SUCCINCT CONSIDERATIONS ABOUT MEMORYFerchmin 2015

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’sdiseases.3]Memory consolidation, the role of the medial temporal lobe,amygdala, adrenals.4] The hippocampus, its anatomy and use as experimental model tostudy memory. 5]Long-Term Potentiation (LTP) and Long-Term Depression (LTD).6] Interaction with cortex and memory storage.5] Neurogenesis and memory6] 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 list of several modalities or examples of learning and memory. The items of this list are loosely related among themselves. Some categories overlap while others are exclusive.

1) Habituation and sensitization are the simplest non-associative forms of learning. 2) Classical conditioning: Pavlov's dogs learned to associate the bell (CS) with food (US).3) Operant conditioning: Shock avoidance or reward seeking learning.4) 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 opened 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 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 systemsThe 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 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 border between them became a bit blurry .

An ever-present implicit learning is priming in which a recently used or frequently repeated word becomes preferentially used and determinant of behavioral choices.

Certain implicit learning functions like mirror drawing which requires visual and motor coordination do not depend on the basal ganglia but the cerebellum and the visual cortex. Findings from PD patients demonstrated that the basal ganglia support trial-by-trial learning, driven by error correcting feedback as well as sequencing behavior. This appears to be independent of whether learning is implicit or explicit. Moreover, data from PD, supports the notion that the 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 in building flexible, relational representations that are well suited to guide behavior in novel contexts.

Radial maze and working memory

Working memory could be thought of like the RAM* of our brain.

*)Random access memory

What is working memory?

Working memory has been conceived and defined in three different, slightly discrepant ways: as short-term memory applied to cognitive tasks, as a multi-component system that holds and manipulates information in short-term memory, and as the use of attention to manage short-term memory.

Working memory is a temporary storage and manipulation of information for cognitive tasks. Working memory includes a central executive system (CES) to control attention and information flow to and from verbal and spatial short-term memory buffers. The prefrontal cortex is involved in human working memory.

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.

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 longer).

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.

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.

Behavior,output

Short-termmemory

Long-termmemory

Cognitive processes, retrieval, remainders, interference, etc .....

Memory loss (amnesia) can be recovered by various processes indicatingthat amnesia might be some times a problem of retrieval. Distortion of memory takes place by a dynamic interaction with experience.

Input

Accessing synapses makes LTMvulnerable to modification in amanner similar to STM

Memory is not a static storage of information

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.

To avoid confusion, this is a “human” brain not to be confusedwith the rat brain which you will see later

How to understand the structure of the hippocampusfrom 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.

Proliferation and migration of NSCs from the DNe region within the primordial hippocampus to form the laminar organization and cytoarchitecture of the postnatal DG. NSCs give rise to INPs,

which migrate and eventually give rise to Prox1+ granule neurons in the DG. In the postnatal brain, NSCs reside in the SGZ and continue to generate Prox1+ granule neurons.

Diana X. Yu et al. Development 2014;141:2366-2375

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

The hippocampus played an important role in the initial studies of memory in humans and animals

How LTP was discovered and how it was studiedThe rat brain

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.

Pyramidal neuron

Incoming afferents

GABAergic neurons (in red)It must be clarified that there are many type of interneurons with distinct anatomical, functional and biochemical characteristics.

Simplified hippocampal CA1 neuronal circuit. Similar circuits are found in Dentate Gyrus, CA2 and CA3

Stimulation with a hippocampus specific frequency θ or theta burst stimulus (TBS) induces long-term potentiation (LTP) while low frequency stimulation induces long-term depression (LTD).The fig below shows LTP and LTD recorded as field or population EPSPs. A similar effect can be observe recording the sum of axon potentials of a population of neurons called population spike.

Remember LTD!

Graphic model of STMconsolidation as LTM.

Object location

Object qualities

Hippocampus

http://www.pbs.org/wgbh/nova/body/corkin-hm-memory.html history of patient HM

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.

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.

Diagram of a cross-section of the mouse hippocampus. The hippocampal subregion CA3-CA4 is indicated in black. Black areas: suprapyramidal (SP), intra- and infrapyramidal (IIP) and hilar (CA4) mossy fiber terminal fields originating from the dentate gyrus. Stippled area: strata oriens (OR) and radiatum (RD). Hatched area: stratum lacunosum-moleculare (LM). CA1, subregion of the hippocampus without mossy fibers; FI, fimbria hippocampi; FD, fascia dentata; OL and ML, outer and middle molecular layers of the fascia dentata; SG, supragranular layer; GC, granular cells. 

Glutamate receptors are involved in LTP induction and memory storage

Several other glutamate receptors and other voltage and ligand gatedchannels that are not mentioned here are also involved in LTP.

We will see some molecular and synaptic aspects of possible mechanisms of memory

Did you get a lecture about the NMDA receptors?How is your familiarity with cell signaling?

Voltage sensitive Ca2+ channel

HyperpolarizatrionDependentMg2+ block of theNMDA receptor

NMDAglutamate receptorClosed!!! Na+

K+

Ca2+

A Normal synaptic transmission

AMPA or kainateglutamate receptor

B During strong depolarization

NMDAglutamate receptorOpen!!!

Ca2+

Na+

Ca2+

Ca2+

Na+

Na+

K+ K+

AMPA or kainateglutamatereceptor

closedopen

Voltage sensitive Ca2+ channel

displacedMg2+

Interplay between NMDA and non-NMDA receptors

L-VGCC or L-VDCC refers to voltage gated (or dependent Ca2+

channels.

Protein synthesis is needed for Late-LTP. Protein synthesis and degradation is needed for memory consolidation

CalciumTrk and other

effectors

↓Ras

↓Raf

↓MEK

↓ERK-1,2

↓Rsk

↓CREB

↓New RNA

and proteins

↓LTP

Two ways of representing the signal transduction involved in LTPRole of the RAS/Raf/MEK/ERK/CREB cascade in LTP and memory

CAMs are celladhesion molecules

Model of RIN1 action in RAS-mediated pathways controlling learning and memory.

Dhaka A et al. J. Neurosci. 2003;23:748-757

Take home message:there is a protein involved in regulatingaversive memories.

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. We have shown previously that lateral amygdala (LA) neurons with increased cyclic adenosine monophosphate response element–binding protein (CREB) are preferentially activated by fear memory expression, which suggests that they are selectively recruited into the memory trace. We 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) after learning blocked 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 deficiencysleep deprivationuse of alcohol or drugs and some prescription medicationsanesthesia (short-term memory)cancer treatments such as chemotherapy, radiation of the brain, or bone marrow transplanthead injury or concussionlack of oxygen to the brainepilepsy and seizures in generalbrain tumor or infectionbrain surgery or heart bypass surgerymental disorders such as depression, bipolar disorder, schizophrenia, and dissociative disorderemotional traumathyroid dysfunctionelectroconvulsive therapytransient 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 beveragessuch 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 neurodegenerativediseases and diabetes mellitus. However, our knowledge still appears too limited for formulationof 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).

What do you really have to know?1. There are different modalities of memory: explicit, implicit. and others.2. Memory goes through stages: sensory, short, long, etc.3. Short term memory can be disrupted by relatively mild treatment.4. Hippocampus and the medial temporal lobe are essential for explicit

memory and basal ganglia for implicit memory.5. Memory storage is dependent on cell signaling and anatomical changes.6. Surprisingly “disposable” neurogenesis is involved in consolidation 7. 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.

8. LTP and LTD in hippocampal slices is a well studied (and generally accepted) model of memory.

9. There are specific mechanisms to form and erase aversive and probably other types of memory.

I wish you a good memory!