Neurobiology of Memory

Dr Ravi SoniSenior Resident-I

Dept. of Geriatric Mental HealthKGMC, LKO

Discussion over…• Anatomical and Functional organization of memory• Hippocampus formation• Afferents and efferents from hippocampus formation• Learning and memory• Types of memory• Cellular and molecular process in Short term and Long term

Memory• Molecular mechanisms in Implicit memory• Molecular mechanisms in Explicit Memory• Long term Potentiation in Hippocampus• Plasticity

ANATOMICAL AND FUNCTIONAL ORGANIZATION OF MEMORY

Introduction to the Limbic System

• Anatomically refers to areas surrounding the diencephalon (limbus = border) and bordering the cerebral cortex.

• The “C”-shaped hippocampal formation and includes the amygdala, cingulate and parahippocampal cortices.

The key to learning, memory, and behavior (including emotional behavior) – of paramount importance in psychiatry.

The Limbic System

Look!!

Posterior section: Hippocampus, Fornix

Divisions or nuclei of hippocampal formation

Parasagital section

Note the hippocampal formation, fornix, and amygdala

I. Anatomical Location and Overview.

A. Limbic association cortex – surrounding diencephalon-medial + inferior (orbital) surface cingulate gyrus, parahippocampal gyrus, orbital gyrus, temporal pole.

Limbic System: Cortical Areas

Note: surroundingdiencephalon, medial +inferior (orbital) surface [cinglulate gyrus, parahippgyrus, orbital gyrus, temporal pole].

B. the Hippocampal Formation and Amygdala.Note the “C” shape, along with the major output paths for the hippocampus: the fornix.

II. Hippocampal Formation:ComponentsA subcortical structure composed of allocortex.A central function: Consolidation of STMs intoLTMs (+ many other limbic functions through complex interconnections).

Note the 3 components

Neocortex and Allocortex

More on these 3layers later

Hippocampal Formation:CircuitryA.Components and structure – a banana-shaped structure with its components (dentate, hipp,subiculum) folded upon one another like a “jelly roll”.Inputs are from entorhinalcortex, which collects infofrom other association areasdentate gyrus hipp formation + subculumoutput to fornix andalso back to entorhinal cortex

Hippocampal Formation:Input and Output

Afferent

Efferent

Serial and Parallel Processing of Hippocampal Circuits

Hippocampal Circuits

Fornix

bran

ch

(Postcomm

isuralBranch)

Fornix

(Pre

com

miss

ural)

(septal-hippocampal pathway) Affects - Theta rhythm (4-8Hz)

(Hippocampal commissure)

(Perforant & alvear path)

AfferentsEfferents

HIPPOCAMPUS(Cortico-entorhinal projections)

ERC/Sub(PHG)

Cortex

Septal nuclei

Mammillary Body

ContralateralHippocampus

1. & 2.

3. 4.

The Hippocampus Dentate Complex(HC-DG)

Afferent Pathways

Pyramidal cell(CA1,2)

PHG (ERC, Sub)

1. Perforant Pathway: PHG (ERC) --> DG Also ….2. Alvear Pathway: PHG --> CA1 3. Septo-hippocampal path (via fornix): Septal nuclei --> DG4. Hippocampal commissure (connects bilateral hippocampi)

Dentate gyrus (granule cells)

(mossy fibers)

Pyramidal cell(CA3)

(schaffer collaterals)

1. (perforant path)

(Also note: this efferent path closes the HC circuit loop!)

2. (alvear path)

Septal nuclei3. (septo-hippocampal path - thru fornix)

Papez’ Circuit:

Fornix mammillary bodies

Anterior Thalamic nucleus

mammillothalamictract

Cingulate gyrus

Entorhinal cortex

Hippocampalformation

Input for memory consolidation

• Korsokoff’s Syndrome: thiamine deficiency (i.e., from alcoholism) degeneration of mammillary bodies.

• Other output: via entorhinal cortex to a number of association areas, involve the prefrontal cortex (control of mood and behaviours).

C. Anatomy and Information Flow in Greater Detail.

Cytoarchitechture dimensions of hippocampus (Ammon’s horn): CA1, CA2, CA3, CA4 (hilus) [CA = coronus ammonis].

Medial Temporal Circuitry

Adjacent MTL cortices : Entorhinal (ERC), Perirhinal (PRC) Parahippocampal (PHC)

Hippocampus (HC) proper : Dentate Gyrus (DG), CA3, CA1, and Subiculum (Sub)

PRC

PHC

ERC

Sub

DG CA 3

CA 1

Fornix

Pyramidal cells

Pyramidal cells

Schaffercollaterals

Pyramidal cellsGranule cells

Mossyfibers

The HippocampusCA fields

A) Lateral Ventricle, B) ependymal glia (ventricular surface), C) Alvear Layer, (pyramidal axons) 3 layers of hippocampus (archicortex):

1. Polymorph Layer (pyramidal axons & basket cells (-))2. Hippocampal pyramidal layer (pyramidal cell bodies)

3. Molecular Layer (pyramidal dendrites)

A) Lateral ventricleB) Ependymal glia

C) Alvear layer

1. Polymorph Layer

2. Pyramidal Layer

3. Molecular Layer(pyramidal dendrite)

(pyramidal axon)

(pyramidal cell body)

(Corkin, Amaral, Gonzalez, Johnson and Hyman J. Neuro, 1997)(Scoville and Milner, 1957)

Patient H.M. and the Human MTL

• Suffered head injury @age 9

– Developed severe epilepsy

• Surgeon surgically removed the medial temporal lobe bilaterally

• HM suffered severe anterograde and temporally graded retrograde amnesia

• Spared skill learning

Different regions of brain involved in specific memory

Cellular and Molecular Mechanisms of Memory

Learning

• Learning: relatively permanent change in an individual's behavior or behavior potential (or capability) as a result of experience or practice.

1. Change in behavior2. Change takes place due to practice or experience3. Change is relatively permanent

MEMORY

• Memory: is complex cognitive or mental process that involves encoding, storage and retrieval of the information.

I. Encoding: is process of receiving input and transforming it into a form or code, which can be stored.

II. Storage: is process of actually putting coded information into memory.

III.Retrieval: is process of gaining access to stored, coded information when it is needed.

Two Types of Memory

Explicit Memory• Factual knowledge of people, places, things, and events, along with

concepts derived from this knowledge

• Well developed in vertebrate brain

• Explicit (declarative) memory is recalled by conscious effort, and can involve assembly and association of many pieces of information in different modalities

• Dependent on the structures like medial temporal lobe of the cerebral cortex and hippocampus formation

• Declarative memory can be further classified as episodic or autobiographic memory and semantic memory.

Types of Explicit Memory

Episodic memory:

• allows us to remember personal events and experience and, being a link between what we are and what we have been, gives us the sense of our individuality.

Semantic memory:

• is a sort of public memory for facts and notions, be they general or autobiographical

• Over time, autobiographical memory shades into semantic memory so that the experience of an event is remembered as the simple occurrence of such event

Implicit memory• It refers to information storage to perform various reflexive or perceptual tasks is also

referred to as non-declarative memory because it is recalled unconsciously.

• When we use implicit memory, we act automatically and we are not aware of being recalling memory traces.

• Implicit memory is a heterogeneous collection of memory functions and types of learned behaviors such as

– reflexive learning (sensitization, habituation),– classical conditioning, – fear conditioning, – Procedural memory (for skills and habits) and – priming (the recall of words or objects from a previous unconscious exposure to them).

• Here simple associative form of memory are classical conditioning etc.

• Non associative forms such as sensitization and habituation

• It involves the cerebellum, the striatum, the amygdala, the neocortex and in the simplest cases, the motor and sensory pathways recruited for particular perceptual or motor skills utilized during the learning process

DifferenceImplicit Memory

• Implicit memory, such as learning to ride a bike, takes time and many attempts to build up

• Implicit memory is much more robust and may last for all our life even in the absence of further practice

Explicit Memory

• Explicit memory, such as learning a page of history or a telephone number, is more immediate and implies a smaller effort.

• explicit memory fades relatively rapidly in the absence of recall and refreshing,

From short- to long-term memories: memory consolidation,forgetfulness and recall

• Learning induces cellular and molecular changes that facilitate or impair communication among neurons and are fundamental for memory storage.

• If learning brings about changes in “synaptic strength” within neuronal circuits, the persistence of these changes represents the way memories are stored.

• Short-term memory is believed to involve only functional changes in pre-existing neuronal networks mediated by a fine tuning of multiple intracellular signal transductions systems.

• These short-lived changes can undergo either of two processes: – either fade out with time (forgetfulness) or – be reinforced and transformed into long-term memory by a process called memory

consolidation

• Forgetfulness is at least as important as consolidation.

• To be consolidated, functional changes have to be followed by gene transcription and protein synthesis that produce permanent phenotypic changes in the neuron associated with structural rearrangements in neuronal networks.

• Thus, consolidation of memories is abolished by mRNA and protein synthesis inhibitors.

Cellular and Molecular processes in STM

1. changes in the excitation-secretion coupling at the presynaptic level promoted by changes in channel conductances due to phosphorylation and Ca2+ influx;

2. Ca2+ influx at the postsynaptic level through NMDA glutamate receptors by Ca2+/calmodulin kinases, protein kinase C and tyrosine kinases promoting phosphorylation of neurotransmitter receptors and generation of retrograde messengers (such as nitric oxide and arachidonic acid) that reach the presynaptic terminal and increase neurotransmitter release in response to action potentials.

• The activation of the molecules involved in these signaling pathways can last for minutes and thereby represent a sort of short-term “molecular memory”

Role of CaMKII and PP1• A very important role in the establishment of short-term memories is

played by the balance between Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1).

• Upon Ca2+ influx during training, CaMKII undergoes an autophosphorylation reaction that transforms it into a constitutively activated kinase. The “switched-on” CaMKII, however, is returned to the resting state by PP1 that thereby has an inhibitory effect on learning

• Thus, the antagonistic interactions between CaMKII and PP1 represent a push-pull system that plays a fundamental role during learning as well as in the delicate balance between maintaining and forgetting stored memories

Consolidation into Long Term Memory• The sustained activation of the same pathways promotes memory consolidation by

affecting the gene transcription and translation.

• Sustained stimulation leads to persistent activation of the protein kinase A (PKA) and MAP kinase Erk (MAPK) pathways.

• PKA phosphorylates and activates the transcriptional activator CREB1a, whereas MAPK phosphorylates and inactivates the transcriptional repressor CREB2.

• The CREB family of transcription regulators is highly conserved across evolution and represents the major switch involved in the transformation of short-term memory into long-term memory.

• The CREB target genes, whose transcription is regulated during consolidation, include a set of immediate- early genes (such as C/EBP or zif268) that affect transcription of downstream genes.

• This results in changes, both increase and decreases, in the expression of an array of proteins involved in protein synthesis, axon growth, synaptic structure and function

Molecular mechanisms of short- and long-term memory.

From Synapses to memory• Memory is a special case of the general biological phenomenon of neural plasticity.

• Neurons can show history-dependent activity by responding differently as a function of prior input, and this plasticity of nerve cells and synapses is the basis of memory.

• Experience can lead to structural change at the synapse, including alterations in the strength of existing synapses and alterations in the number of synaptic contacts along specific pathways.

Plasticity• Neurobiological evidence supports two basic conclusions.1. Short-lasting memory: which may last for seconds or

minutes, depending on specific synaptic events, including an increase in neurotransmitter release.

2. long-lasting memory: depends on new protein synthesis, the physical growth of neural processes, and an increase in the number of synaptic connections

• implicit memory can also be studied in a variety of simple reflex systems, including those of higher invertebrates, whereas explicit forms can best (and perhaps only) be studied in mammals.

Aplysia Californica• Implicit memory can be studied through the gill- and siphon withdrawal reflex of the marine

invertebrate Aplysia californica (sea snail)• Aplysia is capable of associative learning (including classic conditioning and operant conditioning) and

nonassociative learning (habituation and sensitization).• Aplysia is able to learn very peculiar behaviors that, upon practice, can be consolidated into long-term

memories.

• The animal learns to respond progressively more weakly to repeated innocuous stimuli (e.g. a light tactile stimulus), a behavior called habituation, and to reinforce the response to repeated noxious stimuli (e.g. a painful electrical shock), a behavior known as sensitization.

• THESE IMPLICIT MEMORIES ARE STORED IN SPINAL REFLEX PATHWAYS

Nonassociative Learning in Aplysia

• Sensitization had been studied using the gill-withdrawal reflex, a defensive reaction in which tactile stimulation causes the gill and siphon to retract.

• When tactile stimulation is preceded by sensory stimulation to the head

or tail, gill withdrawal is facilitated.

• The cellular changes underlying this sensitization begin when a sensory neuron activates a modulatory interneuron, which enhances the strength of synapses within the circuitry responsible for the reflex.

• This modulation depends on a second-messenger system in which intracellular molecules (including cyclic adenosine monophosphate [cAMP] and cAMP-dependent protein kinase) lead to enhanced transmitter release that lasts for minutes in the reflex pathway.

Habituation in Aplysia

• If the siphon of the animal is stimulated mechanically the animal withdraws the gill, presumably for protection.

• With repeated activation, the stimulus leads to a decrease in the number of dopamine-containing vesicles that release their contents onto the motoneuron.

Synaptic Depression

Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright ©

2007 Lippincott Williams & Wilkins

Nonassociative Learning in Aplysia

Sensitization of the Gill-Withdrawal Reflex

Synaptic Potentiation

Long-term storage of implicit memory for sensitization involves changes shown in last slide plus changes in protein synthesis that result in formation

of new synaptic connections.

• With only short-term tail stimulation, the sensitization will fairly quickly disappear when tail stimulation ceases.

• However, the sensitization can be made relatively permanent by repeated tail stimulation.

• This long-term sensitization (and also long-term habituation) occurs because there are structural changes that occur in the presynaptic terminals (sensory neuron 1, for example).

• With sensitization, there is an up to 2-fold increase in the number of synaptic terminals in both sensory and motoneurons.

• Alternatively, with habituation, there is a one-third reduction in the number of synaptic terminals. Both of these changes require altered protein synthesis by mechanisms shown in Fig. 18-7.

Neuroscience: Exploring the Brain, 3rd Ed, Bear, Connors, and Paradiso Copyright ©

2007 Lippincott Williams & Wilkins

Associative Learning in AplysiaClassical conditioning CS-US pairing

Associative learning in Aplysia

The molecular basis for classical conditioning in Aplysia

Long term Potentiation• A large amount of studies demonstrated that LTP is indeed a valid model

of “memory storage”:• LTP is observed when a postsynaptic neuron is persistently depolarized

after a high-frequency burst of presynaptic neural firing. • LTP has a number of properties that make it suitable as a physiological

substrate of memory.• It is associative, in that it depends on the co-occurrence of presynaptic

activity and postsynaptic depolarization.• LTP occurs prominently in the hippocampus, a structure that is important

for memory.• The induction of LTP is known to be mediated postsynaptically and to

involve activation of the N-methyl-D-aspartate (NMDA) receptor, which permits the influx of calcium into the postsynaptic cell.

• LTP is maintained by an increase in the number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; non-NMDA) receptors in the postsynaptic cell and also possibly by increased transmitter release.

Experimental setup for LTP

• A. Experimental setup for demon-strating LTP in the hippocampus. The Schaffer collateral pathway is stimulated to cause a response in pyramidal cells of CA1.

• B. Comparison of EPSP size in early and late LTP with the early phase evoked by a single train and the late phase by 4 trains of pulses. (Kandel, ER, JH Schwartz and TM Jessell (2000) Principles of Neural Science. New York: McGraw-Hill.)

• During normal synaptic transmission glutamate binds to non-NMDA receptors allowing cations to flow through the channels and the cell membrane to hypopolarize.

• Glutamate also binds to metabotropic receptors, activating PLC, and to NMDA receptors.

• NMDA receptor channels can bind glutamate but no current will flow through the channels unless the Mg++ that binds to the channel lumen is displaced. The latter event can be effected by hypopolarizing the cell.

• the high-frequency stimulation opens non-NMDA glutamate channels leading to hypopolarization.

• This dislodges Mg++ from the NMDA glutamate channels, and Ca++ enters the cells. • The calcium triggers the activity of Ca-dependent kinases, PKC and Ca-calmodulin, and

tyrosine kinase. Ca-calmodulin kinase phosphorylates non-NMDA channels, increasing their sensitivity to glutamate and a messenger is sent retrogradely to the presynaptic terminal to increase the release of transmitter substance.

• In the late phase of LTP, calcium enters the cell and triggers Ca-calmodulin, which in turn activates adenylyl cyclase and cAMP kinase.

• The latter translates to the nucleus of the cell and starts processes that lead to protein synthesis and to structural changes, i.e., the formation of new synapses. Many scientists believe that this is the substrate for long-term memory–the formation of new synapses.

Facts to be highlighted• LTP induced by an experience, is inhibited by a novel experience

administered soon (within 1 hour) after the first one, whereas an LTP established for more than 1 hour is immune to this reversal mechanism.

• Critical event in determining the retention of information may consist in the stabilization of the potentiated Hippocampal synapses in order to resist to LTP reversal upon new information.

• Although hippocampus is fundamental to acquire new memories, it appears to be dispensable after the memory has been fully consolidated.

• Permanent memories are distributed among different cortical regions according to the various perceptual features and that these various aspects are linked so that, upon recall, the different components of a memory are bound together to reproduce the memory in its integrity.

• hippocampus is still necessary to bind together the components of recent memories, whereas more remote explicit memories can be recalled independently of the hippocampus as the connections between cortical representation strengthen.

Plasticity-Some facts• Plasticity by Santiago Ramon y Cajal as “the property by virtue of which

sustained functional changes occur in particular neuronal systems following the administration of appropriate environmental stimuli or the combination of different stimuli”.

• Most distinctive feature of the nervous system is the astonishing ability to adapt to the environment and to improve its performance over time and experience

• Synaptic connections that are scarcely used become weaker and weaker and eventually disappear

• Synapses that are heavily used become stronger and stronger and eventually increase in number

Continued…..• Neural plasticity represents the basis of the higher brain functions such as

learning and memory• Built-in property of neural plasticity allows experience to shape both

functionally and structurally the nervous system.

• synaptic strength can be finely tuned over – a short or even a long time scale by a combination of factors including previous activity

of the network, generation of second messengers, functional changes in pre- and post-synaptic proteins as well as regulation of the expression of genes implicated in growth, survival and synaptic transmission

• This results in changes in the efficiency of synaptic transmission– That can last from fraction of seconds to minutes in case of short-term synaptic

plasticity (including paired-pulse facilitation or depression, augmentation, depression, post-tetanic potentiation)

– That can last to hours, days and months in case of long-term synaptic plasticity (long-term potentiation, long-term depression).

THE END

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