The Mechanisms of Memory and Loss of Memory

R. BrandtR. Brandt(Email: (Email: [email protected]@biologie.uni--osnabrueck.deosnabrueck.de))

Fachbereich Biologie/ChemieFachbereich Biologie/Chemie

The Mechanisms of Memory and Loss of MemoryThe Mechanisms of Memory and Loss of Memory

The Mechanisms of Memory The Mechanisms of Memory and Loss of Memoryand Loss of Memory

Program:Program:

1.1. Mind and brainMind and brain2.2. Memory formation in health and disease Memory formation in health and disease

2.1 2.1 Pathways for memory formationPathways for memory formation2.2 2.2 The hippocampus and declarative memoryThe hippocampus and declarative memory

3. 3. A molecular approach to cognitionA molecular approach to cognition3.1 3.1 Genetic enhancement of memoryGenetic enhancement of memory3.23.2 AlzheimerAlzheimer‘‘s disease and s disease and „„smart drugssmart drugs““3.2 3.2 Language genesLanguage genes

Rene Descartes Rene Descartes (1596(1596--1650)1650)

Dualistic solutionDualistic solution: :

res cogitansres cogitans res extensares extensa

Psychophysical problemPsychophysical problem: :

Relation between mind and brainRelation between mind and brain

1.1. Mind and brainMind and brain

Karl R. Popper, John C. Eccles „Das Ich und sein Gehirn“

Piper, 1989

Dualistic InteractionismDualistic Interactionism: :

MindMind Quantum Physics Quantum Physics BrainBrain

Antonio R. Damasio: Antonio R. Damasio: Descartes‘ Irrtum: Fühlen, Denken Descartes‘ Irrtum: Fühlen, Denken

und das menschliche Gehirnund das menschliche Gehirn, , dtv, 1998dtv, 1998

Cognitive abilities depend on the presence and functioning of prCognitive abilities depend on the presence and functioning of precise brain ecise brain regionsregions

Antonio R. Damasio: Antonio R. Damasio: Descartes‘ ErrorDescartes‘ Error, ,

Penguin Books, 2005Penguin Books, 2005


Phineas Gage (1848)Phineas Gage (1848)

Brain lesions selectively influence planning of actions in realBrain lesions selectively influence planning of actions in real--life life situationssituations

Lesion in the frontal lobe and the limbic systemLesion in the frontal lobe and the limbic system


Neurodegenerative diseases with a „functional knockout“ of speciNeurodegenerative diseases with a „functional knockout“ of specific fic brain regions:brain regions:

DiseaseDisease Affected brain regionAffected brain region

Parkinson‘s diseaseParkinson‘s diseaseSubstantia nigraSubstantia nigra (part of the (part of the

extrapyramidal system of motor extrapyramidal system of motor coordination) coordination)

Amyotrophic lateral Amyotrophic lateral sclerosis (ALS)sclerosis (ALS) motor neurons of the spinal cord motor neurons of the spinal cord

Alzheimer‘s diseaseAlzheimer‘s disease HippocampusHippocampus, entorhinal cortex , entorhinal cortex (part of the limbic system) (part of the limbic system)


„Über einen eigenartigen schweren

Erkrankungsprozeß der Hirnrinde“

(Tübingen, 1906)

Dr. Alois Alzheimer(1864-1915)

• Konrad und Ulrike Maurer, „Alzheimer: Das Leben eines Arztes und die Karriere einer Krankheit“ München: Piper, 1999• Roland Brandt und Hartwig Hanser „Alzheimer-Demenz: Kahlschlag im Gehirn“ Gehirn und Geist (Spektrum der Wissenschaft) 3/2003, 30-35

2. Memory formation in health and disease2. Memory formation in health and disease

Implicit and explicit memoryImplicit and explicit memory::

Types of long term memoryTypes of long term memory2. Memory formation in health and disease2. Memory formation in health and disease

Senile (amyloid) plaquesSenile (amyloid) plaques

Neurofibrillary tangles (NFTs)Neurofibrillary tangles (NFTs)


MRI imageMRI image


Dual function of the entorhinal cortex: main input and main outpDual function of the entorhinal cortex: main input and main output of the ut of the hippocampal formationhippocampal formation

explicit memory formationexplicit memory formation


Kandel, Auf der Suche nach dem Gedächtnis, 2007


Anatomy of the hippocampal formationAnatomy of the hippocampal formation


Entorhinal cortexEntorhinal cortex

Gyrus dentatus Gyrus dentatus (granule cells)(granule cells)

CA1 (small pyramidal CA1 (small pyramidal neurons)neurons)

CA3 (large pyramidal CA3 (large pyramidal neurons)neurons)

Microanatomy of the hippocampal formationMicroanatomy of the hippocampal formation


Gyrus detatusGyrus detatus

CA1CA1

CA3CA3

Schaffer collateralSchaffer collateral

Mossy fiberMossy fiberTractus perforansTractus perforans

AlveusAlveus

The trisynaptic pathwayThe trisynaptic pathway


Connections in the hippocampus (Schaffer collateral and mossy Connections in the hippocampus (Schaffer collateral and mossy fiber) are modified according to experiencefiber) are modified according to experience

High frequency stimulation increases the amplitude of the excitaHigh frequency stimulation increases the amplitude of the excitatory tory postsynaptic potential in the target cells postsynaptic potential in the target cells longlong--term potentiation (LTP)term potentiation (LTP)

Gyrus dentatusGyrus dentatus

CA1CA1CA2CA2CA3CA3

Mossy fiberMossy fiber

StimulusStimulus

RecordingRecording


Molecular basis of LTPMolecular basis of LTP


Amyloid plaques cause a decrease in spine density and impaired Amyloid plaques cause a decrease in spine density and impaired memory formation in an animal model of Alzheimer‘s disease memory formation in an animal model of Alzheimer‘s disease


„„Morris water maze“Morris water maze“

„„Barnes maze“Barnes maze“


Different types of events (air blast, elevator disaster, earth qDifferent types of events (air blast, elevator disaster, earth quake) induce uake) induce characteristic activity patterns in the CA1 region („neural cliqcharacteristic activity patterns in the CA1 region („neural clique ue assemblies“) assemblies“)

Lin et al. (2006) Organizing principles of real timeLin et al. (2006) Organizing principles of real time--time memory time memory encoding: Neural clique assemblies and universal neural codes. encoding: Neural clique assemblies and universal neural codes. Trends Trends Neurosci.Neurosci. 29:48.29:48.

Tsien (2007) Der GedächtnisTsien (2007) Der Gedächtnis--Kode. Kode. Spektrum der WissenschaftSpektrum der Wissenschaft10/2007: 4610/2007: 46--53. 53.

Cellular basis of memory encodingCellular basis of memory encoding2. Memory formation in health and disease2. Memory formation in health and disease

Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory.

DoogieDoogie--mousemouse (1999):(1999):

(for a review:(for a review: Cooke and Bliss (2003) Cooke and Bliss (2003) „„The genetic enhancement of memoryThe genetic enhancement of memory““. . Cell. Cell. Mol. Life SciencesMol. Life Sciences 6060:1:1--5)5)

Tang et al. (1999) Genetic enhancement of learning and memory in mice. Nature401:63-69.

Overexpression of a particular NMDAOverexpression of a particular NMDA--receptor subunit (NR2B) in transgenic micereceptor subunit (NR2B) in transgenic micecauses improvement in standard learningcauses improvement in standard learning-- and memory tests (e.g., and memory tests (e.g., „„Morris Morris watermazewatermaze““): NR2B shows extended kinetics ): NR2B shows extended kinetics longer window for coincidence longer window for coincidence detectiondetection

3. A molecular approach to cognition3. A molecular approach to cognition

Treatment of symptoms of Alzheimer‘s diseaseTreatment of symptoms of Alzheimer‘s diseaseDonepezil, Rivastigmin, Galantamin Donepezil, Rivastigmin, Galantamin Inhibitors of acetylcholinesterase Inhibitors of acetylcholinesterase

AcetylcholinesteraseAcetylcholinesterase


Ascending arousal (modulatory) systemAscending arousal (modulatory) system

Integrating system for the coordination of brain activityIntegrating system for the coordination of brain activityCharacterized by specific types of neurotransmitters („chemoarchCharacterized by specific types of neurotransmitters („chemoarchitectonic“)itectonic“)

General roleGeneral role: : -- arousal systemarousal system-- Control of emotional behavior and mood Control of emotional behavior and mood


The hippocampus is strongly influenced by ascending projections The hippocampus is strongly influenced by ascending projections from the brain stemfrom the brain stem

nicotinicnicotinic as well as as well as muscarinicmuscarinic cholinergic receptorscholinergic receptors

Role in controlling general brain activity (arousal system) and Role in controlling general brain activity (arousal system) and wake/sleep wake/sleep states states


Positive effect of acetylcholinesterasePositive effect of acetylcholinesterase--inhibitor inhibitor „„DonepezilDonepezil““ in normal, middlein normal, middle--aged private pilots during complex aged private pilots during complex tasks in flight simulatorstasks in flight simulators(Yesavage et al. (2002)(Yesavage et al. (2002) Donepezil and flight Donepezil and flight simulator performance: Effects on retention of simulator performance: Effects on retention of complex skills.complex skills. NeurologyNeurology 5959:123:123--125)125)


Cannabinoids: Retrograde neuronal mdulatorsCannabinoids: Retrograde neuronal mdulators

Cannabis Cannabis sativasativa var. var. indicaindica


(aus: (aus: Gehirn&GeistGehirn&Geist 4/2006)4/2006)

Endocannabinoids: Endocannabinoids: 22--arachidonoylarachidonoyl--glycerol glycerol

(Anandamid)(Anandamid)

FoxP2FoxP2LaiLai et al. (2001) a et al. (2001) a forkheadforkhead--domaindomain genegene isis mutatedmutated in a in a severesevere speechspeech and and languagelanguagedisorderdisorder. . NatureNature 413413:519:519--523.523.

Mutation in a Mutation in a singlesingle genegene severelyseverely impairsimpairs languagelanguage

•• FoxP2FoxP2--knockout knockout micemice areare unableunable to to produceproduce certaincertain vocalizationsvocalizations((ShuShu et al. (2005) et al. (2005) AlteredAltered ultrasonicultrasonic vocalizationvocalization in in micemice withwith a a disruptiondisruption in in thetheFoxp2 Foxp2 genegene. . ProcProc. . NatlNatl. . AcadAcad. . SciSci. USA. USA 102102:9643:9643--9648)9648)

InvolvementInvolvement of FoxP2 of FoxP2 onlyonly in in mechanicalmechanicalaspectsaspects oror on on cognitivecognitive sideside??

•• Human Human versionversion of FoxP2 of FoxP2 differsdiffers byby fewfew basebase pairspairsfromfrom thatthat of of chimps chimps ((EnardEnard et al. (2002) et al. (2002) MolecularMolecular evolutionevolution of FOXP2, a of FOXP2, a genegene involvedinvolved in in speechspeech and and languagelanguage. . NatureNature418418:869:869--872)872)


Strong FoxP2 expression in the basal ganglia which are crucial fStrong FoxP2 expression in the basal ganglia which are crucial for stringing or stringing together detailed sequences of actions in the correct ordertogether detailed sequences of actions in the correct order

FromFrom: The Scientist, Oct. : The Scientist, Oct. 24, 200524, 2005

FoxP2 is not a FoxP2 is not a „„gene for gene for speechspeech““, but a window to , but a window to

analyze speechanalyze speech


The Mechanisms of Memory and Loss of MemoryThe Mechanisms of Memory and Loss of Memory

•• Some cognitive functions such as declarative memory formation Some cognitive functions such as declarative memory formation can be tracked down to the function of individual cells, synapsecan be tracked down to the function of individual cells, synapses, s, and proteinsand proteins

•• Cognitive abilities depend on the presence and functioning of Cognitive abilities depend on the presence and functioning of precise brain regionsprecise brain regions

•• Modulation of synaptic transmission has therapeutic potential aModulation of synaptic transmission has therapeutic potential and nd may enhance cognitive abilitiesmay enhance cognitive abilities

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The Mechanisms of Memory and Loss of Memory