imprinting: Hen-chicken bonding depends on a critical period.
Could be important in humans.
9) Instantaneous or sensory memory, short term and long-term memory (LTM).
10) Working memory. The memory actively evoked to solve current problems.
Notice: In the next 12 slides we will address the behavioral aspects of memory. After
that we will move into the cellular-molecular substrate of memory and learning
The following is a non-exhaustive list of modalities of learning and memory
The items of this list are loosely related among themselves. Some categories
overlap while others are exclusive.
1)
2)
3)
4)
Habituation and sensitization are the simplest non-associative forms of learning.
Classical conditioning: Pavlov's dogs learned to associate the bell (CS) with food (US).
Operant conditioning: Shock avoidance or reward seeking learning.
Aversion learning: One trial association between taste and texture of food and
visceral malaise. The nucleus of the solitary tract is involved.
The taste (cranial nerve VII, IX, X) and texture (cranial nerve VII) of food is sensed
by the tongue. The intestinal malaise (cranial nerve X) becomes associated with
the type of food (taste and texture) and the one trial aversion memory lasts for years.
Recall your personal aversion learning event.
5) Conditioned fear: Can be an exaggerated fear.
Is measured in animals as fear potentiated startle response.
6) Latent learning: effect of previous exposure on later learning.
7) Observational learning: learning by observing but without an opportunity to perform.
8) Imprinting: Hen-chicken bonding depends on a critical period.
Could be important in humans.
9) Instantaneous or sensory memory, short term and long-term memory (LTM).
10) Working memory. The memory actively evoked to solve current problems.
Declarative (explicit) memory refers to conscious recollections of facts, maps, events, etc. and
depends on the integrity of the medial temporal lobe (MTL). Nondeclarative (implicit) memory refers
to a collection of abilities, skills, etc. and depends on the basal ganglia. Implicit memory alters
behavior without conscious intervention in the learning process.
The division of long-term memory (LTM) into declarative and non-declarative provided a
powerful framework for understanding the organization of memory. It has led to major
advances in understanding the role of the MTL in declarative memory and has indicated a
separate role for the basal ganglia in non-declarative memory.
Multiple memory systems
The concept of multiple memory systems originated from neuropsychological research with
patients with specific patterns of brain damage. The most famous case is of the patient H.M. with
bilateral surgical damage to the hippocampus and surrounding medial temporal lobe cortices
that led to a severe impairment to form explicit memory.
Parkinson's disease (PD) is the most influential model of basal ganglia dysfunction. PD
patients, known for their motor deficiencies, have cognitive and mnemonic impairments of
implicit memory.
Patients with mild cognitive impairment (MCI) due to medial temporal lobe (MTL) pathology
exhibit robust implicit learning that support the notion that the MTL does not contribute to
implicit learning. In contrast, PD patients conserve explicit learning but exhibit poor implicit
learning.
This double dissociation was central in advancing the notion that the basal ganglia and MTL
support two dissociable memory systems. Although further research confirmed this
dissociation the boundary between them became a bit fuzzy.
Using sophisticated behavioral tests it is possible to differentiate HD and PD from AD patients with 90%
accuracy. Delayed memory recall provides the highest discrimination accuracy when comparing
primarily cortical with subcortical dementias.
Certain implicit learning functions like mirror drawing which requires visual and motor coordination do
not depend on the basal ganglia but on the cerebellum and the visual cortex.
The basal ganglia support learning driven by error correcting feedback (trial-by-trial) as well as
sequencing behavior. This appears to be independent of whether learning is implicit or explicit. Basal
ganglia are specialized for forming specific and inflexible representations that do not easily generalize
to new choices. This contrasts with the role of the hippocampus which allows to building flexible,
relational representations that are well suited to guide behavior in novel contexts.
Henry Gustav Molaison, known widely as the H.M. patient, is the
best known single patient in the history of neuroscience. His severe
memory impairment, which resulted from experimental
neurosurgery to control seizures, was the subject of study for five
decades until his death in December 2008. Work with H.M.
established fundamental principles about how memory functions
are organized in the brain. H.M. had been knocked down by a
bicycle at the age of 7, began to have minor seizures at age 10, and
had major seizures after age 16. He worked for a time on an
assembly line but at the age of 27 he had become incapacitated by
his seizures, despite anticonvulsant medication. He died on
December 2, 2008, at the age of 82.
It can be said that the early descriptions of H.M. inaugurated the modern era of memory
research. Before H.M., due to the influence of Karl Lashley, memory functions were
thought to be widely distributed in the cortex and to be integrated with intellectual and
perceptual functions. The findings from H.M. established the fundamental principle that
memory is a distinct cerebral function, separable from other perceptual and cognitive
abilities, and identified the medial aspect of the temporal lobe as important for memory.
The implication was that the brain has to some extent separated its perceptual and
intellectual functions from its capacity to lay down in memory the records that ordinarily
result from engaging in perceptual and intellectual work.
Returning to types of memory …..
Sensory memory is the shortest-term element of memory. It is the ability to
retain impressions of sensory information after the original stimuli have ended.
It is the memory that results from our perceptions automatically. Generally it
disappears in less than a second. It includes two sub-systems: iconic memory
of visual perceptions and echoic memory of auditory perceptions.
Short-term memory acts as a “scratch-pad” for temporary recall of the
information which is being processed at any point in time.
It can be thought of as the ability to remember and process information at
the same time. It holds a small amount of information (typically around 7 items
or even less) in mind in an active, readily-available state for a short period of
time (typically from 10 to 15 seconds, or sometimes up to a minute).
H.M. did not show impairment of sensory or short-term memory
What is working memory?
Radial maze and working memory
Working memory could be thought of like the RAM* of our brain.
*)Random access memory
Working memory is a temporary storage and manipulation of information
for cognitive tasks. Working memory includes:
Central Executive: Drives the working memory and allocates data to the
visual-spatial and verbal subsystems (loops). It deals with cognitive tasks
such as mental arithmetic and problem solving.
Visual-Spatial subsystem stores and processes information in a visual or
spatial form. Also it is used for navigation.
Verbal or phonological subsystem is the part of working memory that
deals with spoken and written material. It can be used to remember a
phone number. It consists of two parts, one holds speech information (i.e.
spoken words) for seconds, the other rehearses and stores verbal
information.
There is an ongoing debate about the brain areas involved in different types of working
memory tasks.
Most of us are unabashed to concede that we have bad memory but few are ready
to accept that they have poor intelligence. The caveat is that working memory is a
good correlate of what we usually consider intelligence.
Fortunately, recent data has shown that working memory can be increased by
training. These studies have shown that 25 days of computerized, adaptive training
improves capacity, and that this training effect generalizes to non-trained working
memory tasks and to cognitive tasks known to rely on working memory.
Memory goes through stages that are characterized by different biochemical
pathways, physiological features, and behavioral processes.
Short-term memory is depends on the hippocampus and associated areas in the medial temporal lobe (MTL).
During consolidation memory stops to depend on the MTL and becomes cortical.
Memory is not a static storage of information
Memory loss (amnesia) can be recovered by various processes indicating
that amnesia might be some times a problem of retrieval.
Distortion of memory takes place by a dynamic interaction with experience.
Input
Short-term
memory
Long-term
memory
Accessing synapses makes LTM
vulnerable to modification in a
manner similar to STM
Cognitive processes, retrieval,
remainders, interference, etc .....
Behavior,
output
Although absolute, objective truth does exist independently of any observer, often untrue sincere
recalls are not true because the memory of the events were distorted by emotions and time.
Propaganda, coercion and other life events can form false memories. This has medical, legal, and
political implications.
Many brain areas interact to analyze the perceived experience, store the memory and alter behavior
Experiences activate time-dependent cellular storage processes in various brain regions involved in
the forms of memory represented. The experiences also initiate the release of the stress hormones
from the adrenal medulla and adrenal cortex and activate the release of norepinephrine in the
basolateral amygdala, an effect critical for enabling modulation of consolidation. The amygdala
modulates memory consolidation by influencing neuroplasticity in other brain regions.
Next 5 slides deal with the structure and function of the hippocampus
To avoid confusion, this is a “human” brain not to be confused
with the rat brain which you will see next.
The hippocampus played an important role in the initial studies of memory in humans and animals
Drawing of a transversal slice of the hippocampus by Ramon y Cajal (1911)
"the flight of fancy which led Arantius, in 1587, to introduce the term 'hippocampus'.... recorded in what is perhaps
the worst anatomical description extant. It has left its readers in doubt whether the elevations of cerebral
substance were being compared with fish or beast, and no one could be sure which end was the head." -- lewis
How to understand the structure of the hippocampus
from its development
The medial-temporal lobe includes: dentate gyrus, hippocampus
proper (cornu Ammonis or CA1 and CA3), subiculum, entorhinal
cortex and amygdala.
The hippocampus, CA1 and CA3 areas, are the most vulnerable areas of the
brain. It deteriorates with age, epileptic seizures and anoxia by stroke.
Basic anatomy of the hippocampus
The wiring diagram of the hippocampus is traditionally presented as a trisynaptic loop. The major input is carried by axons of the perforant path, which
convey polymodal sensory information from neurons in layer II of the entorhinal cortex to the dentate gyrus. Perforant path axons make excitatory
synaptic contact with the dendrites of granule cells: axons from the lateral and medial entorhinal cortices innervate the outer and middle third of the
dendritic tree, respectively. Granule cells project, through their axons (the mossy fibres), to the proximal apical dendrites of CA3 pyramidal cells which, in
turn, project to ipsilateral CA1 pyramidal cells through Schaffer collaterals and to contralateral CA3 and CA1 pyramidal cells through commissural
connections. In addition to the sequential trisynaptic circuit, there is also a dense associative network interconnecting. CA3 cells on the same side. CA3
pyramidal cells are also innervated by a direct input from layer II cells of the entorhinal cortex (not shown). The distal apical dendrites of CA1 pyramidal
neurons receive a direct input from layer III cells of the entorhinal cortex. There is also substantial modulatory input to hippocampal neurons. The three
major subfields have an elegant laminar organization in which the cell bodies are tightly packed in an interlocking C-shaped arrangement, with afferent
fibres terminating on selective regions of the dendritic tree. The hippocampus is also home to a rich diversity of inhibitory neurons that are not
shown in the figure. Neves G, Cooke SF, Bliss TVP. Synaptic plasticity, memory and the hippocampus: a neural network approach to
causality. Nat Rev Neurosci 9: 65-75
Simplified hippocampal CA1 neuronal circuit.
Similar circuits are found in Dentate Gyrus, CA2 and CA3
Incoming afferents
GABAergic neurons (in red)
It must be clarified that there are many type of
interneurons with distinct anatomical, functional
and biochemical characteristics.
Pyramidal neuron
The rat brain
How LTP was discovered and how it was studied
The entorhinal cortex (EC) and the hippocampal neuronal networks contain two major excitatory circuits, the
trisynaptic pathway (EC layer II/dentate Gyrus/CA3/CA1/EC layer V) and the direct pathway (EC layer
III/CA1/EC layer V), that converge onto a common hippocampal output structure, the CA1 region. Do not
memorize this clarification about specificity of connections between layers.
Long-Term Potentiation
Time course of LTP induced in rats by 250 Hz stimulation and blockade of induction by NMDA receptor antagonists.
(A) Perforant path LTP induced by 250 Hz stimulation. Traces illustrate positive-going population EPSPs and
population spikes recorded by a micropipette positioned in the cell body layer of the dorsal blade of the dentate
gyrus. The graph illustrates average population-spike amplitude (± SD) as a percent of baseline before and after 250
Hz stimulation. After testing for 1 h, another set of three 250 Hz trains was delivered (repotentiate), which
produced additional LTP. (B) LTP is blocked when the micropipette recording electrode contains MK801 (10 mg/mL).
Traces illustrate positive-going population EPSPs and population spikes recorded by a micropipette positioned in the
cell body layer. In this experiment, three bouts of 400 Hz stimulation were delivered, and then three bouts of 250 Hz
stimulation. Neither produced the LTP that is otherwise seen.
LTP induces synaptic changes during LTP in acquisition
Spine splitting and LTP. Model of spine splitting to enhance connectivity between hippocampal
neurons
Did you have a lecture about the NMDA receptors?
How is your familiarity with cell signaling?
We will see some molecular and synaptic aspects of possible mechanisms of memory
Glutamate receptors are involved in LTP induction and memory storage
Several other glutamate receptors and other voltage and ligand gated
channels that are not mentioned here are also involved in LTP.
Interplay between NMDA and non-NMDA receptors
Protein synthesis is needed for
Late-LTP. Protein synthesis and
degradation is needed for memory
consolidation
L-VGCC or L-VDCC refers to
voltage gated (or dependent Ca2+
channels.
Object
location
Graphic model of STM
consolidation as LTM.
Object qualities
Studies monitoring the use of
cerebral glucose, immediate
early gene activation, and
dendritic spine formation have
indicated that rapid encoding of
explicit (episodic) memory in
the hippocampal area can be
followed by temporally graded
neural changes in specific
cortical areas.
Hippocampus
Role of adult neurogenesis in hippocampal-cortical memory consolidation.
Kitamura T, Inokuchi K (2014), Molecular brain 7:13.
It appears that information from networks of various neocortical regions is rapidly
and temporarily linked through the hippocampus. The hippocampus activates the
neocortex during periods of inactivity and sleep via sharp-wave ripples (SPWs),
during which connections between cortical regions gradually develop. The source
of SPWs is synchronous population bursts in the CA3 region generated by
recurrent excitatory circuits. The hippocampus gradually strengthens the weak
connections between neocortical areas. Eventually, the cortex can represent the
memory of the original event independently of the hippocampus.
It is remarkable that mossy fibers have a mainly inhibitory effect on CA3. It is
possible that this increases the signal to noise ratio.
Jin-Hee Han, et al. Selective Erasure of a Fear Memory, Science vol 323, p 1492 (2009).
Memories are thought to be encoded by sparsely distributed groups of neurons. However,
identifying the precise neurons supporting a given memory (the memory trace) has been a
long-standing challenge. The authors have shown previously that lateral amygdala (LA)
neurons with increased cAMP response element–binding protein (CREB) are preferentially
activated by fear memory expression, which suggests that they are selectively recruited into
the memory trace. They used an inducible diphtheria-toxin strategy to specifically ablate these
neurons. Selectively deleting neurons overexpressing CREB (but not a similar portion of
random LA neurons) blocked the expression of that fear memory. The resulting memory loss
was robust and persistent, which suggests that the memory was permanently erased. These
results establish a causal link between a specific neuronal subpopulation and memory
expression, thereby identifying critical neurons within the memory trace.
Proper controls were tested to exclude the possibility that loss of aversive memory was not
produced by a decrease in motivation or perception.
In the above work the authors used sophisticated molecular biology methods to specifically
kill the neurons involved in aversive learning.
Conditioned fear is a growing field of interest for psychiatry and could show up in the boards.
Many factors can cause memory loss. Among them are:
vitamin B-12 deficiency
sleep deprivation
use of alcohol or drugs and some prescription medications
anesthesia (short-term memory)
cancer treatments such as chemotherapy, radiation of the brain, or bone marrow
transplant
head injury or concussion
lack of oxygen to the brain
epilepsy and seizures in general
brain tumor or infection
brain surgery or heart bypass surgery
mental disorders such as depression, bipolar disorder, schizophrenia, and
dissociative disorder
emotional trauma
thyroid dysfunction
electroconvulsive therapy
transient ischemic attack (TIA)
neurodegenerative illnesses such multiple sclerosis (MS), migraine, Alzheimer’s,
Huntington’s and Parkinson’s diseases.
Diet and nutritional supplements. Effect on learning and memory
There is a lot of legends, ignorance and deception in this field. The
control by FDA of nutritional supplements is limited at best.
Fruits and vegetable (FVs) might have a differential effect on cognition
according to groups of FVs and type of cognitive function. Further research
using sensitive and reliable measures of various types of cognitive function is
needed to clarify the effect of individual FV groups and nutrients. This trial is
registered at clinicaltrials.gov as NCT00272428. Am J Clin Nutr
2011;94:1295–303.
Polyphenols are the most abundant antioxidants in the diet. Their total dietary intake could be as high
as 1 g/d, which is much higher than that of all other classes of phytochemicals and known dietary
antioxidants.
For perspective, this is 10 times higher than the intake of vitamin C and 100 times higher that the
intakes of vitamin E and carotenoids. Their main dietary sources are fruits and plant-derived beverages
such as fruit juices, tea, coffee, and red wine. Vegetables, cereals, chocolate, and dry legumes also
contribute to the total polyphenol intake.
Despite their wide distribution in plants, the health effects of dietary polyphenols have come to the
attention of nutritionists only rather recently. Until the mid-1990s, the most widely studied antioxidants
were antioxidant vitamins, carotenoids, and minerals. Research on flavonoids and other polyphenols,
their antioxidant properties, and their effects in disease prevention truly began after 1995. Flavonoids
were hardly mentioned in textbooks on antioxidants published before that date.
The main factor that has delayed research on polyphenols is the considerable diversity and complexity
of their chemical structures.
Current evidence strongly supports a contribution of polyphenols to the prevention of cardiovascular
diseases, cancers, and osteoporosis and suggests a role in the prevention of neurodegenerative
diseases and diabetes mellitus. However, our knowledge still appears too limited for formulation
of recommendations for the general population or for particular populations at risk of specific diseases.
There are caveats to mention. Vitamin E increases the chance of sudden death. Too much vitamins
taken by adults were reported to be too good for cancer cells, beta-carotene increases the risk of cancer
in smokers, etc… be moderate with the supplements.
Be skeptic of everything. Eat a good diet with plenty of fruits and vegetables and remember,
‘”What was good for the Cro-Magnons and Neanderthals” it is still good for you.
In addition, “if man made it do not eat it” (Jack Lalanne).
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What do you really have to know?
There are different modalities of memory: explicit, implicit. and others
Memory goes through stages: sensory, short, long, etc
Short term memory can be disrupted by relatively mild treatments.
Hippocampus and the medial temporal lobe are essential for explicit
memory and basal ganglia for implicit memory
Memory storage is dependent on cell signaling and anatomical changes.
Surprisingly “disposable” neurogenesis is involved in consolidation
The following are involved in memory storage: glutamate receptors of
various types, protein kinases including ERK-1,2, calcium ions, CREB
phosphorylation and new protein synthesis and protein degradation.
LTP and LTD in hippocampal slices is a well studied (and generally
accepted) model of memory.
There are specific mechanisms to form and erase aversive and probably
other types of memory.
I wish you a good memory!