Distinct memory systems mediating declarative, emotional and procedural memory functions AIO Course – Cognitive Neurosciences January 28, 2002

Distinct memory systems mediating declarative, emotional and procedural

memory functions

AIO Course – Cognitive Neurosciences

January 28, 2002


memory functions

In this lecture the general features of the multiplicity of memory systems

that subserve distinct categories of memory functions are described. The

experimental paradigms that are used to study declarative and

nondeclarative (procedural) learning are analyzed with especial emphasis on

animal models of associative learning, i.e. classical and emotional

conditioning and of declarative memory. The corresponding anatomic circuits

and neuronal elements are considered in general terms. The neurobiological

mechanisms that likely underlie the formation of memory traces in such

neuronal circuits at the cellular and molecular levels (long-term synaptic

potentiation and depression) are examined.

How these mechanisms relate to the processes of encoding and retrieval of

information in the brain are critically discussed.

Brain cell diagram of Gregor Reich (1503)

1st cell is inscribed:

“Sensus communis,

imaginativa, fantasia”;

2nd cell: “cogitatia,

estimatia”;

3rd cell: “memorativa”.


memory functions

Main anatomic memory systems:

• Declarative memory;

• Emotional memory; fear conditioning;

• Motor conditioning;

• Skills and Priming.


memory functions






Taxonomy of Memory

Declarative(explicit)

Procedural(implicit)

Episodic(working)

Semantic(reference)

Skills Priming Conditioning Non-associative

Emotionalresponses

Motorresponses

Striatum Cortex Amygdala CerebellumReflexpaths

(Adapted from L.R. Squire: “Memory and the Brain”, 1987)

MTL:(para)hippocampal

cortex& Diencephalon


cortex

Taxonomy of memory



Episodic(working)

Semantic(reference)


Emotionalresponses

Motorresponses




cortex

Diencephalon


cortex

Systems mediating declaractive memory functions

Evidence for the importance of hippocampal and parahippocampal systems in declarative memory in human:

“H.M. appears to have a complete loss of memory for events [anterograde amnesia] subsequent to bilateral medial temporal lobe resection 19 months before, together with a partial retrograde amnesia for the 3 months leading up to his operation, but early memories are seemingly normal and there is no impairment of personality or general intelligence” in Scoville and Milner J. Neurol. Neurosurg. Psychiatry 1957, 20: 11-21.

“Every day is alone, whatever enjoyment I’ve had and whatever sorrow I’ve had” (H.M.)

MRI images

of patient

H.M.:

Bilateral

anterior

lobectomy.

The delayed non-match to sample task

(Mishkin and Appenzeller 1987)

This task served to investigate which structures of the medial temporal lobe are critical for declarative memory (see Larry Squire Box 19.3 “Neuroscience” Bear, Connors and Paradiso 1996).

Monkeys with lesions of:

H+: hippocampal formation, parahippocampal cortex.

H++: idem and and perirhinal cortex.

Zola-Morgan et al 1993

Performance of the delayed non-matching to sample task for normal (N), and lesioned monkeys (H+ and

H++).

Association areas:frontal, temporal, parietal,

occipital

Postrhinal & perirhinalcortices

Medial & lateralentorhinal cortices

Subiculum

CA1

DG/CA3

sensory map

sensory map &novelty detection

septal area

relevance

Hippocampal formation

Hippocampal memory systems

Lopes da Silva et al 2000


memory functions






Amygdala

Taxonomy of memory



Episodic(working)

Semantic(reference)


Emotionalresponses

Motorresponses




cortex

Diencephalon


cortex

Sagittal view of the brain showing the location of the amygdaloid complex of nuclei in the temporal lobe.

Coronal section through the forebrain at the leveel of the amygdala.

(Purves et al “Neuroscience”, 2nd edition, 2001, Box B, p.634)

Neural circuits involved in conditioned emotional responses, specifically

fear conditioning.

(LeDoux, J.E. Emotion: clues from the brain. Annu. Rev. Psychol. 1995, 46: 209-235).

Simple fear conditioned task, aversive classical conditioning:

Temporal pairing of a neutral stimulus (CS=sound) with an aversive event (US) (foot shock).

Conditioned response: freezing with autonomic and hormonal components.

LeDoux, Annu. Rev. Psychol. 1995, 46: 209-235).

.

Pathways that mediate the association of auditory and aversive stimuli.

(Purves et al “Neuroscience” 2nd edition, 2001, p. 637)

Model of associative learning in the amygdala relevant to emotional conditioning (Rolls, 1999).

Conditioned fear-induced changes in the receptive field (RF) properties of single neurons in the amygdala.

Neuron’s best response to a tone frequency: BF.

BF determined before conditioning = Pre;

After conditioning = Post.

After conditioning the BF of the neuron shifted to the frequency of the CS tone.


memory functions


•Declarative memory;

•Emotional memory; fear conditioning;



Cerebellum

Taxonomy of Memory



Episodic(working)

Semantic(reference)


Emotionalresponses

Motorresponses

Striatum Cortex AmygdalaReflexpaths



cortex& Diencephalon


cortex Cerebellum

Classical conditioning as it develops in the course of training:

The response is the eyelid closure shown as an upward deflection of the trace.

US: air puff to the cornea.

CS: neutral tone.

The Cerebellum plays an essential role in classical conditioning of motor resposnses such as in the eye blink reflex, elicited by a corneal air puff.

Scheme of the eye blink conditioning circuit.

US (air puff) path:

N V (trigeminus) cranial nerve, inferior olive (IO) climbing fibers (CF), Purkinje cells.

CS (tone) path: Cochlear nerve, pontine nuclei (PN), mossy fibers (MF), granule cells (GR), parallel fibers (PF).

Efferent path: Purkinje cells, Interpositus nucleus (Int), red nucleus (RN), motor nuclei (VI and VII cranial nerves).

Responses of cerebellar interpositus neurons in eye blink conditioning: before CS-US pairing and

at days 1 and 2 after pairing.

Total trace duration: 750 ms;

CS – US onset interval: 250 ms.

(From McCormick and Thompson , Science 1984)

Memory systems

Are the hippocampal memory systems also engaged in this form of classical conditioning (eye blink reflex)?

Patients with temporal lobe anterograde amnesia are able to learn the acquisition of the eye blink conditioned response, but cannot recall the learning experience.

However this ability depends on the complexity of the conditioned task. If the task is to blink to tone if, and only if, preceded by light, they show also impairment.


memory functions






Regions exhibiting skill learning and priming -related changes in fMRI activity:

Increases:

R Cerebellum (-21);

L Inferior Frontal (+33);

L Inferior Temporal (-12);

Anterior Cingulate;

Tail of Caudate (+15);

Decreases:

L Cerebellum; (-21)

L Hippocampus (-18).Poldrack and Gabrieli, Brain 2001, 124:67-82

Memory systems

All regions exhibiting significant learning-related changes also exhibited increased repetition priming effects, suggesting common neural substrates for priming and skill learning.

The results of the study of Poldrack and Gabrieli indicate the importance of striato-frontal neural networks for the memory for skills.


memory functions






Memory systems

One region that did not emerge specifically in the previous analysis is the prefrontal cortex.

Is this region also relevant as a part of memory systems?

Which?

The prefrontal cortex has been suggested to be necessary for strategic memory processes and for retrieval. These strategic processes may facilitate episodic learning.

This study examined strategic memory with PET using a verbaal encoding

paradigm that manipulated semantic organization in differenty conditions.

Three tasks:

1. Spontaneous – words were related in four semantic categories but subjects were not aware of this beforehand;

2. Directed: in this condition the subjects were instructed that there were 4 semantic categories;

3. Unrelated: words did not share any semantic relationship.

Regions of activation represent voxels where rCBF increased in a graded fashion: directed> spontaneous>unrelated:

L lateral prefrontal cortex;

L Inferior frontal gyrus.

Region most activated: orbitofrontal cortex.

Memory systems

Understanding the neurobiology of memory processes involves not only the identification of the memory systems that are anatomically involved in the storage of information but also the equally important question of how information is stored.

Hebb pointed out already in 1949 that memories can result from subtle changes at the level of synapses. This basic assumption has led to search for the physical basis of memories in synaptic plasticity.

“The assumption, in brief, is that a growth process accompanying synaptic activity makes the synapse more readily traversed.”

According to this hypothesis,

“an intimate relationship is postulated between reverberatory action and structural changes at the synapse, implying a dual trace mechanism”.

Hebb hypothesis led to the experimental strategy that revealed the existence of long-term potentiation by Bliss and Lomo in 1966 – 1968.

Typical set-up to demonstrate the existence of LTP in the synapses that the Schaffer collaterals of CA3 neurons make with the dendrites of CA1 neurons of the Hippocampus.

(Malinow et al 1989)

Varieties of synaptic plasticity:

Neurons receive either strong (S) or weak (w) stimuli. Postsynaptic potentials before inducing stimulation are given as solid lines; after stimulation as dotted lines.

Long-term synaptic depression (LTD)

caused by low-frequency stimulation (1Hz).

(Mulkey and Malenka 1992)

Main events leading to LTP or to LTD. If both LTP and LTD are triggered by [Ca2+]i, how are the induction processes different?

(Zigmond et al “Fundamental Neuroscience” 1999, p. 1444)

The hypothesis is that high [Ca2+]i

(>5mM) activates a protein kinase leading to LTP, while if [Ca2+]i does not increase more than 5mM a phophatase is activated causing LTD.

According to Shi et al LTP and LTD can arise from the rapid redistribution (insertion in LTP or retrieval in LTD) of Glutamate AMPA receptors after synaptic NMDA receptor activation depending on the stimulus properties.

(Science 1999, 284: 1811-16)

Long-term depression (LTD) in the cerebellum

Experimental set-up to study synaptic plasticity in the Cerebellum

Mechanism of LTD in the Cerebellum:

Glutamate released by a parallel fiber activates both AMPA and metabotropic (mGluR) receptors, that release DAG and IP3.

Activation of the Climbing fiber opens voltage-gated Ca2+ channels.

DAG and IP3 interact with Ca2+ resulting in an alteration of AMPA receptors and in the weakening of the parallel fiber synapse.

(Purves et al “Neuroscience” 2nd edition, 1999, p. 552)

Early and late LTP:

the former is elicited by one single train of stimuli at 100 Hz; the latter by 4 trains at 10-min intervals.

Kandel, E.R., Science 2001, 294: 1030- 1038)

A model of the late LTP.

Repeated trains of stimuli recruit adenyl cyclase which activates cAMP- dependent kinase (PKA) that is transported to the nucleus where it phosphorylates CREB.CREB activates genetic targets that lead to growth and structural changes.

(Kandel Science 2001, 294:, p. 1036)

Memory Mutants

In 1992 Susumu Tonegawa and Alcino Silva st MIT were able to isolate and then delete the a form of the calcium-calmodulin-dependent protein kinase II in mice.

These mice had a clear deficit in LTP in the hippocampus and neocortex.

When tested in the Morris WaterMaze they displayed a severe memory defect.

Can we conclude that the missing protein is a “memory molecule”?

No. The mutants showed also other behavioral deficits but appear to be more “stupid” than matched controls.

Rats were trained in a context conditioning situation.

Transgenic rats express a mutant form of the regulatory subunit of PKA that blocks the action of PKA. These mutants have a selective defect for long-term contextual memory.Kandel, Science 2001, 294: p. 1037

Ultrastructural changes associated with LTP in the hippocampus. New dendritic spines can be visualised approximately 1 h after a LTP inducing stimulus

(Engert and Bonhoeffer 1999).

Memory Systems

From Hebb, Organization of Behavior” 1949:

“ It is feasible to assume that synaptic knobs develop with neural activity and represent lowered synaptic resistance.

It is implied that the knobs appear in the course of learning, but this does not give us a means of testing the assumption”. (p. 66, edition 1961).

Memory SystemsMain bibliography:

Purves et al, Neuroscience, 2nd Edition, Sinauer Ass, Sunderland, Mass, 2001.

Zigmond et al, Fundamental Neuroscience, Academic Press, San Diego, 1999.

Bear et al Neuroscience, Exploring the brain, William and Wilkins, Baltimore. 1996.

Squire, L.R. and Kandel, E.R. Memory: from mind to molecules, Scientific American Library, New York, 2000 (nederlandse vertaling bij de Wetenschappelijke Bibliotheek van Natuur en Techniek 2001).

Kandel, E.R. The molecular biology of memory storage:a dialogue between genes and synapses. Science 2001, 294: 1030-38.

Documents

Distinct memory systems mediating declarative, emotional and procedural memory functions AIO Course – Cognitive Neurosciences January 28, 2002