Sensory-Motor integration Flashcards
What is the brain-machine interface?
• Brain-machine interface: an artificial process that allows the brain to exchange information directly with an external device
What are the three levels of movement control?
o Lowest level- Spinal cord
o Second level- Brain stem
o Highest level- PMC, premotor cortex and SMA
Describe what the lowest level of movement control controls (and what it is controlled by)
o Lowest level- Spinal cord
Neuronal network (spinal cord interneurons) for execution
• Control reflex and voluntary stereotypic behaviours
• Convergence on motor neurons
• Controlled by descending pathways
Contain simple circuits that control simple actions
Describe what the second level of movement control controls
o Second level- Brain stem
Two parallel neuronal systems, medial and lateral for tactics (how movements are going to be done)
• Control of posture, integration of vestibular and visual information
• Control of distal muscles for goal directed movements (rubrospinal tract)
Describe what the highest level of movement control controls and its components
o Highest level- PMC, premotor cortex and SMA
Three cortical areas that connect to spinal cord (corticospinal tract) and to brain stem- for strategy
• Primary motor cortex- execute action
o Provides direct input to the motor neurons and to interneurons
• Premotor cortex- coordinate and plan
• Supplementary motor area- coordinate and plan
How is voluntary movement governed and organised?
- Voluntary movement is governed by conscious planning
* It is organised around performance of a purposeful task
How does voluntary movement performance improve?
• Task performance improves with experience and learning
What initiates voluntary movement?
- Voluntary movement can be initiated internally without a sensory stimulus trigger
- Sensory stimuli do not dictate the resulting movement, although they guide the specified task
What are the two main descending pathways that control motor neurons innervating the skeletal muscle, what is their origin and what do they do?
• Indirect pathway
o Originates in brainstem
o Cortex provides input
o Control of posture; some reflexes
• Direct pathway
o Originates from cerebral cortex
o 90% of the fibres cross to contralateral side at the medulla
o Voluntary movement
What are different types of brain signals that carry information for movement production?
• Changes in neurotransmitter concentration
• Changes in membrane potential (continuous)
• Spiking pattern/profile
• Hemodynamic profile
o Changes in blood flow in specific brain areas
What is the best type of brain signal for movement production available for reading the code? Why?
• Spiking pattern/profile- best candidate to give measurement for coding motor events
o Spikes can provide local information and precise information about the timing of the activation of the neurons
How is spiking pattern/profile best measured for reading motor code and why? How does this measuring processes work?
Local field potential (electric potential in the extracellular space around neurons- reflects changes in synaptic activity) and multi-unit activity (spiking profiles of multiple neurons) could be best measurement for coding motor events because of their temporal course
• Multi-unit activity measurement:
o Electrophysiological signals recorded with extracellular electrodes are spatially restricted but have good temporal resolution
Take raw microelectrode signal and filter it to extract action potentials
Electrode picks up signal from multiple neurons (evident due to differing amplitude of neuronal recording)
Further filter high frequencies to extract low frequency local field potential (micro EEG)
Why are electroencephalograms a promising but unsuitable method for motor code measurement?
Electroencephalograms could provide access to most cortical areas, but temporal and spatial resolution are relatively poor (coarse type of recording)
What is the key to being able to interpret measures of neural activity that have a large spatial spread and why? What is the consequence of this?
o Local homogeneity is key to being able to interpret measures of neural activity that have a large spatial spread
By recording from individual neurons in a column, information about the selectivity properties of all the neurons in that column can be obtained
If record from many different columns, can potentially rebuild properties of the whole cortex
What does local homogeneity mean?
Local homogeneity means that particular area of the cortex contains neurons that have similar selectivity properties
• Columnar organisation of neurons
How is movement direction recorded in the brain?
- Movement direction is encoded by populations of neurons rather than by single cells
- Population vector seems to have tight correlation with direction of movement
What is a population vector?
o Population vector- vector sum of every cell in the population
How is information in sensory and motor systems frequently encoded and what suggested this?
• Information in sensory and motor systems is frequently encoded in tuning curves
o Single unit recordings from motor cortex suggests that these neurons are organized according to their preferred directions
Whilst preferred orientation will give the strongest response for a neuron, neurons can also respond to other certain orientations but will give weaker responses
Describe the findings of Fritsch and Hitzig (1870)
• Fritsch and Hitzig (1870)-
o Electrical stimulation of primary motor cortex produced contraction of contralateral muscles
o Somatotopic mapping
Describe the input, output and function of the supplementary motor area and premotor cortex
• Supplementary motor area and premotor cortex
o Input: prefrontal cortex
o Receive sensory information from: parietal, temporal
o Efferent: primary motor cortex
o Function: planning of movement
Describe the input, output and function of the primary motor cortex
• Primary motor cortex
o Input: supplementary motor area, premotor cortex, frontal association cortex
o Function: fine motor control
o Neurons in the primary motor cortex (M1) carry information about various aspects of movement, including force, distance and direction
Individual M1 neurons are broadly tuned to the direction of movement
• Increase/inhibition of firing rate depending on movement direction
How can prosthetic devices restore movement after SCI and what is the foundation of knowledge essential for the production of these devices? Describe
• Restoration of movement after SCI
o Implantation with multi-electrode arrays in area of the brain that controls restricted movement
Contains 100 electrodes
• 10x10
Each electrode is separated by 400 microns
1 mm long
o Works as neurons in the pre-motor cortex, primary motor cortex and supplementary motor cortex activated when the patient plans the movement irrespectively of whether the movement is executed or not
On this, patient is trained to think about particular types of movement so researchers can look at the activity of the different neurons and establish a correlation between the intention of the movement and the neuronal activity that can be recorded by the electrodes
• Establishment of code
Describe a brain-spine interface device and the advantage of such a device
• Correlation and conversion of online neural decoding of extension and flexion with an electrical stimulator that controlled contraction of muscles
• Advantages:
o Allows free movement with no restrictions and no cables attached
• Brain/spine interface can restore locomotion of the paralysed limb of the subject
Describe the stimulus-behaviour pathway
• Stimulus (environment)—> change in membrane potential (sensory receptors) -> action potentials (neural pathways)-> perception (cerebral cortex)-> behaviour (organism)
What does understanding the neural code require?
• Understanding the neural code requires knowledge of the representation of the external world at all stages of the neural pathway and of how sensory information is communicated from the periphery to higher areas in the brain
Describe the nature of stimuli and how this contrasts to the nature of nerve signals
• Nature of stimuli and nerve signals o Stimuli vary in continuous manner over time o Output (action potentials) is a sequence of essential identical discrete events
Describe the specificity of receptive fields as a sensory pathway progresses in function complexity and an example of this
• As we go along a sensory pathway, complexity of receptive fields increases and receptive fields become more abstract
o For example, circular receptive fields in retina and LGN are transformed into the elongated receptive fields in V1 and become more specialised as we move away from V1
Does the brain need complete information to build a percept?
• Brains can build percepts with little or partial information
Describe the contribution of Muller in the 19th century towards making a dictionary of the nervous system
• 19th century Johannes Muller
o Law of specific nerve energies
o Stated the principle that the kind of sensation following stimulation of a sensory nerve does not depend on the mode of stimulation but rather on the nature of the sense organ
Describe the contribution of von Helmholtz in the 19th century towards making a dictionary of the nervous system
• 19th century Hermann von Helmhotz
o Place theory of frequency discrimination
o Perception of sound depends on where each component frequency produces vibrations along the basilar membrane in the cochlea in the inner ear
Pitch of a musical tone is determined by the areas where the membrane vibrates based on frequencies corresponding to the tonotopical organisation of the primary auditory cortex
Describe the contribution of 1952 Adrian towards making a dictionary of the nervous system
• 1952 Edgar Adrian
o Stimulus amplitude is related to impulse frequency and that the constant presence of stimulus induces adaptation
Describe the contribution of 1930s Hartline century towards making a dictionary of the nervous system
• 1930s Haldan Hartline
o Feature selectivity of responses reflecting local contrast (Mach bands)
Is it likely that there is a unique code across a sensory pathway?
• There is most likely not a unique code across a sensory pathway
o Instead, there is mostly a code at each processing level
How can neural coding be studied?
• Neural coding can be studied through a classical approach based on tuning curves
• Neural coding can be studied through stimulus reconstruction methods
• Deep neuron networks
o Created artificial stimuli that can produce responses much stronger than those previously recorded with any sort of other stimuli
Describe how neural coding can be studied through a classical approach based on tuning curves and a limitation of this
• Neural coding can be studied through a classical approach based on tuning curves
o A stimulus parameter is systematically changed whilst the responses are recorded
o Tuning curve assesses how a feature is encoded by a neuron from the experimenter’s point of view
Dependent variable- neuronal response
Experimenter’s goal- to determine neuronal response for each feature within a set of stimuli
o Problem: made by artificial stimuli so is not accurate to what neurons typically respond to
Describe how neural coding can be studied through stimulus reconstruction methods and how this method can be enhanced
• Neural coding can be studied through stimulus reconstruction methods
o Attempt to determine the stimulus that causes each neuronal response rather than analysing what type of response is produced by each stimulus
o Experiment decodes the neuronal response to provide a reconstruction of what feature of the stimulus was present preceding that response
o Represents organism’s point of view
• Presentation of natural stimuli
o Closer to what neurons typically respond to
Describe the rate coding hypothesis of information transmission
• Rate coding-
o Information transmitted by the firing rate: average number of action potentials in a given time
Describe the temporal coding hypothesis of information transmission
• Temporal coding-
o Information transmitted by neurones during certain small intervals of time
o Precise timing, or pattern, of spikes
o Synchronicity in neuronal firing within and across groups of neurones is involved in carrying information
Describe the population coding hypothesis of information transmission
• Population coding
o Information pooled from groups of broadly-tuned neurones in which each neuron has a distribution of responses over a set of inputs: responses of many neurones is combined to determine the input (population vector)
Describe the sparse coding hypothesis of information transmission
• Sparse coding
o Information is encoded by the strong activation of a relatively small set of narrowly tuned neurones
o Cost of individual spikes in terms of energy consumption is very high
Imposes limits on number of neurons that can be active at the same time
o More efficient coding time
List the different ways in which spike train components can transmit information
- Rate coding
- Temporal coding
- Population coding
- Sparse coding
Describe Britten (1992)’s experiment on the capability of individual neuronal outputs to contain behavioural information: his procedure and findings
• Britten (1992)
o Fields of moving dots with different degrees of movement correlation to each other to observe the threshold of sensitivity of MT neurons to direction of movements
o Also recorded the behavioural response (whether animal was able to detect movement)
Animal had to fixate on a point
Stimulus was displayed with dots of different movement correlation
• Some were in the preferred direction of the neuron, some weren’t
At the end, removed fixation points and stimulus
Lit up two LEDs (one in the preferred direction, one in the null direction) and animal had to indicate in which direction the dots had been moving
o Found that animals are extremely sensitive and can detect movement when there is a low degree of correlation
o For most of the neurons, the threshold for the behavioural response was almost the same as that of the neuronal response
Found that neurometric data (neurophysiological data) and psychometric data (behavioural response) was perfectly matched in some neurons but not matched at all in other neurons
Describe how reverse correlation of action potentials can be used to assess neuronal function
o Reverse correlation
Select 10-15 frames previous to each action potential
Action potentials and screens are aligned in time
By making an average of the screen, one can isolate the most efficient stimulus that can trigger the activity of the neuron
• Can obtain spike-triggered average- gives information about changes in intensity of a specific pixel that produces an action potential
Describe Nirenberg et al.’s (2001) experiment using the principle of reverse correlation of action potentials to assess neuronal function
• Nirenberg et al. 2001
o Reverse correlation to determine whether retinal ganglion cells encode independently
o Found that:
90% of the activity of the information carried by individual ganglion cells can be explained if they behave as independent encoders
Describe Stanley et al.’s 1999 experiment using stimulus reconstruction methods
• Stanley et al. 1999
o Reconstruction of natural scenes from the responses of a population of LGN neurons
o Recordings have been done with multi-electrode arrays and the activity of 150-200 cells in the LGN have been recorded whilst movies are being played after characterising spike response functions of the specific neurons
o By looking at spike train, researchers tried to reconstruct the movie that was played to these neurons
By looking at the spike activity of array of neurons and knowing their input/output functions, researchers reconstructed the movie scenes from the neuronal output
Are neural codes general in all sensory systems of all organisms? Give a specific example of a system and function
• Areas in which there are differences in the auditory system between owls and humans is in the range of frequencies in which interaural time differences are used
o Owls use it between 3-9 kHz
Owls can phase lock for signals up to 8-9 kHz
o Humans use it below 2 kHz
Humans can phase lock for frequencies above 3 kHz
How can knowledge of the neural code be used in more practical situations? In particular, describe one successful and widely used example
• Understanding the neural code could help to treat some diseases of the brain
• Improve the function of healthy brains
• Smart sensory: feature extraction, speech recognition, locomotion
o Cochlear implants
Can partly restore hearing
Device with microphone picks up soundwaves from the air
Another device carries out analyses of these sound waves and converts them into patterns of electrical impulses delivered by electrodes implanted in the cochlea
Electrodes stimulate the nerve endings at locations approximately similar to where the fibres could respond to specific sound frequencies
• Program computers with human capabilities
o Deep Blue
What is memory?
• Memory- retrievable, stored knowledge of our surroundings/world that we can use to act on events in the present
What are the three types of memories?
Declarative (explicit)
Nondeclarative (implicit)
Temporal
What is declarative memory and what are the two types of declarative memory?
Declarative (explicit) • Conscious, deliberately accessible, flexible • Two types: o Episodic Autobiographical o Semantic Factual
What is nondeclarative memory and what are the two types of nondeclarative memory?
Nondeclarative (implicit)
• Unconscious, rigid
• Two types:
o Procedural
Acquisition of habits or perceptual skills
o Emotional
Affective biases (preferences aversions)
What are the two types of temporal memory? Describe
Temporal
• Working memory (short term)
o Ability to recall immediately acquired information
• Long term memory
o Can be declarative or non declarative
o Retrieved based on associations formed from distant past
What is learning?
acquisition of knowledge
What is the result of learning?
Formation of memories
What are the two main types of learning?
Non-associative (non-associative response to stimulus itself, but to stimulus context)
Associative (make specific association to stimulus itself)
What are the two types of non-associative learning and when do they occur?
• Habituation
o We start not to care about non-salient stimuli in our environment
o Start to ignore stimulus-> not due to nature of stimulus, but due to past experience with stimulus
• Sensitization
o Because of past experiences, exhibit exaggerated responses to some type of stimuli in the environment
o Start to pay a lot of attention to stimulus-> not due to nature of stimulus, but due to past experience with stimulus
What are the two types of associative learning and when do they occur?
Associative (make specific association to stimulus itself)
• Classical conditioning
o A neutral stimulus, if presented close in time with an unconditioned stimulus, that leads to an unconditioned response, will ultimately lead to an association between the conditioning/neutral stimulus and the response
• Operant/instrumental conditioning
o Cue leads to an action which leads to presentation of reward
o Action will be associated with positive outcome
What are the two types of fear conditioning? Give examples.
Fear conditioning
• Cued
o Neutral cue associated to aversive stimulus so it manifests aversive response
E.g. tone association with electric shock-> leads to freezing
• Contextual
o Neutral context associated to aversive stimulus so it manifests aversive response
E.g. room associated with electric shock-> leads to freezing
What are the brain areas responsible for declarative memories?
o Sensory/ association cortex, medial temporal lobe, medial diencephalon, basal ganglia
What is the basal ganglia responsible for in declarative memories?
Basal ganglia may be involved in the selection of relevant declarative memories for acting on the environment
Describe the declarative memory pathway
o Pathway: association cortex-> perirhinal and parahippocampal cortices-> entorhinal cortex-> hippocampus
What is the role of the association cortex in formation of declarative memory?
Association cortex: sensory information starts to converge and is funnelled into medial temporal lobe
What are the roles of the perirhinal and parahippocampal cortices in the formation of declarative memory?
Perirhinal (anterior) and parahippocampal (posterior) cortices: provide different types of information to different targets
• Parahippocampus responsible for spatial information relay and relays to posterior hippocampus
• Perirhinal responsible for formation of more general associations of features in the environment and relays to anterior hippocampus
What is the role of the entorhinal cortex in the formation of declarative memory?
Entorhinal cortex (EC): entorhinal cortex provides main source of cortical input to hippocampus through perforate pathway
Describe the internal pathway of the hippocampus in memory activities
• Internal pathway:
o Entorhinal cortex (superficial) to dentate gyrus (DG) granule cells via Perforant pathway
o DG to pyramidal neurons in CA3 via the mossy fibres
o CA3 to pyramidal neurons in CA1 via the Schaffer collaterals
o CA1 projects out of the hippocampus or to the subiculum
Describe the output pathways of the hippocampus to other structures during memory activities
o Go back to superficial entorhinal cortex via perforate pathway
o Via the subiculum to deep layers of the entorhinal cortex
o Via C1 and subiculum to PFC
o Via fornix-> projects output of pyramidal projecting neurons from the hippocampus out to, through the mamillary bodies:
Anterior thalamic nuclei: to prefrontal cortex and hippocampus
Lateral and medial septal nucleus: cholinergic efferents to hippocampus
• Ach important for augmenting/modulating synaptic efficacy in hippocampal circuits (important for learning and memory)
Basal nucleus of the forebrain: cholinergic drive to rest of cortex
o Other output to amygdala, basal ganglia
Describe the brain structures involved in non-declarative memories
o Frontal cortex, basal ganglia, cerebellum, amygdala
Describe the direct pathway in non-declarative memories
o Direct pathway: frontal cortex-> basal ganglia (striatum)-> inhibits globus pallidus internal which leads to greater thalamus activity-> drives cortical activation
Describe the indirect pathway in non-declarative memories
o Indirect pathway: frontal cortex-> basal ganglia (striatum)-> inhibits globus pallidus external-> inhibits subthalamic nucleus-> excites globus pallidus internis-> inhibits thalamus which inhibits cortical activation
Describe the role of the frontal cortex in non-declarative memories
Frontal cortex
• Consolidation
• Command and plan actions
Describe the basal ganglia structures involved in non-declarative memories and what their specific functions are
Basal ganglia
• Different nuclei, different functions
o Striatum (caudate/putamen): dorsomedial, dorsolateral, ventral portions (includes nucleus accumbens which is heavily involved in behaviour related to reward-seeking)
Dorsomedial area is thought to be involved in goal-directed learning
Dorsolateral area is thought to be involved in habit formation and sensorimotor integration
o Substantia nigra pars compacta + ventral tegmental area
Dopaminergic modulation of circuits
VTA projects to nucleus accumbens and frontal cortex
Dopamine facilitates learning
VTA also projects to the hippocampus
• Suggests that it interacts with declarative memory
Describe the role of the basal ganglia in non-declarative memories
- Tighten motor output and regulate certain forms of learning
- Feedback to cortex
- Affected by neurodegenerative disorders
What brain area is most directly associated with non-declarative memories
Basal ganglia
What brain areas are most associated with fear conditioning
Amygdala and dentate gyrus
What brain areas are associated with working memory?
• Working
o Cortex, possibly medial temporal lobe, possibly basal ganglia
Are the areas for different memory types completely seperate or interconnected?
• However, these areas are all connected to each other: no type of memory is completely separate
Describe what was observed from HM and what was learnt from him
• H.M. (Henry Molaison)- Bilateral resection of the medial temporal lobes
o No formation of new declarative memories but retention of old memories
o Could form new non-declarative memories
• Provided evidence for distinction between memory systems
What brain system is most directly associated with declarative memory formation?
• Suggested that the hippocampus is most directly, although not exclusively, associated with declarative memory formation
What brain area is involved in memory formation, consolidation, storage and retrieval?
• Hippocampus is involved in memory formation, consolidation, storage and retrieval
What are the declarative memory processes?
- Encoding
- Consolidation
- Storage
- Retrieval
What is encoding?
• Encoding
o Formation of a representation of knowledge
Integrate experiences
What is consolidation?
• Consolidation
o Conversion to long-term persistent memory
What is storage?
• Storage
o Persistent memory transferred over time to permanent storage location
What is retrieval?
• Retrieval
o Process of accessing stored memory to serve behaviour
What is the distributed storage theory, who was it supported by and how was it found/evidence
Distributed storage
• Lashley 1931; Hoffman and McNaughton, 2002
o Specific inhibition of areas and superficial acute damage did not affect rats’ ability to recall information
o Upon acquiring a certain task, areas across the brain showed greater correlative activity than before learning that association
o Suggests that in time, there is greater correlation across brain areas that are potentially relevant to type of stimulus presented/learning
o If activity is a proxy for memory, in time, areas across the brain become more correlated when presented with that information-> areas are somehow related to specific knowledge
o Memories are stored in a distributed fashion
Describe what type of memory is stored in the inferotemporal cortex and how this was found?
Inferotemporal cortex (IT): ventral visual stream
• Damage in humans leads to visual agnosia- a selective deficit of visual object recognition
• In non-human primates, involved in coding of complex visual shapes and of association between pairs of shapes that primates learnt to associate
o Cells can respond to pairing of images
• “Pair-coding” and “pair-recall” cells in primate anterior IT (Sakai et al., 1994)
• Learnt associations sourced in primate perirhinal cortex (Sakai et al., 1994)
What are engrams?
Engrams- Unit of cognitive information inside the brain, theorized to be the means by which memories are stored as biophysical or biochemical changes in the brain (and other neural tissue) in response to external stimuli
How were engrams first found and by who? Where and what construct was used?
• Found through activation of expression of rhodopsin only when cells are active when a memory is being formed in an animal (Tonegawa, Liu, Ramirez, Redondo 2015)
o Injected animal dentate gyrus with viral construct containing rhodopsin linked to promoter of immediate early gene (CFos)
Immediate early gene- genetic/protein marker for activation
• If a cell is active, it expresses CFos
o Did fear conditioning to animal, which would lead to activation of subset of cell which encode fear learning
o These subsets of cells would now be expressing rhodopsin channels which, when stimulated with fibre optic, could reactivate fearful experience
o Demonstrated that by linking a fluorescent dye with rhodopsin not only could they see the fact that only a subset of dentate gyrus cells were labelled during the fear conditioning learning episode but that if they stimulate those cells the animals relieved their fearful experience
What are the parts of the brain important for memory retrieval?
o Parts of brain for memory retrieval
Frontal cortex: ACC
Hippocampus
• Default retrieval component
How was the hippocampus found to be important for memory retrieval?
• Precise inactivation of hippocampus through photooptics led to inhibition of a long-term memory of contextual fear conditioning (if turned on during the process of contextual fear conditioning, did not encode this memory)
o Don’t see this effect in pharmalogical interventions as cortex can compensate for hippocampus if hippocampus is not immediately inactivated
What is Hebb’s rule?
• Hebb’s rule: When an axon of cell A is near enough to excite cell B and their repeatedly and persistently takes part in firing it, some growth process of metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased
o Cells that fire together, wire together
Describe requirements of a feasible memory system and one such candidate
• Mechanism would require some form of persistent, activity-dependent change in synaptic strength
o If a circuit is relevant to the recollection of an experience, than the way in which they communicate with each other would presumably change/become more efficient so that if we wanted to recall the memory efficiently, we could call upon that specific network
• Potential memory mechanism
o Long term potentiation (LTP)
What is LTP (long-term potentiation)?
Under certain learning conditions, can change synaptic efficacy
Change is persistent and makes communication between cells more efficient
Is LTP in both vertebrates and invertebrates?
LTP has been demonstrated at the level of both vertebrates and invertebrates to be a potential mechanism underlying learning and memory
Describe how Bliss and Lomo (1973) demonstrated the existence of LTP
Bliss and Lomo (1973)
• Stimulation of the perforant pathway resulted in potential field epsp’s in granule cell layer of DG
o In rabbits and placed recording electrodes in dentate gyrus
• After stimulation with many pulses and then just a single pulse (conditioning), could see increase in epsp amplitude
o Before conditioning, there was a lower epsp amplitude
• Basically increase in epsp’s after they’ve already experienced the stimulus multiple times that seems to persist
o Subsequent tetanic stimulus episodes led to further increases in post-synaptic field potential amplitudes
In what models has LTP been demonstrated?
• Demonstrated in in vitro and in vivo experiments
o Early experiments (80s + 90s) have focused on in vitro experiments (living brain slices of the hippocampus)
What are the paradigms that can induce LTP?
• Induced through naturalistic spiking patterns:
o Artificial paradigms
Tetanic stimulation (e.g. stimulation at 100Hz for 1 sec)
Natural spike trains
Theta burst
o STDP
Describe how tetanic stimulation can induce both LTP and LTD
• Low frequency stimulation can result in LTD
o Decrease in efficacy of synaptic transmission (Long Term Depression)
• Frequency in which the presynaptic cells stimulate the postsynaptic cells is important
Describe how natural spike trains can induce LTP
Natural spike trains
• Record activity in brain region whilst a subject is engaged in some process and recapitulate that natural activity pattern by stimulating a circuit that connects to the target in that manner
• Record activity of target
Describe how theta bursts can induce LTP
Theta burst
• Brain rhythm activity (4-12 Hz in rodents) can be synchronised if you package high frequency stimulation in low frequency window that follows theta
o E.g. have 8 pockets of 100 Hz stimulation
Describe what is so special about STDP induction of LTP and what it stands for
o STDP
Spike-timing-dependent plasticity
Naturalistic mechanism by which synaptic level changes can occur in the living brain
Do LTPs only occur in one area? List evidence for/against
• Can occur in various brain areas
o Rogan, Staubli and Le Doux 1997- Fear conditioning potentiates responses in the amygdala of awake behaving rats
o Xiong, Znameskiy and Zador 2014- Acquisition of an acoustic discrimination task induces corticostriatal plasticity
Evidence suggests that LTP is an important contributor to the encoding of memories and can be done in multiple circuits
What are the classical properties of LTP and their definitions?
o Cooperativity
The greater the drive, the greater likelihood of potentiation
o Associativity
Pre-post co-activation leads to increased likelihood of potentiation
o Specificity
Potentiation specific to activated synapses
Explain the concept of associativity in LTP
- If the pre-synaptic cell fires but the post-synaptic cell doesn’t respond, it would seem that the relationship between those two cells isn’t that fundamentally important-> doesn’t need to be facilitated
- If downstream cell responds regularly to upstream cell, relationship seems important and connection would be facilitated
Describe the problem of classical associativity in LTP
There is a problem to associativity: both pre- and post-synaptic cells have to be firing at the exact same time for NMDA receptors to lead to long term potentiation. However, if time activation of pre- and post-synaptic cells in a particular order, can induce potentiation or depression of transmission
What classical property of LTP is most important in memory content and representation?
Specificity
How do the fundamental classical properties of LTP lead to LTP itself?
• Activation leads to a change in the intracellular calcium concentration in key compartments of pre-and/or post-synaptic cells which leads to changes via the transcription of genes that ultimately leads to generation of proteins or activate engines that will allow for processes to facilitate synaptic communication between the pre- and post-synaptic cells
o Allows for LTP to manifest in circuits
What channel allows classical LTP associativity occur? How is it activated, what is its purpose and where can it be found?
o Associativity occurs due to NMDA receptors
Can be presynaptic or postsynaptic
Ligand gated- neurotransmitter agonist
• Glutamatergic receptor
Voltage gated
• In order for NMDA to allow calcium to pass through its channel, the membrane in which the NMDA receptor channel is embedded in has to be depolarised due to magnesium block during polarisation
Underlies plasticity and learning
Ideal for this purpose as needs to receive pre-synaptic signalling via the ligand receptor but it also needs the postsynaptic membrane to be depolarised
Where does most knowledge of LTP come from?
Hippocampus
What are three types of LTP in the hippocampus?
NMDA receptor dependent
NMDA receptor independent (non-classical LTP)
Class I mGluRs (NMDA receptor independent)
Describe NMDA receptor dependent LTP in the hippocampus in terms of:
- Location
- Associativity
- Activation dependency
NMDA receptor dependent
• Occurs at CA3 to CA1 synapse
o Between Schaffer collaterals and pyramidal neurons
CA1 pyramidal neurons express NMDA receptors-> LTP manifests at that connection
• Associative: requires both pre-and post-synaptic activation
• Both ligand (glutamate) and voltage dependent
o Ligand release of Schaffer collaterals and depolarisation of pyramidal neurons
o Voltage dependent release of magnesium block necessary to open channel- may require back-propagating AP
o Allows calcium to enter post synaptic terminal (where NMDA is)
n/a
n/a
Describe NMDA receptor independent LTP in the hippocampus in terms of:
- Location
- Associativity
- Mechanism
NMDA receptor independent (non-classical LTP)
• Occurs at (e.g.) Mossy fibre (output of granule cells of dentate gyrus) and CA3 synapse
• Non-associative: does not require simultaneous pre- and post-synaptic activation
• Pre-synaptic voltage gated calcium channels (VGCC) allows direct influx of calcium into pre-synaptic terminal: leads to calcium-calmodulin-cAMP-PKA messenger cascade that results in changes at the pre-synaptic side (e.g. increasing likelihood of neurotransmitter release for potentiation)
• At the mossy fibre synapse, LTP dependent on the increase in calcium concentration in the pre-synaptic terminal
Describe class I mGluRs-based LTP in the hippocampus in terms of:
- Pathway
- Testing
- Speed
• Activates second messenger cascades: pathway
o Activates phospholipase C (PLC)
o Yields diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3)
o Modulate channel activity via protein kinase C (PKC)
o Open intracellular stores of calcium respectively- leads to changes in genetic transcription and hence induction of LTP
• Tested using pharmaceutical antagonists
• Slower than direct channel LTP manifestation
What is spike time dependent plasticity dependent on? Describe when potentiation occurs and when depression occurs during STDP
o Dependent on timing of pre and post synaptic spiking
Positive (potentiating) vs negative (depressing) timing vs window
• Potentiation- when pre-synaptic cells fire action potentials just prior to the post-synaptic cell
• Depression- when post-synaptic cell fires an action potential prior to pre-synaptic cell
May vary between cell types (excitatory vs inhibitory)
What is the mechanism of spike time dependent plasticity?
o Mechanism
post-synaptic NMDA for potentiation
NMDA desensitization, mGluR, pre-synaptic NMDA for depression
In what model can spike time dependent plasticity be observed?
o In vivo
What is early LTP? Describe in terms of:
- Timeframe
- What occurs during it
- How it is regulated
- Protein synthesis requirement
- What memory system it is associated with
• Early LTP (association with working memory)
o 1 to 3 hours after LTP has been manifested
o Elevated intracellular calcium levels
Mostly at pre-synaptic terminal but can also occur at post-synaptic side
o May be regulated by increased probability of transmitter release at the pre-synaptic terminal
Calcium can act as a catalyst for activating enzymes that can phosphorylate channels/proteins that can lead to increased docking/ release of neurotransmitter
o Can make post-synaptic side receptors more sensitive to ligand
o Does not require new protein synthesis
What is late LTP? Describe in terms of:
- Timeframe
- What occurs during it
- How it is regulated
- Protein synthesis requirement
- What memory system it is associated with
• Late LTP (association with long-term memory)
o At least 24 hours after LTP has been manifested
o Requires new RNA and protein synthesis
o Over the long term, LTP activates adenylyl cyclase, which in turn activates a cAMP dependent kinase that translocates to the cell nucleus, phosphorylating CREB. CREB activates targets that eventually lead to structural changes
Embedding of more receptors
Encouraging cytoskeletal synthesis
Increase contact of pre-and post-synaptic elements
What are the possible changes aiding LTP at the pre-synaptic level and how?
o Pre- synaptic level: increased likelihood of glutamate release-> increased likelihood that post-synaptic cell will respond to that signal
Increased probability of neurotransmitter release
Increased number of pre-synaptic release sites
Increase in the number available vesicles
What are the possible changes aiding LTP at the post-synaptic level and how?
o Post-synaptic level: receptors more receptive to signal coming in
Increased receptor sensitivity
• Through calcium or kinases
Increased number of functional receptors
Affect the way in which previously silent receptors respond
• Due to calcium
What are the possible changes aiding LTP at both the pre- and post-synaptic level and how?
o Both
Pre-and post-synaptic morphological changes
• Protein synthesis can lead to formation of new, more efficient synapses
o Synapses are dynamic
• Want to increase likelihood that pre-synaptic activation will lead to post-synaptic response
What is the critical period, what does it do and what system is it best characterised in?
• Critical period
o Brief period of time during post-natal developed heightened plasticity in neural circuits
o Experience during this time shapes connections and functions that later become consolidated
o Best characterized in the visual system
o Critical period is the period between which parvalbumin cells begins to mature and when it reaches maturity at a physiological level (reflected by parvalbumin)
Describe Hubel and Wiesel’s 1977’s characterisation scheme of individual cell responsivenesses to presentation of stimuli
o Hubel and Wiesel-1977
Made scheme to characterise the responsiveness of individual cells to presentation of stimuli to either the right eye or left eye
• Category I- most responsive to presentation to the contralateral eye
• Category VII- most responsive to presentation to ipsilateral eye
Are ocular cells mostly monocularly mapped or bilaterally mapped in the visual cortex?
Find that cells are mostly monocularly driven (respond most to either left eye or right eye)
• Only a fraction are truly bilaterally driven
When there is artificial inactivation of an eye, what does the map of the visual cortex do and when does it do this?
o When an eye is closed (artificial inactivation of right eye) only during the critical period, most of the cells within the visual cortex become responsive to the open eye and less cells are responsive to the closed eye even after you reopen it
When can ocular dominance plasticity occur and why?
o Ocular dominance plasticity can only occur when performed during the critical period
When circuit is immature- do not have anatomical or physiological segregation of eyes at the visual cortex-> most eyes respond to binocular input
When circuit is mature- get anatomical and physiological segregation of eye domains-> most eyes respond to monocular input
What happens if an animal has been manipulated in an activity dependent manner during the visual critical period?
o There are long term anatomical and physiological changes if animal has been manipulated in an activity dependent manner during the visual critical period
Does the capacity to induce LTP increase or decrease with age? What is the evidence behind this?
LTP capacity changes with age-> capacity to induce LTP decreases as subject becomes older
• Kirkwood, Lee and Bear 1995
o Take slice of primary visual cortex and stimulate white matter using theta burst stimulation and record from layer III in long-Evans rat
o When done during critical period, can generate LTP
o When done after critical period, LTP does not occur
What is the critical period permissive of?
• Critical period is permissive of activity dependent changes in circuits even at the level of the synapse, the anatomical level and the physiological level
What is the critical period characterised by?
• The critical period is characterised by heightened levels of plasticity and increased capacity for LTP
What is the main mechanism responsible for critical periods?
o Mechanism: excitatory/inhibitory balance of cells across many areas in the CNS
What is Fagiolini and Hensch’s (2000) evidence of the importance of excitatory/inhibitory balance for critical periods?
• Decreased inhibitory drive can prolong the potential for plasticity (e.g. Fagiolini and Hensch, 2000)
o Examined a mouse model that was missing one of the proteins associated with synthesis of GABA (inhibitory neurotransmitter)
Found that, in this model, mice exhibited cortical plasticity not limited to the normal age where the critical period would be expected to occur
o When increased the inhibitory drive pharmalogically, induced a critical period-like change: termination of heightened plasticity
o Suggests that inhibitory drive is extremely important for the establishment and limitation of plasticity
What is Huang et al. (1999)’s evidence of the importance of excitatory/inhibitory balance for critical periods?
• Huang, Kirkwood et al. 1999- LTP can be induced after critical period with local GABAA inhibition using picrotoxin
o If inactivate inhibitory drive, can recapitulate LTP
o Record population responses of layer III cells to white matter theta burst stimulation
o Suggests that maturation of inhibitory drive limits plasticity
What is the main factor that determines the onset and offset of the critical period?
Delayed maturation of parvalbumin interneuron and inhibitory networks that determines onset and offset of critical period-> parvalbumin inhibitory networks mature in the post-natal cortex (later than the excitatory drive)
• Parvalbumin expressing inhibitory fast-spiking interneurons are critical for excitatory/inhibitory balance and defining critical periods
What determines the degree of plasticity manifesting within circuits during the critical periods?
Balance of excitatory/inhibitory drive within the cortex is vital for determining degree of plasticity manifesting within circuits during the critical periods
When does the critical period end and what makes this possible?
Critical period ends when inhibitory networks mature as the excitatory networks
• Inhibitory network has delayed development compared to excitatory network
What other structural change occurs when parvabulmin neurons mature?
Extracellular matrix structures made of chondroitin sulfate proteoglycans called perineuronal nets form lattice like networks/nets around parvabulmin cells- happens with the maturation of parvabulmin neurons
What is the significance of the formation of perineuronal nets for the critical period?
• Formation of perineuronal nets serves as a marker for closure of critical period and are important in closing the critical period
Describe what neuronal structures the perineuronal nets surround
o These perineuronal nets surround soma and proximal dendrites
What are the functions of the perineuronal nets?
• Functions of perineuronal nets-
o Titre the immediate extracellular environment to accommodate the rapid transfer of ions across the membrane
o Consolidation of synaptic input onto inhibitory neurons-> fix the circuits that they are associated with
Mechanically, what is critical period offset determined by?
• Mechanistically, the critical period offset is determined by:
o A delayed maturation of inhibitory drive
o An onset of parvalbumin expression
o Increased density of perineuronal nets
Can activity define critical periods?
Yes
What is dark-rearing and how does it influence the critical period?
Dark rearing can delay the critical period
Dark-rearing: raise animals in complete darkness
What is Kirkwood, Lee and Bear’s 1995 evidence for the importance of activity in determining the critical period
o Kirkwood, Lee and Bear 1995- Dark rearing can delay the critical period
• Delay the onset of the critical period
o If compare a mature animal that has been dark-reared vs a mature animal of the same age that have already gone through the critical period, see that dark-reared animals have the capacity for LTP generation just when first exposed to light despite the fact that their critical period should already have passed
Suggests that the activity is necessary to drive the naturation of inhibitory networks that allow for the critical period to manifest itself
Does environmental enrichment accelerate or decellerate critical period closure? What is the proposed mechanism for this?
Environmental enrichment (EE) accelerates critical period closure Suggests that the degree in which LTP can be generated has been shifted earlier-> EE mice lose the capacity to generate LTP earlier due to expedited maturation of inhibitory circuits earlier in postnatal life
What is environmental enrichment and what does it do to neurons?
• Environmental enrichment- a means of stimulating the animal multimodally such that they potentially increase the degree of activity manifested in circuits. Can:
o Enhance learning and hippocampal neurogenesis
o Ameliorate or correct neural dysfunction
o Accelerate neural development, including maturation of inhibitory circuits
What are ten-m3 KO mice and what defects do they have?
• Ten-m3 KO
o Uncrossed retinal axons are mistargeted in the thalamus of Ten-m3 KO mice
o Ten-m3 KO have a different mapping to wild-type:
Ipsilateral input mapping on LGN
• WT- Dorsomedial portion
• Ten-m3 KO- Lamina along the LGN
Describe Eggins et al. 2019 experiment on Ten-m3 KO mice and his conclusion
• Eggins et al. 2019- Environmental Enrichment can induce correction of miswired projections in Ten-m3 KO
o Raised Ten-m3 KO animals in environmental enrichment from birth for 6 weeks
o Most miswired portions of the terminals were pruned-> enrichment improved miswiring only in critical period (not able to change wiring after 3 weeks of age)
What is the effect of environmental enrichment in Ten-m3 KO mice and how is this tested?
Environmental Enrichment can induce correction of miswired projections in Ten-m3 KO
• EE can restore visually mediated behaviour in Ten-m3 KO
o Tested by using visual flash to induce fleeing behaviour in mice to assess vision
What is the advantage of inducing increased plasticity?
• Advantages: If you induce increased plasticity, can lead potential benefits
o Early maturation in the developing animal
o Increased neurogenesis in adults
o Improved cognitive and learning function
What is the disadvantage of inducing increased plasticity?
o An imbalance of E/I drive in the medial prefrontal cortex can affect social behaviour as well as conditioned learning
What is Yizhar et al.’s (2011) proof that increased plasticity can be a disadvantage?
Yizhar et al. 2011
• Expressed channel rhodopsin in excitatory neurons in the prefrontal cortex
• Rationale: shift excitatory/inhibitory drive from a balanced state to a more excitatory heavy state
• Found that this shift towards excitatory drive made animals deficit in social behaviours and in fear conditioning
What is the effect of environmental enrichment during adulthood in the adult visual cortex?
Environmental enrichment during adulthood can recapitulate LTP in the adult visual cortex
What is Sale et al. (2007)’s evidence of the effect of environmental enrichment during adulthood
• Sale et al. 2007- Environmental enrichment during adulthood can recapitulate LTP in the adult visual cortex
o Took mouse model of amblyopia and environmentally enriched them as adults
Animal during critical period did not experience same visual information in both eyes for a period of time
Cortex became particularly accentuated in its monocularity after the critical period
o Found that upon enriching adult mice, density of parvalbumin-causing fast-spiking interneurons and perineuronal nets seemed to decrease
Decrease in density of inhibitory neurons suggested that there might be a shift in balance in excitatory vs inhibitory neurons
o When did white matter theta burst stimulation on layer III of the visual cortex, found that LTP could be induced only in environmentally enriched animals and also observed visuo-functional recovery in adult enriched animals
How can environmental enrichment result in improved behavioural performance?
• Environmental enrichment can increase adult neurogenesis in the dentate gyrus-> correlated with improved behavioural performance
What does environmental enrichment promote in the hippocampus?
• Environmental enrichment promotes sparse coding of space in the hippocampus
What is sparse coding?
o Sparse coding- representation of items by the strong activation of a relatively small set of neurons
Why is sparse coding desired?
Increased capacity to record more memories with smaller sets of cells-> the less active cells you need (and the more sparse coding) to record a memory, the more memories you can encode
Is environmental enrichment enough to induce changes in plasticity during adulthood?
• Short of a dramatic change or manipulation to change normal function, environmental enrichment is largely not enough to induce changes in plasticity during adulthood
o Suggests plasticity isn’t locked down once critical period ends
What is the difference of the effect of environmental enrichment when done in adults vs in early development?
• In early development, environmental enrichment leads to an acceleration of maturation. In adults/later in life, environmental enrichment leads to a regression in maturation towards a more plastic cortex.
