1 Traces of memories In the brain
2 - Features of the memory trace (engram),- Memory types, memory systems
3 Richard Semon (1859-1918) and the concept of engram” (engramme, memory trace)Die Mneme Engram is a persistent alteration in the brain as a result of a specific event. The content of the engram is linked to the information perceived during encoding and predict what can be recalled later. A major feature of engram is ecphory, the ability to change behavior when reactivated with the appropriate keys. The engram is in a dormant state between encoding and retrieval. “ Engram is the enduring though primarily latent modifications in the irritable substance produced by a stimulus…” “Ecphory awakens the engram out of its latent state into one of manifested activity… “
4 Plasticity and the substrate of engram at different levels of organizationSynaptic (LTP) (pre-, postsyn. receptors etc) Nuclear (CREB,hiszton, c-fos, Arc, synaptic tag) Dendritic spines (size, shape, longevity) Neuronal networks (subnetworks sparse, dense code) Brain regions, memory systems
5 The “life cycle” of the engramJosselyn et al., 2015 NRN
6 The engram in case of fear memory
7 Neuronal representations of engramsNat Rev Nsci 5:361 Nakazawa, Persistent, linked to a special event Linked to the perceived information Able to change behavior Gets into a dormant state (sleep replay only for 24 hours) Running 5 mp 0 mp Kis animáció, a felső rajz helyett. Patkány jobbról balra megy Amikor a szalag közepére ér felette megjelenik annyi pácika ahány a fenti képen a piros , Csak 1 sejtet ábrázolunk a koncepció (MI A HELYSEJT?) megértéséhez. Kesöbb ez az abra mar nem kell latszódjon csak a pati. 2) Patkány uaz mint 1. Ahogy megy fut vele az középső ábra 10 vonala es mutatja, hogy melyik sejt mikor aktív. Idotengely kell, vegen kiírja hogy 5 mp 3) Alsó sor, patkány alszik, sejtek aktivitása megjelenik idoben egymas utan (lehet folyamatos vonal, hogy hasonlítson az előzőhöz) vegen megjelenik, hogy 0,15 mp telt el. A ket ido villog a végén (a magyarazat alatt) During sleep Neuron 36:1183 Lee, Wilson 0 mp 0,15 mp
8 Replay of the engram during sleep and memory consolidationAfter encoding the engram reactivates spontaneously during sleep The degree of reactivation is correlated with the degree of engram retention (memory) Inhibiting reactivation impairs the memory trace Sensory stimuli present during encoding may recall the engram at a later phase.
9 Specificity of coding and recalling the engram in humans9
10 The dormant state of the engramHow can we study or demonstrate the existence of the dormant engram? (sleep replay only for 24 hours)
11 Labeling (dormant) engram cellsActivity dependent neuronal labeling: immediate early genes – c-fos, Arc, zinc finger 268 linked to markers which are expressed permanently - GFP, LacZ, Channelrhodopsin!!! Halorhodopsin How can we label the specific cell population which participates in coding a given engram? Tet Tag method tetracyclin response element (TRE) – regulates the transcription of an immediate early gene (IEG) tetracyclin transactivator protein (tTA) – binds and activates to TRE !! BUT NOT in the presence of tetrecyclin!! Condition A - tetracyclin provided (in the drinking water) – no IEG transcription Condition B - tetracyclin removed – IEG (and the marker) will be expressed in a GIVEN time window. Subject the animal to a learning situation THE RESULT: SPECIFIC MARKERS ARE EXPRESSED IN THE CELL POPULATION WHICH WAS ACTIVATED DURING THE LEARNING SITUATION
12 Optogenetic activation and inactivation of labeled engram cellsContext specific excitation/inhibition of engram cells alters behavior Ecphory (engram criteria 3!)
13 Labeling the dendritic spines!! which are involved in coding an engramHayashi-Tagaki et al., Nature 2015
14 Elimination of only those spines which are involved in coding an engramHayashi-Tagaki et al., Nature 2015
15 The effect of eliminating the spines involved in the engram in case of motor learningCtr Venus Venus Venus
16 STEP FUNCION OPSINS AND DREADDsAllocation – insert given neurons to the engram Basic idea Neurons which are spontaneously more depolarized than the average during the learning situation are more likely to participate in establishing the engram If we are able to slightly depolarize a given cell population we can promote their participation in the engram STEP FUNCION OPSINS AND DREADDs Designer Receptors Exclusively Activated by Designer Drugs
17 DREADD – and the chemogenetic activationDesigner Receptors Exclusively Activated by Designer Drugs Designer receptor (DR): A G protein coupled receptor which has no ligand in the mammalian nervous system (excitatory/inhibitory, M2/M4) Designer Drug (DD): A drug which can be injected systematically, crosses the bold-brain barrier and acts on DRs at nanomolecular concentration Experiment: Express DR in a well-defined cell population Inject DD Subject the animals to a learning situation Labeled cell will more (or less) likely to participate in the engram
18 The effect of excitation and inhibition of the cells allocated to the engram
19 SUMMARY Studying Semon’s four postulates of engrams in the 21st century Strucutral basis of engram Long term Ca-imaging, electron microscopy 2) Content of the engram recording the activity of neuronal networks, fMRI 3) Ecphory , the effect of engram on behavior Opto- and chemogenetic experiments 4) Sleeping engram
20 All memory works according to these principles?How many types of memory we have?
21 Memory impairments of HM bilateral temporal lobectomy (1953)New events, autobiographic data New words, new persons Spatial navigation, new places Recognition tests (longer than 5 min) Retrogád amnesia (11 years) ”...forgetting of the events of daily life as quickly as they occur” (Scoville and Millner, 1957) HM - Henry Gustav Molaison
22 MRI of HM The lobectomy involved the majority of hippocampus parts of the amygdala and entorhinal cortex.
23 The selectivity of memory impairments in case of H.M:Impaired: Memory of events Intact: Mirror drawing
24 Intact - Perceptual Priming –Two versions of recalling words After reading 20 words Free recall: What did you read? Complex, contextual learning Hippocamal lesion - Impaired Perceptual priming: What word comes to your mind? Simple association Hippocampal lesion - Intact. Ép marad – Rövid távú memória
25 Different types of memory?Different memory systems?
26 Motor memory (Procedural, Implicit) Requires training, practice Can be recalled in situation identical to the learning situation (rigid) Can be distructed by learning similar things Can display plasticity in case of brain damage Sport, typing, driving, dancing, priming, operant and classic conditioning Event memory (Declarative, explicity) Requires a single event Can be recalled in various situations More difficult to distruct No recovery after damage Personal events, persons, data, spatial navigation, words Fear memory, reward memory In case of significant events single association may be sufficient Can be recalled in situation identical to the learning situation Highly pronounced vegetative responses (heart, breathing, sweat) foot shock, kokain
27 Temporális kéreg Hippokampusz Basal ganglia/ CerebellumMotor memory circuit Event memory circuit Temporális kéreg Hippokampusz Frontal cortex Thalamus Thalamus Mammillary body Basal ganglia/ Cerebellum Iplastic synapses
28 Fear memory Prefrontal cortex Thalamus Amygdala Autonom centers
29 MEMORY SYSTEMS – 1. Hippokampus Mamillary bodyAnterior talamus Parahippocampal, perirhinal and posterior cingulate cortices Event memory circuit, Papez-circuit ...and Dracula
30 The effect of anterior thalamic lesion on hippocampus dependent spatial memory task4 arm maze Fewer arm entry – better performance SHAM - kontroll lesions AM/AV/AD- anterior thalamic nuclei Aggleton et al,. 1996
31 MEMORY SYSTEMS – 2. Motor memory circuits (Reward memory)
32 MEMORY SYSTEMS – 3. Fear memory midline thalamusmedial prefrontal cortex amygdala (lateral, basolateral, central)
33 Plasticity and the substrate of engram at different levels of organizationSynaptic (LTP) (pre-, postsyn. receptors etc) Nuclear (CREB,hiszton, c-fos, Arc, synaptic tag) Dendritic spines (size, shape, longevity) Neuronal networks (subnetworks sparse, dense code) Brain regions, memory systems