Contemporary advances in neuroplasticity Flashcards
Topic1: Adult hippocampal neurogenesis: Can new neurons regulate my mood and improve my memory?
What was the first thought of an indirect indication of postnatal neurogenesis?
mitotic activity in the postnatal hippocampus, 1960s
What was the timeline of the thought of adult neurogenesis from 1960 - 2010?
Refinement of immunostaining techniques
corroborated the idea of neurogenesis in the adult hippocampus.
What happened in 2011 regarding adult neurogenesis?
Snyder’s paper showed a double-stained cell in the sub-granular zone of the mouse hippocampus.
Cell expresses proliferation marker (BrdU, in green), a marker of immature neurons (DCX, in red) and a marker of mature neurons (NeuN, in blue).
Prior to 2013 what was the common thought regarding adult neurogenesis?
Does adult hippocampal neurogenesis occur in humans?
What happened in the year 2013 regarding adult neurogenesis in the hiccocampus?
Jonas Frisen and colleagues:
Post-war atmospheric C14 levels were high. C14 was absorbed by plants and via consumption made its way to humans,
They found that neurons were continually generated years after people’s birth. Adult hippocampal neurogenesis does take place.
Where does Adult hippocampal neurogenesis occur?
in the dentate gyrus.
What do the signalling molecules present?
neurogenic niche
the neurogenic niche is so important for neurogenesis
to happen that cells derived from non-neurogenic areas like the spinal cord will actually display neurogenic activity if implanted in the neurogenic niche.
true or false?
TRUE
Are progenitor cells able to generate new neurons if taken away from the neurogenic niche?
No
Explain the neurogenesis circuit?
1) Neurons in the dentate gyrus receive information from the entorhinal cortex
2) through the perforant path
3) send projections to area CA3 of the hippocampus, through mossy fibres.
4) CA3 neurons communicate with neurons in CA1 through the Schaffer collaterals.
5) After being processed information will be sent to several cortical and subcortical areas of the brain, via the subiculum
adult hippocampal neurogenesis is not about the generation of any neuron. It is about the generation of excitatory neurons in the granule cell layer of the dentate gyrus of the hippocampus
true or false?
TRUE
Is adult hippocampal neurogenesis a process that occurs in stages or all at once?
occurs in stages
Explain the stage process in more detail?
1) Radial glia-like cells (type 1)
> divide >
2) intermediate progenitor cells (type 2a) and neuronal phenotype (type 2b)
> migration >
3) neuroblast (type 3)
> maturation >
4) extend dendrites to the GCL in the dentate gyrus, and axon to CA3
What can molecules do to each of the neurogenic stages?
Direct or inhibit each stage
Adult hippocampal neurogenesis: a highly regulated process. What are the names of the 4 steps of process?
1) proliferation
2) differentiation
3) migration
4) integration
What is the purpose of newborn neurons?
Participate in the regulation of functions that are classically known to be regulated by the hippocampus.
learning
mood
anxiety
memory
What signalling protein has been shown to increase proliferation?
Wnt
Disruption of neurogenesis is associated with what?
A disruption in learning
What is apoptosis?
A process of cell death
What is a known pro-apoptotic protein?
BAX protein
Adult hippocampal neurogenesis is important to regulate anxious behaviour
true or false?
TRUE
Adult hippocampal neurogenesis: Stress
What is the stress cascade (response)? 3 things
1) Disturbance of an individual’s environment – a perceived stressor
2) Release of molecules (stress mediators) bind to receptors and exert effects
3) Physiological, behavioural, emotional and cognitive responses are triggered - adaptation
Is stress always bad
No, not all stress is detrimental to the brain and mental health.
The stress response has been conserved over millions of years of evolution (enhanced chance of survival).
What are 2 types of stressors?
Physical:
A threat to one’s physical integrity
Psychosocial:
A threat at a more social level
What is cortisol and how does it act in the body?
A steroid hormone produced by the adrenal cortex in response to stress.
How does cortisol mediate the stress response?
Amygdala sends projections to areas such as the brainstem and hypothalamus.
The body identifies a threat, the hypothalamus will do 2 things. What are they?
Both things regard the fight-flight response and include the CRH
{A}
(1) Paraventricular nucleus releases corticotropin-releasing hormone (CRH)
2) activates the sympathetic nervous system (NS)
3) triggers ‘fight-flight’ response.
{B}
1) CRH released
2) stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH)
3) stimulates the adrenal cortex to secrete cortisol
4) exerts effects on the body (increase in energy)
5) prepare for the ‘fight-flight’ response.
High levels of cortisol can do what?
Can impair neurogenesis and contribute to depressive- like behaviour.
Chronic stress leads to higher concentration of cortisol
Cortisol is associated with higher rates of cell death in the dentate gyrus
true or false?
true
Adult hippocampal neurogenesis may be inhibited by two techniques?
- irradiation (method for inducing cell death)
* generation of a transgenic mouse line
BrdU is an analogous of?
thymidine
Cells that express both BrdU and doublecortin
have survived as a result of the activation of the transgenic system.
true or false?
FALSE
Cells that express both BrdU and doublecortin
have died as a result of the activation of the transgenic system.
Adult hippocampal neurogenesis is important to buffer the stress response; supports the idea that without neurogenesis, animals are prone to exhibiting anxiety and depressive- like behaviour.
true or false
true
Can antidepressants increase neurogenesis and restore mood?
YES
social and environmental stress will activate the what area?
hypothalamus and the amygdala towards the presentation of an adaptive stress response
Is adult neurogenesis plastic?
YES
Is it involved in the regulation of functions closely related to neuropsychiatric conditions?
YES
Part 2
Adult hippocampal neurogenesis and inflammation
Perturbation (injury/infection) to brain functioning will trigger what?
microglial activation and the release of several types of mediators of inflammatory response.
What do cytokines do?
- regulatory proteins released by microglial cells and peripheral cells
- offer immune protection (clear damaged and dead neurons)
- can be detrimental to the neurogenic niche and can cause neuronal death
What disorders may Pro-inflammatory cytokines cause?
Implicated in neuropsychiatric disorders such as depression, Azheimer’s and Parkinson’s.
Name the 3 types of cytokines?
IL:
Interleukins= Released by leukocytes
IFNs:
Interferons= Activate macrophages
TNFs:
Tumour necrosis factors= Cause cell death
Major depressive disorder shows an increased immune activation in what type of cytokines?
1L-1beta, 1L-6, TNF-alpha
Alzheimers and PD show an increase in what?
Hyperstimulation of the microglia, increased production of inflammatory cytokines.
Explain the communication from the periphery to the brain when there is an infection. 4 step process
1) The body responds to infection
2) Immune system activated
3) Cytokines secreted
4) Microglial cells activated
Cytokines and molecules associated with pathogens (PAMPs) activate primary afferent nerves during abdominal and visceral infections.
true or false?
true
What happens in the humoral pathways with PAMPs?
(a) PAMPs bind to toll-like receptors (TLR) in local macrophage-like cells
(b) These cells produce pro-inflammatory cytokines that cross the blood-brain-barrier.
High levels of inflammation will be associated with disruption of the stress and anxiety/fear response, leading to mental health issues.
yes or no?
yes
What is the cognitive load theory (John Sweller)?
- our working memory has limited capacity
* not a problem in normal conditions
Explain cognition during inflammation?
Interoceptive sensations of sickness would:
- augment the load on working memory
- limit the ability of the hippocampus to extract information about the temporal contingencies between nociceptive and environmental stimuli
Cell proliferation is just the beginning of the neurogenic process
true or false
true
Treatments targeting the molecular mechanisms of proinflammatory cytokines could be promising
true or false
true
The microbiota-gut-brain axis
What is the microbiota-gut-brain axis and what may it affect?
Microbiota in the gut can affect and modulate behaviour,
brain plasticity and cognition
Is there a pathway of communication between the gut and brain and which is modulated by gut microbiota?
yes
The gut microbiota participates in important metabolic processes: what are 3 processes?
• breaking down complex sugars
• regulation of gut motility and
homeostasis of the
gastrointestinal barrier
• can contribute to disease if
disrupted
What is known about gut microbiota relates to mechanisms rather than effects.
true or false?
FALSE
What is known relates to effects rather than mechanisms.
Gut microbiota has an influence in what areas of the body? 4 areas
GI function (fat storage and energy balance)
CNS circuitry (barrier function)
ANS (ENS vagus) (low grade inflammation and stress reactivity)
immune system (behaviour)
How do researchers investigate the effects through which the gut and brain communicate and affect one another? 5 studies
Germ free studies:
maintaining animals in a sterile environment after birth so post-natal colonisation does not take place
probiotic studies:
Can be useful to our understanding of rescuing optimal microbiota function and gut-brain communication.
Infection studies:
Investigate the effects of pathogenic bacteria on brain and behaviour.
Antibiotic studies:
Investigate the role of the gut microbiota on behaviour.
Faecal transplantation studies:
Investigate the function and impact of these specific microbiota on the gut-brain axis.
In germ free studies hyperactivity of the HPA-axis was normalised by what?
Hyperactivity of the HPA-axis was normalised by colonisation with Bifidobacterium infantis.
Gut microbiota is important for the development of the what axis?
HPA axis
Brain plasticity is highly likely to be disrupted in germ-free mice.
true or false?
TRUE
Ly6Chi monocytes are important for adult hippocampal neurogenesis
true or false?
true
Ly6Chi monocytes are important for adult hippocampal neurogenesis
Antibiotic treatment perturb the gut microbiota, decrease levels of adult hippocampal neurogenesis and cognitive performance.
true or false
true
What treatments can rescue the effects of antibiotics?
Treatment with probiotics and physical exercise can rescue these deleterious effects.
There is some indication that such effects are partially mediated by what type of monocytes?
There is some indication that such effects are partially mediated by Ly6Chi monocytes which could be therefore an important player in the gut-brain axis through the immune pathway.
Cancer treatment
We need to understand adult hippocampal neurogenesis in the context of cancer treatments. What is the purpose of cancer treatment & What may cancer treatment do to cells?
Purpose: Cancer treatments are designed to target dividing cells in an attempt to inhibit tumour growth.
Cancer treatments are absolutist (not specific against tumorous cells).
Cancer treatments will disrupt cell proliferation in the dentate gyrus.
Because cancer treatment is absolutist, what may these treatments contribute to?
Cognitive decline
Increase in depressive states
Topic 2
Sleep to remember and sleep to forget: sleep, memory and
adult hippocampal neurogenesis
Humans sleep on average how many hrs per day?
8hrs a day
Roughly, A 90-year old person has slept for how many years?
32 years
circadian rhythms do not depend on the environmental cues. They are generated internally.
true or false?
TRUE
What is the endogenous agent responsible for the circadian rhythm?
suprachiasmatic nucleus
What happens if the suprachiasmatic nucleus is injured?
Rhythmicity is abolished
Where is the suprachiasmatic nucleus (SCN) located?
Located in the hypothalamus near the optic chiasm
How does light information reach the SCN? what photoreceptors are responsible for this
The cells responsible are photoreceptors known as cones and rods.
In animals without cones and rods or humans with blindness due to the destruction of cones and rods, is light detection by the suprachiasmatic nucleus still observed?
YES
Why is this?
Retinal ganglion cells expressing melanopsin emits information to the SCN.
Light sensitive at the wavelength of the colour blue.
Blue light disturbs the maintenance of circadian rhythms.
As a person falls asleep
EEG:
slows to theta range of what?
4-7 hertz
As sleep deepens
EEG: shows the person does what?
- slows further
- very slow delta waves appear
- sleep spindles occur
Deeper stages of sleep (N2/N3) on the
EEG: shows what?
- slower frequencies
* high delta activity
After 45mins of sleep what does the EEG machine show?
- increase in frequencies
* from deep slow-wave to lighter stages of sleep
During the REM sleep ‘Rapid eye movement’ what occurs?
transition to desynchronise
• virtual absence of muscle tone (atonia) occurs • eye movement • people report dreaming during awakening from REM • longer dreams involving social interactions
What are Sleep spindles?
waxing-and-waning periods of alpha-frequency
At what stage of sleep are the complex K and the sleep spindles observed?
Stage 2
Sleep is divided into two states which are?
Non-REM and REM sleep
Non-REM sleep is divided into 4 stages. true or false?
TRUE
Part 2
Neurobiology of sleep
During WW1, the neurologist Constantin Von Economo observed what?
- patients complained of excessive sleep (up to 20hrs per day)
- patients complained of insomnia
What did all the patients have in common?
All were affected by lethargic encephalitis, a condition caused by a virus
He identified two brain areas that, when affected by the inflammation caused by the disease, led either to one or the other behaviour. What were the 2 brain areas?
Prolonged insomnia: anterior hypothalamus
Prolonged sleepiness: caused by a lesion at the junction of the brain stem and forebrain
Transection midcollicular level is known in influencing what?
acute loss of wakefulness
What are the two main ascending pathways that keep us awake?
(2) Cholinergic projection
Cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei primarily innervating the thalamus
(1) Aminergic projection:
Monoaminergic neurons passing through the lateral hypothalamus to the basal forebrain and cerebral cortex
The first pathway contains cholinergic neurons which are made up of what neurotransmitter?
acetylcholine
what neurotransmitters make up the 2nd pathway? 3
Tuberomammillary nucleus: Histamine
Raphé nucleus: Serotonin
Locus coeruleus: Noradrenaline
What are the patterns of activations in the cholinergic systems ?
explain the 3 systems wakefulness, non-REM sleep and REM sleep
Wakefulness: Activity increases
Non-REM sleep: activity dramatically decreases
REM sleep: activity increases
What are the patterns of activations in the aminergic systems ?
explain the 3 systems wakefulness, non-REM sleep and REM sleep
Wakefulness: Activity increases
non-REM sleep: Activity decreases
REM sleep: Activity almost non-existent
what is the system responsible for inducing sleep?
Some of Von Economo’s patients had insomnia, possibly as a result of injuries to their sleep induction system.
The major source of inducing sleep comes from neurons that produce what 2 neurotransmitters?
neurons in the anterior hypothalamus,
particularly neurons from ventrolateral pre-optic nucleus (VLPO).
Such neurons produce GABA and galanin. Galanin is an inhibitory neuropeptide.
Neurons from VLPO are active during sleep
true or false?
TRUE
what is the relationship between VLPO and cholinergic-aminergic pathways. 4 steps?
1) Awake
2) Activation of VLPO
3) Inhibit ascending lining nuclei
4) asleep
Wakefulness system inhibits Sleep system
Sleep system inhibits wakefulness system
both inhibit each other.
true or false?
true
Inhibition must be effective, avoiding fluctuations/destabilisations from one state to another.
What may cause abrupt fluctuations?
Problems with stabilising agents
Abrupt fluctuations may cause what type of disorders?
narcolepsy
What is a known stabilising agent?
Orexin
What area in the brain produces orexin?
Lateral hypothalamus
What is the role of orexin neurons?
They may influence both the awake and sleeping inducing systems.
Like a light switch system
Reduction of orexin production is directly implicated in the onset of narcolepsy symptoms
true or false?
TRUE
What could be a possible treatment plan for this?
Administration of orexin may reverse the symptoms
During wakefulness, we might accumulate substances that induce the transition to sleep. An important candidate is what?
adenosine
What is adenosine?
a degradation product of ATP whose levels increase with brain metabolism.
Low levels of adenosine lead to sleepiness
true or false?
FALSE
high levels of adenosine lead to sleepiness
As sleep disturbances are present in several mental disorders, could this be an area to target treatment?
possibly
How can sleep be related to the immune system?
Sleep disturbance results in:
• hormone activation of the glucocorticoid receptor in leukocytes
• suppression of antiviral gene programs
• release of neurotransmitter norepinephrine in organs and tissues
The suppression of immune response is thought to contribute to what?
increased susceptibility to disease and reduced response to vaccines.
Sleep deprivation and gene expression
Sleep promotes what type of translation?
mRNA
Sleep deprivation affects genes containing what type of response element?
affects genes containing a cAMP-responsive element
Extended wakefulness impacts clusters of genes (including those essential for memory encoding)
true or false?
TRUE
Sleep deprivation may impair memory consolidation by reducing synthesis of proteins needed to support synaptic plasticity.
TRUE OR FALSE?
TRUE
What happens with CREB phosphorylation in the hippocampus during sleep/wake cycle?
Elevates during REM sleep
Reduces after five to six hours of sleep deprivation
The cAMP-PKA pathway
Why is this pathway important?
Critical for long-lasting forms of hippocampal synaptic plasticity and memory storage.
Related to the cellular model of learning.
Slow-wave sleep does what to synapses?
- synaptic strengthening
* synaptic downscaling
Can both of these events happen at the same time but in different regions of the brain?
perhaps
Explain in steps the cAMP-PKA pathway?
1) Subunit of activated G Protein
2) Activates adenylyl cyclise
3) Production of cAMP from ATP
4) cAMP activates PKA
5) PKA activates CREB
6) CREB interacts with the DNA molecule
What is CREB?
The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons
sleep deprivation impairs consolidation of new memories
TRUE OR FALSE?
TRUE
TOPIC 3
Microscopy in neuroscience
Microscopy in neuroscience is an essential technique for neuroscience research
What can we visualise? 4 things
• cellular and subcellular anatomical details
• individual cells and the structures within them
• interaction between cells
• three-dimensional assemblies of
neurons and functional activity
What are the limitations of optical microscopy? 3 things
1) There is a limit to the size of structures that can be visualised
2) Magnification: You can keep magnifying and things will look larger, but you won’t necessarily see more detail.
3) Maximum obtainable resolution:
Depends on wavelength used, and the quality of your optics and hardware.
Explain resolution in optical microscopy?
The shortest distance between two points that can be distinguished.
The shorter the distance that can be distinguished, the better the resolution.
What is the resolution formula?
- ——- - - Wavelength of light
Distance = ————————————-
——– —- — Numerical aperture x 2
- ——- - - Wavelength of light
What are the limits on resolution?
Green light = 540 nanometres (nm)
Numerical aperture = 1.4
nothing past 193nm can be resolved
What is the benefit of Electron microscopy?
Electron microscopy can be used to see smaller details than as visible with light microscopy
Why can we see smaller structures?
Electrons have smaller waves
compared to light = higher resolution.
samples are labelled with what? and include what to achieve the result?
samples can be labelled with metals
electrons are scattered by the labelled parts and projected onto a detector
What are the limitations of electron microscopy?
• samples have to be fixed (dead)
• you can’t label multiple different
structures easily
If two molecules are too close and merge into one, they can be viewed sequentially (or separated temporally).
true or false?
TRUE
What is super resolution?
Techniques that can allow us to see structures beyond
the limit of resolution for normal light microscopy
What is an example of super resolution?
localisation microscopy
What are the principles of localisation microscopy?
Molecules emitting these points of light are much smaller than they appear.
What does the point spread function describe?
and how is it graphed?
describes the appearance of molecules (looking larger than they are)
it can be graphed as a curve of intensity
How do you use the point spread function?
Using an algorithm, we work out the centre of each point spread function.
We then work out the approximate location of the molecule.
When molecules are imaged sequentially, they can be seen individually and the centre of each can be calculated.
How accurately we can approximate this location of molecule depends on what?
- quality of the optics
- means of acquisition
- algorithm used
How does this work in practice?
Illuminating molecules sequentially allows us to build high resolution images of our specimens.
What are the steps for this? 3 step process
1) Samples labelled with dyes which can blink (molecules appear at different times).
2) In each frame, different points are illuminated.
3) Calculate the approximate location of the emitting molecule.
How do we build an image?
100s-10,000s frames are taken to build up the whole image.
This requires what?
This requires fast acquisition and high processing power.
What are examples of techniques?
- STORM (stochastic optical reconstruction microscopy)
* PALM (photo-activated localisation microscopy)
Localisation microscopy can achive between 10-50 nm resolution, compared to about 200 nm with conventional microscopy.
true or false?
TRUE
Using super resolution to investigate plasticity
Many events underlying plasticity take place at the synapse.
What are these events?
• rearrangements of molecules
would these changes be seen using normal light microscopy?
No
How can we see these events?
Investigated with electrophysiology
Corroborated with super resolution
What are Interneurons in relation to plasticity?
• instrumental to plasticity of the cortex
• sustain balanced interaction between excitation
and inhibition
• pivotal in controlling sensory-related responses
and learning
Cells change their intrinsic properties, and outputs to other cells change in response to sensory experience – dysfunction is linked to what?
impaired cognition and psychiatric disorders.
What are Perineuronal nets?
- specialised extracellular matrix structure that enwraps parvalbumin-expressing interneurons
- promote synapse stabilisation
- limit synaptic rearrangement
• degradation of components in adults reactivates
plasticity (enhances learning)
What is plasticity?
The ability of the nervous system to adapt to sensory experience.
Investigating the role of brevican in plasticity can be done using?
brevican mutants and knockdowns
electrophysiological
imaging (STORM) biochemistry techniques
Brevican is a component of what?
perineuronal nets
In order to understand Brevican (BCAN) localisation. What can be done?
Used super resolution microscopy (STORM) to look at the localisation of brevican at the synapse.
What should be look at?
Looked at synapses apposed to parvalbumin- expressing interneurons (parvalbumin expressing interneurons are on the postsynaptic side).
How can labelling be done?
Labelled synaptic proteins Bassoon and Homer in parvalbumin expressing interneurons and the synapse opposed to it.
Brevican: Controls synaptic plasticity by regulating what receptors?
AMPA receptors
What are AMPA receptors?
• glutamate receptors in excitatory synapses
• voltage-gated iron channels
• trafficked in and out of synapses in an activity-
dependent manner
What are 4 AMPA subunits?
- GluA1
- GluA2
- GluA3
- GluA4
What are the 2 characteristics of AMPA receptors?
- changes in number, subunit composition or phosphorylation state modify synaptic strength
- important form of synaptic plasticity
Subunit composition determines characteristics such as what?
• determines characteristics such as ion permeability
What do we know so far with regards to Brevican and AMPA receptors? 4 things
Synaptic AMPAR currents are different between BCAN mutant and WT mice.
Synaptic activity is different in brevican mutant mice.
Membrane levels of AMPARs are different between BCAN mutant and WT mice.
Less GluA1 in synapses of brevican mutant mice.
More GluA1 in the general membrane.
Brevican controls the expression of GluA1 at the synapse.
true or false?
TRUE
Brevican containing perineuronal nets might enwrap the cells and stabilise synaptic characteristics during what periods?
Periods of development
Short-term memory is decreased, but long-term memory is enhanced in brevican mutant and knockdown mice.
true or false?
TRUE
