Learning and memory: Organization and pathways

of the hippocampal formation

1. Learning and memory: Brain

regions and major pathways

2. Organization of the hippocampal

formation

2.1 Anatomy and microanatomy

of the hippocampus

2.2 Principles of function of the

hippocampus

Additional Literature:

Eric Kandel „In Search of Memory: The Emergence of a New Science of

Mind“, Norton & Company, 2007

Types of memory

Working memory:

studied in most detail: BA46 (frontal

lobe); small lesion produces deficits

in „delayed response task“

Structural base: firing of neurons (<30s)

Implicit and explicit memory:

Types of memory

Brain regions associated with declarative memory

Studies of patients with specific lesions

- surgery (e.g., H.M.)

- neurodegenerative diseases (e.g., Alzheimer‘s disease)

Specific memory deficit (amnesia)

- normal short-term memory

- good long-term memory (but

evidence for some retrograde

amnesia)

- unchanged IQ

- normal learning of motor

skills

H.M.: Bilateral removal of

regions of the temporal

lobe

(L.R. Squire (2009) The Legacy of Patient H.M.

for Neuroscience. Neuron 61: 6-9)

→ Central role of hippocampus in declarative memory

Alzheimer‘s disease

Specific deficit in explicit memory (early stages)

Early changes (neuron

death) in temporal lobe

(entorhinal cortex and

hippocampus)

Major pathway for acquiring declarative memory

Dual function of the entorhinal cortex: main input and main output of the

hippocampus

EC and H are temporary way stations but not site of storage

Anatomy of the hippocampus and neighboring brain

structures

Part of the archicortex (1-layer-

structure)

Hippocampus: Develops from a

special fold at the edge of the cerebral

cortex

Visible in coronal sections with large

variations dependent on the position

Dentate gyrus

(granule cells)

CA1 (small pyramidal

neurons)

CA2 (large pyramidal

neurons)

CA3 (large pyramidal

neurons)

Anatomy of the hippocampal formation

Dentate gyrus

CA1CA2CA3

Tractus perforans

Input: tractus perforans, contacts dendrites of the pyramidal neurons and

granule cells of the dentate gyrus

Output: axons of pyramidal cells that

form the alveus

Alveus

Input and output

of the

hippocampus

(from: Kahle, Taschenatlas der Anatomie)

Axons of granule cells form mossy fibers that contact the dendrites of the

pyramidal cells

Backward collaterals (Schaffer collaterals) from the axons of the CA3

pyramidal neurons to dendrites of the CA1 region

Dentate gyrus

CA1CA2CA3

Schaffer collateral

Connections

within the

hippocampus

Mossy fiber

Dentate gyrus

CA1CA2CA3

Schaffer collateral

Mossy fiber

The hippocampus as temporary way station:

The trisynaptic pathway

Tractus perforans

Alveus

How does the hippocampus work in

memory formation?

I. Hippocampus receives no direct somatosensory information but is highly

connected to the cortex (including several association cortices)

→ Key function may be that highly processed information from the cortex is

modified and sent back to the cortex

Note: In mouse, EC only involved in olfactory information procession

(from: Eric Kandel „In Search of Memory: The

Emergence of a New Science of Mind“)

Gyrus dentatus

CA1CA2CA3

Mossy fiber

Stimulus

Recording

II. The pathways within the hippocampus (Schaffer collateral pathway and

mossy fiber pathway) are sensitive to the history

Brief high-frequency train of stimuli increases the amplitude of the excitatory

postsynaptic potential in the target cells → long-term potentiation (LTP)

Stimulus

Recording

Structural basis of LTP is different in the two pathways:

Mossy fiber pathway: presynaptic → Ca2+-influx that activates second

messenger cascade

Schaffer collateral pathway: postsynaptic → mediated via glutamate receptors

Ca2+ Ca-dependent

adenylylcyclase

cAMP

ATP

PKA++

+

Downstream-effects probably similar in both cases:

activation of

transcription factors

(e.g. CREB)gene expression

Homosynaptic LTP

→ Plasticity that depends on

previous experience

Associative LTP

→ Coincidence

detector

Molecular basis of long term potentiation in

Schaffer collateral fibers

Genetic enhancement of memory ?

Doogie-mouse (1999):

Genetic enhancement of memory ?

Doogie-mouse (1999): Overexpression of a particular NMDA-receptor subunit (NR2B)

→ Improvement in standard learning- and memory tests (e.g., „Morris watermaze“)

NR2B shows extended kinetics → longer window for coincidence detection

Normal development: expression of NR2B receptor unit decreases with age

but:1. Decrease in NR2B expression correlates with sensitivity to pain: Doogie-mouse

develops symptoms of chronic pain

2. „Enrichment“ of environment improves performance of control animals but not of the

Doogie-mouse (capacity may be at biological limit)

(Literatur: Cooke and Bliss (2003) „The genetic enhancement of memory“. Cell. Mol.

Life Sciences 60:1-5)

Non-genetic enhancement of memory (Endocannabinoid

system) ?

Endocannabinoids act as retrograde signals at CNS synapses (e.g.,

pyramidal neurons in the hippocampus (modulating activity)

Acute administration of exogenous cannabinoids disrupts neuronal signalling

May be involved in forgetting traumatic events

→ treatment of posttraumatic stress disorder (PTSD) with Cannabis

One stimulus train: early phase (1-3 hrs): no protein synthesis required

>4 stimulus trains: late phase (<24 hrs): requires RNA and protein synthesis

III. LTP has different time scales

Network-oscillations (cooperative firing) occur in the hippocampus with different

frequencies:

e.g., theta oscillations (4-10 Hz) and gamma (40-100 Hz) oscillations

May have a role in triggering the generation of synchronous network activity in

the neocortex that strengthens synaptic contacts

IV. The connectivity in the hippocampus may cause oscillations

The hippocampus is strongly influenced by the ascending projections from the

brain stem and by connections of the limbic system (the „emotional brain“)

nicotinic as well as muscarinic (mainly M1) cholinergic receptors

Cholinergic input may be important for function of the hippocampus

according to the two-state-model of memory formation (Hasselmo, 1999):

„on-line“ state: active, explorative phase

high activity of the cholinergic system, new information is internally stored

„off-line“ state: during sleep phase

decreased cholinergic activity, internally stored information is read out and

stored in neocortex

Involvement of gamma-(35-80 Hz) and theta-(5-12 Hz) oscillations:

cholinergic induction of gamma oscillations occurs via muscarinic (M1)

receptors

(for a review: Alzheimer and Wess, „Muskarinische Acetylcholinrezeoptoren und die

neuronalen Mechanismen kognitiver Leistungen“ Neuroforum 2 (2005))

Nicotine and nicotinic agonists improve cognitive function in aged or

impaired subjects

In some epidemiologic studies: Smoking is protective against development

of neurodegenerative diseases (?)(Picciotto and Zoli (2002) J. Neurobiol. 53:641-655(Review))

Information storage occurs in „memory engram cells“

‘‘Engram cells’’ are a population of neurons that are activated by learning, have enduring

cellular changes as a consequence of learning, and whose reactivation by a part of the

original stimuli delivered during learning results in memory recall.”

(Tonegawa et al. (2015) Memory Engram Cells Have Come of Age. Neuron

87: 918-931)