NBL Module 12

Module 12

Video Lecture 1

• Ancient people thought about memory using analogies of what was available at the time

• Ancient greeks- memory in tablets

  • Written down in mind

• Medieval society

  • Hydraulics, movement of water through pipes and valves

  • Movement of info through pipes in the brain

• 17th century

  • Memory was the interaction of different years- like a clock works

• 20th century

  • Memory was similar to how computers store information

• All of these people were right to a certain extent

  • Contributed something to our understanding of memory

• Memory- considered to be engrams- written down in brain

  • Info flows through axons = pipes in the brian

  • Neurons work in circuits- strengthening of specific circuits underlies memory

  • APs use something similar to a binary code- different types of memory stored within our memory banks similar to computers

  • Memory can be accessed through parallel pathways

• Memory has been defined by neuroscientists and biopsychologists for many decades

  • One- memory is the procession which info is encoded, stores, and retrieved

  • Two- memory are lasting representations that are reflected in thoughts, experiences and behaviours

• 3 components of long term memory

  • Encoding

  • Storage

  • Retrieval 

• Another term for encoding is registering

  • Memory register

• Encoding- reception, processing and combination of info that we take into the CNS

  • Involves acquisition of altered behavior- change in behavior or our thinking- thoughts as a result of an environmental stimulus in which that info was stored

• Storage of info- process of creating permanent records of encoded info

  • Once the info is learned or encoded, it is stored in specific circuits in different regions of the brain

• Retrieval- aka recall or recollection

  • Memories are called back from stored places in response to some cue

  • Used to process or think

• 3 different types of memory- defined by time courses

  • Short-term

  • Long-term

  • Sensory 

• 3 different types of memory systems in terms of time course of how info is processed

• First- sensory register/sensory memory

  • Only half-life of a few milliseconds or hundreds of milliseconds

  • Involves quick scan of environment for important/salient info

  • Aka precoding

  • Modality-specific- there is a sensory register for our visual, auditory, touch, etc

  • Very little, if any combination of info that involves sensory systems

• Working memory/short-term memory

  • Has a lifetime of a few minutes

  • Type of memory that involves coding

  • Can be enhanced by rehearsal or chunking

  • Aka recoding

  • Involved in the flow of info into our memory systems

  • Memories can be retrieved from long-term memory stores into short-term memory stores so that the info can be used or manipulated to help us solve problems and do short-term thinking

• Long-term memory

  • Lifetime of many days to many years

  • Can be stored for a lifetime

  • Memory that is going to be stored into memory banks

  • When we recall or retrieve a memory, we retrieve long0term memory from these long-term memory stores

  • Placed in short-term memory 

• Atkinson and Shiffrin came up with the multi-store model for how memory functions

  • First defined these 3 memory systems and the connections among the systems

  • Even though there are these different types of memory systems and each has its own mode of operations, they are very highly interconnected and co-operate with each other

• Idea is that info flows first into sensory memory, through process of attention, info that is most important enters into short-term working memory

  • Info that is worth retaining are encoded into long-term memory

  • Info that is stored in long-term memory can be retrieved back into short-term memory

• Sensory and short-term memory are necessary steps in formation of long-term/lasting memory

• Long-term memories involve biochemical and morphological changes to circuit activity that are thought to underlie storage of long-term memory

• Sensory- ability to retain impressions of sensoyr info for just a few millisecond to seconds after the original stimulus has terminated

• Sensory memory has specific characteristics

  • Only present for 200 ms to 2 sec

  • Info is not integrated in sensory memory and is modality-specific

  • We have iconic memory- for visual system

  • Haptic memory for somatosensory system

  • Auditory, olfactory and taste memory

  • Iconic memory has been most well-characterized

  • Can be unconscious or conscious

    • Can be consciously aware of focusing on a stimulus or can just be receiving sensory info without being consciously aware of it

  • High capacity for detail and resolution

    • Emerges from sensory systems- have high capacity for detail and resolution

    • Decays very rapidly, info is not stored in sensory info

    • No mechanisms to increase timing that these memories are present- cannot be prolonged by rehearsal

• Iconic- idea about being able to ses an object or something in our visual system

  • Fireworks or sparklers- can see impression of where sparklers were for a few milliseconds

• Echoic memory

  • Same types of tests- space out time between listening and recall

• Haptic memory

  • Touch- 2 seconds

• Olfactory and gustatory memory

  • Know less about this

• Info is not stored but present for enough time to be present in short-term memory

• Sensory cortices, including primary, secondary and association cortices are involved

  • Info will be transmitted to visual system, will be processed by visual system

  • Visual info will travel to association areas including PPC and in the dorsal stream and the inferior temporal region

  • Info will be combined with other sensory info to the PFC

  • PFC- areas for transmission that we find to be most important 

  • When we attend to our sensory systems, info is sent to PFC and parietal cortex

• Mechanisms for sensory memory- involves depolarization of neurons that occurs for a few hundred milliseconds after the sensory stimulation has passed or is gone from the environment

  • Persistent synaptic transmission involved in the process

• Info obtained from the sensory memory can be converted into short-term memory via attention

  • Info that is most important will be transmitted to short-term memory

• Attention is defined as the cognitive process of selectively concentrating on one aspect of the environment while ignoring other aspects

  • Filters stimuli to only those of things that we find interesting

• Short-term usually refers to storage of info but not manipulation of organization or material- that is the job of working memory

  • Short-term and working memory are highly interconnected with each other

• Working memory- circuits in the brain in which our short-term memory stores can be accessed, manipulated, and used for things like problem solving

  • Short-term memory- the actual store

• Short-term memory requires attention

  • Unlike sensory memory which has very high capacity for detail and resolution, short-term memory has a much lower capacity

  • 7 plus or minus 2 items: Miller and colleagues

  • Groups of students were asked to remember objects, numbers, colors etc

  • Was 9 plus or minus 2, but has been revised

  • Miller used undergrad college students as his test subjects - have a much higher capacity than adults and the rest of the population

  • Also short-term- duration is 10-30 seconds or a minute

  • Mechanisms involve neural network activity

• Different brain components

  • Short-term emmory is stored in parietal lobe

  • Working memory involved PFC and parietal lobe

  • There are components of short-term memory that involve the temporal lobe as well

• Unlike sensory memory, our short-term memory can be modulated

  • Can be enhanced is using a process called chunking

  • You could chunk the process where we assign a specific meaning to each acronym- can remember objects as a group- can increase capacity twofold

• Working memory- applied to a specific cognitive task

• Atkinson-Shiffrin- component that temporary stores and holds info

  • Allows for manipulation of info present in short term memory

• Incorporates ability to remember semantic info and info that might be present on a test but also to take that info and be able to manipulate it and do problem solving

• Baddeley and Hitch- model for working memory, divided it into several different components

  • Same for multi-store memories that we have- sensory memories, integration of info and short-term storage and info that we decide is most important can be stored into long-term memory

• Central executive

• Phonological loop and visuo-spatial sketchpad

• Added episodic buffer- where info goes to when being retrieved from LTM

• Another aspect- where info can be enhanced is the process of rehearsal

  • Inner voice or inner eye- can go back and repeat the info

  • Through this process, can increase the time where this info can remain in short-term memory store

• Short-term working memory

  • Executive functions- working memory is a critical component of executive functions

  • Are we accomplishing what our goals are or do we need modifications?

• 2 major regions of the brain where activity is high:

  • PFC and regions of the motor and parietal cortex

• PFC- 2 major regions involved in working memory

  • Has been very well studied for spatial and non-spatial object memory

  • PFC serves as executive

    • Components of parietal lobe also contribute to this

• PFC has domain

  • vlPFC- involved in non-spatial working memory

    • Aspects of objects 

  • dlPFC- involved in spatial memory

  • Studies were conducted in 1990s by Goldman Rakeesh and coworkers

    • Used animal models 

    • Recorded electronic activity

• Both dl and vlPFC receive info from association cortices

  • 2 streams of info that flow from association cortices into pfc

• PPC- combines info from somatosensory, visual, and auditory

• Dorsal stream- where/how pathway

  • Location of objects and ourselves within space

• Ventral stream- what

  • Object and facial recognition and identification

  • Transmits info primarily to vlPFC

  • Within PFC, how dlPFC receives spatial info

  • vlPFC- object and facial recognition

• Parts of the temporal lobe, including IT receives info from visual system

  • Combines with auditory info as well

  • Implicated in short-term working memory

• Short-term memory- stored in circuit activities

• Reverberating circuits- some neuron providing input

  • Forms a synapse with a target neuron

  • Through these connections, the target neurons can receive feedback and feedforward info

  • If you stimulate at excitatory synapses, all the neurons that use glutamate as the receptor- initial input of APs that stops, then will induce another train of APs in downstream neurons

    • Can send axon back to initial neuron

    • Even after initial output response

• Circuit fires in a reverberating circuit

  • Loss of glutamate

  • APs will decrease in frequency

  • Time course- 30 sec to a few minutes

  • Reverberating AP firing underlies working memory 

  • Can diffuse out of synapse- APs can be lost and decay

  • Repetitive firing actively encodes and holds info in working memory

  • This type of circuit activity is not thought to involve biochemical changes or permanent changes in the neuron

  • APs die out, synapses go back to quiescent states

• Some long-term memory is only stored for a few months or years, some is stored for a lifetime

• LTM involves 3 phases: Encoding, storing, and retrieving

  • Storage- consolidation of activity, biochemical and morphological changes to neurons and neuronal circuits

• There are different types of long-term memory

  • Declarative/explicit memory

  • Nondeclarative/implicit memories

  • Involve different regions of the brain

• Hippocampus and adjacent entorhinal cortex

  • Involved in episodic and semantic info

  • Also where spatial info is encoded

  • Hippocampus is required for encoding for types of memory

  • Medial temporal is not where memories are stored

    • Stored in different circuits throughout cerebral cortex

• Implicit memory: 4 subdivisions

  • Procedural memory- how to do things, skills and habits. Involves basal nuclei, striatum and cerebellum

  • Priming- neocortex. If exposed to a type of info before being actually exposed to it, neocortex “primes” your brain

  • Non-associative learning- reflex pathways

  • Emotional responses- amygdala

• All long-term memory uses the overall same type of mechanism

  • Epigenetic modifications that control transcription and translation

  • Type of biochemical change that occurs within neurons that affect synapses

  • Biochemical changes result in physiological and morphological changes in structure of synapses

  • Physiological changes in responses from neurons

• Engrams are stores in structure of the brain

  • Involve synaptic plasticity as well as synaptic and system consolidation- long term changes in circuits

Video Lecture 2

• Declarative memory- can explain to someone else about

  • Includes 2 subdomains- semantic and episodic memory

• Semantic memory- facts, ideas we have learned like in school

  • Include data info about the types of people, names, dates, etc

• Episodic memory- memory of episodes

  • Can be either autobiographical or external events that we watch

• These 2 subdomain require the medial temporal lobe to form and encode those memories

  • Hippocampus and entorhinal cortex are essential

• MT lobe is also involved in spatial memory- maps, where things are in space relative to other things

• Hippocampus and entorhinal cortex- types of cerebral cortex

  • Don’t have typical neocortical layered structure

  • Hippocampus is allocortex- archicortex

  • Hippocampus and olfactory cortex are the 2 regions in the archicortex

  • Contains GABAergic and glutamatergic neurons, 3 to 4 layered type of structure

  • Entorhinal cortex projects majority of into into hippocampus

• Hippocampus is involved in declarative and spatial memory

  • Type of cortex

  • Because temporal lobe curls in on itself, entire hippocampal region that forms the cortex is enclosed within the cerebral cortex

  • This is why we call it the medial temporal lobe- one of the oldest parts of the cerebral cortex- close to evolutionary ancient parts of the brain

  • Has many connections with anterior cingulate cortex and limbic system

• Short-term working memory- requires PFC and parts of the parietal cortex as well

• Long-term memory that doesn’t involve MT lobe- procedural memory/implicit memory

  • Different types of implicit memory 

• Procedural memory involves striatum and cerebellum for some types of learning

  • Motor learning- skills and procedures

  • Implicit memory- difficult to explain to somebody

  • Requires other brain regions

• Cerebral cortex- involved in priming 

• Amygdala-very close to hippocampus

  • Subcortical structure- emotional memory and emotional input

• Hippocampus is a tube

  • End- amygdala

  • Thalamus, underneath that the hypothalamus, then basal nuclei- regulation of motor systems

  • Lot of subcortical structures, very closely packed together in medial regions

  • Hippocampus is the one region of brain essential for learning and encoding of explicit memories

  • Synaptic consolidation- biochemical and morphological changes of synapses in response to incoming info processing

  • Systems consolidation- info is transferred from hippocampus to other circuits within neocortex of cerebral cortex

  • Spatial memory and navigation

    • Certain neurons in hippocampus that are dedicated to helping us navigate our way in the environment

    • Part of the hippocampus is involved in processing of emotional info as well

• Synaptic consolidation- transfer of info from cortical networks into networks of hippocampus

  • Can change to changes in strength of synapses in these circuits

  • Hippocampus will transfer that info to other regions of the cerebral cortex- involves different phases of sleep

  • Hippocampus is not required for retrieval of memories

    • Once these memories have been transferred back to the cerebral cortex, hippocampus is no longer required and is involved in processing of new memories and activity

  • Hippocampus- just a few days to months for transfer to cortical networks

    • Not hte place where the majority of long term memories are thought to be stored

• Majority of long-term memory is thought to be stored in duplicated circuits found throughout cerebral cortex

  • Once the memories have been formed, for types of declarative memory, doesn’t require hippocampus to retrieve that 

  • Info has to be transmitted back to hippocampus

• H.M

  • Passed away in 2008

  • During the latter half of his life, he was unable to form new long-term memories

  • Single most studied individual in clinical medicine

  • Through use of EEG, researchers found that his epileptic seizures were in both left and right temporal lobe

• Most cases of epilepsy that involve MT lobe is usually on one side of brain

  • Foci present on both sides of temporal lobe- underwent bilateral medial lobectomy

  • Parts of the brain were removed to help cure the epilepsy

• Surgery solved his epilepsy but he was unable to form new long-term memories

  • This type of condition is referred to as anterograde amnesia

  • Some retrograde amnesia- couldn’t remember info from a year before the surgery

  • Had significant amount of remote memory- for semantic parts of remote memory

  • Some autobiographical memory was disrupted as well 

  • Autopsy after he passed away.

• Surgeons and clinicians didn’t know about hippocampus and there weren’t many anti-epileptic drugs that were available

  • For scientific world- patient HM was extremely helpful in understanding of role of hippocampus

  • Many individuals before this in 20th century had hippocampus removed

    • One intact hippocampus- you can still form new long-term memories

  • Bilateral hippocampus damage is rare

    • Surgery was never performed again

• Hippocampus is involved in encoding or acquisition of declarative and spatial memory

  • Not required for implicit or non-declarative memory

  • Hippocampus sits around thalamus and basal nuclei

  • Hippocampal formation- has a similar type of structure as rest of neocortex

• Hippocampus looks like a seahorse

• Hippocampus- CA regions, dentate gyrus

  • Major input to hippocampus is through entorhinal cortex

  • Perirhinal and parahippocampal cortex- close to entorhinal cortex

    • Triad of structure

  • Entorhinal cortex receives info from perirhinal and parahippocampal cortex

  • Hippocampus receives info from both PFC and PPC and association cortices integrating sensory and motor info as well

• Hippocampus represents interesting loop- info can be transmitted back out to subcortical regions like subiculum and amygdala

  • Most info is sent back to entorhinal cortex

  • Processed and re-processed many times

• DG- gyrus just like other gyri

  • If you look at morphology- has teeth-like overall look

  • CA1, CA2, CA3- CA1 and CA3 represent 2 other regions of hippocampus

• Majority of info transmitted out of hippocampus is transmitted out of CA1 → majority to subicular complex → some is transmitted to other subcortical regions, most is transferred back to entorhinal cortex

• Entorhinal cortex receives info from PR and PH, which receive info from unimodal and polymodal association areas

• There are other direct projections from non-cortical regions

  • Brain stem and basal forebrain

  • Monoamine and dopaminergic neurons also send direct projections into entorhinal cortex and can project to specific regions in the hippocampus like CA1

• Fairly simple circuitry, but there are some loops

• Entorhinal cortex- type of neocortex

  • Axons project to DG

  • Within DG, neurons that receive that input are called Dentate Granule cells

  • DG cells project to CA3 neurons 

  • CA3 neurons project to CA1 neurons

  • CA1 neurons project to subiculum

• DG granule cells are small- excitatory glutmaatergic neurons 

  • Granule morphology

  • CA3 and CA1- excitatory pyramidal neurons

  • CA regions- cornu ammonia ram’s horn

  • Has structured type of layers- has stereotypical inputs into the DG neurons

    • Those neurons project to CA3

  • Axonal pathways- studied using electrophysiology

    • Define specific axonal pathways

• Perforant pathway- involve entorhinal glutamatergic projection pyramidal neurons neurons

• DG neurons and CA3- mossy fiber pathway

• CA3 and CA1 pathway- Schaffer collateral pathway

  • Received name from investigator

  • Investigators can place electrodes in hippocampus to record activity in those 3 different pathways

• Have different types of electrophysiological properties and all show plasticity

  • Synapses within those regions undergo either short-term or long-term changes

  • Synaptic plasticity underlies mechanism of encoding

• CA1 has some other direct outputs

  • Septum nucleus

• Other direct projections- axons from noncortical brain regions can send info directly to hippocampus bypassing entorhinal cortex

  • Schaffer collaterals extend their axons and form synapses on dendritic spines on CA1 neurons

  • Millions of synaptic connections occur

• Hippocampus has inhibitory GABAergic neurons

  • These GABAergic neurons provide inhibition to CA1 dendrites as well

  • Inhibitory activity is required in maintaining E/I balance

  • More excitatory activity has been linked to seizures in hippocampus

  • Direct inputs into CA1 neurons- from brainstem or basal nuclei

  • Monoamines bind to respective monoamine receptors 

    • Serve in a modulatory functions

  • Cholinergic input- one of the first type of neurons that undergoes neurodegeneration in Alzheimer’s disease

    • Loss of cholinergic input are responsible for initial loss of memory

• Along hippocampus length- not homogenous but has different regions

• Rat- hippocampus is tilted up slightly

  • Dorsal vs ventral region

  • Human hippocampus- much more extended along horizontal axis

  • Happened during primate evolution- hippocampi in monkeys is similar to that in humans

• Rodent entorhinal cortex is found along the tube

  • Human- entorhinal cortex is localized along the end of the tube

  • NOt as much contact in humans vs rodents

• Cross-section- tube is flattened, we can see that each part of the tube has the overall type of structure

  • DG- can only see when you take a specific cross-section

• Hippocampus has different subregions with different functions

  • Dorsal (rats) analogous to posterior in humans- involved in cognifitve functions and memory encoding, as well as spatial memories

  • Ventral part (Rats) analogous to anterior (humans)- ivnvolved in emotion and affect, closest to amygdala

    • Different function in processing and contributing to processing of emotional info- how we present ourselves to the outside world

• Damage to hippocampus- rodents are unable to perform specific memory tasks

  • Run specific mazes, respond to different environmental cues

• 1960s- investigators studying electrophysiological responses

  • Used electrodes to record activity in different pathways

  • Lomo and Bliss- Dr. Anderson’s Lab

• Using wake rabbits, if they inserted an electrode into perforant pathway and recorded activity in DG layer…

  • Specific stimulations can increase responsiveness of granule cells

  • Extracellular recordings- how you can use this type of recording

  • Stimulate axons to produce APs, then record in DG layer

  • Changes in synaptic responses in neurons

• Schaffer collaterals

  • Response- LTP- actually occurs in all 3 circuits of hippocampus

  • Studies are predominantly focused on Schaffer collateral pathway

  • Bliss and Lomo used in vivo slices, most today use slices

  • Cross-section- every cross section has a similar type of circuitry

• Hippocampus is the one way in the cerebral cortex where you can excite one type of axons but you can record a response from another set of axons

  • Simple circuitry

  • Could be difficult to know which axon inputs to be able to stimulate to record from that activity in different regions of the brain

• LTP- stimulated axons in perforant pathway but were monitoring responses in granule dendrites

  • If they initially stimulated and recorded at a low frequency- before conditioning response

  • If they did a very rapid, pre-stimulation- extremely high-frequency- after this, they found that they would record a larger response in dentate neurons

  • Response could last minutes to hours

    • Many hours in vitro

    • Many days or weeks in vivo

  • Type of plasticity before rapid high frequency conditional- control response

  • After- increased response of dendrites within DG neurons

• Using these results, scientists have been able to apply different pharmacological agents and drugs and target different pathways

  • Studies on genetically modified animals to identify specific genes and proteins

  • Dendrites within CA1 neurons are recorded

• Most investigations into LTP involve extracellular recording

• Glutamatergic neurons produce excitatory depolarizing response

  • Involves extracellular electrodes

  • In EPSP, sodium moves into the dendrite- depolarizes membrane potential inside the cell

  • Because the electrodes are measuring the extracellular fluid, the ECF is becoming hyperpolarized as Na+ ions are moving into dendrites and dendritic spine region

  • These responses represent the collective responses of thousands o

    • Being stimulated con-commitantly- can measure changes in what’s going on outside the neuron because so much Na+ is flowing inside to produce the EPSPs to detect a change in extracellular fluid

• When we have excitatory glutamatergic synaptic transmission- produces an EPSP

  • Depolarization of membrane potential, moves it toward 0

  • GABAergic IPSP involves hyperpolarization of membrane potential

• Using intracellular electrode leads to depolarization of membrane potential because we have Na+ ions moving in through glutamatergic ionotropic receptors

• Studies- electrode is placed outside the cell

  • Much easier to do

  • Electrode doesn’t have to penetrate the cell membrane

• When you stimulate thousands of teh Schaffer collateral axons- you get EPSPs through dendritic spines

  • Inside of the cell depolarizes- causes hyperpolarization of ECF around dendritic spines

  • Called field potential- measures response in large field of dendritic spines

• Robust stimulation- tetanus to induce LTP

  • After this robust stimulation- go back and measure the typical responses

  • Response would increase

  • Technique used to measure LTP

• Types of studies have been overwhelming in numbers- investigators want to understand mechanisms involved

  • Also so we can develop responses 

Video Lecture 3

• LTP- refers to long-term increase in synaptic response

  • LTP is one of the types of long-term synaptic plasticity

  • Has been extensively studied in rodent hippocampal schaffer collaterals

  • Electrodes are placed in CA1 axons- stimulate axons to fire APs and responses are recorded in dendritic regions

    • Records field potentials

  • Field potential- summed from many dendritic responses

    • Usually hyperpolarization of external solution

• Type of stimulation originally used was called tetanus

  • After tetanus- there was an increase in response that was generated by just a single few pulses of stimulation

• Inputs are from the perforant path

• LTP has been demonstrated in all synaptic pathways

  • Schaffer collaterals is most easily recorded

• Investigators stimulate with a very small type of stimulation from the electrode

  • Measure short- lived and small response in CA1 dendrites

  • Every 30 seconds or so with short stimuli- represent control response

  • High-frequency tetanus

  • Like a switch on and off

• LTD- long term decrease in synaptic response induced by a different type of stimulation in Schaffer collateral

  • Low-frequency stimulation- every tens or hundreds of stimulation

  • If you take the slice and apply the low-frequency stimulation → synaptic responses after the stimulation get smaller

  • 50-60% smaller

  • Initial larger decrease- due to short-term depression

  • In synapses in hippocampus, these synapses constantly undergo LTD and LTP depending on the type of input

  • These changes in synaptic strength underlie process of learning and memory

• Difference in induction- rely in nature of stimulation and how robust or modest this stimulation may be

  • Changes in pres-synaptic and postsynaptic regions are responsible for depression or potentiation of the response

  • Responses are reversible

• Strength = magnitude of response to incoming AP

• LTP and LTD are activity dependent

• Synaptic plasticity- type of property that glutamatergic synapses undergo all throughout the brain

  • Not only in hippocampus, but in cortex and basal nuclei and many other regions like cerebellum

  • Undergo changes in synaptic responses in LTD and LTP

• Glutamatergic synapses serve as a model for all CNS synapses that undergo plasticity

  • Malenka- can occur at all excitatory synapses in mammalian brain

  • LTP and LTD are involved in synaptic plasticity underlying learning and memory

  • All synapses within brain and spinal cord can undergo those types of plasticity changes

• well before identification of LTP, electrophysiologists noticed there were activity-dependant changes in electrophysiological responses in neurons being recorded

  • Early as 1940s and 1950s

• Hebb- synaptic strength can change to dsscribe changes in responsiveness

  • CHange in synapse depends on activity of particular neuron forming the synapse

• Neurons that fire within a similar type of time frame- synapses will be strengthened

• Electrophysiology paradigm that Bliss and Lomo used to induce LTP was not a physiological type of response

  • Hebb- if we have neuron A which is firing and projects to neuron B, if there are additional inputs to Cell B that occur within a similar time period and is con-commitment, the synapse between Cells A and B will be strengthened

• Response- change in synapse required both input activity from Cell A and activity produced from Cell B

  • Either caused by activity from Cell A or from concomitant inputs from cell B

• LTP and LTD- important property to demonstrate

  • If not reversible- slice could be losing its energy source, synapses were becoming weaker

  • LTP could be some non-physiological effect- artificial situation leading to non-physiological response

• Synapse specific

  • Only the synapse would be strengthened

  • If there were other synapses- they would not be strengthened

  • Only active synapses are either strengthened or depressed

• Associative and cooperative

  • 2 inputs to Cell B- can work together to affect LTP and LTD leading to a response in that cell

  • Not enough response- may not be enough to induce activity

• Saturable

  • Maximal response in terms of depression and potentiation

  • There are biochemical mechanisms that underlie the specific processes

    • Changes, receptors, activities present on synaptic membrane

    • CEiling

• Persistent

  • Lasts for many hours

• Synapse is involved in encoding info

  • That particular region of the brain will go back to the baseline state after the info has been transmitted to storage locations

• 3 parts/phases

  • Induction

    • Within first few seconds after stimulus has been applied

  • Early LTP

    • First 30 minutes

  • Late LTP

    • Persistent part

  • Each phase involves different biochemical mechanisms to induce potentiation or depression

• Bliss and Lomo- tetanic stimulation

  • Paradigm- 2 one second stimulations, 100 Hz trains with 20s interval

  • Extremely high frequency stimulation 

  • Non Physiological type of stimulation

  • Theoretical maximum limit is 1000 Hz

  • Extremely robust, non physiological

  • Will never reach that type of stimulation

    • Useful in laboratory as it will produce LTP

• What’s actually happening within hippocampal CA1 neurons for LTP?

  • Theta burst stimulation

• 4 pulses with 200 ms rest in between each of the pulses

  • Much closer to what rapidly firing CA1 neuron would look like

  • Theta waves- type of stimulation is thought to underlie theta waves in hippocampus

• Third type of stimulation- physiological concept- incoming activity and neuron is being stimulated by incoming activity

• Loq frequency stimulation of CA1 neurons was induced

  • Depolarization using stimulating electrode

  • Concomitant depolarization of CA1 neuron at the same time CA3 neurons were being stimulated

  • If there is a low frequency stimulation paired together with post-synaptic stimulation, that is able to produce LTP

  • Low-frequency stimulation alone does not produce LTP

• All require presynaptic stimulation

  • Can be robust or modest

  • Can be low-frequency as long there is post-synaptic depolarization

    • Within hundreds of milliseconds

  • True for theta burst

• Other neurons that form synapses on depolarizing postsynaptic cells- if no presynaptic stimulation, they will not be strengthened

  • IF there is no incoming response, that will not produce LTP either

  • Coincident pre and post synaptic activity to produce LTP

• AMPA receptors and NMDA receptors

  • @ RMP- only AMPA receptors are going to be able to conduct sodium and produce EPSP

  • NMDA is blocked by magnesium there

  • Depolarization of membrane potential is sensed by NMDA receptor and then kicks Magnesium out- now NMDA receptor can participate in synaptic transmission

• NMDA receptors have additional depolarization requirement to open

  • Need glutamate and depolarization

• While they are both nonselective cation channels that allow sodium and potassium to flow through channel, NMDA receptor is also permeable to Calcium

  • Allows calcium to flow in- one of teh triggers for induction of LTP

  • If you block NMDA receptors, LTP induction is going to be blocked

  • Intracellular inhibitors of Ca2+ like chelators to prevent binding- also blocks LTP

• For induction of LTP- requires calcium influx through NMDA receptors so that calcium will be able to mediate and intiaitite the different biochemical processes

  • With tetanus- so much glutamate is released, many AMPA receptors will produce large postsynaptic current that activates NMDA receptors

• Even low frequency stimulation, when paired with post synaptic depolarization, can also lead to strengthening of the synapse

  • GLutamate would be released and bind to AMPA receptors 

  • Additional inputs would be coming into neurons under artificial conditions- would produce enough depolarization that together with low level of glutamate- NMDA receptors are now able to mediate the calcium current that initiates LTP 

  • Only when there is small amount of glutamate- as long as there is glutamate present and a small post-synaptic response- produces LTP

• Once activity at the synapse has been produced → sets into motion the other phases of LTP- early and late phases

• 3 different protein kinases in early phase

  • Involved in phosphorylation

  • No changes in levels- purely an affect of protein kinases that affect existing proteins

• Late phase of LTP

  • Requires new protein synthesis 

  • New mRNA synthesis

• LTP expression refers to what are the specific mechanisms that lead to an increase in postsynaptic response?

  • Initially it was thought both presynaptic and postsynaptic changes

  • Presynaptic changes- increase in glutamate release

    • Occurs for several minutes after stimulation

    • Not actually the mechanism that underlies LTP

• Changes in number of active synapses- unsilencing of active synapses

• Post-tetanic potentiation

  • Phase after the stimulation- can see an even greater increase in response of synapse

  • Very rapidly decays back 

  • Short-term plasticity- involves increase in glutamate release at synapse, doesn’t contribute as much to LTP, has been implicated in short-term working memory

• Increase in synaptic glutamate levels

  • Caused by calcium increase

  • Or there might be more vesicles

  • Provides potential models- increase in number of vesicles found in presynaptic active zones- some vesicles could be more easily be released, more VGCa2+Cs, some biochemical and structural changes

  • Decays after a few hundred milliseconds

• E-LTP is expression of LTP

  • Involves NMDA receptors and influx of post-synaptic calcium

  • Involves activation of specific protein kinases

    • Phosphorylate proteins using ATP

  • After NMDA receptors have been activated and Calcium levels have been increase, protein kinases will be persistently activated for several minutes after induction has occurred

  • Independent of original signals that activated them

• Phosphorylation can affect proteins by different mechanisms

• LTP: both serine/threonine and tyrosine kinases are involved

  • Initial part of LTP- serine/threonine kinases

  • Late phase- both serine/threonine and tyrosine kinases

  • Both take gamma phosphate from ATP - change overall conformation of protein

  • Depending on function of protein, can change different aspects of protein

  • Phosphorylation can increase or inhibit enzymatic activity

  • Ion channel- can change ability of ion channel to detect whatever its regulator is

    • Can also affect channel properties

  • Can affect cytoskeletal protein and transcription factor characteristics

• Proteins can be specifically localized to membrane domains and compartments

  • Phosphorylation can change that 

  • Some transcription factors need to be dephosphorylated to enter the nucleus or need to be phosphorylated to recruit transcription machinery

  • For some proteins, phosphorylation can be a signal for degradation

• Regulation of protein activities and localization are involved in underlying the control of proteins involved in LTP