Learning and memory

What is memory?

the changes in the nervous system that support the acquisition, retention and retrieval of information about the world and life experience

What is memory for?

• support behavioural adaptation to the world we live in

• enable sensible choices

• avoid repeating actions with negative consequences

• prepare for the future

What is the reductionist explanation for the physical nature of memory?

• modification due to a stimulus

• memories are engrams

  • set of neurons that form a trace of what you’re learning

  • combination of activated neurons firing together

• Richard Semon

Where are memory traces located?

• Karl Lashley

• local vs distributed

• argued due to experiments that show when you section/lesion area probbaly not localised

What is evidence against the local storage of memories?

• Grandma cell

• depending on modality - may be more and less specialised circuits

Useful study on engrams??

• rodent in shock context, using optics/lasers

• stimulation in different context

• causally manipulating reinduces state

DONT KNOW WHO - TUTORIAL

How can a memory be represented by neural activity?

• Hebb

• cell assembly hypothesis

• cells that fire together wire together

How are new memories formed if the pool of neurons is roughly stable?

• the Hebbian plasticity theory of learning

• metabolic change takes place when two cells repeatedly firing together or near enough to excite the other, efficiency increases

Diagram for memories

What is evidence for the hippocampus being a key brain circuit for memory of places and events?

HM

• anterograde amnesia

• retrograde amnesia

What does HM still having access to some memories suggest?

• transfer model

  • memories shift away from hippo over time

• or multiple trace theory

  • hippo always involved if episodic

What are various behavioural tasks to study learning and memory in animals?

• fear conditioning box

• barnes maze

• watermaze

• T maze

• 8-arm radial maze

• Y maze

How might we be able to uncover the neural pathways of learning and memory?

look at the laminar organisation of the hippocampus circuit

What are 4 main areas of the hippocampus?

CA1, CA2, CA3, dentate gyrus

Which area receives info from both entorhinal cortices?

• CA1

• maybe how memory is mapped within

How may we be able to identify the building blocks of a memory ‘engram’?

• use Immediate Early Genes

  • class of genes that are rapidly and transiently activated in response to signalling cascases

  • eg transcription factor c-Fos

• establish causality and demonstrate that these neurons are active

How can we use neuronal tagging to do this and who?

Xu Liu et al, 2012

• if neuron gets active, express protein c-Fos

• design transgenic approach that allows to taf with a molecular the neurons that have expressed c-Fos

• manipulate with light

  • shock rat and they will express opsin

  • then don’t shock but have laser and they will still freeze -reinducing state

How can you assess electrophysiological activity of single neurons vs neuronal populations?

• patch and intracellular electrodes

  • can measure amplitude of synaptic currents and slope of synaptic potential

• extracellular electrodes

  • measure local field potentials

  • can extract amplitude, freq etc

  • look at first spike when about to enter or leave to know where are in space

Examples of the many ways information caan be represented in the hippocampal network?

• local field potentials

• spike trains

How can individual neurons represent information during active behaviour?

• using a rate code

• AP = information

• firing rate - binary or graded response

What is an example of a rate code?

• discovery of place cells in hippocampus of rodents

• O’Keefe and Dostrovsky (1971)

What does the hippocampal population provide?

• map like representation of the whole environment

• if one neuron reponds the most in specific location then gradually less in surrounds then combination of the neural firing can map environment

What does short timescale coactivation of multiple neurons form?

cell assemblies

What can neuronal spiking activity be related to?

various network oscillations

How to define an oscillation?

repetitive variation of a variable in magnitude or position around a central value (often a point of equilibrium) or between two or more different states

What are biological rhythms like in respect to oscillations?

• rarely strictly periodic and usually non stationary

• often fluctuate irregularly over time and their individual cycles not truly regular

What is phase assignment for neuronal spiking?

• llows temporal coding for information representation

  • the timing of an AP can carry info

• in respect to the ongoing phase of an oscillation

• can determine relative timing between cells in neuronal circuits

What pattern was shown in Dupret’s lab on neural oscillations while exploring and while asleep?

• neural oscillations have temporally structured neuronal spiking correlates

• same patterns shown when asleep as when awake showing memory strengthened in sleep

What did Wilson and McNaughton (1994) show?

• waking firing patterns are replayed during offline ripples in the hippocampus

• look at rippled to see high frequency then look at time lock to see if neurons coactivated

• when active together during running, active together when sleep

What is the replay?

• time compressed?

• most important?

More evidence for hippocampal activity correlating with memory processing during offline and online episodes?

O’Neill et al (2010)

How else might memory be stored?

synaptic plasticity

What is an example of synaptic level LTP?

• hippocampal CA1 glutamatergic synapse as a cellular model

• NMDA and AMP tong term potentiation

What are the two ways we see activity-dependent changes in CA3-to-CA1 synaptic strength?

• long term potentiation

  • Bliss and Lomo (1973)

• long term depression

  • Ito and Kano (1982)

What are the two ways we can see molecule-by-molecule dissection of signalling pathways for synaptic plasticity?

• pharmological blockade

  • eg APV to selectively block NMDA receptors

• transgenic manipulation

  • CRISPR-based genetic deletion of CaMKII protein

• these show how memory can be affected when long term potentiation is stopped

What did Silva et al () - my study look at?

• LTP studied as mechanism for hippocampus dependent learning and memory but evidence still incomplete

• Mutated mice - hippocampus is deficient in LTP but maintains intact postsynaptic mechanisms

  • Inhibiting NMDAR function also disrupts synaptic function so might alter information processing

• Pharmacological studies have implicated the CaMKII holoenzyme in the induction of LTP in hippocampus

• Mutant mice shown CA1 hippocampal region exhibit little to no LTP although postsynaptic transmission appears normal

• Impaired in performing a task that requires learning the multiple spatial relations among a hidden proximal object and visible objects in surrounding distal environment

• Mutant mice deficient in LTP in the CA1 region of hippocampus therefore likely that this deficit in LTP is responsible for the impairment in spatial memory

Another study = Song-Hai Shi et al (1999)

What can LTP induce?

• structural remodelling of synapses and formation of new contacts

• strengthens - mayb for memory

• Toni et al (1999)

General conclusion from lecture?

• info can be represented many different ways

• different ways of looking at building blocks of memory

What other type of plasticity can take place at non-synaptic sites?

• neuronal intrinsic plasticity

• involves enduring changes in the number, distribution or activation of various ion channels central to a neurons intrinsic excitability affects the flow of information within a neuron by following the course of synaptic inputs from the dendrite to the axon terminal and impacts on the threshold for synaptic changes

What did Moyer et al, 1996 show?

• learning-related intrinsic palsticity of hippocampal neurons

• animal given air puff with a tone which makes eye blink response

• CA1 neurons recorded before learning, 24 hours after and 14 days after

• found reduction in the hypepolarisation potential soon after initial learning allowing neurons to fire more spikes in a burst avoiding the typical spike freq adaptation

• not seen in naive or recordings 14 days later

• intrinisc mechanism to allow neurons to remember the pairing

How is memory thought to be stored?

• after learning there is a unique pattern or ratio of activity in the neurons

• it is a distributed memory with no single neuron representing

• means graceful degredation leads to representations blending together

What is the anatomy of the hippocampus like?

• two thin sheets of neurons folded onto each other

• dentate gyrus and Ammons horn

  • Ammons hoen has 4 divisions

  • including CA1 and CA3

Who found that brief and high frequency electrical stimulation of the perforant path synapses of the dentate gyrus produced LTP?

Bliss and Lomo (1973)

Differences with spike timing-dependent plasticity for LTP and LTD?

• LTP can result when the EPSP caused by synaptic glutamate release precedes an AP in the postsynaptic neuron

• LTD can result instead when EPSP causes by glutamate release follows a postsynaptic AP

 

What is synaptic tagging?

• Memory formation appears to initially involve rapid modifications of existing synaptic proteins

What did Didi’s study look at?

• synaptic modification threshold

• mice raised in light or dark and their response to light later

• found those raised in dark if in light for 2 days then respond same as the light ones

• 2 days of light cancelled out whole life of dark