Untitled Flashcards Set

Neural Tube Origins & Organization

1.             Give an example of how transcription factors and/or morphogens affect the anterior/posterior and dorsal/ventral patterning of the CNS.

Morphogens: chemical inducers/proteins that determine cell fate

  • Synthesised and secreted at signaling centres at tissue boundaries of embryonic cells

  • Regulate expression through concentration-dependency in diffusion

  • How? Establish and regulate gradient of transcription factors to allow cell specialisation 

    • Neurons destined for anterior neocortex express increased levels of Pax6

    • Neurons destined for posterior neocortex express increased levels of Emx2

  • Methodology:

    • Differences in transcription factors ->

    • Differences in gene expression & protein production ->

    • Signals to attract neural precursor cells to appropriate destinations

Dorsal-ventral patterning: sonic hedgehog

  • Important for neural tube closure & establishing identity of ventral motor neurons in spinal cord

  • Expressed highly in notochord and floor plate

    • Increased Shh: Increased ventral-like motor neurons

    • Decreased Shh: increased dorsal-like interneurons

  • Blocking Shh:

    • Prevents transcription -> inhibits differentiation of motor neurons

  • Effects depend on:

    • Patched (Ptc1) & smoothened (Smo) surface receptors 

    • Transcription factor Gli1 which promotes motor neuron differentiation

    • Shh absent:

      • Ptc1 inhibits Smo 

      • This prevents Gli1 from translocating to nucleus

      • Decreases motor neurons

    • Shh present:

      • Binds to Ptc1

      • Translocation of Smo to cilium

      • Gli translocation to nucleus

      • Increased transcription and differentiation of motor neurons



2.             How do BMPs contribute to neuroectoderm formation? Where do BMPs come from (what secretes them)? How are BMPs inhibited?  List examples of these inhibitors and where they come from.

  • Bone Morphogenic proteins:

    • Growth factors secreted by ectoderm in cell-to-cell signaling that leads ectoderm to become skin

  • BMP inhibitors: 

    • Secreted by DBL that block BMPs and permit the default state of the dorsal ectoderm to become nervous tissue

    • Examples:

      • Noggin

      • Chordin

      • follistatin

3.             Describe the stages of neurulation.

  1. Neural plate formed 2 weeks post fertilisation

  2. Centre will drop inwards forming the neural groove

  3. 2 edges of neural plate thicken and fold forming neural folds

  4. 2 edges of fold fuse at centre creating neural tube

4.             What are the three primary germ layers? What do they give rise to? Be able to label figures of neurulation and gastrulation processes        

  • Prosencephalon/forebrain

    • Telencephalon 

      • Olfactory bulb, cerebral cortex, hippocampus, basal ganglia

    •   diencephalon        

      • Retina, thalamus, hypothalamus

  • mesencephalon/midbrain

    • Mesencephalon

      • Midbrain

  • rhombencephalon/hindbrain

    • Metencephalon

      • Cerebrum, pons

    • Myelencephalon

      • medulla             






 

Developing Cortex: proliferation, migration, & differentiation

1.         Draw interkinetic nuclear migration (IKM).  What happens at each of the 5 stages?

  1. Cell attached to ventricular surface and pial surface

  2. Cell migrates towards pial surface

    1. DNA replication happens here

  3. Nucleus contains 2 DNA copies, migrates towards ventricular surface

  4. Cell retracts its process from pial surface

  5. Mitosis occurs, symmetrical division occurs to produce new RGS progenitor cells which will go on to divide 

2.          What does it mean that the cortex develops inside-out?  What method was used to prove this?  How does this method work (in detail)?

  • Deepest cortex layers formed first, superficial layers then added on top

    • Neurons born earlier will reside more interior 

  • Subplate:

    • Temporary structure important for proper wiring of cortical neurons

    • Site of initial thalamic synaptic connections

    • The layer disappears after development is complete

      • Neurons migrate away

      • Thalamic afferents go to cortical plates to specify type of neuron

  • Cortical plate

    • Next earliest cells born migrate to the cortical plate, then settle in the deepest layer (layer 6)

    • Cells that are born later migrate to more superficial layers

  • Tritiated thymidine experiment

    • Inject gestating rheus monkey w/ radio-active thymadine to attach to alanine

      • The earlier the thymadine is given in cortical neuro-development, the deeper in the cortex it should be (layer 6)

      • This helps label birth dates of cells

3.          What are 2 chemical signals are secreted by the marginal zone that influence a) migration, and b) differentiation?

  • Reelin: stop signal produced by cajal-retzius cells in marginal zone

    • Signal: stop migrating neurons

  • Semaphorin 3A: protein secreted by marginal zone

    • Important for differentiating the characteristic architecture of cortical neurons

    • Signal:

      • Repels growing axons from pial surface

      • Attracts growing dendrites towards pial surface

 

Wiring the Brain: Initial connections, rearrangement, & critical periods

1.             Compare and contrast Sperry’s (chemoaffinity) and Hebb’s (exuberant connections) hypotheses on axon pathway formation.

  • Chemoaffinity hypothesis: form precedes function

    • Chemical markers/signals lead azons to find their targets

  • Exuberant connections hypothesis: functions form connections

    • Axons are initially connected to multiple targets and are slowly refined based on how well they work/their function

2.             Describe the 2 experiments performed by Roger Sperry that proved the chemoaffinity hypothesis.

  • Newt experiment

    • Surgically rotate a Newt’s eye 180 degrees

    • Severed the optic nerve and let it regrow

    • Tested to see whether the nerve will regrow to its original connection or if it will form a new connection based on the eye rotation

    • Placed the newt in a body of water and placed bait floating above it

      • Said that if newt swam up then its sight is no longer upside down and the optic nerve formed new connections to fix it (hebb was right)

      • But if the newt swam down then that means that the optic nerve grew back to where it was originally connected (sperry was right)

    • The newt eventually swam downwards, proving the chemoaffinity hypothesis correct

  • Strip assay experiment: established chemoaffinity presence, how do they work?

    • Background info:

      • Temporal retinas usually synapse onto the anterior tectum

      • Nasal retinas usually synapse onto the posterior tectum

    • Conducted an experiment where he layed out stripes of alternating anterior and posterior tectum, then brought axons from both the nasal and temporal retinas and wanted to see how they would grow based on stripes

    • Saw that in terms of the nasal retina, it grew equally onto both stripes with no evident preference

    • But with the temporal retina, he saw that it only grew on the anterior tectum and not posterior, why? Well there are multiple hypothesis

      • The anterior tectum produces an attracting signal

      • The posterior tectum produces a repellant signal

      • Both

    • In order to answer why, sperry heat-inactivated the tectum stripes one at a time starting with the anterior

      • He saw that there was no difference in growth

    • Then he heat-inactivated the posterior tectum and saw that the axons then spread equally across the stripes

      • This indicated to him that the posterior tectum had a repellent signal

    • The chemorepellant is ephrin A5

      • The anterior tectum had low concentrations of it

      • The posterior tectum had high concentrations of it 

      • Nasal retina cells had low levels of ephrin A5 receptors, therefore they could not detect its presence and grew equally

3.             Explain the main findings of the Verhage paper. 

  • Munc 18 is a crucial protein for synaptic transmission but not development 

  • The cortex can develop normally without it, but once synaptic transmission needs to start occurring and it can’t, the synaptic silence causes degeneration of the cortex

4.             Compare and contrast experience-dependent vs. activity-dependent synaptic rearrangement. Provide examples of each

  • Activity dependent rearrangement: requires correlated activity

    • Spontaneous correlated activity between ipsilateral retina and postsynaptic LGN

  • Experience dependent: requires correlated activity and sensory experience

    • Development of barrel fields happens postnatally based on experience

5.             Describe how segregation of LGN layers and ocular dominance columns forms. Relate this to experience-dependent and activity-dependent mechanisms

  • Ocular dominance columns are columns of the V1 that respond to the ipsilateral/contralateral eye

  • Retinal ganglion cells make connections with the LGN thalamic inputs to project to certain layers of the LGN

  • LGN then projects to the visual cortex

6.             What are the cellular/synaptic mechanisms that cause the shift in ocular dominance columns following monocular deprivation during the critical period?

  • Hubel & weasel cat experiment

    • Briefly deprived a cat from sight in one eye from birth to 2.5 months, then measured its visual abilities at 38 months

    • Saw that the cat only uses the non-deprived eye for vision, the deprived eye does not have any activated cells and there is no evidence of binocular vision

    • This proves that there was a shift in the ocular dominance columns based on the visual inputs received postnatally

    • Critical period: 0-2.5 months for ocular dominance columns in cats

7.             Define strabismus.  How are critical periods important to this?

  • Uncorrelated eye movement (do not move in unison)

  • Not pointed in the same direction

  • About 5% of newborns are born with this condition, critical period is crucial because if not fixed during it then it will be impossible to fix due to experience dependent rearrangement bc the V1 is now used to uncorrelated activity

Intro to Learning & Memory and Anatomy of Memory

1.           Differentiate between declarative and non-declarative memory (and their sub-categories) and the brain regions involved.

  • Declarative: facts and events

    • Medial temporal lobe, diencephalon

    • Semantic: facts

    • Episodic: events

  • Non-declarative

    • Procedural memory

      • Operant conditioning, striatum

      • Learning skills and habits that need repetition

    • Skeletal musculature

      • Classical, cerebellum

      • Muscle memory

    • Emotional response

      • Classical, amygdala



2.           Describe the deficits of patient H.M. From this knowledge, what can conclude regarding systems consolidation of memory (which model is correct)?

  • Lesion caused amygdala & entorhinal cortex damage

    • Most of EC & hippocampus missing, perirhinal cortex not intact and medial mammillary nucleus shrunken

  • Had normal procedural memory as it doesn’t require hippocampus

    • But had no memory of the specific experiences when he was taught

  • Had normal working memory as it doesn’t require hippocampus

    • Could remember a list of 6 numbers but would forget them if distracted

  • HM suffered from anterograde amnesia (inability to form new declarative memories) & temporal retrograde amnesia (memories right before lesion)



3.           Explain how the “what” (meaning, a coherent concept) of memory is stored.  Define distributed memory and Hebb’s cell assembly and relate this to the “what” of memory.

4.           Draw the circuit involved in sensitization and habituation of the gill withdrawal reflex in the Aplysia.

a.           What is the mechanism of habituation? (i.e. what cellular changes cause reduced response)

  • Touching the siphon -> activates sensory neurons -> form excitatory synapses w/ motor neurons

  • Transmission between sensory & motor neurons is depressed

  • This leads to decreased ability of siphon stimuli to evoke gill contraction

  • Depression is presynaptic and is likely due to decrease in number of synaptic vesicles available for release & inactivation of voltage-dependent calcium channels

b.          What is the mechanism of short-term and long-lasting sensitization? (i.e. what cellular changes lead to increased response? What is the role of S-type K-channels?)

  • Short-term sensitisation: activation of serotonin release onto motor neurons

    • Prior to tail shock, siphon stimulation evokes AP in sensory nerves

      • AP has a short duration due to quick membrane repolarisation by:

        • Standard voltage gated K+ channels

        • S-type K+ channels (always open)

    • Tail shocks activate sensory neurons in tail

    • Sensory neurons excite modulatory interneurons that release serotonin (5HT) onto presynaptic terminal of sensory axons

    • Serotonin enhances glutamate release from sensory axons

    • Increased glutamate release causes larger EPSP in motor neuron which causes a larger response (sensitisation)

  • More in depth details

    • Serotonin released on sensory neuron, binds to metabotropic serotonin receptors

    • Binding of serotonin stimulates cAMP production

    • cAMP binds to PKA which liberates catalytic subunits of pKA

    • Catalytic subunits phosphorylate S-type K+ channel

      • Phosphorylation causes a conformational change causing them to close

      • When they close, they can’t help repolarise the membrane

      • This prolongs AP, longer depolarisation, increased glutamate release

  • Long-term maintenance:

    • larger/more tail shocks increases 5HT release on sensory neuron

    • This increases PKA which shuts down s-type K+ channels but also activates CREB via phosphorylation

      • Transcription factor

    • Phosphorylation of CREB

    • pCREB binds to DNA, induces ubiquitin hydrolase

      • Ubiquitin hydrolase: prevents ubiquitin from degrading proteins

    • Prevents pKA degradation

      • This causes inc. channels close which prolongs AP and increases glutamate release

    • Activates other transcription factors

    • Results in long-term increase in synapse and synaptic growth



5.           What are place cells? Grid cells? Where are these cells located? How do these cells differ?

  • Place cells

    • In hippocampus

    • Have receptive fields that fire at certain areas/places

  • Grid cells

    • In entorhinal cortex

    • Fires based on where you are in grid pattern in space

    • This forms a comprehensive map of where one is in space

    • Each grid cell fires in multiple location in space forming the grid pattern of the spatial receptive field

6.           What are the phases of classical conditioning? What is involved in each?

  1. Acquisition: higher value of US & more salient CS results in better conditioning

  2. Extinction: presenting CS without US

  3. Spontaneous recovery: CR reappears after some time

 

Cellular Mechanisms of Learning & Memory

1.             List the 3 requirements for LTP. Describe experimental evidence that proves these things as requirements for LTP.

  • pre/post synaptic neurons must be active at the same time

    1. Cooperativity: helps form associations between experiences

  • Presence of NMDARs

    1. Act as coincidence detectors

      1. Mg-block requires sufficient depolarisation to unblock

    2. Are also permeable to calcium

  • Presence of calcium

    1. Glutamate release -> AMPARs allow for sufficient depolarisation to unblock NMDARs

      1. Calcium enters via NMDARs, binds and activates camKII

2.             Describe the two processes that maintain synaptic homeostasis

a.             Metaplasticity

  • Sets threshold for LTP depending on synaptic history

    • If LTP is induced before, threshold increases making it harder to continue

    • NR2B NMDARs: Promote LTP (dec. threshold)

    • NR2A NMDARs: promote LTD (inc. threshold)

b.            Synaptic Scaling

  • Absolute synaptic effectiveness is adjusted to preserve homeostasis synaptic weight

  • CAMK IV induces the insertion/removal of NMDARs/AMPARs to balance activity

3.             What is spatial summation? How does it contribute to cooperativity of memory encoding? How is this different from temporal summation?

  • Spacial summation: many pre-synaptic inputs are simultaneously stimulated

  • Temporal summation: 1 cell sends multiple signals to 1 dendrite



4.             What are synaptic tags? What is their importance/function? What molecule is a suspected synaptic tag and what proteins might it be tagging?

  • A weak stimulation that induces early LTP provides a tag to the synapse that allows them to capture newly synthesised proteins induced by strong stimulating synapse

  • Transient (2-3 hours)

  • Newly synthesised proteins consolidate LTP at weak synapse to convert it to late LTP

  • CAMKII is suspected to be a synaptic tag

  • Proteins

    • Densin: cell adhesion molecule (allows CamKI to bind to other proteins)
      ABP: adds anchoring sites for AMPARs

    • Cad: enlarges both pre and post synapses 

5.             Describe the actions of CamKII as it relates to LTP (early and late).

  • Early LTP

    1. CamKII is an important 2nd messenger in LTP

      1. Phosphorylated serine 831 in AMPARs to increase conductance

        1. Increases conductance, entrance of Na+, and allows for depolarisation in less time

      2. Increases number of AMPARs in the membrane

      3. Phosphorylates stargazin on AMPARs to immobilise them in the membrane

        1. Stargazin: protein that allows AMPARs to be anchored to the membrane

          1. Permanently locate them there and reduce likelihood to get recycled

  • Late LTP: required for long-lasting spine enlargement

    1. Calpain: protease that breaks down cytoskeleton of spine

    2. AVC: provide proteins to rebuild

    3. RC: contain AMPARs

    4. Polyribosomes: site of active translation of proteins 



 

Working Memory & Reconsolidation

1.             What is reconsolidation? How does this relate to creating false memories? What influences how well something is remembered?

  • Reconsolidation: recalling a memory after it had been stored, rendering it an unstable state were it is prone ot perturbations

  • Influences on how well we remember something:

    • Sleep deprivation

    • Attention

    • Emotional saliency

    • Whether its been exposed to you before

 

Motivation

1.            Compare and contrast the 3 theories of motivation discussed in class.  Describe an example of each theory in real life. (Drive reduction theory, Anticipatory Contrast, Response Deprivation).

  • Drive-reduction theory: motivation drives us towards homeostasis

    • Set point compares to internal state and produces a behavioural output

    • Hedonic impact: “liking” the pleasure gained from a reward

    • Incentive salience: “wanting” motivation that drives to obtain a reward

  • Anticipatory contrast: the value of a reward is dependent on our previous experience and expectations

    • Running speed of mice varies based on expectation and outcome

  • Response deprivation: any behaviour can serve as a reinforcer or punisher if access to behaviour is limited

    • Behavioural bliss point: all behaviours have a preferred frequency

2.            Does dopamine mediate liking or wanting?  What is the experimental evidence for this?

  • Dopamine encodes incentive motivation to obtain a reward

3.            Locate the midbrain dopamine neurons on a figure and know where they project to.  How do dopamine neurons fire during reward learning, and how does this relate to reward prediction error (E.g., Figure 16.17)?

  • Rewards often occur after reward-predicting stimuli

  • Reward prediction errors occur when there is a mismatch between what is expected and what is received

  • Dopamine neurons fire to a predictive cue