post-midterm

An on-center ganglion cell fires most when the center is bright AND the surround is dark! (t1
- Fires when light is shone on cente and when surround is in darkness
Time intervals = epochs (t0, t1..)

Surround cones are depolarized.
Surround cones release glutamate onto horizontal cells.
horizontal cells depolarize. horizontal cells release GABA
onto the center cone.
The center cone hyperpolarizes more: similar to if it got more light!
- Surround cones also impact centre cones
- Centre cone has Gaba receptors
- This is why having darkness causes the hyperpolarization of centre cone
Detect contrast

- Also influenced by surround
Darkness in centre, brightness in surround

We have both on and off centre cells because they allow us to tell whether our environment has gotten darker or lighter

http:/etina.umh.es/webvision/imageswv/colorop.jpeg
(GABAergic)

Visual field - what you're seeing
Nose is not blocking anything in binocular vision because the other eye's vision makes up for it

- Contralaterality
- The left visual field goes to the right occiptal lobe
- The areas where the binocular and monocular portions go are separated by the calcarine suculus
-
Macula is area around fovea
Small dark green area of visual field is activating a large area in the occipital lobe - over magnification and disproportionate retinotopy

Optic nerve (CN II): axons from one eye.
Optic tract: axons from both eyes.
Contralaterality: caused by decussation of the nasal retinal axons at the optic chiasm.
Temporal retinal axons stay ipsilateral
Nasal retinal axons decussate
Both go to thalamus
Tracts have axons from both eyes

- The suprachiasmatic nucleus is anove the chiasm, and it is involved in circadia rhythm (when you get tired acorrding to where you live)
- The pretectum is involved in pupil reflex
- The superior colliculus is involved in orienting towards movement in our environment

Damage to left temporal and nasal

Damage to left and rigth nasal areas
Caused by Pituitary adenoma
- Benign tumour that grows in pituitary gland
Above optic chiasm and can cause bitemporal hemianopsia

damage to left nasal area and right temporal area
- Caused by an infection of tumour in the optic tract

Damage right temporal area, lower right nasal area, left nasal area and lower left temporal area
- Caused by stroke

- Caused by posterior artery stroke
- Damage to left nasal area, right temporal area and both fovea of both

- Cat put to sleep with general anesthetics
- Pentobarbital increases GABA and puts you to sleep
- You get sensory input even when unconscious
- You can hear the Aps firing
- Hubel and Wiesel cat experiment
Listened to Aps in receptive field of cat's LGN
Respond best to a bar of light in particular orientation

- Same preferred orientation in one column, and the next column will have a different one

David Hubel, Torsten Wiesel
- characterized “information processing in the visual system”

- The LGN in the thalamus has 6 layers that are not related to each other
- Extraceullular recordings can be taken through oblique electrode penetration and light can be shone in each eye separately and V1 AP recordings can be taken

- Plotting which eye activated the most neurons
- Found that eyes alternated as electrode took recordings through each column
Equal response is the border between two eyes
Blue corresponds to one eye, green corresponds to another
One eye dominant in one column, other eye dominant in other column

- Radiation amino acids are injected in the eye
- Transynaptic transport through the LGN terminates in layer 4 of the primary visual cortex
- Terminiations are visible as bright bands on the autoradiogram
- In the retina, there is uptake and incorporation in the proteins and labeled amino acids
- Transneuronal transport of the labels happens in the thalamus
- The terminals are labeled in the cortex

Left ocular dominance column contains the individual orientation columns
then Right ocular dominance columns and its orientation columns

1) Bathe brain tissue with caged glutamate
2) Flash UV light to uncage with high spatiotemporal resolution

Caged glutamate is connected to another molecule and it cannot bind to a receptor
- By bathing CSF in vivo with glutamate
Shine laser light at just right frequency to cleave off cage (focal photolysis) and activate one neuron

- Bathed living slice with caged glutamate and activated neurons with laser
- Every trace in image on right is all neuron 2 and what happens to voltage at each location
○ Light shone on neuron 16 does nothing but neuron 10 does
Map out radius of influence

Each vector represents one neuron in V1
The direction of the vector is the neuron’s preferred orientation The magnitude of the vector is the neuron’s firing rate

- Light hitting temporal area of both eyes, brain infers it's closer to you
Light hitting both nasal areas, brain infers it is far away
Two objects at the same depth from the observer: red object image at identical location on the two retinae (no disparity)
Brain uses where rays fall on retinas to determine where the other object is in comparison to the fixation point - for objects not in line with each other

Two objects at different depths from the observer: red object image at different location on the two retinae (disparity)
If you didn't have left eye, how could you tell if the object was to the left of the focal point at the same depth
Need both eyes for depth and direction (R or L)

If you could make your left eye look at two dots at the same time while right eye looked at the two blue fixation points, you would see what is on the left

- Causes cerebral akinetopsia
- Involved in detecting motion of entire visual field
- Optic flow of everything while looking out of a window activates this area
○ Cannot perceive movement
Won't see traffic as moving - will see it as a snapshot

- Causes ahromatopsia
- Loss of colour vision in cortex and not in cones

Each vector represents one neuron in MT
The direction of the vector is the neuron’s preferred motion direction The magnitude of the vector is the neuron’s firing rate

You would see the waterfall moving up after watching it flow down
The illusion results from adaptation followed by inference. The “downward” cells in MT adapt during the viewing of the
waterfall stimulus.
Normally, a stationary image activates all MT cells equally.
When the waterfall video stops, however, the adapted (downward) cells will have lower firing rates than the other cells (e.g., the upward cells).
The waterfall therefore appears to moving upwards!
- MT Neurons that prefer upward movement fire as much as neurons that prefer downwards movement
- Vector addition is 0
Downward neurons are fatigued, upward neurons are not

Sound is a vibration of air molecules and they become dense and pushes air and compresses air and pulls back and molecules spring back and get less dense
Air molecules move like slinkies

The time taken for one up-down cycle is the period
To make an up-down cycle, the wave must move a distance of 1 wavelength Therefore, distance / time = speed = wavelength / period
The frequency (in cycles per second or Hz) is 1 / period
Therefore, speed = wavelength x frequency

The speed of sound in air is 344 m / s
Therefore, for a 1 kHz sound (frequency = 1,000 cycles / s),
= speed = (344m/s) = 0.344m≈1ft frequency (1,000 / s)

- The more mass on the fork, the slower it vibrates

- A xylophone is like a series of tuning forks

men women
frequency
100 Hz - men
200 Hz - women
wavelength
3.44 m (11.3 ft) - men
1.72 m (5.6 ft) - women

- Sound arrives first and louder on ear closest to it
- Sound arrives later and softer in other year
- Connections between neurons on either side enable the compairson of very slight differences in the sound stimuli that arrive in each ear

20 cm (1m/100 cm) (1/344m)(1000ms/s)=0.6 ms

R^2=5m^2 + 10m^2 = 125^2
L^2 = 5.2^2 + 10^2 = 12.04 m^2
R = 11.8
L = 11.27
L-R = 0.09
0.09 x (1/344)( 1000ms/s) = 0.3 ms

Humans can hear sounds that range from 20 Hz to 20,000 Hz
Lower frequencies correspond to the apex of the cochlea and higher frequencies correspond to the base of cochlea
onotopic map - different parts of apex to respond to different frequencies
Rostral to caudal is lower to higher frequencies

The superior olivary complex contains 2 nuclei for sound localization: lateral superior olive (LSO) - determines loudness behind the ears
medial superior olive (MSO) - determines arrival time between ears

Lateral Superior Olive (LSO)
Monitors interaural intensity difference for high-frequency sounds.
The head blocks sounds that have wavelengths smaller than the diameter of the head.
frequency = speed/wavlength = 344/<20cm > 2HZ
Therefore, high-frequency sounds (> 2,000 Hz) are blocked by the head: sound shadow!
- Low frequency with big wavelength is not blocked by head
- 20 cm is about diameter of head
LSO will determine loudness when sound is greater than 2KHZ

Each cochlear nucleus excites the ipsilateral LSO and contralateral MNTB
Each MNTB inhibits the ipsilateral LSO

- One branch goes to LSO and releases gutamate
Other decussates and then goes to MNTB nucleus and releases glutamate
- Neurons in MNTB nuclei have inhibitory neurons and they synapse on same side of LSO they are on and release their gaba or glycine
Right LSO axon is excited by sound in right ear and inhibited by sound in left ear (spatial summation EPSPs and IPSPS)

More aps in one axon, louder sound on that side

- Hyperpolarizing the left Lso on right side
- More Aps louder sound
-

Monitors interaural time difference for low-frequency sounds.
The head does not block sounds that have wavelengths greater than the diameter of the head.

- Difference in distance changes across MSO - some neurons closer to left ear, some closer to right
- Just one EPSP, not sufficient to reach AP, from both axons can do AP
- If sound reaches right ear later, then left ear is getting a head start - no spatial summation because left side has head start
- Neuron E is furthest from left axon
- So maybe neuron E is fired the same time as when sound reaches the right ear and by that time the left axon has sent EPSP and reached neuron E
- Detecting when excitatory action is happening at the same time

- Concha funnels sound into external auditory meatus
- Pinna amplifies sound signal
- From EAM sound vibrates tympanic membrane
- In middle brain you have ossicles
○ Malleus, incus and stapes
- Stapes pushes against oval window and divides middle and inner ear
- Tympanic membrane divides external and middle ear
- Eustachian tube equalizes pressure in middle and external ear
Important bc if pressure was greater on one side of tympanic membrane, the membrane would not be able to vibrate bc it would bulge out in one area

- Inner ear is in cochlea
- When stapes pushes in, round window pushes out due to fluid pressure
- Stapedius muscle attaches to stapes and tympani muscle attaches to tympanic membrane and stops them from vibrating too much
Too much vibration can be damaging to ea

1) The oval window is much smaller than the tympanic membrane. Thus, force is funnelled to a smaller area, increasing pressure!
2) The stapes displaces the oval window with about 1/10 the displacement of the tympanic membrane, but with much greater force! The ossicles are a mechanical advantage lever system!
- Creating larger distance move with a small handle-able movement
Small force x big distance = same amount of work

Bones amplify pressure of soundwaves
Compression and rarefaction pressures are amplified when they push up on oval window because there is fluid behind it and it is harder to push a fluid than it is to push a flappy membrane in the air

- 32 mm
- The whole cochlea is the size of a pea when rolled
Vibrates in the same place as the perilymph

- The apex is wide and floppy
- The base is narrow and stiff
- The apex is 500 um wide
- The base is 150 um wide and correlates to sound freuqency that produces the maximum vibration

- Swings also have a resonance frequency
- If parent pushes at same frequency of swing, it will create a big amplitude of swing and will oscillate
Vibration on one part of xylophone activates the same part in the basilar membrane

- Humans are 20 to 20,000 Hz
- Elephants and moles can hear infrasound
- Dogs and cats start hearing a bit above our hearing range (20,000 Hz more so 40,000) - but do not hear as low as us (ultrasound)
- Bats hear abot 160,000 Hz into ultrasound and not as low as us

- Each axon receives glutamate from hair cells
- Brain can interpret where the basilar membrane is vibrating due to the tonotopic organization
Even a soft sound at a particular frequency can activate an auditory axon

- Organ of corti is where you have basilar membrane and hair cells
- We are looking at one width of the basilar membrane
- Hair cells embedded into supporting cells
Perilymph pushes this entire structure up to vibrate

- The endolymph has high K+ concentration (150 mM)
- The perilymph has low K+ (7 mM)

- Inner hair cells are closer to middle axis of cochlea
- Outer hair cells
Little hairs are stereocilia
- More outer hair cells
- Inner hair cells are responsible for acoustic transduction
- There are about 15,000 hair cells each ear and 3500 inner hair cells
- 95% of afferent axons innervate inner hair cells

- When the whole thing pishes up yo get a sheearing force
- The stereocilia have a collision and rotate to the right
Shearing force lets in ions into hair cells

- Each stereocilia is higher than the one next to it
- There are protein filiaments that link the side by side stereocilia
○ Called gating springs or tip links
- On top of each cell, there is a gated ion channel
- Distance between tips increases during excitation
- Adds force to gated ion channel and opens it
- Endolymph
- Selectively permable to K+ and Ca++
○ Flows into stereocilia and they depolarize the hair cell
○ Mechano(acoustic) transduction
○ Ca++ binds synaptotagmin and vesicle fusion and releases glutamate
Released onto afferent axons that go to cochlear nucleus

- Negative bundle displacement is the opposite direction of how they'd normally shift
- There are leak channels, so potassium is always leaving
So if you shut out the gated channels that, you'd get hyperpolarization

Depolarization causes the outer hair cell to contract.
- Assist transduction by changing shape
- They have a molecular motor prestin, and they get shorter
- When depolarize, they contract
Pulls basilar membrane up and tectoral membrane down and pushes them together

Prestin: the motor protein in the outer hair cell membrane
Depolarization
causes the OHC to
contract
Hyperpolarization
causes the OHC to
lengthen

- Vibration is impeded from reaching inner ear
-Can be caused by ear wax
Can be caused by otitis media - Infection of the middle ear, causes pus and inflammation and tympanic membrane do not vibrate
- Can also be caused by otoscleorisis - stapes fuses permantly to bone around it and cannot vibrate

- Can be caused by occupational deafness
- Can be caused presbycusis which is loss of hearing with age
- Can be antibiotic ototoxicity - which ic caused by antibiotics
- Can be caused by acoustic neuroma which is a schwann cell tumour also known as vestibular schwanoma

- Bilateral conductive hearing loss from young age
- Allowed him to block out talking around him and he read books

Edison's Tinfoil Phonograph
First device that recorded sound and played it back

- City traffic is 85
Lawn mower is 90
Inside a subway car is 95
Rock concert is 110
- Hearing damage accumulates and doesn't show up until later

Rotation around X axis, rotation around y-axis, rotation around z axis

- Endolymph is shared
Neutrally orthogonal structures

Two otolith organs (utricle and saccule): detect head tilt and linear acceleration Three semicircular canals: detect head rotation
The vestibulocochlear nerve consists of the vestibular nerve (CN VIII) and audtitory nerve (CN VIII)

- Uses same hair cells as auditory system
- Detect head tilt and linear acceleration
- Systematic arrangement of where longest hair cell is - arranged around the striola (midline)
- The surface they occupy is different (each one in different plane)
- When head tilts, hair cell bundles depolarize and release glutamate onto axons
- Otoconia - CaCO3 crystals
Add mass which causes shear force when head is tilted

- Tip links hyperpolarize on left half because the longest side of their stereocilia is deflected
On right half they'll depolarize as the "correct" side of them is deflected (shortest side)

Calcium Carbonate CaCo3
1-5 microns in diameter
- Add mass and inertia to the otolithic membrane

- Resistance to changing with velocity

The tip-link motor is impeded by intracellular Ca++ The motor slips when intracellular Ca++ is high.
- Gating spring attaches stereocilia adjacent to each other
- Spring is not fixed to stereocilium on right
- Actin filament moves and can cause tension in tip link
Tension causes motor to slip and reduce tension, this causes channels to close

- During transduction, tip link tension rises and it opens K+ and Ca++ channels, and the depolarization causes us to sense the head tilt/linear acceleration
- During adaptation there is a lot of Ca++ inside the stereocilium with cuases the slippage of the tip link motor and closes and K+ and Ca++ channels

Cupula: gelatinous substance in which the hair cell bundles (stereocilia) are embedded
Ampulla: bulge in the bony canal
Crista: epithelial cell layer in which the hair cell bodies are embedded

No rotation: The cupula is straight
Rotation: The intertia of the endolymph causes deflection of the cupula
- Bottom of cupula moves to the left
- Endolymph has inertia so it doesn’t have to rotate the same way
Cupula collides with stationary endolymph - deflects cupula

During sustained constant rotation, the endolymph in the semicircular canal “catches up” to the speed of rotation - i.e., it starts to rotate with the same speed as the head (the canal wall). This means that the cupula is no longer deflected, so the hair cells are not activated.

Eyes moving In equal and opposite direction when shaking head
Shaking towards right activates right horizontal semicircular canal

- Scarpa ganglion releases glutamate onto medial vestibular nucleus
- Axon decussates onto left side of pons
- Reduces glutamate onto abducens nucleus
- Abducens nucleus axons go to abducens nerve and hen lateral muscle
- Causes muscles to shorten and eyes move towards right

How left eye moves to right
- From abducens nucleus, axons decussate again
- Go rostrally to midbrain
- Release glutamate onto oculomotor nucleus
- Go to medial longitudinal fasciculus
- Neurons in oculomotor nucleus, send axons to medial rectus muscle and left eye moves to right
if you want to mve the left eye to right, you want to make sure that its lateral rectus is relaxed
- Lateral/medial recti are antagonists

The oculomotor nerve is responsible for eye movements, pupillary constriction and accomodation, muscle of the upper eyelid

The abducens nerve is responsible for the eyes' abduction or lateral movements

The vestibiulocochlear auditory nerve is responsble for hearing and a sense of balance

1. The hair cells of the left horizontal semicircular canal
2. The left vestibular nucleus
3. The right abducens nucleus right lateral rectus muscle 4. The left oculomotor nucleus left medial rectus muscle
- more action potentials the faster you move, cupula deflects faster

bilateral loss of VOR; causes apparent motion of objects and blurring of vision; can result when hair cells are destroyed by ototoxic medications such as streptomycin.

dislodged otoconia from utricle enter posterior semicircular canal; causes dizziness in certain head positions.

alcohol enters cupula, making it lighter than endolymph - buoyant, and therefore deflects in certain head positions

Size of BA 4 (proportion of body wt) is constant across species, but BA 6 is 6x larger in humans than macaque monkeys.
Area sends axons down to brain stem and spinal cord
Upper motor commanding lower motor neurons
- Damage in this area can cause difficulty or losing the ability to move (paralysis or paresis)

-Commands' primary motor cortex
- Lesions to premotor area can cause apraxia: loss of the ability to plan and execute complex voluntary motor tasks.

Cortex to spinal cord - corticospinal tract

Face axons go to corticobulbar tract (cortex to brianstem)

- Areas of M1 (legs, hands, arm) sending axons to corticospinal tracts
Cortex to spinal cord
- Layer 5 sends axons to cortex
Hypoglossal nucleus sends axons to layer 5 of
M1 and then goes to cortex

90% of the CST axons
decussates in the medulla
terminates contralaterally in the lateral part of the ventral horn limb movement, especially distal muscles (feet, hands, fingers)
- Release acetylcholine
- ventral horn is motor
-lower motor neurons go to hands and feet

10% of the CST axons
does not decussate in the medulla
terminates bilaterally in the medial part of the ventral horn axial/proximal muscle movement (neck, shoulder, trunk, hip)

Midline areas like shoulders, waist, hips don't require as much final motor control
Damage to left shoulder region of VCST would paralyze left shoulder and cause only some movement issues on right side

- Trained rhesus monkey from central position to where LED light lights up
Record APs and how many action potentials neurons make based on where monkey moves its arm

- Inserting multiple elctrodes for cell recordings
- Can allow for things like a mechanical arm to be controlled through brain reocrdings

- Send axons directly to muscle (alpha motor or lower neuron)
Pool innervates a single muscle
Motor unit is single neuron and all the muscle fibres it innervates (muscle fibres contract)
- Motor pool is not confined to one segment
Can come from neighbouring pools

Single alpha motor neuron branches to 1000 leg fibres, 10 finger muscles, etc..
Every time an alpha motor neuron is activated, you can see how much the muscle contracts and with more neurons you can see finer control
Finer control seen by activating different neurons
Number of muscle fibers per motor unit:
large leg muscles: 1000 fingers: 10
extraocular muscles: 3

The fibers innervated by a single alpha motor neuron are distributed throughout the muscle.
This makes the firing of each motor neuron cause a distributed contraction (smoother muscle dynamics)
Muscle fibers innervated by a single alpha motor neuron

- acetylcholine is released for skeletal muscle conrtraction
Each synaptic vesicle of an alpha motor neuron contains about 10,000 ACh molecules.
One acetylcholinesterase (AChE) enzyme can break down 5,000 molecules of ACh per second!
- Important for acetylcholine to not stay in synaptic cleft, otherwise you'd be performing an action for longer than you need
Acetylcholinesterase breaks down acetylcholine so it cannot bind to receptor

death of lower and upper motor neurons flaccid paralysis, areflexia, muscle atrophy aka Lou Gehrig’s disease

death of skeletal muscle
x-linked recessive genetic mutation
gene for a muscle cytoskeletal protein (dystrophin)

autoimmune destruction of skeletal muscle ACh receptors alpha motor neurons and muscle not damaged
normal life expectancy with treatment
- For example if you have something like ptosis - 1 min after an IV injection of acetylcholinesterase inhibotr eyes can open and muscles are getting overstimulated

- 1B afferent neuron detects force between muscle and tendon
- Causes APs when bicep is contracted
- Synapse in inhibitory neuron in dorsal horn
- Reflex causes inhibition of alpha motor neuron but not so much to the point where the firing stops
○ Leads to smoother movement
- Inhibiting very same neuron that is excited
Alpha motor neuron going to tricep is being activated and helps with smoother movement
disynaptic autogenic inhibition
disynaptic excitation of antagonist

- As you lift one leg, you need to extend opposite leg to maintain body weight
- Painful stimulus detected by axon, synapses and then you
Inhibition of flexor

the capcity of continous alteration of the nueral pathways and synpases of the living brain and nervous system in response to experience or injury that involved the formation of new pathways and synapses and the living brain and synpases and the elimination or mofication of existing ones

water enters gills - which extract oxygen - and exits siphon
• tentacles at head: tactile sensors
• rhinophores: chemical sensors (look like rabbit ears)
• gastropod invertebrate; coastal waters in California and Mexico • adult ~ 1 foot long
- Does not have a spinal cord
- Parapodial flaps help them push water to swim
- Releases dye when disturbed

- Sensory neuron works kind of like a nocirecptor c axon
- A stimulus to the siphon causes the animal to withdraw its gill
- The gill is the most important thing to protect because then it won't be able to breathe
Shocking the siphon skin innervates sensory neuron to motor neuron that release acetylcholine onto gill and the gill withdraws into the body

a progressive decrease in response to a repeated stimulus
the sensory neuron releases less glutamate with each action potential

- Research Question
- Cycle between hypothesis, predictions, data

a heightened response to an innocuous stimulus, caused by a previous noxious stimulus (to the tail).
- Multiple shocks cause long term memory
- Seen when tail is shocked and siphon is touched

Whne siphon is shocked, the sensory neuron releases glutamate onto sensory neuron and motor neuron releases acetylcholine onto gill

Sensory neuron from tail goes to many places but the interneuron modulatory/faciilitatory interneuron ithat is sertonergic recieves glutamate from sensory neuron and then synapses at axoaxonic synapse and this contracts gill

Tail shock causes a broadening of the action potential in the siphon sensory neuron’s axon terminal. This causes more Ca++ entry into the siphon sensory neuron’s axon terminal and consequently more glutamate release and a greater motor neuron EPSP.
- Sensory neuron AP changes shape during after sensitization
- Due to shape change, the depolarization lasts longer
Sensory neuron releases more glutamate onto motor neuron when siphon is tapped

- Metabotropic serotonin receptor
Tail shock activates the tail sensory neuron
• Tail sensory neuron (glutamatergic) excites the modulatory (facilitatory) interneuron
• The modulatory interneuron releases serotonin onto siphon sensory neuron axon terminal (axo-axonic synapse)
• Inside the sensory axon terminal, the enzyme adenylyl cyclase converts ATP into cAMP
• cAMP activates the enzyme protein kinase A
• Protein kinase A phosphorylates (adds PO4 to) voltage-gated K+ channels
• This reduces the probability that the K+ channels will open during AP
• This prolongs the AP falling phase (depolarization of axon lasts longer)
• Now siphon stimulation → prolonged action potential in siphon sensory axon terminal → more Ca++ entry than normal → more glutamate release than normal → greater motor neuron response!

The stimulating microelectrode can be metal (e.g., tungsten) or a glass micropipette such as would normally be used for patch recording.
Note Cochlear implants work through extracellular electrical stimulation!
- Inject negative charge and cause CSF to be negative
- Negative charge attracts positive charge from inside
Depolarizes axon

Advantages:
Convenient, relatively easy to accomplish
Can stimulate neuronal cell bodies or axons directly

But Beware:
Suppose that a neuroscientist decides to stimulate extracellularly in Nucleus B in an effort to determine whether Nucleus B sends axons to Nucleus C. What’s a potential problem that could occur?

- Not sure if axons from b to c exist
How can you tell you aren't stimulating axons from a to c?

glutamate photo-uncaging!
(focal photolysis)
- Bathe CSF for caged glutamate and then cleave the cage which releases glutamate
Glutamate won't activate blue axons that are passing through

High-frequency stimulation (“tetanus”) of axon 1 causes an increase in the EPSP amplitude evoked by a subsequent single stimulus of axon 1 (but no change to EPSP evoked by axon 2).
- Caused many Aps in one second
○ Tetanus
- Stopped after tetanus and then gave a single pulse
EPSP of single pulse was bigger (2x amplitude)
- This effect is long lasting potentiation

- 1 axon sends strong stimulation and the other axon is inactive
Ca++ enters the dendrite at synapse 1 only, because:
1. The postsynaptic cell is depolarized (everywhere), but 2. Glutamate is present only at synapse 1.

One axon sends strong stimulation and the second one sends weak stimulation
- Single pairing or few pairings induces LTP and flipping both would cause the same effect
Ca++ enters the dendrite at both synapses, because:
1. The postsynaptic cell is depolarized (everywhere), and 2. Glutamate is present at both synapses.

Weak stimulation from both axons and many repititions are required to obtain LTP
Ca++ enters the dendrite at both synapses, because:
1. The postsynaptic cell is eventually depolarized (by the joint action of both synapses), and
2. Glutamate is present at both synapses.

Stimulus causes APS in presynaptic neuron by stimulating
This whole cell patch clamp electrode records EPSPs and also used to inject current to depolarize the cell
- If the cell is already depolarized you can get LTP even without tetanus

The NMDA receptor channel opens when glutamate binds, but the channel is blocked by Mg++.
When the postsynaptic cell is depolarized, Mg++ pops out of the NMDA receptor channel.
The NMDA receptor channel is permeable to Na+, K+, and Ca++.
LTP is initiated when Ca++ enters the dendrite.

When Ca++ enters the postsynaptic dendrite, LTP occurs at that location.
For Ca++ to enter the dendrite, two conditions must be met: 1. The postsynaptic cell must be depolarized, and 2. Glutamate must be present
Conditions (1) and (2) ensure that the Mg++ will pop out of the NMDA receptor channel, and therefore Ca++ will be able to enter.

Enhancement of existing AMPAreceptorconductance
Insertionof newAMPAreceptors
- Calcium is an important second messenger
- Activates CAM kinase 2
- Phosphorylates AMPA receptor
- Causes increase in conductance, receptor opens widely
- Cam kinase activation can cause more insertion of ampa receptors
Same spine has more glutamate receptors so more channels open so you get more EPSPs

- Avaiable to conciousness
- Daily episodes
- Words and their meanings
- History
- I remember that

- Generally not available to conciousness
- Motor skills
- Associations
- Priming cues
- Puzzle solving skills
- I know "how" to do this

loss of previously stored memories

inability to form new memories

-Older region of cortex
Not a part of the neocortex
- Involved in consolidation of new, explicit long term memory
- NOT involved in long term storage of explicit memories
- Consolidation or storage implicit memories

- Had severe epilepsy
- Started in hippocampal temporal lobe area
- Brain firing too many Aps
- Removed hippocampi and neighbouring structures
- Could not acquire new memories
Anterograde amnesia
H.M. (born 1926), suffered from intractable epilepsy.
Had a bilateral hippocampectomy (along with related structures) in 1953.
This resulted in profound anterograde amnesia.
For several years after the operation, whenever he was asked his age and the date, he would answer "27" and "1953."
Did not remember meeting people just minutes earlier.
HM also experienced temporally graded retrograde amnesia: lost memory of some events in the decade preceding surgery. Older memories from earlier life were intact.
Could acquire new implicit memories, and had normal working memory.

Hippocampus is like a librarian
A lot of explicit long term memories reside in the cortex, put there by the hippocampus
- Widespread projections from association neocortex converge on the hippocampal region
- The output of the hippocampus is ultimately directed back to these same neocortical areas

1. Simultaneous sight and smell of rose cause cooperative LTP at synapses A and B
2. Subsequent (not necessarily simultaneous) smell and sight of rose cause associative LTP at synapses C and D, respectively.
3. Spontaneous action potentials fired by the hippocampal neuron over months or years cause associative LTP in synapses E and F.
4. The memory is now stored in cortex! Synapses A, B, C, and D can be re-weakened so that the same hippocampal neuron can be used to acquire new memories.

- Initially hippocampus has weak connections to the cortical neurons
○ May get small EPSP but not AP
○ Neurons respond to fragrance and sight (olfactory and visual cortical neurons)
- Kid smells and sees rose for the first time
- Olfactory and visual cortical neurons fire APs due to strong input
○ Cause weak EPSPs
- Cooperative LTP, synapses strengthen, produce big EPSPs and APs
- Let's say kid goes out and sees rose but is too far away to smell it
○ Synapse B is strong so it will fire, causes weak synapses in C and D, depolarization is caused by sight of rose
○ Strong input from sight is coupled from weak input through hippocampus -> causes LTP
- If kid cannot see rose but smells it it can strengthen synapse C
- If kid does not see or smell rose then (weak connection between E and F - when one fires, weak connection in other one) - weak LTP
- But eventually the synapses between E and F should strengthen and result in associative LTP
- Memory is now stored
- Once memory is stored by through E and F, the neuron can be reused to acquire new memories

When there are approx 16 cells (could be more but has to be at least 16) and occurs at days 3-4

At 5-9 days and has to have at least 128 cells - this is what becomes the embyo

Ectoderm - Brain, skin
Mesoderm - Muscle, blood, bone, cartilage
Endoderm - lung, gut, liver
Germaline - sperm, egg

18 days - the neuroectoderm morphs into the nervous system through the neural plate

20 days - the neural plate grooves become the midline of the embyo and there are crest cells on the grooves. In the mesoderm, the notochord becomes the vertebral column

Day 22: Then the mesoderm becomes the somite and then the somite develops into the skeleton and skeletal muscle. The neural crest is pinched off and the neural tube becomes the CNS

The neural tube becomes the CNS, the neural crest becomes the PNS and the skeleton and axial muscles are formed by the somites. The sensory ganglion becomes a dorsal root and chemicals released from the floorplate can influence neural development

The lumen has a hollow interior, and the pial membrane is the protective member of the brain. At this point, cells are now specialized and neural stem cells that contributes to the nervous system are created. Neural stem cells divide either symmetrically to produce two stem cells or asymmetrically to produce a neuroblast and a stem cell. Neuroblasts are neuron precuroses. They become neurons without further cell division and they migrate to their destination

They use radial glial cells that were previously neural stem cells and they later become astrocytes. Migrating neurons crawl up the glial cells and they create a new neural population

They develop in an inside out squence - newly born neurons have to travel further up to form the new neural layer

The neural tube fails to caudally. The rostral part becomes the brain but the caudal part is what is affected and it causes there to be an opening in the skin to the spinal cord. it cna cause infections, organ failure and paralysis. One risk factor for this is insufficent vitamin b9/folate consumption which is required for the productio of DNA and RNA for mitosis. Exposed nerves may result in infection, bladder and bowel function problems and can cause paralysis

Spina Bifida Oculta in a much more mild form which nerves don't pertrude through skin. It usually has no symptoms

The neural tubes fail to close rostrally. The same folate deficiency is the cause. Much of the brain doesn't form and baby doesn't survive long after birth

Cell migration does not occur properly. DCX (doublecortin) is a protein that normally stabilizes microtubles during cell migration
Lissencephaly can occur from a mutation of the (DCX) gene, which is on the x-chromosome. In males, the migration of all neurons is affected, resulting in lissencephaly. The cortex in this case has only 4 partially formed layers.
In heterozygote females, only some neurons are affected, so migration is disturbed in these cells and they stop migrating early. This results in layers of neurons misplaced in the cortical white matter, so that the appearance is of two cortices (ergo the name doublecortin).
Symptoms include eating and swallowing difficulties, seizures, and intellectual impairment. No sulci or gyri. Females end up having multiple cortex layers and all neurons are affected in males but females have better migration

Each cochlear nucleus excites the ipsilateral LSO and contralateral MNTB Each MNTB inhibits the ipsilateral LSO
How does such an elaborate neural circuit develop? How do the axons "know" where to grow, whether to decussate or not, and where to synapse? In fact, the circuit must be even more precise than shown here, because of what it can do!

Looks like multiple fingers, one finger is a filopodium

Attracted towards growth cues and repels repulsive cues

Substrates are touched by growth cones

Growth cone grows by assembling its own cytoskeleton and then disassembling its own cytoskeleton

Actin filament controls filopodium changes

Freely soluble monomers/Globular G actin and F-actin

Actin subunits added at one end and removed at another
Growth cones typically advance on the order of a mm per day (e.g., 0.5 - 2 mm/day), a speed similar to slow axonal transport.

Axon Guidance factors
Tropic molecules attract growing axons towards a source (e.g., netrins). Other guidance molecules repel growing axons (e.g., slit, semaphorins). Some guidance molecules are non-diffusible (e.g., ephrins)
Depending on the receptor, type, the same chemical can be an attraction or repulsion

Mouse optic nerves, chiasm, and tracts. Right eye labeled with fluorescent dye. Temporal retinal axons, which express the EphB1 receptor, are repelled by glial cells at the chiasm that produce ephrin-B2 (a contact repellent). Note: in mouse, only about 3% of the axons remain ipsilateral normally.
Most axons don't stay ipsilateral
- Only 3% of axons are the ones that are red


- Axons that don't decussate, express EphB1 - genetically programmed to not decussate
- Optic chiasm has Ephrin B2
○ On the glial cell
○ If growth cone touches it, the ephb1 repels??

Most axons don't stay ipsilateral
- Only 3% of axons are the ones that are red


- Axons that don't decussate, express EphB1 - genetically programmed to not decussate
- Optic chiasm has Ephrin B2
○ On the glial cell
○ If growth cone touches it, the ephb1 repels??

Slit is a chemorepellent that binds to the Robo1 and Robo2 receptors on growth cones Netrin is a chemoattractant
Both are produced by floor plate (midline) cells

- Less expression of Robo at midline - Robo detects slit
- Without robo, slit is not detecting but it can detect netrin so it goes towards midline at this point
More robo is expressed so it is sensitive to slit and then it comes closer to midline?

Axon expresses less robot so it is insensitive to slit and then when it expresses more robo, it is more sensitive to slit so it decussates?

Note: Robo (“Roundabout”) receptors were originally discovered in fruit flies! In fruit flies, the ligand for the Robo receptors is the chemorepellant, slit.

Similar Robo receptors were subsequently discovered in many other species. However, in mammals the action of one of these receptors, Robo3, is different...
In mammals, the Robo3 receptor does not bind to Slit. Its ligand and mode-of-action are not fully understood.
However, it appears to play an important role in attracting the axon towards the midline for decussation.
Furthermore, after an axon decussates, it quickly reduces its expression of Robo3 (so as not to be attracted back towards midline again!).

TG - trigeminal ganglion
PrV - principal trigeminal nucleus (in the pons)
ION - infraorbital nerve (part of CN V, trigeminal nerve) VPM - ventroposterior medial thalamic nucleus
TCA - thalamocortical afferent axons
Plucking out whiskers does not allow cortex cells to form :(

Abnormal ipsilateral and contralateral projection. Axons that should decussate do not

VCN sends axon that decussates at MNTB which sends projections to cochlear nucleus

Each of cochlear nuclei projects to the same side - failure of decussation

Without decussation, you cannot inhibit the contralateral LSO so cannot detect interaural intensity differences

medial longitudinal fasciculus (mlf) development is disrupted in Robo3 mutant mice.

Trophic factors, produced by target tissue, support presynaptic neurons and promote dendritic and axonal elaboration once the target is reached.
Trophic factors include:
Nerve Growth Factor (NGF)
Neurotrophins (NTs)
Brain-Derived Neurotrophic Factor (BDNF)
Axons and dendrites can branch multiple times when exposed to trophic factors

Discovered by Rita Levi Montalcini and Stanley Cohen
discovered Nerve Growth Factor (NGF)
Purified NGF from mouse tumours; showed NGF’s effect on chick embryonic neurons

TrkA= NGF
TrKb = BDNF, NT4/5 and sometimed NT3
TrkC = NT-3
p75= all of them

Because trophic molecules are in limited supply from the target tissue, presynaptic axons compete for space and survival.
Muscle fibres produce NT-4/5 and BDNF.
As axons attempt to innervate a muscle fibre, only one will win and the rest will not survive

“When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes
part in firing it, some growth process or metabolic change takes place in one or both cells
such that A's efficiency, as one of the cells firing B, is increased.”
Hebb DO (1949) The Organization of Behavior: A Neuropsychological Theory

Neurons that fire together wire together
Out of sync, lose your link - if one neuron is not causing another to then you may lose that connection

Looked at developmental plasticity of ocular dominance column
Monocular deprivation caused open eye to gain territory during development (one eye was sutured shut()

amblyopia: impaired vision that is not caused by problems with the eye itself.

- Reopened eye after a deprivation period before suturing it closed again
- Critical period - if they reopened the eye within the time window, the cat may still be able to recover vision
- Opening after critical period, vision will never recover
After critical period, if eye is reopened (considering it was closed after critical period too) everything would be normal

Wireless, done in vitro sometimes in vivo
Colour change indicates calcium level change
- Excite a fluorophore by shining a light of a particular wavelength of light on it

Higher frequency -> Higher energy
Shine back with light with lower energy and gives off heat difference
- Can be altered in a way that when Ca++ binds, their excitation state changes
Amount of green light shining back is changing, more Ca++ indicates stronger change

For Fura-2, the binding of Ca++ causes a change in the intensity of 510 nm emitted light in response to excitation with 340nm vs. 380nm.

Fill patch pipette with fluorophore and enter neuron
Electrical current pushes fluorophore into neuron
Beads

- Using antibodies to stain tissues and view certain protiens and using histochemistry

Foreign molecules that are recognized by antibodies and antibodies attack them
- Antibodies attack to the antigens through antigen bonding sites
They also have a tail (antibodies)

- Isolate for eg glutamate recepotrs
- Inject them into animal like rabbit
- Rabit sees glutamate receptors from humans so it makes antibodies
- Then you isolate the antibodies and use it as a binding tool to see where glutamate receptors are
- Then you put a fluorescent marker and bathe in a wavelength of light and use it to see where the glutamate receptors are

- Make an antibody with another animal lke a goat
- Inject rabbit antibodies into goat
- Goat makes antibodies against rabbit antibodies
- Tail is made of same proteins regardless of antibody
- All you have to do is tag the goat anti-rabbit antiibody
- Better because you don't need to make another tag for for a different rabbit antibody because all you have to do is tag the goat antibody
- You can get a stronger signal because many antibodies can bind to the same tail of the same antibody so you get more light

- Bathe neural tissue and help us look at things like cochlear nerve degeneration
- Exposed mice to sounds like a rock concert
- Labelled synaptic ribbon protein with pink? and used a green immunofluoresence and labelled neurofilament proteins in auditory nerve axons
- Found that mice had loss of synapses and had a disordered appearance of cell bodies

- Shoot DNA fragments into a neuron like a BB gun through gold particles coated in DNA
- Aim gun at neuron and some pellets will pass through the lipid bilayer and land in nucleus and taken up by cellular machinery that can be translated into protein and the protein can be made that the DNA codes for

- Did it with mice and two fluorescent proteins
- Fluorescent proteins come from kelly fish

- Digitze images to identify where synapses are
- Necessary to have computers because actual images can be noisy

Once a postsynaptic cell is depolarized, silent synapses can transmit robutst postsynaptic electrical responses
- Transmission at these synapses can be turned on and off according to postsynaptic membrane potential

- Found in hoppocampus, cortex and spinal cord
- Prevalent in development

The silence of these synapses is evidently due to the volt- age-dependent blockade of NMDA receptors by Mg2+
At the normal resting membrane potential, presynaptic release of gluta- mate evokes no postsynaptic response at such synapses because their NMDA receptors are blocked by Mg2+. Howev- er, depolarization of the postsynaptic neuron displaces the Mg2+, allowing glu- tamate release to induce postsynaptic responses mediated by NMDA receptors.

Glutamate released at silent synapses evidently binds only to NMDA receptors. How, then, does glutamate release avoid activating AMPA receptors? The most like- ly explanation is that these synapses may have only NMDA receptors. Immunocy- tochemical experiments demonstrate that some excitatory synapses have only NMDA receptors. Such NMDA receptor-only synapses are particularly abundant early in postnatal development and decrease in adults.

Silencing of glutamatergic synapses has also been reported to re- sult from the use of the recreational drug cocaine. Thus, at least some silent syn- apses are not a separate class of excit- atory synapses that lack AMPA receptors, but rather an early stage in the ongoing maturation of the glutamatergic synapse

Evidently, AMPA and NMDA receptors are not inextricably linked at excitatory synapses, but are targeted via
independent cellular mechanisms. Such synapse-specific glutamate receptor composition implies sophisticated mech- anisms for regulating the localization of each type of receptor. Dynamic chang- es in the trafficking of AMPA and NMDA receptors can strengthen or weaken syn- aptic transmission and are important in LTP and LTD, as well as in the maturation of glutamatergic synapses.

eventually they would reach some level of maxi- mum efficacy, making it difficult to encode new in- formation. Thus, to make synaptic strengthening useful, other processes must selectively weaken specific sets of synapses, and LTD is such a pro- cess.

In the late 1970s, LTD was found to occur at the synapses between the Schaffer and the
the CA1 pyramidal cells in the hippocampus. Whereas LTP at these synapses requires brief, high-frequency stimulation, LTD occurs when the Schaffer collaterals are stimulated at a low rate—about 1 Hz—for long periods (10–15 minutes).

This pattern of activity depresses the EPSP for several hours and, like LTP, is specific to the activated synapses (Figure 8.16A,B). Moreover, LTD can erase the increase in EPSP size due to LTP, and conversely, LTP can erase the decrease in EPSP size due to LTD. This complementarity suggests that LTD and LTP reversibly affect synaptic efficiency by acting at a common site

Both require activation of NMDA-type gluta-
mate receptors and the resulting entry of Ca2+
into the postsynaptic cell. The major determi-
nant of whether LTP or LTD arises appears to
be the nature of the Ca2+ signal in the postsyn-
aptic cell: Small and slow rises in Ca2+ lead to
depression, whereas large and fast increases in
Ca2+
trigger potentiation.

As noted above, LTP
is at least partially due to activation of protein
kinases, which phosphorylate their target pro-
teins. LTD, in contrast, appears to result from
activation of phosphatases, specifically PP1 and
PP2B (calcineurin), a Ca2+-dependent phosphatase
Evidence in support of this idea is that inhib-
itors of these phosphatases prevent LTD but do not block
LTP. The different effects of Ca2+ during LTD and LTP may
arise from the selective activation of protein phosphatases
and kinases by the different types of postsynaptic Ca2+
signals occurring during these two forms of synaptic plas-
ticity

Just as LTP at this synapse is associated with insertion of AMPA receptors,
LTD is often associated iwth a loss of synaptic AMPA receptors which arises from internallization of AMPA receptors into sorting endosomes in the postynaptic cell due to the same clathrin dependent enocytosis mechanisms used for synaptic vesicle recylcing in the presynaptic terminal

A quite different form of LTD is observed in the cerebel- lum. LTD of synaptic inputs onto cerebellar Purkinje cells was first described by Masao Ito and Masanobu Kano in Japan in the early 1980s. Purkinje neurons in the cerebel- lum receive two distinct types of excitatory input: climb- ing fibers and parallel fibers LTD reduces the strength of transmission at the parallel fi- ber synapse (Figure 8.17B) and subsequently was found to depress transmission at the climbing fiber synapse as well. This form of LTD has been implicated in the motor learning that mediates the coordination, acquisition, and storage of complex movements in the cerebellum

Like many forms of motor learning, cerebellar LTD is
associative because it occurs only when climbing fibers and
parallel fibers are activated at the same time In this case, associativity arises from the combined actions of two distinct intracellular signal transduction pathways that are activated in the posytsynaptic Purkinje cell in response to activity of the climbing fiber and paralllel fiber synapses

Glutmate released from the parallel fiber terminals activate the AMPA and metabotropic glutamate receptors. Glutamate binding to the AMPA receptor re-
sults in mild membrane depolarization, whereas binding
to the metabotropic receptor produces the second messen-
gers inositol triphosphate (IP3) and diacylglycerol (DAG) Glutamate released by climbing fibers also
activates AMPA receptors, which strongly depolarizes the
Purkinje cell membrane potential and initiates a second
signal transduction pathway: an influx of Ca2+ through
voltage-gated channels and a subsequent increase in intracellular Ca2+ []. IP3 and Ca2+ cause an amplified rise in intracellular Ca2+ [] by acting on IP3 receptors which triggers Ca2+ from intracellular stores and leads to synergistic activation of PKC of Ca2+ and DAG Other
protein kinases also act to sustain the acti-
vation of PKC beyond the time that IP3 and
Ca2+ concentrations are elevated.

PKC phosphorylates several down-
stream substrate proteins, including
AMPA receptors. The main consequence
of PKC-dependent phosphorylation is to
cause an internalization of AMPA receptors
via clathrin-dependent endocytosis. This loss of AMPA receptors
decreases the response of the postsynaptic +40 Purkinje cell to glutamate released from the
presynaptic terminals of the parallel fibers

in contrast to LTD in the hippocam-
pus, cerebellar LTD requires the activity of
protein kinases, rather than phosphatases,
and does not involve Ca2+ entry through –60 NMDA receptors. However, the net effect
is the same in both cases: Internalization of postsynaptic AMPA receptors is a com- mon mechanism for decreased efficacy of both hippocampal and cerebellar synapses during LTD

CREB appears to be required for a late phase of cerebellar LTD. It is not yet known which proteins are synthesized as a consequence of CRE activation.

The net difference in firing rates then leads to slow movements of the eyes counter to the turning motion; in a conscious per- son with normal vestibular function, a fast saccade (see Chapter 20) resets the eye position when the eye reaches its far
excursion. This process is referred to as physiological nystagmus, which means “nodding” or oscillatory movements of the eyes

Physiological nystagmus is an adaptive process that enables the subject to fixate on a visual target despite ongoing rotational move- ments of the head and body.

Pathologic spontaneous nystagmus can occur if there is unilateral damage to the vestibular system. In this case, the silencing of output from the damaged side results in an abnormal difference in firing rate between the two sides (see Figure B2). This difference causes nys- tagmus even though no head move- ments are being made, often resulting in vertigo sufficiently severe to trigger falls and vomiting.

Meniere’s disease, named after the nineteenth Century French physician Prosper Meniere, is one cause of acute unilateral vestibu- lar dysfunction and can be particularly

disabling for the patient; another is ves- tibular nerve section, which is often an unavoidable consequence of surgical removal of a vestibular Schwannoma (also known as an acoustic neuroma, a benign tumor of the nerve sheath around the vestibular and acoustic nerves).

spontaneous nystagmus slowly diminishes following unilateral vestibular nerve section, pre- sumably because of central compen- sation and plasticity. In contrast, Me- niere’s disease is typically progressive, initially affecting only one ear but slowly encompassing both ears, and is also usually accompanied by tinnitus and a sensorineural hearing deficit in the af- fected ear(

hey can be useful in assessing the in- tegrity of the brainstem in unconscious patients. If the individual is placed on the
horizontal canals lie in
an almost vertical orien-
tation. Irrigating one ear
with cold water will then
lead to spontaneous eye
movements because con-
vection currents in the ca-
nal and direct cooling of
the nerve mimic rotational
head movements away
from the irrigated ear

In normal individu-
als, these eye movements
consist of a slow movement
toward the irrigated ear
and a fast movement away
from it. In patients who are
comatose due to dysfunction of both ce- rebral hemispheres but whose brainstem is intact, saccadic movements are no longer made, and the response to cold water consists of only the slow move-
ment component of the eyes toward the side of the irrigated ear (Figure D). In the presence of brainstem lesions involving either the vestibular nuclei themselves, the connections from the vestibular nu-
clei to oculomotor nuclei (cranial nerves III, IV, or VI), or the peripheral nerves ex- iting these nuclei, vestibular responses are abolished or altered, depending on the severity of the lesion.